emerging technologies and therapeutics report 1 · 2020-02-27 · emerging technologies and...

EMERGING TECHNOLOGIES AND THERAPEUTICS REPORT 2

Landscape Review and Evidence Map of Gene Therapy, Part I: Adenovirus, Adeno-associated Virus, and Clustered Regularly Interspaced Short Palindromic Repeats Andrea Richardson, Eric Apaydin, Sangita Baxi, Jerry Vockley, Olamigoke Akinniranye, Jody Larkin, Aneesa Motala, and Susanne Hempel RAND Corporation March 2019 Revision [February 2020] Since the completion of this report a gene therapy herein described as AVXS-101 has been approved by the FDA as Zolgensma therefore the report was revised in November 2019 to reflect that change. All statements, findings, and conclusions in this publication are solely those of the authors and do not necessarily represent the views of the Patient-Centered Outcomes Research Institute (PCORI) or its Board of Governors. This publication was developed through a contract to support PCORI's work. Questions or comments may be sent to PCORI at [email protected] or by mail to Suite 900, 1828 L Street, NW, Washington, DC 20036. ©2019 Patient-Centered Outcomes Research Institute. For more information see www.pcori.org

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Table of Contents Executive Summary ......................................................................................................... 5 Introduction of Report Series .......................................................................................... 7

History of Gene Therapies ............................................................................................ 7 Aim of the Report ......................................................................................................... 7 Methodology Overview ................................................................................................ 7 Data Sources ................................................................................................................ 8

Figure 1. Content and Data Sources ................................................................................... 9 Organization of the Report Series and Organization of This Report ............................. 9

Description of Interventions/ Technologies ................................................................... 11 Table 1. Intervention Descriptions ................................................................................... 11 Table 2. FDA-approved Therapies .................................................................................... 12 Table 3. Potential Pipeline Gene Therapies ....................................................................... 13

Adenoviral, AAV, and CRISPR Gene Therapy .............................................................. 16 Adenoviral Therapy Indications ........................................................................................ 16 AAV Therapy Indications ................................................................................................. 17 CRISPR Therapy Indications ............................................................................................ 18 Key Question 1a. What different types or modalities of the intervention have been used in clinical practices and clinical research studies? .................................................................. 18 Key Question 1b. What are the potential/presumed advantages and disadvantages in contrast to current practices? ....................................................................................................... 19 Key Question 1c. What are the safety issues or expected adverse events? ........................... 21

Context in Which Gene Therapy Is Used ........................................................................ 23 Key Question 2a. What is the approval process and current approval/certification status for gene therapies? ............................................................................................................. 23 Key Question 2b. Are any additional accompanying resources or technologies required? ....... 23 Key Question 2c. What is the current state of adoption in practice and settings? .................. 24 Key Question 2d. What are the operator factors, such as training and staffing? .................... 24

Ongoing Premarket and Postmarket Gene Therapy Studies .......................................... 25 Ongoing Trial Characteristics ..................................................................................... 25

Table 4. Ongoing Adenovirus, AAV, and CRISPR Trials ....................................................... 25 Key Question 3a. What are the indication/patient inclusion criteria in ongoing trials? ............ 31 Key Question 3b. What are the types of interventions in ongoing trials? .............................. 31 Key Question 3c. What are the study designs/sizes of ongoing trials? .................................. 31 Key Question 3d. What are the comparators in ongoing trials? ........................................... 31 Key Question 3e. What are the previous/concurrent treatments in ongoing trials? ................ 32 Key Question 3f. What is the length of follow-up in ongoing trials? ..................................... 32 Key Question 3g. What outcomes are measured in ongoing trials? ...................................... 32

Current Evidence Supporting Gene Therapy .................................................................. 33 Characteristics of Published Trials ............................................................................. 33

Table 5. Summary of Published Adenovirus and AAV Studies .............................................. 33


Key Question 4a. What are the indication/patient inclusion criteria in published studies? ....... 34 Key Question 4b. What are the types of interventions in published studies? ......................... 34 Key Question 4c. What are the study designs/sizes of published studies? ............................ 34 Key Question 4d. What are the comparators in published studies? ...................................... 35 Key Question 4e. What are the previous/concurrent treatments in published studies? ........... 35 Key Question 4f. What is the length of follow-up in published studies? ................................ 35 Key Question 4g. What outcomes are measured in published studies? ................................. 35 Key Question 4h. What are the adverse events in published studies? .................................. 36

Evidence Map of Ongoing and Completed Gene Therapy Trials .................................. 37 Figure 2. Gene Therapy Evidence Map: Adenovirus, AAV, and CRISPR ................................. 38

Important Issues Raised by Gene Therapy .................................................................... 39 Key Question 5a. What are the implications of the current level of adoption and future diffusion, given the current level of evidence: efficacy/safety, ethical, disparity, resource allocation, and decision making? ...................................................................................... 39 Key Question 5b. What are the key issues pertaining to decisional uncertainty? ................... 40 Key Question 5c. What are potential areas of research focus for PCORI and others? ............. 40

References ..................................................................................................................... 42 Appendix ....................................................................................................................... 72

Appendix A: Report Methodology ............................................................................... 72 Literature Searches ........................................................................................................ 72 Literature Review Procedure ........................................................................................... 73 Inclusion Criteria ............................................................................................................ 73 Data Extraction .............................................................................................................. 74 Evidence Map ................................................................................................................ 74 Evidence Tables ............................................................................................................. 74

Appendix B: Search Strategies ................................................................................... 75 Published Literature ....................................................................................................... 75 Grey Literature .............................................................................................................. 79

Appendix C: Literature Flow Diagram ........................................................................ 82 Appendix D: Stakeholder and Key Informant Interview Information ......................... 83

Interviews ..................................................................................................................... 83 Recruitment ................................................................................................................... 83 Procedure...................................................................................................................... 83 Interview Data Collection and Analysis Strategy ................................................................ 85

Appendix E: Evidence Maps Stratified by Intervention ............................................... 86 Appendix Evidence Map 1. Adenovirus Trials ..................................................................... 86 Appendix Evidence Map 2. AAV Trials ............................................................................... 87 Appendix Evidence Map 3. CRISPR .................................................................................. 88

Appendix F: Evidence Tables Published Trials ............................................................ 89 Appendix Table A1. Published Adenovirus Trials ................................................................ 89 Appendix Table A2. Published AAV Trials ......................................................................... 161


Executive Summary Human gene therapy has evolved rapidly and may be poised to affect mainstream medicine. Gene therapy initially targeted incurable genetic diseases (eg, metabolic diseases) but is now most commonly used to treat certain cancers. In response to the increase in approved gene therapy approaches, the Patient-Centered Outcomes Research Institute (PCORI) commissioned a landscape review. The purpose of this report is to better understand the evidence supporting currently approved gene therapies and those that may be available in the near term in the United States. This is the first of 2 reports and it focuses on adenovirus, adeno-associated virus vector-based (AAV) gene therapy, and clustered regularly interspaced short palindromic repeats (CRISPR).

In November 2018, we reviewed scientific journal and grey literature to identify evaluations of therapies that meet the US Food and Drug Administration’s (FDA) definition of gene therapy. Our overall aim was to provide a current view of the existing evidence on gene therapy and to identify gaps that need to be addressed for the field to move forward in the United States. We reviewed both completed and ongoing trials involving human participants, including both controlled and uncontrolled trials. The literature results are documented in visualizations (ie, evidence maps) and comprehensive evidence tables.

We also conducted semistructured interviews with a diverse set of stakeholders to elicit feedback on challenges, hopes, and important issues related to gene therapy. We selected key informants who provided a range of perspectives, including patients and patient advocates, clinicians, payers, insurers, public policymaker representatives, and industry representatives. This report addresses the description of the interventions, the context in which gene therapy is used, ongoing premarket and postmarket gene therapy studies, and current evidence for the use of gene therapy. The FDA has approved 10 interventions that meet the definition of gene therapy; 2 are included in this report. Luxturna (Voretigene neparvovec) was the first AAV-based therapy, approved in 2017 to treat biallelic RPE65 mutation-associated retinal dystrophy. Zolgensma* (Onasemnogene abeparvovec-xioi) is an AAV-based therapy that was approved in 2019 for the treatment of spinal muscular atrophy.

Our search of the grey literature identified 76 therapies that meet the FDA’s definition of gene therapy and that have not yet been approved by the FDA but may be close to approval. A wide variety of modalities are being tested to treat patients. The most common type of therapy is based on AAV. The identified therapies are being used to treat multiple disease types, including vision disorders (eg, choroidemia), muscular dystrophy (eg, Duchenne), blood disorders (eg, hemophilia), Sanfilippo syndrome, cancer, HIV, and Parkinson’s disease.

In our literature search, we screened 3859 citations and assessed 1817 full-text publications for eligibility. Of these, we identified 251 completed trials that tested adenovirus or AAV interventions. We also identified 19 ongoing trials, including a trial using CRISPR, that have completed patient recruitment.

The indications in the identified completed and ongoing trials were cancer (49%), ocular disorders (9%), cardiovascular disease (9%), neurodegenerative disorders (9%), respiratory conditions (4%), blood disorders (4%), immune deficiency (4%), muscular conditions (3%), inflammatory conditions (1%), and other indications that were not easily categorized (eg, venous leg ulcer disease, 9%). Pharmaceutical companies claim that certain gene therapies have the potential to offer a one-time administration that will cure disease. Results from small trials are promising; however, true durability * This report was updated on February 3, 2020 to reflect the approval of Zolgensma (formerly AVXS-101) for spinal muscular atrophy (approved on 5/24/19).


of treatment remains unclear on the basis of current published results. Further, most existing gene therapy trials are based on single-arm trials or trials with multiple groups who were treated with different levels of the same therapy. However, randomized controlled trials (RCTs) are increasingly being implemented in cancer, cardiovascular disease, immune deficiency, and otherwise categorized indication trials. Sample sizes remain relatively small across the studies, likely owing to the rarity of the indications addressed by gene therapy. We observed larger sample sizes in the RCTs for more common diseases, such as cardiovascular conditions, or for vaccine trials. Most studies evaluated safety and indicators of biodistribution, and relatively few studies tested clinical efficacy.

The potential and presumed advantage of gene therapies is, first and foremost, cures for previously incurable and fatal diseases. However, the potential disadvantages of gene therapies relative to current treatment practices include many unknowns related to the following: (1) how clinically effective treatments are compared with the risk for adverse outcomes; (2) how gene therapies will be implemented in health care systems in which providers may be unfamiliar with requisite procedures and patients are not well informed about what gene therapies are; (3) the ethical implications of altering the genome; and (4) how patients and payers will pay for potentially expensive gene therapy. While adenoviral gene therapies have been tested extensively, AAV therapies may be more promising, given their popularity in trials of therapies in the pipeline. CRISPR’s promise remains to be thoroughly tested, but findings should soon shed light on the future of this therapy.

To address the gaps in knowledge that might support the approval and use of gene therapies, several areas of research may warrant future work. Suggested future research includes examining how Centers of Excellence can ensure that high-quality manufacturing processes and health care delivery standards are followed. In addition, patient registries with long-term follow-up will reduce uncertainty about the durability of gene therapy effects. Other research could examine how training and education programs for providers and patients might improve provider familiarity with procedures and patient understanding of how the therapy works and the risks of unintended effects. Finally, microsimulation modeling of different scenarios of patient access and treatment efficacy might address the uncertainty about how gene therapy will affect disease.


Introduction of Report Series The FDA defines gene therapy as products “that mediate their effects by transcription and/or translation of transferred genetic material and/or by integrating into the host genome and that are administered as nucleic acids, viruses, or genetically engineered microorganisms. The products may be used to modify cells in vivo or transferred to cells ex vivo prior to administration to the recipient.”1 Gene therapies operate by doing one of the following:

• Replacing a disease-causing gene with a healthy copy of the gene • Inactivating a disease-causing gene that is not functioning properly • Introducing a new or modified gene into the body to help treat a disease1

History of Gene Therapies Human gene therapy evolved from bacterial and viral cell transformation studies.2 Experimentation in humans started in the 1990s when the FDA approved a gene therapy trial in 2 children with adenosine deaminase deficiency, a monogenic disease that leads to severe immunodeficiency.3 Some immune responses improved in this small study, and the results suggested that the treatment might be safe and effective. Despite some tragic setbacks, gene therapy research has continued to expand and improve.

Gene therapy initially targeted relatively rare incurable genetic diseases (eg, metabolism diseases) but is now most commonly used to treat certain cancers, including some that are inherited and some that are not. Cancer comprises 65% of indications addressed by current gene therapy clinical trials, followed by monogenic diseases (11%), infectious diseases (7%), and cardiovascular diseases (7%).4 The FDA has approved 16 products that are either cellular products or gene therapies: cord blood products (50%), autologous or allogenic cellular products (25%), and disease-specific therapies (25%).5 Nine of the products meet the criteria in the FDA’s definition of a gene therapy, and they employ multiple intervention modalities to treat specific cancers and vision loss.

Aim of the Report Given the increase in approved gene therapy products and techniques, we sought to better understand the evidence base regarding ongoing and published trials, safety, and efficacy results for currently approved gene therapies and those that might be available in the near term (~5 years) in the United States and to identify gaps that need to be addressed for the field to move forward. This report addresses the existing evidence on gene therapy and outlines evidence gaps.

Methodology Overview Our methods are described in detail in Appendix A. Briefly, we established a landscape review of multiple data sources to cover critical aspects of current and future gene therapy approaches. Specifically, we describe the evidence base for FDA-approved gene therapies that are currently used to treat or cure conditions. In addition, we describe ongoing clinical trials that are testing applications that might be poised to gain FDA approval, as well as the conditions that are relevant for future applications. The search strategy is documented in Appendix B. We applied explicit inclusion and exclusion criteria, and the literature flow is shown in Appendix C. The FDA has approved gene therapies on the basis of the results of single-arm trials when a life-threatening condition has no alternative treatment and its severity6 justifies not performing controlled trials. Thus, we included both controlled and uncontrolled trials in our literature review. The literature results are documented in a central figure and comprehensive evidence tables.


We also conducted interviews with stakeholders who provided a variety of perspectives on gene therapies. We elicited feedback about challenges, hopes, and important issues related to gene therapy. We included patients and patient advocates, clinicians, payers, insurers, public policymaker representatives, and industry representatives and analysts. In semistructured interviews, these key informants contributed to the development of our search strategy and the identification of interventions that could be approved within the next 5 years. We also elicited their perspectives on aspects of beneficial and harmful outcomes, important issues to patients, gene therapy–related challenges and gaps, hopes for future progress, and their thoughts on how to move the field forward. More detail is available in Appendix D. We interviewed the following key informants:

Patient advocates • Sharon Terry, president and chief executive officer, Genetic Alliance • Ben Wakana, executive director, Patients for Affordable Drugs

Clinicians • Flora Lum, MD, vice president of quality and data science, American Academy of

Ophthalmology • Cary Harding, MD, professor of molecular and medical genetics, Oregon Health & Science

University

Insurers • Geoff Crawford, MD, medical director, Anthem • John Yao, MD, staff vice president, Anthem • Naomi Aronson, MD, executive director, Technology Evaluation Center, Blue Shield of

California

Public policymakers • Katherine B. Szarama, presidential management fellow, Centers for Medicare and Medicaid

Services

Industry representatives and analysts • Michael Ciarametaro, vice president of research, National Pharmaceutical Council • Daryl Pritchard, PhD, senior vice president, science policy, Personalized Medicine Coalition

Data Sources The report is based on peer-reviewed literature, grey literature, and key informant interviews. Figure 1 maps data sources to the report’s content; it indicates which sources we used to collect information on each topic. For example, we used the information we gathered from the research databases to inform the content related to the types of studies, safety, and efficacy for each intervention. (For more details on the methodology, see Appendix A and Appendix B.)


Figure 1. Content and Data Sources

Organization of the Report Series and Organization of This Report This is the first of 2 reports on the evidence base for FDA-approved therapies that meet the definition for gene therapy. This report also covers interventions that are not yet approved but that we identified multiple times in our search for therapies in the research pipeline. We focus on adenovirus, adeno-associated virus and clustered regularly interspaced short palindromic repeats gene therapy. A second report will address chimeric antigen receptor T cell (CAR-T), autologous cell, zinc finger nuclease (ZFN), antisense, ribonucleic acid interference (RNAi) therapies and oncolytic viral therapy, which uses a replication-competent, attenuated derivative of herpes simplex virus type 1.

The sheer number of studies, spanning multiple interventions and conditions, necessitates the use of broad summaries. However, we do highlight specific issues that the authors or the key informants believe are especially relevant to the report. For each report, the findings are organized by key questions.


Description of Interventions/Technologies • 1a. What different types or modalities of the intervention have been used in clinical practices and

clinical research studies? • 1b. What are the potential/presumed advantages and disadvantages in contrast to current practices? • 1c. What are the safety issues or expected adverse events?

Context in Which Gene Therapy Is Used • 2a. What is the approval process and current approval/certification status for gene therapies? • 2b. Are any additional accompanying resources or technologies required? • 2c. What is the current state of adoption in practice and settings? • 2d. What are the operator factors, such as training and staffing?

Ongoing Premarket and Postmarket Gene Therapy Studies • 3a. What are the indication/patient inclusion criteria in ongoing trials? • 3b. What are the types of interventions in ongoing trials? • 3c. What are the study designs/sizes of ongoing trials? • 3d. What are the comparators in ongoing trials? • 3e. What are the previous/concurrent treatments in ongoing trials? • 3f. What is the length of follow-up in ongoing trials? • 3g. What outcomes are measured in ongoing trials?

Current Evidence Supporting Gene Therapy • 4a. What are the indication/patient inclusion criteria in published studies? • 4b. What are the types of interventions in published studies? • 4c. What are the study designs/sizes of published studies? • 4d. What are the comparators in published studies? • 4e. What are the previous/concurrent treatments in published studies? • 4f. What is the length of follow-up in published studies? • 4g. What outcomes are measured in published studies? • 4h. What are the adverse events in published studies?

Furthermore, for each report, we also document the available evidence in comprehensive evidence tables, which list key characteristics for all included studies. We stratify the evidence by gene therapy type and by completed and published studies versus potential pipeline therapies in ongoing studies. We also provide an evidence map—a visualization of the evidence. Evidence maps are useful as signposts for health care practitioners, policymakers, and funding agencies. They are ideally suited to providing many different stakeholders with an overview of a broad research area.


Description of Interventions/Technologies The FDA has currently approved 16 cellular or gene therapies. Table 1 describes the 7 intervention types that meet the FDA’s definition of gene therapy.

Table 1. Intervention Descriptions Intervention Type Description Adeno-associated virus vector The virus infects patient cells to deliver a healthy copy

of a gene so that it will be properly expressed, thereby curing the disease.

Antisense Complementary messenger RNA binds to and silences a disease-causing gene.

Chimeric antigen receptor T cell T cells are removed from the patient, genetically modified to attack specific cancer cells, and infused back into the patient.

Genetically modified oncolytic viral therapy using a replication-competent, attenuated derivative of herpes simplex virus type 1

The virus infects and replicates in cancer cells to express protein (eg, granulocyte-macrophage colony-stimulating factor), which results in cell lysis and increased antitumor immunity.

RNA interference Double-stranded RNA degrades RNA that encodes disease-causing protein.

Autologous cell Recovered cells or tissue from a patient are genetically modified, then reintroduced.

Zinc finger nuclease DNA-binding proteins are engineered to create double-strand breaks in DNA at specific targeted locations.

Abbreviations: DNA, deoxyribonucleic acid; RNA, ribonucleic acid.

Table 2 lists the 10 FDA-approved therapies (as of November, 2019) that meet the definition of gene therapy. In January 2013, the FDA approved Kynamro (Mipomersen sodium), the first therapy within the scope of this report to be approved. Kynamro is based on antisense technology and is used to treat homozygous familial hypercholesterolemia. In 2015, the FDA approved Imlygic (Talimogene laherparepvec) to treat melanoma. Imlygic is a genetically modified oncolytic viral therapy that uses a replication-competent, attenuated derivative of herpes simplex virus type 1. The next 3 approved therapies use antisense technology to treat Duchenne muscular dystrophy (Eteplirsen, Exondys 51), spinal muscular atrophy (Spinraza, Nusinersen), and polyneuropathy of hereditary transthyretin amyloidosis (Tegsedi, Inotersen). Luxturna, approved in 2017, was the first AAV-based therapy to treat biallelic RPE65 mutation-associated retinal dystrophy. Subsequently in 2017, the FDA approved 2 CAR-T therapies. Yescarta is used to treat adult patients with relapsed or refractory large B-cell lymphoma, and Kymriah treats children and young adults with refractory B-cell precursor acute lymphoblastic leukemia. In 2018 Kymriah gained additional approval to treat adult patients with relapsed or refractory large B-cell lymphoma. In 2018 the FDA approved an RNA interference drug to treat hereditary transthyretin amyloidosis with polyneuropathy.

A key aspect of gene therapies is their potential to cure disease with one application. For instance, the CAR-T therapies Kymriah and Yescarta are not expected to need repeated procedures, and the AAV therapy Luxturna is expected to be curative with one procedure. However, there has not yet been sufficient follow-up to know whether these treatments are truly curative—the number of treated patients is small, and researchers need to follow patients for several more years. Long-term follow-up trials are under way for Luxturna7; so far, 12-month follow-up results support maximum treatment benefit.8 Similarly, Yescarta has been shown to have durable response after 15 months, as


documented in the CAR-T evidence table in Appendix F.9 Trial results also suggest that Kymriah has a durable response after a median follow-up of 13 months; this trial is ongoing (see section entitled Ongoing Premarket and Postmarket Gene Therapy Studies.10 Most key informants mentioned the need for longer-term studies, spanning at least 10 years, to assess durability.

Table 2. FDA-approved Therapies Modality/Type of Gene Therapy Approach

Name (Brand Name if Applicable)

First FDA Approval Date

Indication Approval Date for Specific Indication

Are Repeat Procedures Expected?

Antisense Kynamro (Mipomersen sodium)

1/29/13 Homozygous familial hypercholesterolemia

1/29/13 Yes

Genetically modified oncolytic viral therapy (replication-competent, attenuated derivative of herpes simplex virus type 1)

Imlygic (Talimogene laherparepvec)

10/27/15 Melanoma 10/27/15 Yes

Antisense Eteplirsen (Exondys 51)

9/19/16 Duchenne muscular dystrophy

9/19/16 Yes

Antisense Nusinersen (Spinraza)

12/23/16 Spinal muscular atrophy

12/23/16 Yes

Antisense Tegsedi (Inotersen)

10/5/18 Polyneuropathy of hereditary transthyretin amyloidosis

10/5/18 Yes

AAV Luxturna (Voretigene neparvovec)

12/19/17 Biallelic RPE65 mutation-associated retinal dystrophy

12/19/17 No

AAV Zolgensma* (Onasemnogene abeparvovec-xioi)

5/24/19 Spinal muscular atrophy

5/24/19 No

CAR-T: CD19-directed genetically modified autologous T-cell immunotherapy

Yescarta (Axicabtagene ciloleucel)

10/18/17 Relapsed or refractory large B-cell lymphoma

10/18/17 No

CAR-T: CD19-directed genetically modified autologous T-cell immunotherapy

Kymriah (Tisagenlecleucel)

8/30/17 Patients up to 25 years of age with refractory B-cell precursor acute lymphoblastic leukemia

8/30/17 No

Adult patients with relapsed or refractory large B-cell lymphoma

5/1/18 No


Modality/Type of Gene Therapy Approach

Name (Brand Name if Applicable)

First FDA Approval Date

Indication Approval Date for Specific Indication

Are Repeat Procedures Expected?

RNA interference; specifically, double-stranded small interfering ribonucleic acid, formulated as lipid nanoparticles for delivery to hepatocytes

Patisiran (Onpattro, ALN-TTR02)

8/10/18 Hereditary transthyretin amyloidosis with polyneuropathy

8/10/18 Yes

Abbreviations: AAV, adeno-associated virus vector; CAR-T, chimeric antigen receptor T cell; FDA, US Food and Drug Administration; RNA, ribonucleic acid. Note: Shading indicates adenovirus and AAV gene therapy. *This table was updated on February 3, 2020 to reflect the approval of Zolgensma (formerly AVXS-101) for spinal muscular atrophy (approved on 5/24/19)

Table 3 lists the identified therapies that have not yet been approved but might be close to approval. To identify these therapies, we searched the grey literature, including a database maintained by the Journal of Gene Medicine and Pink Sheet of Pharma Intelligence (see Appendix B). The table presents the intervention modality, name/brand, FDA designation, and indication associated with the therapies that have yet to be approved. Adenovirus, AAV, and CRISPR therapies are shaded; the unshaded therapies are addressed in the second report.

Table 3. Potential Pipeline Gene Therapies Modality/Type of Intervention Name of Intervention

(Brand Name if Applicable) Indication

AAV A001 (AAV2/5-OPTIRPE65) Leber congenital amaurosis AAV A002 (AAV2/8- hCARp.hCNGB3) Achromatopsia AAV AAV2.REP1 (AAV-mediated REP1 ) Choroideremia AAV NSR-REP1 (AAV2-REP1) Choroideremia AAV rAAV2.REP1 Choroideremia AAV SPK-7001 (AAV2-hCHM) Choroideremia AAV rAAV2tYF-PR1.7-hCNGB3 Achromatopsia AAV AAV-RPGR X-linked retinitis pigmentosa AAV ABO-101 (rAAV9.CMV.hNAGLU) Sanfilippo syndrome type B AAV ABO-102 (scAAV9.U1a.hSGSH) Sanfilippo syndrome type A AAV BIIB087 (rAAV2tYF-CB-hRS1) X-linked retinoschisis AAV BIIB088 X-linked retinitis pigmentosa AAV SB-525 Hemophilia A AAV SHP654/BAX 888 Hemophilia A AAV SPK-8011 Hemophilia A AAV Valoctocogene Roxaparvovec (BMN

270) Hemophilia A

AAV AMT-060 Hemophilia B AAV AMT-061 (AAV5-hFIXco-Padua) Hemophilia B AAV Fidanacogene elaparvovec (SPK-

9001, PF-06838435) Hemophilia B


Modality/Type of Intervention Name of Intervention (Brand Name if Applicable)

Indication

AAV PF-06939926 (BMB-D001) Duchenne muscular dystrophy AAV SGT-001 Duchenne muscular dystrophy AAV AAVrh74.MHCK7.micro-Dystrophin Duchenne muscular dystrophy AAV AVXS-101* Spinal muscular atrophy AAV MYO-101

(scAAVrh74.MHCK7.hSGCB) Limb-girdle muscular dystrophy, type 2E

AAV MYO-102 (scAAVrh74.tMCK.hSGCA) Limb-girdle muscular dystrophy, type 2D

AAV MYO-201 (rAAVrh74.MHCK7.DYSF.DV)

Limb-girdle muscular dystrophy, type 2B /Miyoshi Myopathy

AAV rAAV1.tMCK.human-alpha-sarcoglycan

Limb-girdle muscular dystrophy, type 2D

AAV VY-AADC Parkinson's disease Adenovirus, oncolytic Tasadenoturev (DNX-2401) Brain cancer Adenovirus, vaccine Ad26.ZEBOV Ebola CRISPR-Cas9–CAR-T-cell therapy Anti-mesothelin CAR-T cells Solid tumor cancers CRISPR-Cas9–CAR-T-cell therapy CD7.CAR/28zeta CAR-T cells T-cell acute lymphoblastic leukemia,

T-cell non-Hodgkin lymphoma CRISPR-Cas9–CAR-T-cell therapy PD-1 knockout EBV-CTL Gastric carcinoma, nasopharyngeal

carcinoma, T-cell lymphoma, adult Hodgkin lymphoma, diffuse large B-cell lymphoma

CRISPR-Cas9–CAR-T-cell therapy PD-1 knockout T cells Prostate cancer, bladder cancer, non-small-cell lung cancer, renal cell carcinoma, esophageal cancer

CRISPR-Cas9–CAR-T-cell therapy UCART019 B-cell leukemia or lymphoma CRISPR-Cas9–CAR-T-cell therapy Universal dual specificity CD19 and

CD20 or CD22 CAR-T cells B-cell leukemia or lymphoma

CRISPR-Cas9–autologous CD34+ human hematopoietic stem and progenitor cells

CTX001 Beta-thalassemia

Antisense IONIS-MAPTRx Alzheimer's disease Antisense RG6042 (IONIS-HTTRx) Huntington's disease Antisense Volanesorsen Familial chylomicronemia syndrome,

familial partial lipodystrophy Autologous cell therapy Strimvelis (GSK2696273) Severe combined immunodeficiency Autologous cell therapy Lenti-D Cerebral adrenoleukodystrophy

(Lorenzo’s Oil disease) Autologous cell therapy LentiGlobin (BB305) Beta-thalassemia Autologous cell therapy OTL-101 Adenosine deaminase severe

combined immunodeficiency Autologous cell therapy OTL-200 (GSK2696274) Metachromatic leukodystrophy Autologous cell therapy EB-101 Recessive dystrophic epidermolysis

bullosa Autologous cell therapy FCX-007 Recessive dystrophic epidermolysis

bullosa Autologous cell therapy FCX-013 Moderate to severe localized

scleroderma


Modality/Type of Intervention Name of Intervention (Brand Name if Applicable)

Indication

CAR-T-cell therapy bb2121 B-cell maturation antigen-expressing multiple myeloma, multiple myeloma

CAR-T-cell therapy BCMA (EGFRt/BCMA-41BBz CAR-T cell)

Multiple myeloma

CAR-T-cell therapy JCAR014 Non-Hodgkin lymphoma CAR-T-cell therapy JCAR016 Acute myeloid leukemia, non-small-

cell lung cancer, mesothelioma CAR-T-cell therapy JCAR018 Non-Hodgkin lymphoma, pediatric

acute lymphoblastic leukemia CAR-T-cell therapy JCAR020 Ovarian cancer CAR-T-cell therapy JCAR023 Pediatric neuroblastoma CAR-T-cell therapy JCAR024 ROR1+ cancers (solid tumors, blood

cancers) CAR-T-cell therapy JCARH125 B-cell maturation antigen target in

late-line myeloma CAR-T-cell therapy Lisocabtagene maraleucel (Liso-Cel,

JCAR017) Non-Hodgkin lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, mantle-cell lymphoma, primary mediastinal B-cell lymphoma

Injectable retroviral replicating vector that encodes a prodrug activator enzyme, cytosine deaminase

Vocimagene amiretrorepvec (Toca 511 & Toca FC)

Glioma

RNAi ALN-TTRsc02 Acquired transthyretin amyloidosis RNAi AMG 890 (ARO-LPA) Apolipoprotein A reduction RNAi ARO-AAT Alpha-1 antitrypsin deficiency liver

disease RNAi ARO-HBV Chronic hepatitis B infection RNAi Cemdisiran (ALN-CC5) Complement mediated disease RNAi Fitusiran (ALN-AT3sc) Hemophilia A, B RNAi Givosiran (ALN-AS1) Acute hepatic porphyrias RNAi Inclisiran (ALN-PCSsc) Hypercholesterolemia RNAi Lumasiran (ALN-GO1) Primary hyperoxaluria Type 1 RNAi Revusiran (ALN-TTRsc) Transthyretin-mediated amyloidosis,

familial amyloidotic polyneuropathy, ATTR amyloidosis, familial amyloid neuropathies, mediated familial amyloidotic cardiomyopathy

Wyeth strain vaccinia virus/ granulocyte-macrophage colony stimulating factor expression

Pexastimogene Devacirepvec (Pexa-Vec, JX-594)

Cancer (various)

ZFN SB-318 MPS I (Scheie, Hurler-Scheie, and Hurler syndromes)

ZFN SB-913 MPS II (Hunter syndrome) ZFN SB-FIX Hemophilia B ZFN ST-400 Beta-thalassemia ZFN–CAR-T-cell therapy SB-728-T HIV ZFN–stem cells SB-728-HSPC HIV


Abbreviations: AAV, adeno-associated virus vector; CAR-T, chimeric antigen receptor T cell; CRISPR, clustered regularly interspaced short palindromic repeats; CRISPR-Cas, CRISPR-associated protein; MPS, Mucopolysaccharidosis; RNA, ribonucleic acid; RNAi, RNA interference; ZFN, zinc finger nuclease. Note: Shading indicates adenovirus and AAV gene therapy. *AVXS-101 (Avexis/Novartis) to treat spinal muscular atrophy was approved on May 24, 2019 as Zolgensma

Our search identified 76 therapies that meet the FDA’s definition of gene therapy and that have not yet been approved (ie, pipeline therapies). The most common type of therapy is AAV (37%). The next most common types are CAR-T-cell therapy (13%), RNAi (13%), autologous cell therapy (11%), CRISPR-Cas9–CAR-T-cell therapy (8%), ZFN (5%), antisense (4%), adenovirus (3%), CRISPR-Cas9–autologous CD34+ human hematopoietic stem and progenitor cells (1%), injectable retroviral replicating vector that encodes a prodrug activator enzyme, cytosine deaminase (1%), Wyeth strain vaccinia virus/granulocyte-macrophage colony stimulating factor expression (1%), ZFN–CAR-T-cell therapy (1%), and ZFN–stem cell therapy (1%).

The identified therapies are being used to treat multiple disease types, including vision disorders (eg, choroidemia), muscular dystrophy (eg, Duchenne), blood disorders (eg, hemophilia), Sanfilippo syndrome, cancer, HIV, and Parkinson’s disease.

We asked key informants to name any pipeline therapies that are likely to gain approval in the next 5 years. They identified 6 therapies, which are included in Table 3:

• AVXS-101 (Avexis/Novartis) to treat spinal muscular atrophy (2 nominations) was approved on May 24, 2019 as Zolgensma

• Valoctocogene roxaparvovec (Biomarin) to treat hemophilia A (1 nomination) • SPK-9001(Spark Therapeutics) to treat hemophilia A (2 nominations) • SPK-8011 (Spark Therapeutics) to treat hemophilia B (1 nomination) • AMT-061 (uniQure) to treat hemophilia B (1 nomination) • LentiGlobin (Bluebird bio) to treat beta-thalassemia (2 nominations)

One key informant thought AMT-061 was close to approval, and 2 nominated AVXS-101 and LentiGlobin. One key informant nominated Valoctocogene roxaparvovec, SPK-9001, and SPK-8011. The fact that key informants were aware of these 6 therapies among the large number of potential pipeline therapies we identified suggests that these 6 are closer to approval than the others. AVXS-101, Valoctocogene Roxaparvovec, SPK-9001, and SPK-8011 are AAV interventions; we identified completed trials with promising evidence for AVXS-10111 and for SPK-9001.12 As noted above AVXS-101 was approved as Zolgensma on May 24, 2019. LentiGlobin is an autologous cell intervention; along with Valoctocogene Roxaparvovec, SPK-801, and AMT-061, it might still be undergoing testing in trials that have yet to complete recruitment.

Adenoviral, AAV, and CRISPR Gene Therapy Eligible interventions included those that used adenovirus, AAV, or CRISPR therapies. In the following sections we describe the indications and their US prevalence for approved and as yet unapproved adenoviral, AAV, and CRISPR technologies.

Adenoviral Therapy Indications Unapproved Our search identified one adenoviral-based therapy that targets brain cancer tumor cells. In 2015, an estimated 166 039 people in the United States were living with brain and other nervous system cancer.13 This therapy has not yet been approved by the FDA.


AAV Therapy Indications Approved Luxturna (Voretigene neparvovec, an AAV therapy) is the only approved therapy that falls into the scope of this report. Luxturna is used to treat biallelic RPE65 mutation-associated retinal dystrophy, which currently afflicts approximately 1000 to 2000 individuals in the United States.14 RPE65 is a key isomerase for normal enzymatic processes, and mutations in RPE65 can result in blindness.15 Luxturna acts by delivering the expression of a healthy copy of the RPE65 gene directly to the subretinal space.

Unapproved Multiple AAV therapies are in trials to treat a broad array of conditions.

Ocular disorders • Leber congenital amaurosis is an eye disorder that affects the retina and is associated with

vision impairment. Although it is relatively rare, occurring in just 2 to 3 of 100 000 newborns, it is the most common form of inherited blindness in children.16

• Achromatopsia is associated with partial or total lack of color vision as well as photosensitivity and low visual acuity; it occurs in 1 of 30 000 people globally.17

• Choroideremia begins with impaired vision at night and progresses to reduced visual acuity. Its prevalence is estimated to be 1 in 50 000 to 100 000 among people of European descent.18

• X-linked retinitis pigmentosa expresses only in males; the estimated prevalence is 1 to 5 of 10 000 people.19 Heterozygous females are assumed to be unaffected because they can have a healthy copy of the gene to compensate for the mutated copy; however, carrier females may suffer from symptoms.20

Blood disorders • Hemophilia A is a bleeding disorder that affects 1 in 5000 newborn males; it is 4 times more

common than hemophilia B. An estimated 20 000 people in the United States have hemophilia.21,22

Metabolic disorders • Sanfilippo syndrome is a rare inherited metabolic disorder that leads to progressive

neurocognitive degeneration. The prevalence for all subtypes is estimated to be 1 to 9 in a million people.23

Muscular disorders • Duchenne muscular dystrophy is a genetic disorder that manifests most severely in males (1 in

3500 to 5000 males) and leads to progressive muscle degeneration.24 • Spinal muscular atrophy is a neuromuscular disease that results in muscle weakness and

paralysis. The estimated incidence is 1 in 6000 to 10 000 live births.25 • Limb-girdle muscular dystrophy results in atrophy of the limb-girdle muscles; it can cause

serious disability or may progress slowly and cause minimal disability.26 Prevalence estimates range from 1 in 14 500 to 1 in 123 000 individuals.27

• Parkinson’s is the most common movement disorder; it is characterized by tremors, rigidity, and bradykinesia.28 It is estimated that almost a million people in the United States will have Parkinson’s in 2020.


CRISPR Therapy Indications Unapproved While CRISPR has not yet been approved in the United States, many trials are under way and recruiting patients to treat cancer and blood disorders.

Cancer • Solid tumor cancers (eg, sarcomas, carcinomas, lymphomas) are defined as abnormal masses

that do not contain cysts or liquid areas,29 so they can affect multiple organs (eg, colon). It was estimated that across all types of cancer there were 1 735 350 new cases in 2018.30

• T-cell acute lymphoblastic leukemia is an aggressive type of leukemia31; the estimated incidence in the United States is 0.13 cases per 100 000 people.32

• T-cell lymphoma is a rare malignancy based on a collection of subtypes of non-Hodgkin lymphoma.33 Non-Hodgkin lymphoma accounts for 4% of cancers in the United States; it includes mycosis fungoides, anaplastic large-cell lymphoma, and precursor T-lymphoblastic lymphoma.34 An estimated 74 680 adults and children were diagnosed with non-Hodgkin lymphoma in 2018.35

• Diffuse large B-cell leukemia or lymphoma is an aggressive cancer and the most common type of non-Hodgkin lymphoma in the United States.36 On the basis of 2011-2015 data, the estimated number of new cases in 2011-2015 was 5.5 per 100 000 adults.37

• Gastric cancer is the fourth most common form of cancer. There were an estimated 989 000 new cases globally in 2008.36

• The estimated incidence for nasopharyngeal carcinoma, a relatively rare malignancy, is less than 1 per 100 000 person years.38

• After skin cancer, prostate cancer is the next most common cancer in men; it was estimated that there were 164 690 new cases in 2018.39

• Bladder cancer is the fourth most common cancer in men; it is less common in women.40 It was estimated there were 81 190 new cases in 2018.

• About 80% to 85% of lung cancers are non-small-cell lung cancer; it was estimated that there were 234 030 new cases of lung cancer in 2018.41

• Kidney cancer (also known as renal cell carcinoma) is among the 10 most common cancers in men and women.42 It was estimated that there were 65 340 new cases in 2018.43

• Esophageal cancer is a relatively rare malignancy; it was estimated that there were 17 290 new cases in 2018.44

Blood disorders • A CRISPR-based intervention has been designed to treat beta-thalassemia, which is a rare

inherited blood disorder. The severity of beta-thalassemia can range from mild to severe, in which patients require regular blood transfusions throughout their lives. The incidence of symptomatic cases is estimated to be approximately 1 in 100 000 people globally.45

Key Question 1a. What different types or modalities of the intervention have been used in clinical practices and clinical research studies? Gene therapy interventions either modify or edit a patient’s gene, or they introduce a protein-producing gene into the patient. In the following sections we describe the adenovirus, AAV, and CRISPR interventions according to whether they act by modifying or editing, or by delivering a gene and its expression to a patient.


Gene Editing or Replacement The CRISPR-Cas (CRISPR-associated protein) system was recently identified as a powerful tool for therapeutic gene editing. CRISPR-Cas was first discovered in bacteria and archaea46 as an adaptive defense system that uses antisense RNAs as memory signatures of past invasions.47,48 Functional CRISPR-Cas loci comprise identical repeats, intercalated with invader DNA-targeting spacers that encode the Cas components. The CRISPR-associated protein Cas9 is a dual RNA–guided endonuclease that uses a guide sequence within an RNA duplex to form base pairs with DNA target sequences, allowing Cas9 to create a site-specific double-strand break in the DNA.49,50 The CRISPR-Cas9 system requires only a change in the guide RNA sequence, which avoids substantial protein engineering.51 Both ex vivo and in vivo approaches can deliver CRISPR to patients. In vivo, CRISPR machinery is packaged in a vector, such as a virus, and then delivered directly via injection into the target organ. With the ex vivo approach, cells are extracted from patients, modified with CRISPR technology, grown, and then reintroduced into the patient. Genes can be modified in 1 to 2 weeks, then grown within 2 to 3 weeks.52

Gene Delivery and Expression Adenovirus and AAV vector-based therapies both use a nonpathogenic virus to deliver DNA and gene transfer to patients. They act by incorporating the virus’s genome into a patient’s dividing and nondividing cells. The adenovirus genome is a linear double-stranded DNA between 26 kb and 48 kb in size.53 Adenoviruses can deliver up to 30 kb of DNA and produce gene expression in less than 24 hours, but the expression is transient. Another drawback of this therapy is that administration of adenovirus creates an innate immune response that may include production of pro-inflammatory chemokines and cytokines, thrombocytopenia, coagulopathy, and liver damage.54 AAV is a single-stranded DNA genome that is approximately 5 kb long.54 AAVs can deliver smaller DNA segments than adenoviruses, elicit low immune responses, and can potentially provide long-lasting gene expression. Luxturna (Voretigene neparvovec) is an AAV-based gene therapy to treat children and adults with a confirmed biallelic RPE65 mutation-associated retinal dystrophy that leads to vision loss and can cause complete blindness. Both adenovirus and AAV can be used alone or in combination with other modalities; for example, AAV can be used to deliver CRISPR. Both adenoviral and AAV therapies can be injected locally to the site of disease; for example, Luxturna is injected directly into the retina. Other delivery approaches being tested include systemic delivery targeting the liver, intramuscular injection, and central nervous system delivery.55

Key Question 1b. What are the potential/presumed advantages and disadvantages in contrast to current practices? Advantages Many of the potential and presumed advantages of gene therapies are similar across all types of gene therapy. The first and foremost advantage is to cure previously incurable and fatal diseases. For many diseases the only treatment is supportive care, or the treatment has dire side effects or is very costly. In cases in which a disease has a spectrum of severity, our review of the literature found that gene therapy typically targets the most refractory types. On the basis of our review and interviews with key informants, the greatest advantage of gene therapy is reducing suffering by addressing unmet need. A gene therapy would have an advantage over current therapy if it could negate the need for any future treatment. Theoretically, some gene therapies can cure the targeted condition with only one administration, and some conditions can be manageable with current practices and repeated treatments.


However, high prices for a curative genetic treatment may limit access to the treatment and thus reduce or obviate the therapy’s advantage over current treatment.

AAV is one type of gene therapy that is expected to require only one administration, which would be a significant advantage over current treatments that require repeated procedures. For example, hemophilia is currently managed with repeated transfusions, which are a physical burden to patients and costly to patients and health care payer institutions.56,57 Several AAV therapies are being tested that would treat these patients with one administration, eliminating the need for regular transfusions.

Multiple adenoviral and CRISPR therapies are in trials to cure certain types of cancer. If these therapies are successful, they will replace chemotherapy, which has the potential to cause chemotoxicity in patients.

Disadvantages All types of gene therapies share many unknowns and uncertainty related to the following: (1) their clinical effectiveness versus the risk for adverse outcomes; (2) how they will be implemented in health care systems in which patients are not well informed about what gene therapies are and providers are unfamiliar with requisite procedures; (3) the ethical implications of altering the genome; and (4) how patients and payers will pay for potentially expensive gene therapy. We need more evidence to know whether these unknowns will become disadvantages.

Several cases of gene-related death slowed gene therapy progress in the early years of this research. Jesse Gelsinger was the first patient to die in 1999 after receiving gene therapy that triggered a fatal immune response, which resulted in the suspension of adenoviral trials.58 Later in 2002, a French child developed a leukemia-like illness that was thought to have been caused by the gene therapy.59 Other cases include a death due to a fatal infection after a patient had received immunosuppressive therapy in a gene therapy trial.60 Longer-term disadvantages are related to risks that are not yet understood, including future malignancy. All of our key informants were concerned about the risk of adverse health outcomes, including off-target effects, viral spread, genotoxicity, and alterations to the germline. Viral-delivered gene therapy can induce genotoxic events, including inflammation, immune response, random insertion that can disrupt normal genes, activation of proto-oncogenes, and insertional mutagenesis.61 Specific targeting of disease cells with viral cells is a challenge, and viruses can spread and infect healthy cells. Moreover, a virus might insert DNA into the wrong location, causing off-target effects even in reproductive cell lines, thereby changing the germline. These effects are all possible outcomes of adenoviral, AAV, and CRISPR treatment.

Price may be a disadvantage of these therapies relative to others. New gene therapies are expensive to patients and payers; for example, Luxturna treatment is priced at $425 000 per eye.62 During our interviews, one key informant expressed concern about the viability of small insurers, small self-insured employers, and even large self-insured employers with limited reinsurance in the face of very high treatment prices. Because these therapies may provide large health gains and reduce future treatment prices, manufacturers can charge high upfront payments to reflect the value of the therapy. Such high short-term fees can limit access if the treatment is unaffordable. While the price of a particular therapy might be based on its perceived value, little clinical evidence exists to establish value for money. The Institute for Clinical and Economic Review white paper “Gene Therapy: Understanding the Science, Assessing the Evidence, and Paying for Value” discusses the challenges gene therapy presents in the United States, as well as potential solutions (eg, annualized payments or risk sharing).63

Preclinical work and drug optimization in mice might not translate to human treatment outcomes. For example, AAV serotypes might be very effective in mice or nonhuman primates but might not be optimized for humans, so they would be less effective for human disease treatment. At


the same time, industry might be reluctant to repeat human trials if the therapy doesn’t perform, because industry would have to invest additional substantial financial and labor resources. However, if a treatment doesn’t work and scientists don’t understand why, they might be missing an opportunity to improve the therapy. Key informants noted that the FDA requires multiple preclinical studies to reapprove slightly modified gene therapy vectors for new clinical trials. This can make it more difficult for researchers to learn and adapt from failed clinical trials. Also, key informants noted that the FDA’s emphasis on functional outcomes rather than biomarkers in clinical trials with small sample sizes can make it difficult to find statistically significant effects. Functional outcomes have a higher interpatient variation than biomarkers and posttreatment improvement, so such studies require larger patient sample sizes than studies with biomarker outcomes.64

Even among completed human trials, the patient populations can be very small and evidence about the treatment’s effectiveness can be limited. One key informant noted that patients might be reluctant to participate in trials to assess minimal dosage safety because they want the higher dose. For example, with adenovirus and AAV therapies, one treatment will create host immunity to the vector, so patients have only one chance for treatment; most will not want their chance for a cure to be lost because the dose was too low to be effective. Other disadvantages discussed by key informants were related to manufacturing and the need for greater understanding of the science and mechanisms of action to regulate and ensure quality in manufacturing. Gene therapies are regulated as products, but one key informant suggested that perhaps they should be regulated as procedures, which raises the question of who should be permitted to administer gene therapy. Gene therapies could become like stem cell therapies, which have been administered at certain times and places with little regulation of who provides the therapy. For example, in Australia, autologous cellular treatments were once exempt from the regulatory framework that applies to cell and gene treatments; thus, the use of unproven autologous cell interventions grew markedly in Australia.65 Key informants also noted that the current health care system is not structured to deliver gene therapy, in part because providers are not fully aware of new, nonstandard therapies. Moreover, patients seeking care may have to travel far to the few existing gene therapy treatment centers, which can be costly and place heavy burdens on families.

Key informants expressed concern about several other potential disadvantages. Several were concerned about delivering interventions to target cells more effectively and balancing minimally effective dosages with adverse reactions. And one key informant noted that much of the evidence for gene therapies includes small study samples, even though the indication is prevalent in large populations (eg, patients older than 65). For example, we found in our second report that many of the gene therapy trials treating cardiovascular disease have a relatively small number of participants compared with the burden of the disease in the population. Thus, lack of generalizability of findings is a concern. Most key informants expressed concern about the state of science education, the average person’s understanding of gene therapy, and how patients can weigh the risks and the information about effectiveness.

Key Question 1c. What are the safety issues or expected adverse events? Some therapies produce physiologic responses that can be dangerous if they are not managed clinically. The primary safety concerns mentioned by key informants involved unintended consequences of editing and introducing genetic material to a person. The concerns included malignancy, off-target effects, viral shedding or spread, and genotoxicity, in which integration of the vector DNA can have genotoxic effects. Regarding gene editing, a lack of specificity with CRISPR can have off-target effects that might result in malignancy.66 Immune responses to AAV pose few safety


concerns, although preexisting anti-adenoviral antibodies might stimulate stronger innate immune responses after vector administration,67 which could be a serious concern. Regarding Luxturna (Voretigene neparvovec), some potential adverse events are related to the surgery68; for example, injection can introduce infection and inflammation that can cause vision loss. Other possible adverse events related to the treatment and eye response are retinal abnormalities (eg, tears), increased intraocular pressure, air bubbles, and cataract. The most common adverse events are conjunctival hyperemia, cataract, increased intraocular pressure, retinal tear, dellen (thinning of the corneal stroma), macular hole, subretinal deposits, eye inflammation, eye irritation, eye pain, and maculopathy (wrinkling on the surface of the macula).


Context in Which Gene Therapy Is Used Key Question 2a. What is the approval process and current approval/certification status for gene therapies? In the United States, the FDA’s Center for Biologics Evaluation and Research reviews and regulates the use of human gene therapies, cellular therapy products, and devices related to gene and cell therapy. Within the National Institutes of Health (NIH), the Office of Biotechnology Activities and the Recombinant DNA Advisory Committee (RAC) review gene therapy protocols. While both the FDA and the RAC consider clinical and preclinical issues, the RAC also serves as an open forum for consideration of ethical, legal, and societal issues.69

Gene therapy sponsors submit an investigational new drug application, a biologics license application, and an investigational device exemption application to the FDA. In the investigational new drug application, manufacturers must describe how they will conduct the study, possible risks that might be involved and what steps they will take to protect patients, and the evidence that supports the study. The FDA has published guidance documents70 to facilitate the approval process. Manufacturers of gene therapy products must comply with FDA requirements for safety, purity, and potency before their therapies can be approved and sold. In August 2018, NIH reported that the RAC will no longer review all gene therapy applications and will instead provide guidance in an advisory role.71,72 The FDA will now review and approve gene therapies and biologic products as it does other treatments and drugs.

In cases in which the disease is severe and no alternative treatments exist, the FDA has approved gene therapies on the basis of single-arm phase II trials. Luxturna (Voretigene neparvovec) was approved after one randomized phase III trial reported improved visual acuity 30 days post treatment that persisted 1 year.73,74 Thirteen of the 20 intent-to-treat intervention participants passed the multi-luminance mobility test at the lowest luminance level tested at 1 year, and none of the control participants did. Other evidence came from a small open-label dose escalation phase I trial.75,76 A follow-up trial tested treatment in the contralateral eye and reported persistent improved functional vision after 3 years.77 Ten participants showed improvements in mean mobility and full-field light sensitivity in the injected eye by day 30 that persisted to year 3, but no significant change was seen in the previously injected eyes for mobility or white light full-field sensitivity. Patients who have been treated in both trials will be followed for 15 years.73 It does not appear that longer follow-up was a postmarketing requirement of the FDA, because the applicants included a plan for longer follow-up in their pharmacovigilance plan.78

The FDA’s Regenerative Medicine Advanced Therapy program provides support and assistance for the production of gene therapies that treat serious or life-threatening conditions and address unmet medical needs.79 In December 2016, Congress passed the 21st Century Cures Act, designed to accelerate medical product development in order to treat patients faster and more efficiently.80 In June 2018, the Center for Biologics Evaluation and Research granted the regenerative medicine advanced therapy designation to 24 products.79 The FDA currently has more than 700 active investigational new drug applications for gene therapy81 and recently announced that it plans to provide policy guidance to accelerate approval for the rapid expansion of gene therapy development.82

Key Question 2b. Are any additional accompanying resources or technologies required? Before a patient receives any gene therapy that requires injection delivery, he or she might be given prophylactic antibiotics. In one study, the providers used ultrasound to guide the injection of


adenoviral therapy into the tumor.83 Immunosuppression therapy (eg, methylprednisone) might be given prior to AAV administration. For the specific AAV treatment of ocular disorders, vitrectomy must precede the subretinal injection of the drug (eg, Luxturna). Other cotreatments include disease-related standard of care; for example, chemotherapy might accompany any gene therapy that targets cancer.

Key Question 2c. What is the current state of adoption in practice and settings? Gene therapy is available through standard care when the intervention is approved. For example, Luxturna is available to patients at 10 designated ocular gene therapy treatment centers, 5 of which are in the Northeastern region of the United States. Two centers are in the South and 2 are on the West Coast, so patients might have to travel many miles for treatment.84 Gene therapy is also available through participation in a clinical trial. However, as the field is rapidly advancing, more treatments will likely be approved for use beyond trials.

Key informants noted several challenges facing the adoption of gene therapies and gaps in our understanding of this question. For example, current approaches to payer approval are based on population estimates for risk management and not on personalized medicine. Generally, risks can be spread across populations, but this is less feasible when patients’ specific disease traits (eg, genetics) are used to develop and deliver tailored treatment.

Further, even though high upfront prices can be offset by downstream health benefits, current insurance structures might not be able to cover expensive gene therapies. CMS will reimburse hospitals $400 000 for Yescarta and $500 000 for Kymriah for inpatient treatment. The patient is responsible for a $1340 deductible for inpatient treatment per benefit period.85 However, when patients are treated in outpatient settings they could be responsible for 20% ($79 000-$100 000). How other payers will handle payment is less clear.

Payers and manufacturers are considering alternative payment scenarios that include staggered or long-term payment agreements or linking payment to patient outcomes.86 In August 2018, the Medicare Evidence Development and Coverage Advisory Committee met to discuss whether and how CMS should incorporate patient-reported outcomes (PROs) into coverage decisions for CAR-T and other gene therapies. While committee members expressed confidence in specific tools to measure PROs, some voiced concern about the difficulty of collecting and interpreting such data.87 In February 2019, CMS proposed to cover FDA-approved CAR T-cell therapy if the treatment is in a CMS-approved registry or clinical study and patients are monitored for at least 2 years posttreatment.88

Key Question 2d. What are the operator factors, such as training and staffing? The manufacturing process is a major operator factor in the success of gene therapy. The clinical production process is challenged by consistent process control and by its ability to achieve the scale needed for commercial use. For example, limited cell line availability and lack of manufacturing capacity hinder the consistent production and characterization of cellular products. In July 2018, the FDA published guidance on the manufacturing information required to support the clinical development of investigational human gene therapies.89 The need for rigorous, high-quality biomanufacturing processes increases the demands on staff training and hiring. In fact, staffing challenges might limit commercial-scale production of gene therapies more than facility availability.90 Key informants also noted that the current health care system is not structured to deliver gene therapy, in part because providers are not fully aware of new nonstandard gene therapies.


Ongoing Premarket and Postmarket Gene Therapy Studies

Ongoing Trial Characteristics Table 4 describes 19 ongoing studies we identified that are evaluating adenovirus, AAV, or CRISPR interventions. We identified only one CRISPR study that met our criteria for an ongoing trial that might be close to approval in which patient recruitment is complete. This trial is testing a CRISPR intervention to treat metastatic non-small-cell lung cancer.91 All other currently registered CRISPR trials in clinicaltrials.gov are still recruiting participants.

Table 4. Ongoing Adenovirus, AAV, and CRISPR Trials Indication Author Trial Number Study Design Estimated Completion

Indication Concurrent/Previous Treatments Months of Follow-up

Intervention Comparator

Outcomes Measured

Adenovirus Cancer University of Pennsylvania, 202392 NCT00299962 Trial (multiple groups), planned N = 18 Completion date: 04/2023

Age group: adults Malignant metastatic or pleural mesothelioma Treatment enrollment: none Treatment requisite: none Follow-up: 180

Ad.hIFN-β; BG00001 No comparison group

Tumor regression, time to progression, survival

AAV Blood disorders Shire, 203093 Weber et al, 201894 NCT01687608 Single-arm trial, planned N = 30 Completion date: 10/2030

Age group: adults Hemophilia B Treatment enrollment: hemophilia B with ≥3 hemorrhages per year requiring treatment with exogenous FIX or use of FIX prophylaxis due to history of frequent bleeding episodes Treatment requisite: none Follow-up: 204

AskBio009 No comparison group

Change from baseline in clinical laboratory evaluations; changes from baseline in FIX activity levels, FIX protein levels, and bleeding episode severity and frequency; immune response to AskBio009; detection of AskBio009 genomes in blood, saliva, urine, stool, and semen

Cancer The First People's Hospital of Changzhou, 202695 NCT02496273 Single-arm trial, planned N = 60 Completion date: 12/2030

Age group: adults Stage IV gastric cancer Treatment enrollment: none Treatment requisite: none Follow-up: 1

AAV-DC-CTL No comparison group

ELISPOT assays, overall survival


Indication Author Trial Number Study Design Estimated Completion



Outcomes Measured

Muscular conditions Hospital, 201696 NCT02710500 Single-arm trial, planned N = 2 Completion date: 04/2019

Age group: adults Dysferlinopathy Treatment enrollment: none Treatment requisite: none Follow-up: 24

rAAVrh74.MHCK7.DYSF.DV No comparison group

Toxicity

Muscular conditions Nationwide Children's Hospital, 201897 NCT03375164 Trial (multiple groups), planned N = 12 Completion date: 01/2021

Age group: children Duchenne muscular dystrophy Treatment enrollment: none Treatment requisite: none Follow-up: 36

rAAVrh74.MHCK7.micro-dystrophin No comparison group

Adverse events, Gross Motor Subtest Scaled score, 100 Meter Timed Test, North Star Ambulatory Assessment, Timed Up and Go modified for children, ascend and descend 4 steps, handheld dynamometry, microdystrophin gene expression quantification by immunofluorescence, microdystrophin gene expression quantification by western blot

Muscular conditions Mendell, 201998 NCT01976091 Trial (multiple groups), planned N = 6 Completion date: 02/2019

Age group: children and adults Limb-girdle muscular dystrophy type 2D Treatment enrollment: none Treatment requisite: none Follow-up: 24

scAAVrh74.tMCK.hSGCA No comparison group

Change in 6-minute walk test

Neurodegenerative disorders National Institute of Neurological Disorders and Stroke, 202599 NCT01621581 Trial (multiple groups), planned N = 25 Completion date: 12/2027

Age group: adults Advanced Parkinson’s disease Treatment enrollment: disability despite optimal antiparkinsonian medication therapy Treatment requisite: none Follow-up: 144

AAV2-GDNF No comparison group

Safety, tolerability, potential for clinical responses





Outcomes Measured

Neurodegenerative disorders Weill Medical College of Cornell University, 2020100 NCT01414985 Trial (multiple groups), planned N = 8 Completion date: 12/2022

Age group: children Late infantile neuronal ceroid lipofuscinosis, Batten disease Treatment enrollment: none Treatment requisite: none Follow-up: 18

AAVrh.10CUCLN2 No comparison group

Weill Cornell LINCL Scale, Child Health Questionnaire, Mullen Scale, MRI (percentage gray matter volume, percentage ventricular volume, and cortical apparent diffusion coefficient)

Neurodegenerative disorders Weill Medical College of Cornell University, 2020101 NCT01161576 Trial (multiple groups), planned N = 25 Completion date: 08/2032

Age group: children Batten disease, late infantile neuronal ceroid lipofuscinosis Treatment enrollment: none Treatment requisite: none Follow-up: 18

AAVRh.10CUhCLN2 No comparison group

Weill-Cornell LINCL scale score, disease progression based on change in MRI imaging parameter (percentage gray matter volume), disease progression based on change in MRI imaging parameter (percentage ventricular volume), disease progression based on change in MRI imaging parameter cortical apparent diffusion coefficient), Quality of Life Survey, Mullen Scale score

Neurodegenerative disorders Therapeutics Voyager, 2021102 Single-arm trial, planned N = 16 Completion date: 12/2021

Age group: adults Advanced Parkinson’s disease Treatment enrollment: none Treatment requisite: patients will continue medications for Parkinson’s; patients undergo a neurosurgical procedure with real-time MRI monitoring so that therapy is delivered directly into the striatum Follow-up: 36

VY-AADC01 No comparison group

Columbia-Suicide Severity Rating Scale, change in Parkinson’s medications, motor function, dyskinesia occurrence, mood, cognitive function, compulsive behavior, sleep quality and disturbance, Non-Motor System Scale, quality of life





Outcomes Measured

Neurodegenerative disorders Voyager Therapeutics, 2019103 NCT01973543 Trial (multiple groups), planned N = 15 Completion date: 12/2019

Age group: adults Parkinson’s disease Treatment enrollment: Levodopa therapy Treatment requisite: none Follow-up: 36

VY-AADC01 No comparison group

Parkinson’s symptoms, PET scan imaging (AADC expression)

Ocular disorders Spark Therapeutics, 2019104 NCT02341807 Trial (multiple groups), planned N = 15 Completion date: 01/2019

Age group: adults Choroideremia, CHM gene mutations Treatment enrollment: none Treatment requisite: none Follow-up: 24

AAV2-hCHM No comparison group

Safety and tolerability (assessed by physical exam, vital signs, laboratory changes over time, and adverse events)

Ocular disorders GenSight Biologics, 2018105 NCT02652767 RCT, planned N = 36 Completion date: 09/2019

Age group: adults Leber hereditary optic neuropathy, affected 6 months or less Treatment enrollment: none Treatment requisite: none Follow-up: 24

GS010; rAAV2/2-ND4 Placebo

ETDRS visual acuity, improvement from baseline by 15 ETDRS letters or having visual acuity >20/200, optic nerve retinal nerve fiber layer (RNFL) thickness and the thickness/volume of the retinal layers of the macula, Humphrey Visual Field 30-2, Pelli-Robson Contrast Sensitivity, Farnsworth-Munsell Color 100 Hue Vision Test, immune responses, blood biodissemination of AAV2 vector DNA, Better-seeing Eye Comparison, Visual Functioning Questionnaire-25, 36-item Short Form Health Survey





Outcomes Measured

Ocular disorders GenSight Biologics, 2018106 NCT02652780 RCT, planned N = 36 Completion date: 01/2019

Age group: adults Leber hereditary optic neuropathy, affected for more than 6 months Treatment enrollment: none Treatment requisite: none Follow-up: 24

GS010; rAAV2/2-ND4 Placebo

ETDRS visual acuity, improvement from Baseline by 15 ETDRS letters or having visual acuity >20/200, optic nerve RNFL thickness and the thickness/volume of the retinal layers of the macula, Humphrey Visual Field 30-2, Pelli-Robson Contrast Sensitivity, Farnsworth-Munsell Color 100 Hue Vision Test, immune responses, blood biodissemination of AAV2 vector DNA, Better-seeing Eye Comparison, Visual Functioning Questionnaire-25, 36-otem Short Form Health Survey

Ocular disorders STZ eyetrial, 2018107 NCT02671539 Single-arm trial, planned N = 6 Completion date: 03/2021

Age group: adults Choroideremia Treatment enrollment: none Treatment requisite: none Follow-up: 24

rAAV2.REP1 No comparison group

Best corrected visual acuity in treated eye, absence of vector-related adverse reactions, fundus autofluorescence analysis, central visual field using microperimetry readings, contrast sensitivity, color vision

Ocular disorders Huazhong University of Science and Technology, 2019108 NCT03153293 Single-arm trial, planned N = 40 Completion date: 06/2019

Age group: children and adults Leber hereditary optic neuropathy Treatment enrollment: no eyesight improvement in Leber's optic hereditary neuropathy patients or any other treatment within the past year Treatment requisite: none Follow-up: 12

rAAV2-ND4 No comparison group

Best corrected visual acuity, computerized visual field, visual evoked potential, retinal nerve fiber layer, liver function in plasma, kidney function in plasma





Outcomes Measured

Ocular disorders Spark Therapeutics, 203073 NCT03602820 Single-arm trial, planned N = 41 Completion date: 06/2030

Age group: children and adults Inherited retinal dystrophy Treatment enrollment: none Treatment requisite: none Follow-up: 180

Voretigene neparvovec-rzyl; AAV2-hRPE65v2 No comparison group

Bilateral mobility, full-field light sensitivity threshold, visual acuity, visual field testing, visual function questionnaire

Other: metabolic disorders Institut National de la Santé Et de la Recherche Médicale, France, 2018109 NCT01801709 Single-arm trial, planned N = 5 Completion date: 04/2019

Age group: children Metachromatic leukodystrophy Treatment enrollment: none Treatment requisite: none Follow-up: 24

AAVrh.10cuARSA No comparison group

Tolerance, efficacy to stop disease progression

CRISPR Cancer Sichuan University, 201891 NCT02793856 Trial (multiple groups), planned N = 12 Completion date: 12/2018

Age group: adults Metastatic non-small-cell lung cancer Treatment enrollment: none Treatment requisite: Peripheral blood lymphocytes were collected from each patient and CRISPR-Cas9 technology was used to knock out the programmed cell death protein 1 gene to make PD-1 knockout T cells; patients received a single dose of cyclophosphamide (chemotherapy conditioning) 3 days prior to cell infusion; patients received 6 infusions of knockout cells (2 cycles with 3 infusions each). Follow-up: 24

PD-1 knockout T cells No comparison group

Response rate (per RECIST v1.1), disease control rate (response per RECIST v1.1), progression-free survival, overall survival, peripheral blood-circulating tumor DNA, cytokine (IL-10, TNF-a, IL-6) changes in peripheral blood

Abbreviations: AADC, aromatic L-amino acid decarboxylase; ; AAV, adeno-associated virus vector; CHM, choroideremia; CRISPR, clustered regularly interspaced short palindromic repeats; ; CRISPR-Cas, CRISPR-associated protein; DNA, deoxyribonucleic acid; ETDRS, Early Treatment Diabetic Retinopath Study; INCL, late infantile neuronal ceroid lipofuscinosis; MPS, mucopolysaccharidosis; RCT, randomized controlled trial; RECIST, response evaluation criteria in solid tumors; RNA, ribonucleic acid; RNAi, RNA interference; ZFN, zinc finger nuclease.


Key Question 3a. What are the indication/patient inclusion criteria in ongoing trials? Ocular disorders are the most common indication in the identified studies (32%). Other indications are neurodegenerative disorders (26%),99-103 cancer (16%),91,92,95 muscular conditions (16%),96-98 blood disorders (eg, hemophilia B, 5%),93 and metachromatic leukodystrophy (5%).109

Patient inclusion criteria in ongoing trials differ depending on the indication; for example, the hemophilia B patients had to have had a previous need for factor IX.93 While some of the cancer studies required patients to have failed previous surgery or chemotherapy,110 others required patients to be treatment naïve or did not describe eligibility criteria.92,95 Most of the studies testing treatment for muscular and neurodegenerative conditions, ocular disorders, and metachromatic leukodystrophy described no additional patient inclusion criteria, except for a few that required that patients had showed no improvement despite previous therapy.99,103,108

Patient populations are mostly adult gene therapy candidates (63%)91-93,95,96,99,102-107; however, 21% of the studies are testing interventions specifically in children97,100,101,109 and 16% are testing interventions in both children and adults.73,98,108

Key Question 3b. What are the types of interventions in ongoing trials? The 19 ongoing trials are primarily testing AAV gene therapy approaches (n = 17, 89%).73,93,95-109 However, we also identified an ongoing adenovirus trial (n = 1, 5%)92 and a CRISPR trial (n = 1, 5%).91 The Current Evidence Supporting Gene Therapy section of this report describes a large number of published adenovirus studies. The literature on AAV gene therapy is growing, as documented in the next section.

CRISPR specifically has received a lot of attention because of its ability to correct any region of DNA. Expectations are high that this new approach will be approved as a treatment for multiple diseases, including cancer and blood disorders.111 Trials are under way in the United States,112 but it is difficult to estimate when they will report results. We did identify one ongoing CRISPR trial in China91; the trial is registered in the clinicaltrials.gov database and is no longer recruiting. Given the lack of published findings, it is difficult to know how these trials might lead to FDA approval of CRISPR in the near future. In Table 3 we identified 7 distinct CRISPR therapies in the grey literature that are currently being discussed. The trial testing P-1 and TCR gene-knocked mesothelin-directed CAR-T cells is expected to be complete soon (current estimate is June 2019). The others appear to be further from approval, with completion years ranging from 2022 to 2038. However, even though the trial testing CTX001 to treat beta-thalassemia and sickle cell disease113 is not expected to conclude until 2022, several key informants named CTX001 as an intervention that may be approved within the next 5 years.

Key Question 3c. What are the study designs/sizes of ongoing trials? The most common study design in ongoing studies is a trial with multiple study arms in which patients are treated with different doses of the same therapy (47%).91,92,97-101,103,104 Single-arm trials accounted for 42%73,93,95,96,102,107-109 and RCTs for 11%.105,106 On average, the sample size was 21.4 (SD= 16) and ranged from 2 to 60 enrolled participants.

Key Question 3d. What are the comparators in ongoing trials? All the trials with multiple study arms compare groups of patients that receive different dosages of the treatment. The single-arm trials and trials with multiple study arms in which patients are treated with


different doses of the same therapy have no comparators.73,93,95,96,99,102-104,107-109 The RCTs compare the adenoviral or AAV gene therapy with placebo.105,106 We identified no ongoing nonrandomized trials that included an untreated control group.

Key Question 3e. What are the previous/concurrent treatments in ongoing trials? Most trials required no previous treatment for enrollment (78%),73,91,92,95-98,100-102,104-107,109 although some required patients to have exhausted all previous treatment options (22%).93,99,103,108 Most trials require no concurrent treatment (89%)73,92,93,95-101,103-109; however, patients enrolled in the CRISPR trial receive a single dose of cyclophosphamide (chemotherapy conditioning) 3 days before CRISPR-modified cell infusion.91 In an AAV trial to treat Parkinson’s, patients continue their medications and undergo a neurosurgical procedure with real-time MRI monitoring so the therapy is delivered directly into the striatum.102

Key Question 3f. What is the length of follow-up in ongoing trials? Average length of follow-up is 55.6 months (SD = 66 months) and ranges from 1 to 204 months with variation by indication. The one trial of AAV in hemophilia B has 204 months of follow-up. The cancer trials have the next longest follow-up (mean 68 months), and the trials treating ocular and neurodegenerative disorders followed patients for about 50 months. The group of trials for patients with muscular conditions had, on average, 28 months of follow-up.

Key Question 3g. What outcomes are measured in ongoing trials? Table 4 shows the planned outcomes. Health-related effectiveness outcomes assessed in ongoing trials are mostly indication specific; for example, bleeding episodes and severity rates are being measured for gene therapy intervention in hemophilia patients.93 In studies testing interventions to treat cancer, tumor progression and overall survival are being measured in multiple trials.91,92,95 Change in symptoms (eg, 6-minute walk test, best-corrected visual acuity) are being measured in the muscular condition, neurodegenerative disorder, and ocular disorder trials.73,96-109 Across all trials, safety and toxicity are commonly measured outcomes.


Current Evidence Supporting Gene Therapy Two tables (Tables A1 and A2) in the Appendix F document in detail each of the 251 completed trials that tested either adenovirus or AAV gene therapies. Documented trials were completed and published, partially published in interim analyses, or had their results documented in a trial registry without scientific publication to date. The evidence tables show study details, study design and comparator, sample size, indication, length of follow-up, indication, previous and concurrent treatment, outcomes measured, reported harms, and the authors’ conclusions.

Characteristics of Published Trials In Table 5 we summarize the evidence according to indication and study design for the adenoviral and AAV interventions. All trials in the table have been completed and have reported at least partial results. More published research studies tested adenoviral therapies (74%) than AAV (26%). We did not identify any completed CRISPR studies.

Table 5. Summary of Published Adenovirus and AAV Studies Indication Study Design by Indication Blood disorders (eg, hemophilia) (4%, n = 9)12,114-121 Single-arm trial (56%, n = 5)12,114,116-118

Trial (multiple groups) (44%, n = 4)115,119-121 Cancer (51%, n = 128)7,122-248 Single-arm trial (41%, n = 53)7,127-

129,133,135,136,140,142,147,148,150,156,158,161,164,174,177,181,183-

185,189,190,192,194-198,200,202-204,206,208,210,211,213,216-

220,222,226,228,233,235,241,242,246,247 Trial (multiple groups) (42%, n = 54)122-

126,131,132,134,137,138,141,143-146,151,157,159,160,162,163,165,167-173,175,178-

180,182,186-188,191,193,199,201,205,209,214,223,227,229,231,234,238-240,245,248 Controlled trial (5%, n = 6)155,166,215,221,225,244 RCT (12%, n = 15)130,139,149,152-

154,176,207,212,224,230,232,236,237,243 Cardiovascular disease (10%, n = 24)249-272 Single-arm trial (8%, n = 2)261,262

Trial (multiple groups) (13%, n = 3)249,266,267 Controlled trial (8%, n = 2)250,254 RCT (71%, n = 17)251-253,255-260,263-265,268-272

Immune deficiency (4%, n = 11)273-283 Trial (multiple groups) (18%, n = 2)274,281 RCT (82%, n = 9)273,275-280,282,283

Inflammatory disorders (2%, n = 4)284-287 Single-arm trial (25%, n = 1)287 RCT (75%, n = 3)284-286

Muscular conditions (1%, n = 3)288-290 Single-arm trial (33%, n = 1)289 Trial (multiple groups) (33%, n = 1)290 RCT (33%, n = 1)288

Neurodegenerative disorders (8%, n = 19)11,291-308 Single-arm trial (42%, n = 8)294,296,298-300,303,304,308 Trial (multiple groups) (21%, n = 4)11,295,305,306 Controlled trial (5%, n = 1)292 RCT (32%, n = 6)291,293,297,301,302,307


Indication Study Design by Indication Ocular disorders (8%, n = 19)74,75,309-325 Single-arm trial (37%, n = 7)75,311,315-319

Trial (multiple groups) (47%, n = 9)310,312-314,320-323,325 Controlled trial (5%, n = 1)324 RCT (11%, n = 2)74,309

Respiratory conditions (5%, n = 13)326-338 Single-arm trial (31%, n = 4)328,329,332,334 Trial (multiple groups) (54%, n = 7)326,327,330,331,333,336,338 RCT (15%, n = 2)335,337

Other (8%, n = 21)339-359 Single-arm trial (14%, n = 3)357-359 Trial (multiple groups) (24%, n = 5)344,349,353-355 Controlled trial (10%, n = 2)340,352 RCT (53%, n = 11)339,341-343,345-348,350,351,356

Abbreviation: RCT, randomized controlled trial. Note: Controlled trial, intervention and untreated control group; single-arm trial, case series; trial (multiple groups), multiple groups but no untreated control group.

Key Question 4a. What are the indication/patient inclusion criteria in published studies? Across both adenoviral and AAV therapies, the most common indication was cancer (51%), followed by cardiovascular disease (10%), neurodegenerative disease (8%), ocular disorders (8%), respiratory conditions (eg, cystic fibrosis) (5%), blood disorders (eg, hemophilia) (4%), immune deficiency (4%), inflammatory disorders (eg, arthritis) (2%), and muscular conditions (1%). Twenty-one studies (8%) tested interventions for other conditions such as vaccination studies (eg, Ebola, malaria). Others were trials in healthy volunteers, chronic wound healing in diabetic patients, ornithine transcarbamylase deficiency, and venous leg ulcer disease. Most trials had no specific inclusion criteria regarding previous treatment (74%); however, among the studies that did, patients had to have severe disease or have exhausted all treatment options. For example, in one study, patients had to have received a liver transplant to be eligible.

Of the studies, 89% were in adult patient populations. The remaining studies tested interventions in children (5%) or in both children and adults (6%).

Key Question 4b. What are the types of interventions in published studies? The identified trials tested a large variety of adenovirus (n = 186, 74%) and AAV (n = 65, 26%) gene therapy approaches. The evidence tables in Appendix F provide details for all included studies.

Key Question 4c. What are the study designs/sizes of published studies? The 2 most common study designs in completed gene therapy trials were trials with multiple groups of patients who were treated with different levels of the same therapy (36%) and single-arm trials (33%). RCTs made up 26% of the completed studies. Only 5% were controlled trials; that is, studies that compared an untreated control group in a nonrandomized treatment allocation design.

On average, the sample size was 43 (SD =78), but sample sizes varied widely across indications and trials. The number of enrolled patients in the published gene therapy trials ranged from 3 to 800; a substantial number of the trials had fewer than 10 participants. The trials with large sample sizes were either vaccination trials in healthy volunteers341,343,346-348 or trials with large patient populations, such as cancer or cardiovascular disease.


Key Question 4d. What are the comparators in published studies? Studies with no comparator were the most common in our sample (67%) given the large number of single-arm trials and trials comparing different doses of the same intervention. Other published trials compared against placebo (19%), usual care (8%), or no treatment (3%).

Key Question 4e. What are the previous/concurrent treatments in published studies? Most studies reported no other treatment concurrently administered with the gene therapy (74%). When concurrent treatments were described they differed by indication; for example, concurrent chemotherapy was required for several cancer gene therapies.135,146,149,174,180,203,204,216,218,237,360,361 Enzyme replacement therapy was concurrently administered for a few muscular condition gene therapies,290,362 while prednisolone11,291,292,306 and antibiotics308 were concurrently administered for neurodegenerative and ocular disorder treatments.

Key Question 4f. What is the length of follow-up in published studies? The length of follow-up averaged 18.1 months (SD =23 months) and ranged from less than 4 weeks to 180 months. The length of follow-up varied widely across trials and by indication. Published ocular disorder trials reported the longest follow-up, with a mean of 28.7 months, whereas the trials treating cancer and neurodegenerative disorders followed patients on average 20 months. The group of trials for patients with cardiovascular disease, immune deficiency, inflammatory disorders, respiratory conditions, muscular conditions, and otherwise classified conditions averaged 16, 9, 4, 8, 14, and 8 months of follow-up, respectively.

Key Question 4g. What outcomes are measured in published studies? The evidence tables in Appendix F document all outcomes measured and the authors’ conclusions for adenovirus and AAV gene therapy studies that have been published to date. All identified trials measured safety and toxicity aspects. Health-related outcomes depended on the trial (some studies concentrated on safety alone) as well as the type of indication. While a quantitative summary of results in the form of a meta-analysis was beyond the scope of this report, we describe reported positive clinical benefits versus suggestive or no evidence of benefits based on the study authors’ summaries of their findings.

Trials that tested gene therapy in blood disorders (n = 9) frequently measured bleeding rate, immune responses, and quality of life. Most studies (78%) described a positive clinical health benefit (eg, reduction in factor VIII use), while 2 trials (22%) did not summarize effectiveness results.

Trials in cancer patients (n = 128) that reported on health outcomes other than safety measured tumor response, overall survival, progression-free survival, immune response, death, and quality of life. Judging from the authors’ conclusions, a minority of studies (27%) reported definitive positive clinical benefits (eg, increased survival). Most studies (34%) indicated only suggestive evidence that warranted future research (eg, larger studies), and 6% of studies did not report on clinical or suggestive evidence that the therapy was effective in treating cancer. Forty-one trials (32%) did not summarize effectiveness results.

Cardiovascular-targeted gene therapy trials (n = 24) measured vital signs, death, amputation, exercise capacity, lipid profiles, and quality of life. A minority of these trials (29%) concluded that evidence exists of clear positive clinical benefit (eg, increased survival). Seven studies (29%) indicated only suggestive evidence that warranted future research, and 17% reported no clinical or suggestive


evidence that the therapy was effective in reducing cardiovascular disease. Six trials (25%) did not did not summarize effectiveness results.

Studies that tested gene therapy in immune deficiency (n = 11) collected clinical indicators of immune response; for example, CD4+ and CD8+ T-cell responses were frequently collected in HIV studies.281,282 Only 18% of studies reported definitive positive clinical benefit (eg, antibody response). Results were reported as suggestive, with study authors supporting future work (45%), and 18% of studies reported no clinical or suggestive evidence that the therapy was effective. Two trials (18%) did not address whether the therapy was effective in treating immune deficiency.

Published inflammatory disease trials (n = 4) reported outcomes related to tender joints and hormonal and lipid profiles. Half the studies reported positive clinical benefits (50%) and the other half did not summarize effectiveness results.

Studies of gene therapy in patients with muscular disorders (n = 3) measured muscle transduction and muscle response in addition to safety parameters. Two studies (67%) indicated only suggestive effects that supported future studies. One study (33%) did not summarize effectiveness results.

Among the published gene therapy trials in patients with neurodegenerative disorders (n = 19), the measured outcomes included neurological deficit, motor ratings, timed walking tests, cognition, muscle response, and time to death. A minority of studies (32%) reported positive clinical benefit (eg, improved motor skills). Most studies (42%) concluded that suggestive evidence warrants future research, and 5% reported no clinical or suggestive evidence that the therapy was effective in treating neurological disease. Five studies (26%) did not summarize effectiveness results.

Studies testing gene therapies for ocular disorders (n = 19) reported retinal sensitivity, visual acuity, and function outcomes. Almost half of the studies (42%) indicated positive clinical benefit (eg, improved visual acuity). Five studies (26%) reported only suggestive evidence that warranted future research, and 5% reported no clinical or suggestive evidence that the therapy was effective in treating ocular disorders. Five studies (26%) did not summarize effectiveness results.

Gene therapies that targeted respiratory disease (n = 13) reported pulmonary function and lung response. None of the identified studies concluded that gene therapy resulted in a distinct positive clinical benefit. Most studies (54%) reported only suggestive evidence that warranted future research. A third of the trials (31%) reported no clinical or suggestive evidence that the therapy was effective against respiratory disease. Two studies (15%) did not summarize effectiveness results.

The studies with otherwise categorized indications (n = 21) measured, for example, immune response, seroconversion, parasite response, and wound response. Most of these trials (67%) reported only suggestive evidence that warranted future research. Two trials (9%) reported no clinical or suggestive evidence that the therapy was effective for the indication. Five studies (24%) did not summarize effectiveness results.

The authors’ conclusions for all included trials are documented in the evidence tables in Appendix F, along with more information on the effects of the individual interventions.

Key Question 4h. What are the adverse events in published studies? Adverse events varied by indication, as documented in detail in the evidence tables in Appendix F. The following is a summary of the percentage of adenovirus and AAV interventions that reported severe (grade 3 or higher) treatment-related adverse events by indication. Other studies either reported no serious treatment-related adverse events or did not discuss adverse events. Because many of the studies have no untreated comparator, we cannot use these percentages to assign adverse event rates to the treatments.


In blood disorder trials, 44% of the studies reported serious adverse events (eg, hospital admission for insulin pump infusion placement and myocarditis121). In cancer trials, 39% of the studies reported serious adverse events; for example, some patients experienced neutropenia,138 lymphopenia,214 raised liver enzymes,214 high fever,153 or cytotoxic response.126 In 2% of the studies, adverse events were not discussed. In cardiovascular disease trials, 50% of the studies reported serious adverse events. Across studies, 31 deaths were reported.253,254,270,272 In immune deficiency trials, 18% of the studies reported serious adverse events; for example, some patients experienced increased creatine kinase,284 acute coronary syndrome,284 or lower respiratory tract infection.282 In inflammatory disease trials, 50% of the studies reported serious adverse events; for example, some patients experienced increased septic arthritis286 and one patient died.284 None of the muscular condition trials reported serious adverse events. In neurodegenerative disease trials, 32% of the studies reported serious adverse events; for example, some patients experienced elevated liver enzymes.11

In the ocular disorders trials, 26% of the studies reported serious adverse events; for example, some patients experienced hemorrhaging in the eye.324

In the respiratory condition trials, 23% of the studies reported serious adverse events; for example, some patients experienced toxicity effects.329 In the other group, 24% of the studies reported serious adverse events. Some patients experienced pulmonary embolism352 or neutropenia,353 and one patient died because of systemic inflammatory response syndrome.357 The evidence tables in Appendix F provide a detailed overview and describe the documented adverse effects for all included trials.

Evidence Map of Ongoing and Completed Gene Therapy Trials Figure 2 is a visualization of the currently available evidence on research supporting adenovirus, AAV, and CRISPR gene therapies. In the figure, each of the 270 included trials, reported in 435 publications, is represented as a bubble in the plot, with the bubble size indicating the number of patients in the study. The studies are plotted according to indication category and by study design. (See Appendix E for separate evidence maps for each intervention.)

As Figure 2 shows, the largest amount of evidence is for adenoviral- and AAV-based therapies for treating cancer. These cancer studies are primarily single-arm or multiple-group trials, and they vary in sample size. There are some large RCT trials testing adenoviral or AAV gene therapy in cancer but few controlled trials. Relatively fewer studies have been conducted among patients with muscular conditions or blood, inflammatory, neurodegenerative, ocular, or respiratory disorders, and many of these are based on small sample sizes, probably because the diseases are rare. However, evidence appears to be increasing from RCTs that evaluate the use of adenoviral or AAV therapies in cardiovascular disease, immune deficiency, and otherwise specified diseases.


Figure 2. Gene Therapy Evidence Map: Adenovirus, AAV, and CRISPR

Abbreviations: AAV, adeno-associated virus; Ad, adenovirus; CRISPR, clustered regularly interspaced short palindromic repeats; RCT, randomized controlled trial. Notes: Evidence map is based on searches to November 2018. Single-arm trial, prospective case series; Trial (multiple groups), trial with multiple arms receiving different doses but no untreated control group; Controlled trial, intervention and untreated control group. The bubbles are staggered in their vertical and horizontal placement for greater visibility.


Important Issues Raised by Gene Therapy Key Question 5a. What are the implications of the current level of adoption and future diffusion, given the current level of evidence: efficacy/safety, ethical, disparity, resource allocation, and decision making? In this review we identified 270 complete studies and ongoing trials that evaluate gene therapy treatment using adenoviral, AAV, or CRISPR technologies. Among the ongoing trials, AAV technologies are the most common (n = 17, 89%). We identified only one adenoviral trial (5%) and one CRISPR-based (5%) trial. Among the 251 complete studies, the evidence base differs substantially according to intervention and indication. The most common intervention was adenoviral, perhaps because this vector was one of the first tested in gene therapy. AAV studies currently produce 26% of the evidence from completed studies. While our search identified 7 potential pipeline CRISPR interventions, only one ongoing trial met our inclusion criteria and had completed participant recruitment. This trial has multiple groups but no untreated comparison group and includes 12 metastatic non-small-cell lung cancer adult patients. Results are expected in 2019 (previous estimates indicated December 2018).

Most existing gene therapy trials are based on single-arm trials or trials with multiple groups treated with different levels of the same therapy; however, RCTs are increasingly being implemented in cancer, cardiovascular disease, immune deficiency, and otherwise categorized indication trials. Sample sizes remain relatively small across the studies, probably owing to the rarity of the indications addressed by gene therapy. We observed larger sample sizes in the RCTs for the more common diseases, such as cardiovascular conditions, or for vaccine trials. Most studies evaluated safety and indicators of biodistribution, but relatively few studies tested clinical efficacy. This result suggests that, because many of these interventions are still in early development, the primary outcomes are toxicity and maximum tolerable dose. The studies in which AAV or adenoviral gene therapies were used to treat ocular disorders had the largest proportion of study authors concluding positive clinical benefit. Adverse events varied across indication; cardiovascular studies reported the most, including multiple patient deaths. Because many of the studies had no control group, this finding is difficult to assess, especially as the trials were in high-risk patients with critical conditions. Luxturna (Voretigene neparvovec)—currently the only FDA-approved AAV intervention—was approved after only 2 documented trials: an open-label phase I trial and a randomized phase III trial. The sample size of the phase III trial was small (n = 31), but the follow-up was 1 year and the researchers plan to follow patients up to 15 years. Even though the evidence base for adenoviral and AAV gene therapies is relatively large, few studies to date include multiple years of follow-up. Because the durability of treatments that are expected to cure disease remains uncertain, the lack of long-term studies is an obvious and significant gap in this research area. All key informants interviewed for this report mentioned issues they thought were important to patients; they said patients are mostly concerned about the basic components of obtaining and receiving gene therapy, including treatment availability, effectiveness, safety, cost, price, and risks. However, the key informants were concerned about the lack of scientific education and understanding in the public regarding how gene therapies work. They said patients might have to make decisions about care without a thorough understanding of the intervention, including its risks and benefits.

A few key informants suggested that, since the true (eg, curative) value of gene therapies is still unknown, other factors should be considered in pricing the therapies; for example, more transparency would be helpful regarding the resources invested in research and development, in addition to the social or individual benefit of patients living longer and healthier lives. Finally, one key informant


expressed concern about providing insurance for gene therapies in an actuarially sound manner if rare diseases are collectively common but individually rare. This key informant suggested that an insurance-based solution might not exist and that patients might have to pay for the treatment themselves (eg, through a lifelong loan), despite the fact that this option would be politically unfavorable and regressive. (For a discussion of payment options and their implications, see the Institute for Clinical Research and Economics report.63)

Ethical Challenges Key informants raised several ethical challenges related to gene therapy. Gene therapy has the potential to alter the germline, which could affect the genome of subsequent generations without their consent. Given the many unknowns about policy implications and unanticipated harmful effects of gene therapy, the American Society of Human Genetics holds the position that performing germline gene editing that culminates in human pregnancy is inappropriate.363 Even with somatic cell gene therapy, ethical issues arise when patients are children and consent is given by parents; for example, parents could seek out gene therapy for nondisease or cosmetics enhancement of their children.

While drug pricing presents ethical issues that are not unique to gene therapy, significant ethical concerns for expensive gene therapies may exist. Few groups of patients may be able to afford expensive, lifesaving gene therapies, and the impact of such therapies on payers and insurance premiums could disproportionately burden subpopulations. In addition, some key informants voiced the need for more transparency regarding the balance among pricing, private pharmaceutical company profit, and the public funding of gene therapy research. Key informants were also concerned about the lack of scientific understanding in the general population. Unless we as a society improve science education, patients might not have a strong enough understanding of the potential risks of undertaking certain therapies to give fully informed consent.

Key Question 5b. What are the key issues pertaining to decisional uncertainty? Key informants expressed concerns about the unknown benefits and risks involved in gene therapies. For example, patients might underestimate the risk of a novel gene therapy versus a less efficacious standard therapy because the alternatives are limited. Moreover, patients have to consider the unknown long-term effects of altered genes and the insurance-related and indirect costs (eg, traveling to a gene therapy center, taking leave from work) of receiving new and expensive therapies. Moreover, safety trials treated with the minimum dose may have no clinical benefit, and patients who participate in a safety trial viral-based vector therapy may not be able to participate in a future effectiveness trial because they are immune to the virus. Payers also face uncertainty regarding reimbursement for gene therapy because of the unknowns related to upfront payment, durability, and the impact on later fees. As new therapies are approved, payers will have to decide whether to include them in their plans.

Key Question 5c. What are potential areas of research focus for PCORI and others? To address the gaps in knowledge that might support the approval and use of gene therapies, several areas of research might warrant future work. To help stakeholders understand the effectiveness of treatments versus the risk for adverse outcomes, research could examine in more detail how each intervention type is effective in treating disease, by indication and patient population. Several key informants noted a need for patient registries with long-term follow-up to increase the clinical effectiveness evidence base. Long-term follow-up will be especially important for the CAR-T therapies, in which one treatment is expected to cure. Other research could examine disparities in how


gene therapy is implemented and the implications for treatment success or adverse events; for example, does gender bias exist in preventing pregnancy during gene therapy treatment? Several key informants suggested the development of Centers of Excellence for gene therapies, where training, manufacturing, and intervention delivery can be closely monitored to provide high standards of care. Research could also examine how Centers of Excellence can ensure that high-quality manufacturing processes and health care delivery standards are followed.

Other research could examine how training and education programs of providers and patients might improve provider familiarity with procedures and patient understanding of how the therapy works and the risks of unintended effects. Understanding how people feel about the risks and potential promise of gene therapies and how providers communicate these issues to their patients could shed light on the ethical implications of altering the genome. Qualitative (eg, focus groups) and quantitative (eg, surveys) research could lay the groundwork for a discussion of ethical issues.

Key informants suggested that relaxing some of the regulatory processes that determine FDA approval could streamline drug development. For example, research could optimize vector delivery and gene transfer without having to return to the very beginning of the regulatory process. Key informants also suggested relaxing some of the preclinical requirements; for example, in September 2018, NIH and the FDA eliminated the requirement for Recombinant DNA Advisory Committee review and NIH reporting for gene therapy protocols.364 Future research could determine where and how to address regulatory bottlenecks to facilitate drug development and approval, thus accelerating the delivery of high-quality treatments to patients. Future work also could assess how gene therapy trials change over time and whether methodological concerns arise or can be resolved as studies are completed. Given the tremendous uncertainty about how to pay for gene therapies, we recommend future work that explores microsimulation modeling of different payer policy scenarios. Microsimulations would allow researchers to examine the effects of health care system changes on access to various gene therapies across different interventions and patient populations. Also, given the rapid pace at which research is advancing and results are being published, an automated system to curate and track the mounting evidence might be needed to inform key informants and potentially to update model parameters.


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https://osp.od.nih.gov/wp-content/uploads/2016/08/1524_RAC_Briefing_Slides.pdf

https://www.the-scientist.com/the-nutshell/crispr-to-debut-in-clinical-trials-30508

https://www.the-scientist.com/the-nutshell/crispr-to-debut-in-clinical-trials-30508


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https://osp.od.nih.gov/2018/08/16/nih-releases-proposal-streamline-review-gene-therapy-trials-restore-original-vision-rac/

https://osp.od.nih.gov/2018/08/16/nih-releases-proposal-streamline-review-gene-therapy-trials-restore-original-vision-rac/



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491. Ashtari M, Cyckowski LL, Monroe JF, et al. The human visual cortex responds to gene therapy-mediated recovery of retinal function. J Clin Invest. 2011;121(6):2160-2168. PMID:21606598

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Appendix

Appendix A: Report Methodology This project aimed to produce a landscape review of multiple data sources. Our landscape review includes an evidence map based on the published studies and ongoing trials that evaluate the application of gene therapy approaches.

Literature Searches We searched multiple data sources to cover critical aspects of current and future gene therapy interventions. Specifically, our goal was to describe the evidence base for FDA-approved gene therapies currently used to treat or cure conditions. In addition, we describe the evidence for pending or ongoing clinical trials, testing applications that may be poised to gain FDA approval as well as the conditions relevant for future applications. The FDA has approved gene therapies based on the results of single-arm trials when a life-threatening condition has no alternative treatment and its severity6 justifies not performing controlled trials. Thus, we included controlled and uncontrolled trials. We then described the important issues for stakeholders (eg, patients) that the genetic technologies/interventions raise. To identify FDA-approved gene therapies and applications, we referred to the FDA website that lists approved products (https://www.fda.gov/NewsEvents/ProductsApprovals/default.htm). We first reviewed the list of “Approved Cellular and Gene Therapy” products available on the FDA website (July 2018). We continued to monitor the FDA site for 2018 novel therapeutic approvals not otherwise captured on the aforementioned page, searching each drug name. For each therapy, we used the FDA approval letters and accompanying documentation to determine indication, orphan designation status, approval date for each approved indication, whether additional resources are required to utilize the therapy, whether repeat procedures are expected, summary information on adverse events, and anything else that might impact uptake of the therapeutic. If the FDA approval letter did not specify which clinical trials resulted in the approval, we searched the therapy name (generic and branded) on ClinicalTrials.gov and abstracted all associated registered clinical trials. To collect evidence about the current use of approved gene therapies in patients, we searched for empirical published literature across clinical trials in the databases PubMed and EMBASE. We limited searches to English-language studies of human subjects and focused on trials of at least 3 months’ duration. The search strategy included a combination of indexing terms (MeSH terms in MEDLINE/PubMed and EMTREE terms in EMBASE), as well as free-text terms. Another key source of literature was the Web of Science. The Web of Science systematically catalogues conference abstracts, a source of the latest research information that is often not yet captured in the traditional scientific output (ie, journal manuscripts indexed in research databases). The literature searches were conducted by an Evidence-based Practice Center librarian experienced in transparent and comprehensive literature searches. Effective search strategies often require thorough knowledge of indexing terms and scientific database functionality. Searches explicitly addressed the available evidence on the applications in treating human disease and the current and anticipated applications. The review identified remaining evidence gaps that future research studies should address. To capture new advances that are near approval we searched the grey literature online with a selection of the search terms below and subscribed to the newsletter of Gene Therapy Net (http://www.genetherapynet.com/united-states-of-america.html). We identified ongoing trials in

https://www.fda.gov/NewsEvents/ProductsApprovals/default.htm


https://www.fda.gov/drugs/developmentapprovalprocess/druginnovation/ucm592464.htm

http://www.genetherapynet.com/united-states-of-america.html


clinicaltrials.gov (US research). In addition, we checked a database maintained by the Journal of Gene Medicine (http://www.abedia.com/wiley/search.php) and reviewed information in Gene Therapy Net. We limited our searches to US news releases 12 months prior to November 2018 to identify therapies that may be approved in the near future. Gene Therapy Net also provides information on legislative issues. Many nonacademic government and trade publications discuss promising pipeline technologies and products. For example, Pink Sheet of Pharma Intelligence (https://pink.pharmaintelligence.informa.com) publishes news on gene therapy for pharmaceutical professionals on a wide array of topics, including regulation and research/development/strategies. We also searched Lexis-Nexis Academic (https://advance.lexis.com/) for information on developing technologies. We conferred with content experts and screened pertinent online resources, such as Massachusetts Institute of Technology’s NEW Drug Development ParadIGmS (NEWDIGS) site. New Drug Applications (NDA) represent therapies that are closer to approval than the hundreds of Investigational New Drugs (INDs), so while we explored NDAs we did not include IND in our search for near-approval therapies. The newly released FDA suite of 6 draft guidance documents for industry (https://www.fda.gov/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/guidances/cellularandgenetherapy/default.htm) also provided information for disease-specific clinical and preclinical considerations for gene therapy development. All relevant literature was imported into an EndNote library. As we reviewed the evidence of current and impending gene therapies, we described the prevalence of the indications. We used statistics from published literature and national estimates drawn from the National Cancer Institute Surveillance, Epidemiology, and End-Results (SEER, https://seer.cancer.gov/data/) registry data.

Literature Review Procedure Search outputs were screened by two independent reviewers to avoid missing relevant citations. All citations deemed potentially relevant by at least one reviewer were obtained as full text. Full text publications were screened against the eligibility criteria. We documented the reasons for exclusion in a citation management database. One reviewer abstracted and appraised publications and content and methodological experts checked summaries.

Inclusion Criteria We applied explicit inclusion and exclusion criteria designated a priori following a “PICOTSS” framework, as follows:

• Participants: Participants receiving any gene therapy were eligible for inclusion. Studies may include men and women of all ages but need to include human participants.

• Interventions: Eligible interventions included those that either replaced a disease-causing gene with a healthy copy of the gene, inactivated a disease-causing gene that was not functioning properly, or introduced a new or modified gene into the body to help treat a disease.

• Comparator: Any comparator or no comparator studies were eligible. • Outcomes: Outcomes of interest included disease-related effectiveness/benefit indicators such

as complete response (eg, remission), partial response, disease recurrence, mortality, patient-centered outcomes including psychosocial outcomes such as anxiety and worry, and treatment-associated adverse events/harms (eg, cytokine release syndrome).

• Timing: Any treatment duration and follow-up of included studies were eligible. • Setting: Any setting was eligible.

http://www.abedia.com/wiley/search.php

https://pink.pharmaintelligence.informa.com/

https://advance.lexis.com/



https://seer.cancer.gov/data/


• Study design: Primary clinical research studies were eligible. Publications either self-identified as experimental or described a planned scientific evaluation of gene therapy. Eligible study designs included randomized controlled trials, clinical trials with experimental assignment without randomization, and 1-arm trials (eg, experimental case series). Observational studies were excluded. Conference abstracts were excluded.

• Studies published in English since 1989 were eligible.

Adenovirus, AAV, and CRISPR Report • Interventions: Eligible interventions included all studies that used adenovirus, AAV, or

CRISPR as part of the evaluated gene therapy approach. The literature flow diagram is shown in Appendix C.

Data Extraction We used a standardized form with explicit and pilot-tested categorization rules to extract the data. For each study, we extracted the author and publication year (if applicable), indication/inclusion criteria, type of intervention, study design and study size, comparator, concurrent and prior treatments, length of follow-up, outcomes measures, authors’ conclusions of the effect, and reported adverse events. We used the following categories for indication:

• Immune deficiency • Blood disorders (eg, hemophilia) • Ocular disorder • Neurodegenerative disorders • Cancer • Cardiovascular disease • Respiratory conditions (including cystic fibrosis) • Inflammatory disease (including arthritis) • Muscular conditions • Other

We consolidated all reports of the same participants into one study entry. This often included trial registry records, progress reports, subgroup analyses, and the main trial publication.

Evidence Map The evidence map is based on a bubble plot. Each “bubble” represents an identified study. The evidence map documents ongoing (open bubbles) and published (filled bubbles) gene therapy trials. The evidence map shows the presence as well as the absence of evidence.

Evidence Tables We also provide the reader with evidence tables to provide a concise overview. We differentiated ongoing and partially (eg, preliminary results have been published) or fully published studies. We limited our search to ongoing studies that have completed recruiting and are more likely near the FDA approval stage than non-RCTs that are still recruiting patients.


Appendix B: Search Strategies Published Literature PubMed Run November 2, 2018 Filters activated: Clinical Trial, Clinical Trial, Phase I, Clinical Trial, Phase II, Clinical Trial, Phase III, Clinical Trial, Phase IV, Controlled Clinical Trial, Randomized Controlled Trial, Publication date from 1989/01/01, Humans, English. (((gene-editing[title/abstract] OR “gene editing”[title/abstract]) AND (therap*[title/abstract] OR treatment*[title/abstract])) OR ("gene therapy"[title/abstract] OR "gene therapies"[title/abstract] OR “gene engineering”[title/abstract] OR “gene transfer”[title/abstract]) OR “RNA targeted therapeutic”[tiab] OR “RNA-targeted therapeutics”[tiab] OR ("Gene Editing/ethics"[Mesh] OR "Gene Editing/instrumentation"[Mesh] OR "Gene Editing/legislation and jurisprudence"[Mesh] OR "Gene Editing/standards"[Mesh] OR "Gene Editing/statistics and numerical data"[Mesh] OR "Gene Editing/trends"[Mesh] OR "Gene Editing/utilization"[Mesh] OR "Genetic Therapy/adverse effects"[Mesh] OR "Genetic Therapy/classification"[Mesh] OR "Genetic Therapy/epidemiology"[Mesh] OR "Genetic Therapy/ethics"[Mesh] OR "Genetic Therapy/instrumentation"[Mesh] OR "Genetic Therapy/legislation and jurisprudence"[Mesh] OR "Genetic Therapy/methods"[Mesh] OR "Genetic Therapy/mortality"[Mesh] OR "Genetic Therapy/nursing"[Mesh] OR "Genetic Therapy/psychology"[Mesh] OR "Genetic Therapy/standards"[Mesh] OR "Genetic Therapy/statistics and numerical data"[Mesh] OR "Genetic Therapy/therapeutic use"[Mesh] OR "Genetic Therapy/therapy"[Mesh] OR "Genetic Therapy/trends"[Mesh] OR "Genetic Therapy/utilization"[Mesh] OR "Gene Transfer Techniques/adverse effects"[Mesh] OR "Gene Transfer Techniques/drug effects"[Mesh] OR "Gene Transfer Techniques/immunology"[Mesh] OR "Gene Transfer Techniques/therapy"[Mesh] OR "Gene Transfer, Horizontal/adverse effects"[Mesh] OR "Gene Transfer, Horizontal/drug effects"[Mesh] OR "Gene Transfer, Horizontal/immunology"[Mesh] OR "Gene Transfer, Horizontal/therapeutic use"[Mesh] )) OR CAR-T[title/abstract] OR “CAR T” [title/abstract] OR ("CAR Modified"[title/abstract] AND T[title/abstract]) OR (“chimeric antigen receptor” [title/abstract] AND “T” [title/abstract]) OR CART-19[title/abstract] OR CRISPR/Cas[title/abstract] OR “clustered regularly interspaced short palindromic repeats”[tiab] OR “zinc-finger nucleases” [title/abstract] OR “zinc finger nucleases” [title/abstract] OR “zinc finger nuclease” [title/abstract] OR “zinc finger nuclease” [title/abstract] OR ZFN[title/abstract] OR TALEN[title/abstract] OR “TAL effector nucleases”[title/abstract] OR “TAL effector nuclease”[title/abstract] OR “Transcription activator-like effector nucleases”[title/abstract] OR “Transcription activator-like effector nuclease”[title/abstract] OR “Transcription activator like effector nucleases”[title/abstract] OR “Transcription activator like effector nuclease”[title/abstract] OR "voretigene neparvovec-rzyl" OR luxturna[title/abstract] OR “axicabtagene ciloleucel” OR “Axi-Cel”[title/abstract] OR “KTE-C19”[title/abstract] OR KTEC19[title/abstract] OR yescarta[title/abstract] OR tisagenlecleucel[title/abstract] OR CTL019[title/abstract] OR CTL-019[title/abstract] OR kymriah[title/abstract] OR “talimogene laherparepvec”[title/abstract] OR imlygic[title/abstract] OR Provenge[title/abstract] OR “sipuleucel-T” [title/abstract] OR “adeno


associated virus”[title/abstract] OR “adenoassociated virus”[title/abstract] OR (“adeno-associated virus”[tiab] AND gene*[tiab]) OR (“herpes simplex virus”[tiab] AND gene*[tiab]) OR (HSV[tiab] AND gene*[tiab]) OR tegsedi[tiab] OR inotersen[tiab] OR (("oncolytic virus"[tiab] OR “oncolytic viral”[tiab]) AND (gene*[tiab] OR engineered[tiab] OR modified[tiab])) NOT ("trial protocol"[ti] OR "study protocol"[ti]) Results: 940 (Autologous[tiab] AND cell*[tiab] AND (gene[tiab]OR genes[tiab] OR genetic*[tiab] OR RNA[tiab] OR DNA[tiab])) OR lentiglobin OR bb305 OR 'otl 101' OR 'otl 200' OR gsk269274 OR 'eb 101' OR 'fcx 007' OR 'fcx 013' Results: 315 (RNAi[tiab] OR “RNA interference”[tiab]) OR (“ribonucleic acid”[tiab] AND interfer*[tiab]) OR “interfering ribonucleic acid”[tiab] OR siRNA[tiab] OR miRNA[tiab] OR patisran OR onpattro OR ALN-TTr02 OR ALN-TTRsc02 OR “AMG 890” OR ARO-LPA OR ARO-AAT OR ARO-HBV OR Cemdisiran OR ALN-CC5 OR Fitusiran OR ALN-AT3sc OR ALN-AS1 OR Inclisiran OR ALN-PCSsc OR Lumasiran OR ALN-GO1 OR Revusiran OR ALN-TTRsc) AND (gene*[tiab] AND therap*) NOT (marker* OR biomarker*) Results: 24 (antisense[tiab] AND gene*[tiab]) OR mipomersen OR Kynamro OR eteplirsen OR “exondys 51” OR nusinersen OR spinraza OR tegsedi OR inotersen OR ionis-maptrx OR rg6042 OR ionis-httrx OR volanesorsen Results: 89 Embase Run November 2, 2018 Limits: ([controlled clinical trial]/lim OR [randomized controlled trial]/lim) AND [english]/lim AND [humans]/lim AND [embase]/lim AND [1989-2018]/py (gene-editing):ab,ti OR (“gene editing”):ab,ti AND ((therap*):ab,ti OR (treatment*):ab,ti) OR ("gene therapy"):ab,ti OR ("gene therapies"):ab,ti OR (“gene engineering”):ab,ti OR (“gene transfer”):ab,ti OR (“RNA targeted therapeutic”):ab,ti OR (“RNA-targeted therapeutics”):ab,ti OR (CAR-T):ab,ti OR (“CAR T”):ab,ti OR (("CAR Modified"):ab,ti AND (T):ab,ti) OR ((“chimeric antigen receptor”):ab,ti AND (T):ab,ti) OR (CART-19):ab,ti OR (CRISPR):ab,ti OR (“clustered regularly interspaced short palindromic repeats”):ab,ti OR (“zinc-finger nucleases”):ab,ti OR (“zinc-finger nuclease”):ab,ti OR (“zinc finger nucleases”):ab,ti OR (“zinc finger nuclease”):ab,ti OR (ZFN):ab,ti OR (TALEN):ab,ti OR (“TAL effector nucleases”):ab,ti OR (“TAL effector nuclease”):ab,ti OR (“transcription activator-like effector nucleases”):ab,ti OR (“transcription activator-like effector nuclease”):ab,ti OR (“transcription activator like effector nucleases”):ab,ti OR (“transcription activator like effector nuclease”):ab,ti OR (“voretigene neparvovec-rzyl”):ab,ti OR (luxturna):ab,ti OR (“axicabtagene ciloleucel”):ab,ti OR


(“Axi-Cel”):ab,ti OR (“KTE-C19”):ab,ti OR (KTEC19):ab,ti OR (yescarta):ab,ti OR (tisagenlecleucel):ab,ti OR (CTL019):ab,ti OR (CTL-019):ab,ti OR (kymriah):ab,ti OR (“talimogene laherparepvec”):ab,ti OR (imlygic):ab,ti OR (Provenge):ab,ti OR (“sipuleucel-T”):ab,ti OR (“adeno associated virus”):ab,ti OR (“adenoassociated virus”):ab,ti OR ((“adeno-associated virus”):ab,ti AND (gene*):ab,ti) OR ((“herpes simplex virus”):ab,ti AND (gene*):ab,ti) OR ((HSV):ab,ti AND (gene*):ab,ti) OR (tegsedi):ab,ti OR (inotersen):ab,ti OR (("oncolytic virus”):ab,ti OR (“oncolytic viral”):ab,ti AND ((gene*):ab,ti OR (engineered):ab,ti OR (modified):ab,ti)) NOT (“trial protocol”):ti OR (“Study protocol):ti EXCLUDE: CONFERENCE ABSTRACT; CONFERENCE REVIEW; EDITORIAL; NOTE; REVIEW; SHORT SURVEY; LETTER; CONFERENCE PAPER Results: 515 – duplicates = 251 (autologous:ab,ti AND cell*:ab,ti AND (gene:ab,ti OR genes:ab,ti OR genetic*:ab,ti OR rna:ab,ti OR dna:ab,ti) OR lentiglobin OR bb305 OR 'otl 101' OR 'otl 200' OR gsk269274 OR 'eb 101' OR 'fcx 007' OR 'fcx 013') Results: 177 - – duplicates with PubMed above = 87 ((RNAi):ab,ti OR (“RNA interference”):ab,ti OR (“ribonucleic acid” AND interfer*):ab,ti OR (“interfering ribonucleic acid” OR siRNA OR miRNA):ab,ti OR patisran OR onpattro OR ALN-TTr02 OR ALN-TTRsc02 OR “AMG 890” OR ARO-LPA OR ARO-AAT OR ARO-HBV OR Cemdisiran OR ALN-CC5 OR Fitusiran OR ALN-AT3sc OR ALN-AS1 OR Inclisiran OR ALN-PCSsc OR Lumasiran OR ALN-GO1 OR Revusiran OR ALN-TTRsc AND (gene*):ab,ti AND (therap*):ab,ti NOT (marker* OR biomarker*) Results: 35 – duplicates with PubMed above = 29 ((antisense):ab,ti AND (gene*):ab,ti) OR mipomersen OR Kynamro OR eteplirsen OR “exondys 51” OR nusinersen OR spinraza OR tegsedi OR inotersen OR ionis-maptrx OR rg6042 OR ionis-httrx OR volanesorsen) Results: 266 – duplicates with PubMed above = 223 Web of Science Run November 2, 2018 English: Article Indexes=SCI-EXPANDED, SSCI, A&HCI, ESCI Timespan=1989-2018 (TS=(gene-editing) OR TS=(“gene editing”)) AND (TS=(therap*) OR TS=(treatment*)) OR TS=("gene therapy") OR TS=("gene therapies") OR TS=(“gene engineering”) OR TS=(“gene transfer”) OR TS=(“RNA targeted therapeutic”) OR TS=(“RNA-targeted therapeutics”) OR TS=(CAR-T) OR TS=(“CAR T”) OR (TS=("CAR Modified") AND TS=(T)) OR (TS=(“chimeric antigen receptor”) AND TS=(T)) OR TS=(CART-19) OR TS=(CRISPR/Cas) OR TS=(“clustered regularly interspaced short palindromic repeats”) OR TS=(“zinc-finger nucleases”) OR TS=(“zinc-finger nuclease”) OR TS=(ZFN) OR TS=(TALEN) OR TS=(“zinc finger nuclease”) OR TS=(“zinc finger nucleases”) OR TS=(“TAL effector nucleases”) OR TS=(“TAL effector nuclease”)


OR TS=(“transcription activator-like effector nucleases”) OR TS=(“transcription activator-like effector nuclease”) OR TS=(“transcription activator like nucleases”) OR TS=(“transcription activator like nuclease”) OR (TS=(“voretigene neparvovec-rzyl”) OR TS=(luxturna) OR TS=(“axicabtagene ciloleucel”) OR TS=(“Axi-Cel”) OR TS=(“KTE-C19”) OR TS=(KTEC19) OR TS=(yescarta) OR TS=(tisagenlecleucel) OR TS=(CTL019) OR TS=(CTL-019) OR TS=(kymriah) OR TS=(“talimogene laherparepvec”) OR TS=(imlygic) OR TS=(Provenge) OR TS=(“sipuleucel-T”) OR TS=(“adeno associated virus”) OR TS=(“adenoassociated virus”) OR (TS=(“adeno-associated virus”) AND TS=(gene*)) OR (TS=(“herpes simplex virus”) AND TS=(gene*)) OR (TS=(HSV) AND TS=(gene*)) OR TS=(tegsedi) OR TS=(inotersen) OR (TS=("oncolytic virus" OR “oncolytic viral”) AND TS=(gene* OR engineered OR modified))) AND TS=(“randomized controlled trial”) OR TS=(RCT) OR TS=(“controlled clinical trial”) OR TS=(“clinical trial”) NOT TS=(rat OR rats OR monkey OR monkeys OR primates OR primate OR macaque* OR mouse OR mice OR dog OR canine OR canines OR rabbit OR rabbits) NOT TI=(“trial protocol”) OR TI=(“study protocol”) EXCLUDE: Proceedings Papers; Book Chapters also, in EndNote (all results), pulled out pig/horse articles and some additional “overviews” not called “Reviews” Results: TOTAL: 898 – duplicates = 672 TOTAL: 1863 (TS=(autologous) AND TS=(cell) AND (TS=(gene OR genes OR genetic* OR rna OR dna)) OR TS=(Strimvelis OR Lenti-D OR “elivaldogene tavalentivec” OR Lentiglobin OR BB305 OR OTL-101 OR OTL-200 OR GSK269274 OR EB-101 OR FCX-007 OR FCX-013) AND TS=(“randomized controlled trial”) OR TS=(RCT) OR TS=(“controlled clinical trial”) OR TS=(“clinical trial”) NOT TS=(rat OR rats OR monkey OR monkeys OR primates OR primate OR macaque* OR mouse OR mice OR dog OR canine OR canines OR rabbit OR rabbits) NOT TI=(“trial protocol”) OR TI=(“study protocol”) EXCLUDE: Proceedings Papers; Results: 199 – duplicates with above = 134 (TS=(RNAi) OR TS=(“RNA interference”) OR TS=(“ribonucleic acid” AND interfer*) OR TS=(“interfering ribonucleic acid”) OR TS=(siRNA OR miRNA OR patisran OR onpattro OR ALN-TTr02 OR ALN-TTRsc02 OR “AMG 890” OR ARO-LPA OR ARO-AAT OR ARO-HBV OR Cemdisiran OR ALN-CC5 OR Fitusiran OR ALN-AT3sc OR ALN-AS1 OR Inclisiran OR ALN-PCSsc OR Lumasiran OR ALN-GO1 OR Revusiran OR ALN-TTRsc)) AND (TS=(gene) AND TS=(therap*))


NOT (TS=(marker* OR biomarker*) AND TS=(“randomized controlled trial”) OR TS=(RCT) OR TS=(“controlled clinical trial”) OR TS=(“clinical trial”) NOT TS=(rat OR rats OR monkey OR monkeys OR primates OR primate OR macaque* OR mouse OR mice OR dog OR canine OR canines OR rabbit OR rabbits) NOT TI=(“trial protocol”) OR TI=(“study protocol”) EXCLUDE: Proceedings Papers; Results: 38 – duplicates with above =36 (TS=(antisense) AND TS=(gene*)) OR TS=(mipomersen OR Kynamro OR eteplirsen OR “exondys 51” OR nusinersen OR spinraza OR tegsedi OR inotersen OR ionis-maptrx OR rg6042 OR ionis-httrx OR volanesorsen) AND TS=(“randomized controlled trial”) OR TS=(RCT) OR TS=(“controlled clinical trial”) OR TS=(“clinical trial”) NOT TS=(rat OR rats OR monkey OR monkeys OR primates OR primate OR macaque* OR mouse OR mice OR dog OR canine OR canines OR rabbit OR rabbits) NOT TI=(“trial protocol”) OR TI=(“study protocol”) EXCLUDE: Proceedings Papers; in EndNote (all results), pulled out pig/horse articles and some additional “overviews” not called “Reviews” Results: 79 – duplicates with above = 61

Grey Literature ClinicalTrials.gov Run November 2, 2018 Searching the “other” field—limiting to active, not recruiting, completed, suspended, terminated, withdrawn studies Modalities "Zinc finger nuclease" OR "Zinc-finger nuclease" OR "Zinc-finger nucleases" OR "Zinc finger nucleases" OR ZFN OR "Transcription Activator-like Effector Nucleases" OR "Transcription Activator-like Effector Nuclease" OR “TAL effector nuclease” OR “TAL effector nucleases” OR TALEN OR CRISPR OR CRISPR/Cas9 OR "Clustered Regularly Interspaced Short Palindromic Repeats" OR CAR-T OR "chimeric antigen receptor" OR (Adenovirus AND "gene therapy") OR (Adenovirus AND "gene transfer") OR Oncolytic Virus OR Luxturna OR "Voretigene neparvovec" OR "Axicabtagene ciloleucel" OR KTE-C19 OR Yescarta OR Tisagenlecleuce OR Kymriah OR "talimogene laherparepvec" OR Imlygic OR Tegsedi OR Inotersen Results: 360 Other Biological Approved Products ("Recombinant protein" AND "gene therapy") OR ("Recombinant protein" AND "gene transfer") OR "Allogenic cord blood hematopoietic progenitor cell therapy" OR "Allogenic umbilical cord blood"


OR "autologous cellular product" OR "autologous cellularized scaffold product" OR "autologous cellularised scaffold product" OR Allocord OR Azficel OR laviv OR Andexxa OR Clevecord OR Gintuit OR Hemacord OR Ducord OR ("gene therapy" AND RNA) OR ("gene transfer" AND RNA) OR patisiran OR (lentivirus AND "gene therapy") OR (Lentivirus AND "gene transfer") OR (vector AND "gene therapy") OR (vector and "gene transfer") OR “adeno associated virus” OR “adenoassociated virus” OR (“adeno-associated virus” AND gene*) OR (“herpes simplex virus” AND gene*) OR (HSV AND gene*) OR (“oncolytic viral”) Results: 251 – duplicates with modalities =177 TOTAL: 537 ((autologous AND cell*) AND (gene OR genes OR genetic* OR rna OR dna)) OR Strimvelis OR Lenti-D OR “elivaldogene tavalentivec” OR Lentiglobin OR BB305 OR OTL-101 OR OTL-200 OR GSK269274 OR EB-101 OR FCX-007 OR FCX-013 Results: 4 RNAi OR “RNA interference” OR (“riboneucleic acid” AND interfer*) OR “interfering ribonucleic acid” OR siRNA OR miRNA OR patisran OR onpattro OR ALN-TTr02 OR ALN-TTRsc02 OR “AMG 890” OR ARO-LPA OR ARO-AAT OR ARO-HBV OR Cemdisiran OR ALN-CC5 OR Fitusiran OR ALN-AT3sc OR ALN-AS1 OR Inclisiran OR ALN-PCSsc OR Lumasiran OR ALN-GO1 OR Revusiran OR ALN-TTRsc AND gene AND therap* NOT marker* OR biomarker* Results: 0 (antisense AND gene*) = 0 (mipomersen OR Kynamro OR eteplirsen OR “exondys 51” OR nusinersen OR spinraza OR tegsedi OR inotersen OR ionis-maptrx OR rg6042 OR ionis-httrx OR volanesorsen) = 45 Results: 45 FDA Records We used the list of “Approved Cellular and Gene Therapy” products available on the FDA website (accessed July 2018) and monitored the FDA site for 2018 novel therapeutic approvals. LexisNexis and Web Searches We used the search terms “gene therapy” and “nda” in combination with a source restriction to “Pink Sheet: Pharma Intelligence” and date restrictions of (01/01/2017 and 08/30/2018) or (01/01/2017 and 09/15/2018). We abstracted names of any gene therapies that were mentioned. Next, we searched the name of each of the gene therapies for specific information in ClinicalTrials.gov as well as in the Google search engine. In the Google search engine, we used the name of each gene therapy alone and in conjunction with “FDA designation” to determine the modality, indication, determine/confirm the current phase of the therapy, and determine if it had received any specific FDA designation (fast track, breakthrough, orphan drug, rare pediatric disease, or regenerative medicine advanced therapy).


https://www.fda.gov/drugs/developmentapprovalprocess/druginnovation/ucm592464.htm


Gene Therapy Clinical Trials Worldwide We used a database maintained by the Journal of Gene Medicine (http://www.abedia.com/wiley/search.php) to check for less-frequent therapies to ensure all relevant trials had been identified.

http://www.abedia.com/wiley/search.php


Appendix C: Literature Flow Diagram

Figure notes: AD adenovirus; AAV, adeno-associated virus therapy; CAR-T, chimeric antigen receptor; CRISPR, Clustered Regularly Interspaced Short Palindromic Repeats; RNAi, ribonucleic acid interference; ZFN, zinc finger nucleases


Appendix D: Stakeholder and Key Informant Interview Information Interviews We conducted key informant interviews to gather detailed information about gene therapy from a variety of perspectives. The purpose of the interviews was to collect perspectives from patients or patient advocates, clinicians, payers/insurers, public policy-maker representatives, and industry. The goal was to ensure that perspectives of different stakeholders had been considered and were reflected in the research approach. Our application to RAND’s Human Subjects Protection Committee (HSPC: 2018-0560) was approved for exempt status on August 24, 2018.

Recruitment We developed the key informant list by first selecting relevant stakeholder groups. In a second step, the team identified possible representatives of the stakeholder groups. If we could not reach the key informant or he or she declined, we referred to our list to identify an alternate key informant. We also asked anyone who declined if he or she could recommend someone else. Emails were sent to individuals and organizations requesting their participation in phone interviews. These emails included a 1-page brief description of the assessment, written in plain English. We informed the individual that we contacted him or her because of his or her experience (as a patient or advocacy group member, clinician, payer or insurer, public policy representative, or industry member or industry analyst, depending on the interviewee). At this time, we asked if he or she would agree to participate in our assessment and if there were any other experts he or she suggested we contact for his or her relevant experience. We contacted 45 individuals: 15 clinicians, 7 patient and patient advocates, 8 payers/insurers, 5 public policymaker representatives, and 10 industry/industry analysts. Among those we contacted, 2 clinicians, 2 patient advocates, 2 payers/insurers, 2 public policymaker representatives, and 2 industry analysts participated. We also invited industry professionals, although none agreed to participate.

Procedure Semi-structured telephone interviews lasting approximately 1 hour were conducted with each key informant. The interviews were guided by semi-structured interview protocols following a list of set questions but allowing the interviewee to expand or deviate to other topics that he or she thought were important to discuss. We aimed to understand the process by which potential gene therapies progress from the laboratory bench to patient treatment options and to identify positive and negative impacts of the therapies for many stakeholders, including patients/consumers, payers/insurers, purchasers/employers, and public policymakers. The interviewer asked about barriers and facilitators to gene therapy implementation, adjustments to policies and procedures, safety, efficacy, and cost. The interview questions were designed for a wide set of stakeholder perspectives and not all questions were relevant to each interviewee. Thus, interviewees were free to skip questions he or she felt he or she could not answer.


Informed Consent Protocol Interviewers read the information below before proceeding with the interview. Research Description The goal of this study is to use an evidence map format and landscape review to describe the current evidence base available for gene therapy applications. The evidence map will include a central figure that visualizes the state of the research. The evidence maps provide a visual overview, communicating the results of multiple dimensions to best document a research area. As part of this work, we will conduct key stakeholder interviews to gather detailed information about gene therapy from a variety of perspectives. Informative research questions need to consider a range of stakeholders. In particular, patient-centered outcomes should not be selected by clinicians and policymakers but require engaging patients in the research process. The key informant interviews will include a range of respondents from patients or patient advocates, clinicians, payers/insurers, public policy maker representatives, industry, and industry analysts. The goal is to ensure that perspectives of different stakeholders have been considered and are reflected in the research approach. This project is supported by the Patient-Centered Outcomes Research Institute (PCORI) and facilitated by the RAND Corporation. Risks and Benefits There will be no risks related to participation in this study. During the completion of the interview, if a question is not applicable to you or you feel uncomfortable answering, please complete it to the best of your ability. The project aims to improve our understanding of approved gene therapies as well as those that may become available for use in the next five years, as a critical means to spread knowledge that will benefit patients, researchers, and practitioners. Duration Your participation will last about an hour. Participation and Withdrawal Participation in this study is entirely voluntary. You have the right not to participate at all, to leave the project at any time, and can decline to be acknowledged as a panelist. Deciding not to participate or choosing to leave the study will not result in any negative consequences. If you decide that you cannot participate, we will ask that you nominate someone to join the panel in your place (if possible). Confidentiality Your name will not be linked to your interview responses in any feedback of results to the group and your name and your responses will not be stored together. Your interview responses will be kept confidential. Study results will be accessible only to the study team. Interview responses and discussion points will be documented in aggregate form across participants. You will be asked for consent to be acknowledged as a key stakeholder in future publications describing the results of the project. Contact Information If you have questions about this research, please email Dr. Andrea Richardson ([email protected]) or Dr. Susanne Hempel ([email protected]). If you have questions about your rights as a research participant or need to report a research-related injury or concern, you can contact RAND’s Human Subjects Protection Committee toll-free at 866 697 5620 or by emailing [email protected]. If possible, when you contact the Committee, please reference Study # 2017-0640. Consent Your consent to participate in this project will be implied by selecting the option, “Yes, I consent to participate in this study (continue to survey)" and by submitting your responses after completion.

Interview Guide Introduction Brief Project Background Reason for Reaching Out/Expertise of Stakeholder Representative Questions to Discuss During Phone Conversations:

• Are there interventions missing from our preliminary search strategy? • Which clinical effectiveness outcomes should be assessed when evaluating the effects of gene

therapy? • Which adverse events should be assessed when evaluating the effects of gene therapy? • Which other outcomes should be assessed? • What is an appropriate timeframe for the assessment? • What information is important to patients that has not been the focus of expert discussions or

has been neglected in existing research? • What are the decisional dilemmas for patients? • What considerations will help key stakeholders (will be specified) to decide the value of the

intervention?





• Our evidence map can display only a limited number of dimensions to establish a picture of the existing evidence base. Using the draft example, which dimensions do you think are critical to display (eg, number of patients, number of successful interventions, study design distribution, replication by independent researchers, clinical effectiveness, severity of adverse events, costs, quality of evidence across studies)?

• Which new developments are close to approval? Please do not share any proprietary information that you may know.

• What are the major challenges you see facing gene therapy advances? • Are there ethical considerations that should be discussed? • What are your major hopes you see facing gene therapy treatments? • What are the major gaps in our understanding that need to be addressed to improve the

development of FDA-approved gene therapies? • Is public policy lacking with respect to gene therapy approval and use? • What suggestions do you have to bring more approved gene therapies from bench to bedside?

Interview Data Collection and Analysis Strategy Interviews were conducted by phone with 1 researcher and 1 note taker and, if the interview participant agreed, recorded to ensure information was accurately captured. Results of the interviews were documented in aggregated and deidentified format. We analyzed the content of the interviews by tabulating responses according to the topic addressed.


Appendix E: Evidence Maps Stratified by Intervention Appendix Evidence Map 1. Adenovirus Trials


Appendix Evidence Map 2. AAV Trials


Appendix Evidence Map 3. CRISPR


Appendix F: Evidence Tables Published Trials Appendix Table A1. Published Adenovirus Trials

Indication Citations Design N

Indication Concurrent/Prior Treatments Months of Follow-up


Outcomes Measured Reported Harms Authors’ Conclusions

Blood disorders Li et al, 2012114 Single-arm trial N: 62

Age group: children Hemophilia A Treatments enrollment: none Treatment requisite: none Follow-up: 48

Recombinant adeno-associated virus No comparison group

Development of NAbs None NAbs against AAV2 (43.5%) were observed more frequently and at higher titers compared with both AAV5 (25.8%) and AAV8 (22.6%). NAbs against AAV5 or AAV8 were rarely observed in the absence of coprevalent and higher-titer AAV2 NAbs, suggesting that NAbs to AAV5 and AAV8 were detected following AAV2 exposure due to partial cross-reactivity of AAV2-directed NAbs.

Cancer Chiocca et al, 2008209 BB-IND 9924 Trial (multiple groups) N: 11

Age group: adults Malignant glioma Treatments enrollment: Tumors had to be either recurrent or progressive following prior treatment. Treatment requisite: surgical removal of tumor 4 to 8 days plus additional dose of gene therapy after initial dose Follow-up: 2 to 11 (ongoing as of paper)

Ad.hIFN-beta No comparison group

Time to progressive disease (size of lesions or appearance of new lesions), progression-free survival, overall survival

Unlikely or not related: deep vein thrombosis (grade 3, n = 2), depressed level of consciousness (grade 3, n = 2), thrombosis (grade 3, n = 1), pulmonary embolism (grade 4, n = 1), convulsions NOS (grade 3, n = 1), choroidal infarction (grade 2, n = 1); likely related: confusional state (grade 3, n = 1, resolved; grade 4, n = 1, not resolved)

Direct Ad.hIFN-beta injection into the tumor and the surrounding normal brain areas after surgical removal was feasible and associated with apoptosis induction.






Cancer Sterman et al, 2000168 Sterman et al, 1998365; Molnar-Kimber et al, 1998366; Albelda, 1997367; Benard et al, 1998368 ID NR Trial (multiple groups) N: 10

Age group: adults Malignant pleural mesothelioma Treatments enrollment: none Treatment requisite: placement of a thoracostomy tube for delivery of gene therapy; ganciclovir for 2 weeks for all patients; corticosteroid by intravenous administration (n = 5, started ~10 hours before gene therapy) Follow-up: until death

Ad.HSVtk No comparison group

Tumor response, overall survival

No grade 3 or greater toxicities reported

The results suggest that systemic administration of steroids in the context of adenoviral-based gene delivery may limit acute clinical toxicity but may not inhibit biological responses to adenoviral vectors.

Cancer Sterman et al, 2016245 NCT01119664 Trial (multiple groups) N: 40

Age group: adults Unresectable malignant pleural mesothelioma Treatments enrollment: chemotherapy Treatment requisite: none Follow-up: 6

Ad.IFNalpha No comparison group

Safety, toxicity, and objective response rate, progression-free and overall survival; biocorrelates on blood and tumor were measured

Pleural catheter infection (n = 2), hypoxia (n = 2), supraventricular tachycardia (n = 1), esophagitis (n = 1)

The combination of intrapleural Ad.IFN, celecoxib, and chemotherapy proved safe in patients with MPM.

Cancer Sterman et al, 2011226 NCT01212367 Single-arm trial N: 9

Age group: adults Malignant pleural mesothelioma Treatments enrollment: none Treatment requisite: none Follow-up: none

Ad.IFN-alpha2b No comparison group

Antitumor immunologic responses, antiviral immune responses, gene transfer assessment

None These data show Ad.IFN-alpha2b has potential therapeutic benefit in MPM and it generates antitumor immune responses that may induce anatomic and/or metabolic reductions in distant tumors.






Cancer Sterman et al, 2007206 Sterman et al, 2006369 BB-IND 10603 Single-arm trial N: 10

Age group: adults Malignant pleural mesothelioma (MPM), metastatic pleural effusions (MPE) Treatments enrollment: none Treatment requisite: none Follow-up: 6

Ad.IFN-beta No comparison group

Innate immune responses, humoral responses to known MPM tumor antigens, cellular immune responses

Transient hypoxia (n = 1) elevations in serum transaminases (n = 1)

Intrapleural instillation of Ad.IFN-beta is a potentially useful approach for the generation of antitumor immune responses in MPM and MPE patients and should be investigated further for overall clinical efficacy.

Cancer Sterman et al, 2010218 ID NR, protocol reviewed by NIH-RAC and FDA Single-arm trial N: 17

Age group: adults Malignant pleural mesothelioma, malignant pleural effusions Treatments enrollment: none Treatment requisite: chemotherapy Follow-up: 42

Ad.IFN-beta No comparison group

Safety and toxicity, gene transfer assessment, antiviral immune responses

None This approach was safe and induced immune responses and disease stability. However, rapid development of Nabs prevented effective gene transfer after the second dose, even with a dose interval as short as 7 days.

Cancer Sangro et al, 2004189 ID NR, protocol approved by the Spanish government’s Ethical Committee for Clinical Investigation, the National Biosafety Commission, and the Spanish Agency for the Evaluation of Medicinal Products Single-arm trial N: 21

Age group: adults Advanced digestive tumors Treatments enrollment: none Treatment requisite: surgery, chemotherapy, radiotherapy, transarterial chemoembolization Follow-up: 12

Ad.IL-12 No comparison group

Toxicity, biologic response, antitumor activity

None Intratumoral injection of up to 3 1012 viral particles of Ad.IL-12 to patients with advanced digestive malignancies is a feasible and well-tolerated procedure that exerts only mild antitumor effects.






Cancer Sterman et al, 1998143 ID NR Trial (multiple groups) Completed N: 21

Age group: adults Pleural mesothelioma Treatments enrollment: none Treatment requisite: none Follow-up: 24

Ad.RSVtk No comparison group

Survival, ongoing disease, stable disease, tumor progression

1 moderate neutropenia event

Given these caveats, with a median follow-up of approximately 12 months, 12 of 21 patients have died, with no fatal complications attributable to the gene therapy protocol. Autopsies were performed on 9 patients, uniformly demonstrating progressive mesothelioma, often with widespread metastatic disease as the cause of death. Although no definite tumor regressions were noted, 3 of the initial 18 patients remain clinically stable, with no evidence of tumor growth on serial chest radiographs and chest CT scans.

Cancer Sangro et al, 2010222 Penuelas et al, 2005370; Clinica Universidad de Navarra, 2003371 NCT00844623 Single-arm trial N: 10

Age group: adults Advanced hepatocellular carcinoma Treatments enrollment: none Treatment requisite: none Follow-up: 26

Ad.TK No comparison group

Tumor response and toxicity, imaging

No complications The US-guided administration of Ad.TK was feasible in 100% of cases and no complications associated with the procedure were reported.

Cancer Rosenthal et al, 2015242 NCT01310179 Single-arm trial N: 12

Age group: adults Advanced solid tumors Treatments enrollment: none Treatment requisite: none Follow-up: none

Ad/PNP No comparison group

Tumor size None This first-in-human clinical trial found localized generation of fluoroadenine within tumor tissues using E. coli PNP and fludarabine is safe and effective.






Cancer Alvarez et al, 2000163 Hemminki et al, 2002372 ID NR Trial (multiple groups) N: 15

Age group: adults Recurrent erbB-2-overexpressing ovarian cancer Treatments enrollment: none Treatment requisite: none Follow-up: until death

AD21 No comparison group

Percentage with stable disease, percentage with progressive disease

No vector-related hematological, coagulation, or electrolyte abnormalities but 4 grade 3/4 events: dyspnea (n = 1), circulatory (n = 1), Tenckhoff catheter infections (n = 2)

The study suggests this a feasible approach, but needs more research: “This study suggests that adenoviral-mediated gene therapy using an anti-erbB-2-directed intrabody is feasible in the context of human ovarian cancer."

Cancer Balint et al, 2015150 Morse et al, 2013373 NCT01147965, IND14325 Single-arm trial Completed N: 32

Age group: adults Late-stage colorectal cancer Treatments enrollment: none Treatment requisite: none Follow-up: 29

Ad5 [E1-, E2b-]-CEA(6D) vaccine No comparison group

Survival None observed An overall survival of 20% (median survival 11 months) was observed during long-term follow-up and no long-term adverse effects were reported.

Cancer Kim et al, 2012228 ID NR, protcol reviewed by NICH-RAC and FDA Single-arm trial N: 12

Age group: adults Recurrent gynecologic cancer (epithelial ovarian, primary peritoneal, fallopian tube, or endometrial) Treatments enrollment: conventional surgical procedures and standard adjuvant therapies Treatment requisite: none Follow-up: none

Ad5.SSTR/TK.RGD No comparison group

Toxicity associated with intraperitoneal administration of Ad5.SSTR/TK.RGD, Clinical efficacy

None This study shows the safety, potential efficacy, and possible gene transfer imaging capacity of Ad5.SSTR/TK.RGD in patients with recurrent gynecologic cancer.






Cancer Koski et al, 2010221 Bramante et al, 201483 ID NR Controlled trial N: 21

Age group: children Refractory advanced solid tumors Treatments enrollment: none Treatment requisite: ultrasound to guide intratumoral injection (single dose), 24 hours in-hospital monitoring post-therapy, and 4-week outpatient monitoring Follow-up: until death

Ad5/3-D24-GMCSF No comparison group

Tumor size/response (complete response, partial response, stable disease, progressive disease)

No grade 4 or 5 events, but grade 3 events reported: anemia (n = 1), neutropenia (n = 1), cholecystitis (n = 1), increased alanine aminotransferase (ALT, n = 1), increased aspartate aminotransferase (AST, n = 1), hyperbilirubinemia (n = 1), hyponatremia (n = 1)

Ad5/3-D24-GMCSF seems safe in treating cancer patients, and promising signs of efficacy were observed.

Cancer Kim et al, 2013233 ID NR (title states trial) Single-arm trial N: 10

Age group: adults Recurrent ovarian cancer Treatments enrollment: none Treatment requisite: none Follow-up: none

Ad5/3-Delta24 No comparison group

Clinical efficacy None This study suggests the feasibility and safety of a serotype chimeric infectivity-enhanced CRAd, Ad5/3-Delta24, as a potential therapeutic option for recurrent ovarian cancer patients.

Cancer Freytag et al, 2002142 Freytag et al, 2003374; Freytag et al, 2007375; Freytag et al, 2007376 ID NR (self-identified as trial in abstract) Single-arm trial Completion date: 12/2001 N: 16

Age group: adults Locally recurrent prostate cancer Treatments enrollment: none Treatment requisite: none Follow-up: 60

Ad5-CD/TKrep No comparison group

Recurrence Of the adverse events observed, 94% were mild or moderate (grade 1/2) in nature.

There were no dose-limiting toxicities, and the maximum tolerated dose of the Ad5-CD/TKrep vector was not defined. Together, the results demonstrate that intraprostatic administration of the replication-competent Ad5-CD/TKrep virus followed by 2 weeks of 5-fluorocytosine and ganciclovir prodrug therapy can be safely applied to humans and is showing signs of biological activity.






Cancer Cristofanilli et al, 2006204 ID NR, reviewed by NIH-RAC Single-arm trial Completed N: 13

Age group: adults Locally advanced breast cancer Treatments enrollment: none Treatment requisite: chemotherapy, surgery Follow-up: 41

Ad5CMV-p53 No comparison group

Complete response, partial response, stable disease, progressive disease

SAEs: 2 Ad5CMV-p53 combined with PST is safe, biologically active, and associated with local immunomodulatory effects. The promising clinical activity of this combination deserves further investigation in randomized studies.

Cancer Fujiwara et al, 2006200 ID NR (abstract states trial) Single-arm trial N: 15

Age group: adults Advanced non-small-cell lung cancer Treatments enrollment: none Treatment requisite: none Follow-up: none


Toxicity, vector distribution, antibody formation, tumor response

None Multiple courses of intratumoral Ad5CMV-p53 injection alone or in combination with intravenous administration of cisplatin were feasible and well tolerated in advanced NSCLC patients, and appeared to provide clinical benefit.

Cancer Tolcher et al, 2006136 ID NR (but trial stated in title) Single-arm trial N: 17

Age group: adults Advanced cancer Treatments enrollment: chemotherapy Treatment requisite: none Follow-up: 1


Safety, pharmacokinetics and pharmacodynamics, detection of Ad5CMV-p53 DNA expression in tumor tissue, skin biopsies, urine, rectal swabs, oral rinses, detection of antibodies to adenovirus 5, antitumor activity

None Ad5CMV-p53 can be safely and repetitively administered up to 1 ten(12) virus particles intravenously daily for 3 consecutive days.

Cancer Shimada et al, 2006203 Shimada et al, 2008377 ID NR, protocol reviewed by NIH-RAC Single-arm trial N: 10

Age group: adults Chemoradiation-resistant advanced esophageal squamous cell carcinoma Treatments enrollment: none Treatment requisite: chemoradiation therapy Follow-up: 47

Ad5CMV-p53; INGN 201; ADVEXIN No comparison group

Adverse events, detection of p53 transgene, p21 induction and MDM2 induction

None Observations from this study indicate this treatment results in local antitumor effects in chemoradiation-resistant esophageal squamous cell carcinoma.






Cancer Barton et al, 20087 Barton et al, 2011378 BB-IND 12786 Single-arm trial N: 12

Age group: adults Localized prostate cancer Treatments enrollment: none Treatment requisite: none Follow-up: 12

Ad5-yCD/utTK(SR39)rep-hNIS No comparison group

None None The results demonstrate that noninvasive imaging of adenovirus-mediated gene therapy in humans is feasible and safe.

Cancer Stewart et al, 1999160 Stewart et al, 1997379 ID NR, protocol reviewed by the Health Protection Branch of Canada Trial (multiple groups) N: 23

Age group: adults Metastatic breast cancer, melanoma Treatments enrollment: none Treatment requisite: isolation for 72 hours after injection to check for viral shedding Follow-up: 1

AdCAIL-2 No comparison group

Local tumor regression No grade 3 or 4 toxicities observed

Incomplete local tumor regression occurred at the site of injection in 24% of patients, but no conventional clinical responses were seen.

Cancer Trudel et al, 2003185 ID NR, protocol reviewed by University of Toronto Institutional Review Board and by the Health Protection Branch of Canada Single-arm trial N: 12

Age group: adults Localized prostate cancer Treatments enrollment: none Treatment requisite: none Follow-up: 18

AdCAIL-2 No comparison group

Toxicity, systemic immune responses, tumor response, clinical outcome

None This trial demonstrates the feasibility and safety of intraprostatic adenovectormediated IL-2 gene delivery.

Cancer Lee et al, 2017124 Trial (multiple groups) N: 16

Age group: adults Lung cancer Treatments enrollment: none Treatment requisite: leukapheresis Follow-up: 4

Ad-CCL21- DC No comparison group

Survival, safety No serious treatment-related adverse events reported

Intratumoral vaccination with Ad-CCL21-DC resulted in (1) induction of systemic tumor antigen-specific immune responses, (2) enhanced tumor CD8þ T-cell infiltration, and (3) increased tumor PD-L1 expression.






Cancer Malmstrom, 2010219 Uppsala University, 2009380 NCT00891748 Single-arm trial N: 8

Age group: adults Invasive bladder cancer Treatments enrollment: none Treatment requisite: none Follow-up: none

AdCD40L No comparison group

Safety and toxicity of AdCD40L gene therapym, AdCD40L vector spreading and host antiviral immune responses, CD40L protein expression in biopsies, CD40L-mediated cytokine burst, tumor-infiltrating inflammatory cells, circulating immune cell populations, and antitumor effects

None Local AdCD40L gene therapy was safe, boosted immune activation, and should be further evaluated as a single or an adjuvant therapy for urothelial malignancies.

Cancer Wierda et al, 2010223 Wierda et al, 2000381; Okur et al, 2011382 ID NR Trial (multiple groups) N: 9

Age group: adults Chronic lymphocytic leukemia Treatments enrollment: none Treatment requisite: confirmation of eligibility (clinical history, physical examination, routine laboratory evaluation), leukapheresis, outpatient infusion of transduced cells (test dose followed by remaining dose), scheduled follow-ups (as per eligibility confirmation), option to enroll in long-term study (and additional doses of the therapy) Follow-up: until death

Ad-CD40L No comparison group

Reduction in blood lymphocyte counts, reduction in lymphadenopathy, enhanced/new expression of target for susceptibility for targeting, number of infusions, time to progression, time to salvage therapy, type of salvage therapy, clinical response

1 patient experienced grade 3 headache (dose-limiting toxicity)

Infusions of autologous, ISF35-transduced chronic lymphocytic leukemia (CLL) cells were well tolerated, had biological and clinical activity, and might enhance the susceptibility of CLL cells with del(17p) to chemoimmunotherapy.






Cancer Chia et al, 2012128 ID NR Single-arm trial N: 16

Age group: adults Advanced metastatic nasopharyngeal carcinoma Treatments enrollment: none Treatment requisite: none Follow-up: 7

Ad-DLMP1-LMP2 No comparison group

Safety, immune response None Ad-DLMP1-LMP2 transduced DCs can be successfully generated and safely administered to patients with advanced NPC.

Cancer Sonpavde et al, 2011227 ID NR Trial (multiple groups) N: 19

Age group: adults Localized intermediate or high-risk prostate cancer preceding radical prostatectomy Treatments enrollment: none Treatment requisite: oral broad spectrum antibiotic was taken starting the day before the injection and continued for 4 days after the injection; intraporstate injection of therapy delivered using transrectal ultrasound for guidance; patients were admitted to hospital for 23 hours Follow-up: 1

AdGLIPR1 No comparison group

Changes in pathology (diagnosis, morphology, apoptosis)

Grade 3 toxicities: urinary tract infection (n = 2); no grade 4 toxicities

The intraprostatic administration of GLIPR1 tumor suppressor gene expressed by an adenoviral vector was safe in men, with localized intermediate or high-risk prostate cancer preceding radical prostatectomy. Preliminary evidence of biologic antitumor activity and systemic immune response was documented.






Cancer Baum et al, 2012229 Dental National Institute, 2014383; Alevizos et al, 2017384; Zheng et al, 2010385 NCT00372320 Trial (multiple groups) N: 11

Age group: adults Radiation-induced salivary hypofunction in surviving head and neck cancer patients with Radiation Therapy Oncology Group late grade 2 to 3 toxicity Treatments enrollment: none Treatment requisite: glycopyrrolate received intravenously 30 minutes before administration of gene therapy; dilation of Stensen’s duct for cannulation for infusion of gene therapy Follow-up: 12

AdhAQP1 No comparison group

Improvement in parotid saliva flow rates (absolute volume, proportional change), improvement in visual analog scale assessments of perception of oral dryness and amount of saliva present in their mouth

No deaths, dose-limiting toxicities, or serious adverse events observed because of vector delivery

AdhAQP1 vector delivery to a single parotid gland was safe and increased parotid flow and relieved symptoms in a subset of patients.

Cancer Alvarez et al, 2000165 Alvarez and Curiel, 1997386 ID NR, protocol reviewed by NIH-RAC and FDA Trial (multiple groups) N: 14

Age group: adults Recurrent ovarian cancer Treatments enrollment: Patients had to have failed standard debulking and chemotherapy treatments. Treatment requisite: placement of a Tenchkoff catheter for intraperitoneal administration of gene therapy; 2 days after gene therapy delivery, patients received intravenous ganciclovir for 2 weeks Follow-up: until death

AdHSV-TK No comparison group

Clinical efficacy/disease status

No vector-associated grade 3/4 laboratory abnormalities were observed, but 1 patient died due to a pulmonary embolism 3 weeks post-therapy.

Treatment with AdHSV-TK and ganciclovir in combination is feasible in the context of human ovarian cancer and tolerated at the dosages studied.






Cancer Navai et al, 2016246 ID NR Single-arm trial N: 7

Age group: adults Non-muscle-invasive bladder cancer Treatments enrollment: Patients with non-muscle-invasive bladder cancer refractory to Bacillus Calmette–Guerin therapy who refused radical cystectomy were eligible for inclusion Treatment requisite: none Follow-up: 0

Ad-IFNalpha No comparison group

Urine INFa levels A patient was found to have nonorgan-confined disease with multiple positive lymph nodes at radical cystectomy. He succumbed to the disease 20.1 months after study treatment and 16.7 months after radical cystectomy.

A prior trial with a single instillation compared similarly with the current study, suggesting a second instillation is not necessary to achieve sufficient urinary IFNa levels.

Cancer Castro et al, 2012138 NCT00783874, BB-IND 13046 Trial (multiple groups) Completed N: 15

Age group: adults Chronic lymphocytic leukemia Treatments enrollment: declined chemoimmunotherapy Treatment requisite: none Follow-up: 12

Ad-ISF35 No comparison group

Progressive disease, stable disease, partial response, complete response

SAEs (events): 5 neutropenia, 3 hypophosphatemia, 1 AST elevation

Ad-ISF35 IDI was safely delivered in patients with CLLs and induced systemic biologic and clinical responses. These results provide the rationale for phase II studies in CLLs, lymphomas, and CD40-expressing solid tumors.

Cancer Cunningham et al, 2005194 Tong et al, 2005387 ID NR, protocol reviewed by FDA Single-arm trial N: 22

Age group: adults Resectable solid tumors Treatments enrollment: surgery, chemotherapy, and radiotherapy Treatment requisite: none Follow-up: 1

Ad-mda7; INGN 241 No comparison group

Safety, clinical response Fatigue (n = 1) Intratumoral administration of INGN 241 is well tolerated, induces apoptosis in a large percentage of tumor cells, and demonstrates evidence of clinically significant activity.






Cancer Kubo et al, 2003181 Malaeb et al, 2005388 ID NR, protocol reviewed by FDA Single-arm trial N: 11

Age group: adults Localized and metastatic hormone-refractory prostate cancer Treatments enrollment: lymph node, retropubic prostatectomy, radiation therapy Treatment requisite: none Follow-up: 12

Ad-OC-hsv-TK No comparison group

Safety, titers of anti-adenovirus 5 antibody, bioassay of viral titers in urine and serum, detection of HSV TK gene in biopsy specimens, circulating HSV TK gene

Lymphopenia (n = 1) Data suggest this form of gene therapy requires further development for the treatment of androgen-independent prostate cancer metastasis, although histopathological and immunohistochemical evidence of apoptosis was observed in the specimens treated.

Cancer Shirakawa et al, 2007208 Hinata et al, 2006389; Terao et al, 2009390 ID NR, protocol reviewed by Japanese Ministry of Health, Labor, and Welfare Single-arm trial N: 6

Age group: adults Hormone-refractory metastatic prostate cancer Treatments enrollment: androgen deprivation therapy, hormone therapy, and chemotherapy Treatment requisite: docetaxel and estramustine combination chemotherapy, radical prostatectomy, radiation therapy Follow-up: 34

Ad-OC-TK No comparison group

Adverse events related to gene therapy, PSA response and progression, local antitumor effect

Lymphopenia (n = 3) The phase I/II clinical trial of Ad-OC-TK/VAL gene therapy was completed without any serious adverse events. The efficacy of docetaxel-based chemotherapy in hormone-refractory prostate cancer has been confirmed. Ad-OC-TK/VAL is the first in vivo adenoviral gene therapy used to treat bone metastasis, and the expected response to docetaxel-based chemotherapy was preserved, suggesting potential benefit to future combined approaches for the treatment of hormone-refractory metastatic prostate cancer.






Cancer Nemunaitis et al, 2000161 Weill et al, 2000391 ID NR, protocol reviewed by RAC Single-arm trial N: 24

Age group: adults Advanced non-small-cell lung cancer Treatments enrollment: chemotherapy Treatment requisite: none Follow-up: 1

Adp53 No comparison group

Safety, clinical activity, tumor biopsy

Injection site pain (n = 1)

Intratumoral injection with Adp53 in combination with cisplatin is well tolerated, and there is evidence of clinical activity.

Cancer Ning et al, 2011145 ID NR. All patients were required to sign an informed consent form and the protocol was approved by the institutional ethics committee. Trial (multiple groups) Completed N: 42

Age group: adults Non-small-cell lung cancer Treatments enrollment: none Treatment requisite: docetaxel Follow-up: 20

Adp53 No comparison group

Mean survival time, overall survival, progressive disease, partial response, stable disease

SAEs: 2 patients intervention, 3 patients control (unclear)

For patients with relapsed NSCLC, trans-tracheal injection of Adp53 in addition to docetaxel did not improve overall survival or efficacy. However, direct trans-tracheal injection of Adp53 proved to be a safe procedure, with tolerable levels of toxicity.

Cancer Zhang et al, 2005199 SFDA China project No. 2000-54 Trial (multiple groups) N: 15

Age group: adults Advanced-stage cancer with measurable disease but no distant metastasis Treatments enrollment: none Treatment requisite: All patients received gene therapy and hyperthermia weekly (4-8 total doses per patient); subgroups received radiotherapy (n = 5) or chemotherapy (n = 3). Follow-up: 2

Adp53 No comparison group, other: All patients received gene therapy and hyperthermia; subgroups received radiotherapy (n = 5) or chemotherapy (n = 3).

Tumor size, tumor response (complete response, partial response, stable disease. and progressive disease), low-density area

No dose-limiting toxicity and adverse events noted except transient fever (grade 1 or 2)

Adp53 combined with hyperthermia was safe and effective in patients with advanced cancer, and p53 gene therapy has potential to sensitize advanced cancer to hyperthermia treatment.






Cancer Clayman et al, 1999159 Clayman et al, 1998392; Nemunaitis et al, 2009393 ID NR Trial (multiple groups) Completed N: 15

Age group: adults Squamous cell carcinoma of the head and neck Treatments enrollment: none Treatment requisite: surgery Follow-up: 29

Ad-p53 No comparison group

Disease-specific survival, disease-free interval

None The safety and overall patient tolerance of Ad-p53 has been demonstrated. Of 15 resectable but historically noncurable patients in the surgical arm of a phase I study, 4 patients (27%) remain free of disease, with a median follow-up time of 18.25 months. Surgical and gene transfer related morbidities were minimal.

Cancer Keedy et al, 2008211 Eastern Cooperative Oncology, 2010394; Eastern Cooperative Oncology, 2009395; NCT00003649 Single-arm trial N: 25

Age group: adults Bronchioloalveolar cell lung carcinoma Treatments enrollment: none Treatment requisite: none Follow-up: 16


Safety and determination of MTD, P53 transgene expression, biodistribution of ad-p53, clinical response

Dyspnea, hypoxia, pneumonitis/infiltrates monitored

Ad-p53 can be administered safely with repeated dosing.

Cancer Yen et al, 2000162 ID NR Trial (multiple groups) Completed N: 10

Age group: adults Advanced non-small-cell lung cancer Treatments enrollment: none Treatment requisite: none Follow-up: 0



None Patients in this study had evidence of an antitumoral effect of this treatment with prolonged tumor stability or regression; however, neither Abs to p53 protein nor increased lymphocyte proliferative responses to wild-type or mutant p53 peptides have been consistently detected.






Cancer Lang et al, 2003184 Sidney Kimmel Comprehensive Cancer Center, 2002396 ID NR Single-arm trial N: 15

Age group: adults Recurrent glioma Treatments enrollment: radiotherapy, procarbazine, bis-chloronitrosourea, temozolomide, stereotactic radiosurgery, thioguanine Treatment requisite: none Follow-up: 2

Ad-p53; INGN 201 No comparison group

Toxicity Hemiparesis (n = 1) Transduced cells were found only within a short distance of the injection site. Although toxicity was minimal, widespread distribution of this agent remains a significant goal.

Cancer Swisher et al, 2003179 Swisher et al, 1999397; Roth et al, 1998398 ID NR Trial (multiple groups) Completed N: 19

Age group: adults Nonmetastatic non-small-cell lung cancer Treatments enrollment: none Treatment requisite: radiation therapy Follow-up: 47

Ad-p53; INGN 201 No comparison group

Complete response, partial response, ptable disease, progressive disease

SAEs: 6 patients Intratumoral injection of Ad-p53 (INGN 201) in combination with radiation therapy is well tolerated and demonstrates evidence of tumor regression at the primary injected tumor. Serial biopsies of the tumor suggest BAK gene expression is most closely related to Adp53 (INGN 201) gene transfer.






Cancer Wolf et al, 2004191 National Cancer Institute, 2002399 NCT00003588 Trial (multiple groups) Completed N: 17

Age group: adults Platinum- and paclitaxel-resistant epithelial ovarian cancer Treatments enrollment: platinum- or paclitaxel-based therapy Treatment requisite: none Follow-up: 0

Adp53; INGN 201; ADVEXIN No comparison group

Complete response, partial response, mnor response, progressive disease

SAES: 18 events/patients Multiple dosing of IP Adp53 was well tolerated in this group of heavily pretreated patients; however, the dosing schedule and the amount cannot be concluded from this study. With a negative randomized trial of ovarian cancer in front-line treatment that included an adenovirus p53 plus chemotherapy, further refinement of gene therapy is required before additional trials are undertaken.

Cancer Kumon et al, 2016247 Kumon et al, 2015400 UMIN000004929 Single-arm trial N: 18

Age group: adults High-risk localized prostate cancer undergoing radical prostatectomy Treatments enrollment: none Treatment requisite: none Follow-up: 46

Ad-REIC No comparison group

Changes in serum-neutralizing antibody titer against adenovirus, quantitative kinetic analysis of adenoviral DNA in blood by real-time PCR, quantitative kinetic analysis of adenoviral DNA in urine by real-time PCR, cytopathic effects, lymphocytic infilt

None In the present neoadjuvant study, we believe that the proof of concept of simultaneous induction of selective killing of cancer cells and augmentation of antitumor immunity by Ad-REIC has been successfully established.






Cancer IIdefonso et al, 2010220 ID NR Single-arm trial N: 7

Age group: children Retinoblastoma Treatments enrollment: chemotherapy or radiation therapy Treatment requisite: Patients received an intraocular injection of the vector followed by intravenous ganciclovir for 7 days; patients received topical steroids immediately following the procedure. Follow-up: None

Ad-RSVtk No comparison group

Ocular inflammatory response, humoral immune response

None In contrast to studies showing significant immunogenicity of Ad-RSVtk following injection into extraocular tumors, injection into the eye produces only a mild local inflammatory response without evidence of systemic cellular or humoral immune responses to adenovirus.

Cancer Wang et al, 2018130 NCT01956630 RCT N: 48

Age group: children and adults Acute leukemia Treatments enrollment: chemotherapy Treatment requisite: none Follow-up: 23

Ad-siSSF Usual care: standard donor lymphocyte infusion

Clinical efficacy and adverse events associated with Ad-siSSF-DC treatment, survival, TAA-specific CTL responses in vitro, hDCs in vitro

None This study, with combinatory modifications in DCs, demonstrates the safety and efficacy of SOCS1-silenced DCs in treating relapsed acute leukemia.

Cancer Griscelli et al, 2003180 Molinier-Frenkel et al, 2000401; Tursz et al, 19968; Gahery-Segard et al, 1997402 ID NR, protocol reviewed by French regulatory agencies geverning human biomedical research and genetic engeneering Trial (multiple groups) Completed N: 21

Age group: adults Unresectable lung cancer (stage IIIB or IV) Treatments enrollment: none Treatment requisite: chemotherapy Follow-up: 24

AdTG5327 No comparison group

Remission Safety assessed, no adverse events reported

No adverse effect related to positive culture has been observed, thus consistent with the safety of this therapy.






Cancer Nasu et al, 2007205 ID NR, protcol reviewed by Japanese government Trial (multiple groups) N: 8

Age group: adults Local recurrence of prostate cancer after hormone therapy Treatments enrollment: none Treatment requisite: none Follow-up: 7

Adv.HSV-tk No comparison group

Safety considerations and adverse events, PSA response, detection of HSV-tK gene in biopsy specimens, anti-adenovirus neutralizing antibody response, systematic immunoresponses

None This study confirmed the safety profile and possibility of clinical response at the surrogate marker level in a clinical trial of HSV-tk gene therapy for hormone-refractory prostate cancer.

Cancer Trask et al, 2000140 ID NR Single-arm trial N: 13

Age group: adults Malignant brain tumors Treatments enrollment: none Treatment requisite: none Follow-up: 25

Adv.RSVtk No comparison group

Clinical course during treatment

None We conclude the form of gene therapy used in our phase I trial is safe when the vector dose does not exceed 2 3 1011 VP (1 3 1010 IU).

Cancer Sung et al, 2001170 ID NR Trial (multiple groups) N: 16

Age group: adults Metastatic colorectal adenocarcinoma in the liver Treatments enrollment: none Treatment requisite: none Follow-up: 12

Adv.RSV-tk No comparison group

None Hepatic toxicities were low, with transient grade 1 elevations in serum aminotransferase levels in 3 of 16 patients. Other toxicities were also transient: grade 2 to 3 fevers in 5 of 16 patients, grade 3 thrombocytopenia in 1 of 16 patients, and grade 2 leucopenia in 3 of 16 patients.

These results indicate Adv.RSV-tk can be safely administered by percutaneous intratumoral injection in patients with hepatic metastases and can provide the basis for future clinical trials involving intratumoral adenoviral vector injection.






Cancer Miles et al, 2001171 Herman et al, 1999403; Ayala et al, 2005404 BB-IND 6636 Trial (multiple groups) N: 36

Age group: adults Prostate cancer with local recurrence after radiotherapy Treatments enrollment: none Treatment requisite: All patients received at least one transrectal ultrasound-guided injection of gene therapy into a cancer positive lobe of the prostate; a subgroup received intravenous ganciclovir infusions (n = 29) starting 24 hours later (every 12 hours for up to 28 doses). Follow-up: until death

ADV/HSV-tk No comparison group

Reduction in serum PSA (PSAR), return to initial PSA (TR-PSA), PSA-doubling time (PSADT) where PSA = prostate-specific antigen and PSADT is considered to be a surrogate for tumor doubling time

No patient experienced any toxicity.

Repeated cycles of in situ HSV-tk plus GCV gene therapy can be administered to patients with prostate cancer refractory to radiotherapy with a localized recurrence. Biological responses to this experimental therapy include increases in PSADT, PSAR, and TR-PSA, and activated CD81 T cells present in the peripheral blood.

Cancer Teh et al, 2004187 Teh et al, 2001405 Fujita et al, 2006406 Teh et al, 2002407 ID NR, protocol reviewed by NIH-RAC and FDA Trial (multiple groups) N: 62

Age group: adults Prostate cancer Treatments enrollment: Patients had to be treatment naïve. Treatment requisite: administered broad-spectrum antibiotic beginning day before injections and for 3 more days, gene therapy administered by intraprostatic injections, prodrug valacyclovir administered 24 hours after each injection for 14 days; for hormone and radiation Follow-up: 24

ADV/HSV-tk No comparison group, other: gene therapy with radiotherapy or with hormone therapy and radiotherapy (2 different groups)

Prostate-specific antigen (PSA) local failure, PSA distant failure, biochemical control, disease-free survival, overall survival

2 patients developed allergic reaction to valacyclovir and withdrew

Combined RT, short-course hormonal therapy, and in situ therapy appeared to provide good locoregional control but inadequate systemic control in patients with positive pelvic lymph nodes. Longer-term use of hormonal therapy in addition to gene therapy and RT has been adopted for this group of patients to maximize both locoregional and systemic control.






Cancer Germano et al, 2003186 ID NR Trial (multiple groups) N: 11

Age group: adults Recurrent malignant gliomas Treatments enrollment: Patients must have failed conventional external beam radiation and possibly chemotherapy, and external beam radiation and chemotherapy. Treatment requisite: none Follow-up: 12

ADV/HSV-tk/GC No comparison group

Quality of life, tumor progression, survival

11 serious adverse events (required hospitalization) experienced by 6 patients: tumor progression (n = 4), of which 3 required re-operation for resection of recurrent tumor 12 weeks after gene therapy; leaked CSF from the surgical incision 2 weeks after surgery (n = 1); perioperative status epilepticus followed by prolonged need for intubation, sepsis, and death 4 weeks after gene therapy (n = 1, only 1 considered to be possibly related to the therapy)

The study is still ongoing. “These data show the ADV/HSV-tk/GC complex at the dose used in this study is safe. Additional dose escalation is in progress.”

Cancer Sandmair et al, 2000166 ID NR Controlled trial N: 14

Age group: adults Primary or residive lobar malignant gliomas Treatments enrollment: tumor(s) had to be eligible for surgical removal Treatment requisite: craniotomy and radical tumor resection prior to localized delivery of gene therapy and ganciclovir treatment post surgery (different protocol for controls) Follow-up: until death

Adv/tk Other: transfection with control marker gene

Time to disease progression, survival

No severe adverse effects detected

We conclude that HSV-tk and Adv/tk gene therapy is safe and well tolerated. On the basis of these results, further trials are justified, especially with adenovirus vectors.






Cancer Xu et al, 2009213 ID NR Single-arm trial N: 18

Age group: adults Refractory malignant tumors Treatments enrollment: none Treatment requisite: none Follow-up: none

AdV/TK No comparison group

Safety and tumor response, vector dissemination and biodistribution, detection of neutralizing antibodies directed to adenovirus 5 and herpes simplex virus, Detection of plasma concentrations of GCV

None In summary, the results suggest that AdV/TK /GCV combination suicide gene therapy is safe in Chinese patients and achieved a local response with few environmental effects.

Cancer Immonen et al, 2004193 ID NR Trial (multiple groups) Completed N: 36

Age group: adults Malignant glioma Treatments enrollment: none Treatment requisite: intravenous ganciclovir Follow-up: 54

AdvHSV-tk Usual care

Death or surgery for recurrence, all-cause mortality, tumor progression, QoL

None The median survival time increased from 37.7 to 62.4 weeks. Six patients had increased anti-adenovirus antibody titers without adverse effects. The treatment was well tolerated. It is concluded that AdvHSV-tk gene therapy and GCV is a potential new treatment for operable primary or recurrent high-grade glioma.






Cancer Hasenburg et al, 2001172 Hasenburg et al, 2000408; Hasenburg et al, 2002409 BB-IND 7311 Trial (multiple groups) N: 10

Age group: adults Recurrent ovarian cancer Treatments enrollment: Patients must have completed initial surgery and chemotherapy (cisplatin or carboplatin) and should have been off treatment for at least 6 weeks. Treatment requisite: Topotecan treatment commenced 24 hours after gene therapy injection and continued in 3-week intervals until progression. Follow-up: 60

Adv-HSV-tk No comparison group

Overall survival, survival time, time to disease progression, quality of life

Survival comparable to patients receiving surgery and chemotherapy

Two out of 5 patients were free of tumor. Survival was comparable to that of patients of other studies with secondary cytoreductive surgery in combination with chemotherapy.

Cancer van der Linden et al, 2005196 ID NR, protocol reviewed by Dutch Commission for Genetic Modified Agents and by the Ethics Committee of the Erasmus MC Single-arm trial N: 8

Age group: adults Prostate cancer Treatments enrollment: none Treatment requisite: pelvic lymph node dissection, retro-pubic radical prostatectomy Follow-up: 12

Adv-HSV-tk No comparison group

Toxicity, cellular and humoral immune responses

Cytolysis (n = 1) Neo-adjuvant adenovirus-mediated cytotoxic gene therapy prior to prostatectomy for prostate cancer is feasible and safe in an outpatient setting for intraprostatic vector doses up to 2 1011 viral particles.






Cancer Gilly et al, 1999158 Gilly et al, 1998410 ID NR, protocol approved by French Ministry of Health, French Ethical Committee Single-arm trial N: 6

Age group: adults Unresectable digestive cancer Treatments enrollment: pathologically proven digestive cancer that was revealed to be unresectable through surgical laparotomy Treatment requisite: none Follow-up: none

Adv-IL2 No comparison group

None No adverse effects and no acute toxicity

Intermediate results of this phase I to II trial using a single dose (107 and 108 pfu) of recombinant replication-deficient adenovirus expressing the human IL-2 gene in unresectable digestive cancers showed an excellent clinical, biological, and immune tolerance with no adverse effects and no acute toxicity. No spreading or shedding of AdV-IL2 was observed.

Cancer Aguilar et al, 2015240 Advantagene, 2013411 NCT00638612 Trial (multiple groups) N: 27

Age group: adults Pancreatic adenocarcinoma Treatments enrollment: none Treatment requisite: surgery or chemoradiation Follow-up: 66

AdV-tk No comparison group, other: gene therapy + product as adjunct to surgery or chemoradiation

Progression-free survival, overall survival, clinical response (progressive disease, partial response, stable disease)

Surgical group grade 3: abdominal pain (n = 2), dehydration (n = 1), laboratory tests (n = 17); surgical group grade 4: laboratory tests (n = 7); chemoradiation group grade 3: dehydration (n = 1), laboratory tests (n = 15); chemoradiation group grade 4: laboratory tests (n = 6)

AdV-tk can be safely combined with pancreatic cancer SOC without added toxicity. Response and survival compare favorably to expected outcomes and immune activity increased. These results support further evaluation of GMCI with more modern chemoradiation and surgery as well as PD-1/PD-L1 inhibitors in pancreatic cancer.






Cancer Chevez-Barrios et al, 2005198 ID NR Single-arm trial N: 8

Age group: children Bilateral retinoblastoma with vitreous tumor seeding refractory to standard therapies Treatments enrollment: All patients had experienced treatment failure in prior therapies including chemo, radio, cryo, and laser. Treatment requisite: none Follow-up: 40

AdV-TK No comparison group

Apparent clinical resolution of vitreous tumor seeds.

Inflammation AdV-TK followed by ganciclovir can be administered safely to children with retinoblastoma.

Cancer Chiocca et al, 2011141 Advantagene, 2010412 NCT00751270 Trial (multiple groups) N: 13

Age group: adults Malignant glioma Treatments enrollment: none Treatment requisite: delivery of gene therapy by injection into tumor bed after surgical resection of tumor; all patients received oral valacyclovir 1 to 3 days post–gene therapy delivery for 14 days followed by temozolomide as standard of care; standard radiation therapy began Follow-up: until death

Adv-tk No comparison group, other: resection in combination with valacyclovir and radiation (all patients received radiotherapy along with gene therapy)

Classification of prognostic groups, disease progression, appearance of new lesion or neurologic deterioration, corticosteroid dose stable or increasing, quality-of-life assessment

2 reported serious adverse events that may have been related to gene therapy: patient 5 (fever, hyponatremia, nausea/vomiting, confusion, grade 2 AST and ALT and creatinine increases) and patient 4 (progressive extra-axial fluid had to be collected from under the surgical wound closure)

This gene therapy (AdV-tk) plus valacyclovir can be safely delivered in combination with surgery and accelerated radiation in newly diagnosed malignant gliomas.






Cancer Ji et al, 2016243 Huazhong University of Science and Technology, 2011413 NCT00870181 RCT N: 53

Age group: adults Recurrent high-grade glioma (HGG) Treatments enrollment: chemotherapy completion ≥ 4 weeks to start of trial Treatment requisite: none Follow-up: 8

Adv-TK Usual care: conventional therapy: surgery, chemotherapy, or palliative care

Progression-free survival, overall survival, objective response evaluation, clinical benefit of treatment

Stated no severe adverse events were observed; reported grade 3 events: anemia (n = 1 and n = 2 in treatment and control groups, respectively) and neutropenia (n = 1 in both groups)

The study demonstrated a notable improvement of PFS-6, PFS, and OS in the ADV-TK-treated group, and the efficacy and safety appear to be comparable to other reported treatments used for recurrent HGG. ADV-TK gene therapy is therefore a valuable therapeutic option for recurrent HGG.

Cancer Li et al, 2007207 ID NR RCT N: 45

Age group: adults Advanced hepatocellular carcinoma Treatments enrollment: liver transplant Treatment requisite: none Follow-up: 26

Adv-TK Usual care: liver transplant

Recurrence-free survival, overall survival

Well tolerated and no significant toxicity evident; mild catarrhal symptoms (10/23), slight fever with no chills, light headache

HCC patients with no vascular invasion could be selected for LT followed by adjuvant ADV-TK therapy, regardless of intrahepatic huge or diffuse tumor.






Cancer Rojas-Martinez et al, 2013235 ID NR Single-arm trial N: 10

Age group: adults Prostate cancer Treatments enrollment: excluded if had received previous treatment for prostate cancer Treatment requisite: oral ciproflaxin and phosphate enema on morning of injection; intraprostatic injections guided by transrectal ultrasonography; gancyclovir or valacyclvir after injection (prodrug); radical prostatectomy after injection (9 weeks later on av) Follow-up: median: 136+ ongoing

AdV-tk No comparison group

Clinical response, serum PSA

Grade 3: lymphopenia (n = 1)

In vivo transrectal ultrasound guided instillation of an adenoviral vector into 4 sites in the prostate was practical as an outpatient procedure, was well tolerated, and led to distribution throughout the intraprostatic tumor mass. AdV-tk demonstrated no significant acute or late toxicities.

Cancer Wheeler et al, 2016244 Advantagene, 2015414 NCT00589875 Controlled trial N: 48

Age group: adults Newly diagnosed malignant glioma Treatments enrollment: standard of care (SOC) treatment Treatment requisite: none Follow-up: 88

AdV-tk No treatment

Survival None GMCI can be safely combined with SOC in newly diagnosed malignant gliomas.

Cancer Zhu et al, 2018154 Huazhong University of Science and Technology, 2011415 NCT02202564 RCT N: 86


Adv-TK Usual care: liver transplant

Recurrence-free survival (RFS) and overall survival (OS), safety of double-dose ADV-TK/GCV adjuvant therapy

No evident adverse effects

Double-dose ADV-TK/GCV gene therapy combined with LT was safe and improved RFS and OS in advanced HCC patients without vascular invasion during the 5-year follow-up period.






Cancer Qian et al, 2017129 NCT02851576 Single-arm trial N: 14

Age group: children and adults Hematological malignancies Treatments enrollment: ilogeneic hematopoietic stem cell transplantation Treatment requisite: none Follow-up: 9

Adv-VST No comparison group

Production of ADV-VST, ADV-VST infusion tolerance, Immune reconstitution, ADV response

None Adoptive transfer of rapidly isolated ADV-VST is an effective therapeutic option for achieving in vivo expansion of specific T cells and clearance of viral load, even as a preemptive treatment.

Cancer Aggarwal et al, 2018126 Trial (multiple groups) N: 19

Age group: adults Malignant pleural effusion Treatments enrollment: none Treatment requisite: celecoxib Follow-up: 44

Aglatimagene besadenovec No comparison group

Tumor response, progression-free survival, overall survival, safety

Grade 3 cytotoxic response (n = 1)

Gene-mediated cytotoxic immunotherapy was safe and well tolerated with chemotherapy in patients with malignant pleural effusion and showed encouraging response.

Cancer Small et al, 2006202 ID NR, protocol reviewed by RAC and FDA Single-arm trial N: 23

Age group: adults Hormone-refractory metastatic prostate cancer Treatments enrollment: none Treatment requisite: none Follow-up: 6

CG7870 No comparison group

Treatment-related toxicity; PSA response; neutralizing antibodies; CG7870 in blood, saliva, and urine; cytokines blood levels

Fatigue, fever PSA decreases demonstrated on this trial are the first reported evidence of PSA modulation after intravenous administration of an oncolytic Ad.






Cancer Hamid et al, 2003134 Trial (multiple groups) Completed N: 18

Age group: adults Metastatic colorectal cancer Treatments enrollment: none Treatment requisite: none Follow-up: 17

CI-1042 No comparison group

Complete response, partial response, progressive disease, stable disease

SAEs (events/patients): 1 severe lethargy; 1 increase in partial thromboplastin time

In this phase II study, intravenous CI-1042 was administered safely to patients with advanced colorectal cancer. Toxicity was manageable, consisting primarily of flu-like symptoms. Stable disease was experienced by 7 patients for 11 to 18 weeks

Cancer Palmer et al, 2004188 ID NR Trial (multiple groups) N: 18

Age group: adults Hepatic metastatic colorectal cancer or hepatocellular carcinoma (1 to 5 cm) Treatments enrollment: none Treatment requisite: Gene therapy was delivered by ultrasound-guided intratumoral injection followed by laparotomy and hepatic resection 3 to 8 days later. Follow-up: Until death

CTL102 No comparison group, other: intratumoral injection followed by laparotomy and hepatic resection 3 to 8 days later

Immune responses, immunohistochemical analysis of resected tumors for transgene expression

No dose-limiting toxicity observed, including at the maximum dose of virus particles

Direct intratumoral delivery of CTL102 to patients with primary and secondary liver cancer is feasible and well tolerated with minimal side effects.

Cancer Patel et al, 2009214 ID NR Trial (multiple groups) N: 39

Age group: adults Localized prostate cancer Treatments enrollment: none Treatment requisite: prophylactic ciprofloxacin before injection and for 3 days after Follow-up: 15

CTL102 No comparison group

Change in observed time to PSA progression (TTP)

All adverse events attributable to treatment were transient and no additional treatment was required. Lymphopenia: grade 3 (n = 8), grade 4 (n = 1); raised hepatic enzymes: grade 3 (n = 1); fever: grade 3 (n = 1); amnesia: grade 3 (n = 1)

With further clinical development, it is believed VDEPT can become a new therapeutic option.






Cancer Habib et al, 2001167 ID NR Trial (multiple groups) N: 16

Age group: adults Primary and secondary liver tumors Treatments enrollment: none Treatment requisite: Phase I patients received multiple doses by 1 of 3 methods: intratumoral administration of gene therapy with computed tomography guidance, intraarterial administration through the hepatic artery, or intravenous administration via a vein in the arm. Follow-up: Until death

dl1520 No comparison group

Tumor response by computed tomography scan or tumor markers (complete response, partial response, stable disease, progressive disease)

No serious adverse events

Further improvement in recombinant vector design is necessary to achieve better clinical response.

Cancer Habib et al, 2002176 ID NR RCT Completion date: 08/1999 N: 10

Age group: adults Hepatocellular carcinoma Treatments enrollment: none Treatment requisite: none Follow-up: none

dl1520; ONYX-015 Placebo

Physical examination, liver function test, anti-adenovirus type 5 antibody titer, analysis of adenovirus presence in serum samples using polymerase chain reaction

Fever, rigour, hypotension monitored; vector was well tolerated, although antitumor activity was modest

Although only a few patients were treated in this study, it appears more effective vectors are needed to achieve a useful clinical impact.






Cancer Reid et al, 2001174 ID NR Single-arm trial Completed N: 11

Age group: adults Colorectal carcinoma metastatic to the liver Treatments enrollment: none Treatment requisite: chemotherapy Follow-up: 2

dl1520; ONYX-015 No comparison group


SAEs: 45 events No dose-limiting toxicity, maximally tolerated dose, or treatment-emergent clinical hepatotoxicity were identified following dl1520 infusion. Mild to moderate fever, rigors, and fatigue were the most common adverse events. An objective response was demonstrated in combination with chemotherapy in a patient who was refractory to both 5-FU and dl1520 as single agents. Therefore, hepatic artery infusion of the attenuated adenovirus dl1520 was well tolerated at doses resulting in infection, replication, and chemotherapy-associated antitumoral activity.

Cancer Li et al, 2008137 ID NR, China’s State Food and Drug Administration regulatory authorities Trial (multiple groups) Completed N: 15

Age group: adults Advanced tumors Treatments enrollment: none Treatment requisite: none Follow-up: 1

E10A No comparison group

Tumor response, progressive disease, stable disease

None reported Direct intratumoral injection of up to 1012 vp of E10A to patients is well tolerated, and further studies are necessary to define and increase clinical efficacy.






Cancer Lin et al, 2007144 ID NR, protocol approved by Chinese State FDA and the institutional ethics committees Trial (multiple groups) Completed N: 15

Age group: adults Solid tumors Treatments enrollment: none Treatment requisite: none Follow-up: 1

E10A No comparison group

Minor response, stable disease, progressive disease

None Weekly intratumoral injection of up to 1 × 1012 VP of E10A to patients with solid tumor is a feasible and well-tolerated procedure that exerts mild antitumor effects. A small and sustained elevation of endogenous endostatin in blood possibly has antitumor activity.

Cancer Ye et al, 2014149 NCT00634595 RCT Completed N: 136

Age group: adults Advanced head and neck carcinoma Treatments enrollment: none Treatment requisite: chemotherapy Follow-up: 40.3

E10A Usual care

Objective response rate, objective disease control rate, overall response rate, overall disease control rate, overall survival, progression-free survival

SAEs: 24 intervention, 20 placebo

The overall disease control rate significantly increased from 80.6% in the control group to 92.6% in the test group (P = 0.034). Except for fever, no adverse events were associated with the E10A treatment. In summary, E10A plus chemotherapy is a safe and effective therapeutic approach in patients with advanced head and neck squamous cell carcinoma or nasopharyngeal carcinoma.

Cancer Lu et al, 2004135 ID NR, protocol approved by the State Food and Drug Administration of China Single-arm trial Completed N: 46

Age group: adults Advanced cancerous tumors Treatments enrollment: surgery and/or chemotherapy and/or radiotherapy Treatment requisite: chemotherapy Follow-up: 0

H101 No comparison group

Complete regression, partial regression, minor response, progressive disease, stable disease

SAEs (events): 1 fever, 7 leucopenia, 1 liver dysfunction, 1 alopecia

Intratumor injection of the genetically engineered adenovirus H101 exhibits potential antitumor activity to refractory malignant tumors in combination with chemotherapy. Low toxicity and good tolerance of patients to H101 were observed.






Cancer Yoo et al, 2009216 NCT00017173 Single-arm trial N: 13

Age group: adults Carcinoma of the oral cavity, oropharynx, hypopharynx, and larynx Treatments enrollment: none Treatment requisite: chemoradiotherapy Follow-up: 3

INGN 201 (Ad5CMV-p53) No comparison group

Overall patient status, tumor status, adverse effects, accrual rate, percentage of patients successfully receiving required doses of INGN 201

None Intraoperative INGN 201 gene therapy is technically feasible, but it has many logistical problems when performed in a multi-institutional setting.

Cancer Pagliaro et al, 2003183 National Cancer Institute, 2002416 NCT00003167 Single-arm trial N: 13

Age group: adults Locally advanced bladder cancer Treatments enrollment: none Treatment requisite: none Follow-up: 44


Toxicity, detection of p53 transgene, immunohistochemistry and TUNEL

Safe Intravesical instillation of Ad5CMV-p53 is safe, feasible, and biologically active when administered in multiple doses to patients with bladder cancer.

Cancer Freytag et al, 2014238 Lu, 2011417; Henry Ford Health, 2013418 ID NR Trial (multiple groups) Completed N: 44

Age group: adults Prostate cancer Treatments enrollment: none Treatment requisite: intensity-modulated radiation therapy Follow-up: 24

OAMCGT Other: intensity-modulated radiation therapy

Expanded Prostate Cancer Index Composite, EuroQol EQ-5D

Grade 3/4 AEs: 14 OAMCGT plus IMRT, 10 IMRT only

Combining OAMCGT with IMRT does not exacerbate the most common side effects of prostate radiation therapy and suggests a clinically meaningful reduction in positive biopsy results at 2 years in men with intermediate-risk prostate cancer.

Cancer Chiocca et al, 2004192 ID NR (title states trial) Single-arm trial N: 24

Age group: adults Recurring malignant glioma Treatments enrollment: none Treatment requisite: none Follow-up: 19

ONYX-015 No comparison group

Toxicity assessment None This trial has shown the relative safety of injection of ONYX-015 into the brain surrounding a resected malignant glioma.






Cancer Galanis et al, 2005195 ID NR, protocol reviewed by Mayo Clinic Institutional Review Board Single-arm trial N: 6

Age group: adults Advanced sarcoma Treatments enrollment: none Treatment requisite: none Follow-up: 11


Toxicity, Immunohistochemistry for p53 and mdm2 expression, plasma neutralizing antibody titers, detection of ONYX-015 viral genome in plasma

None Intratumoral administration of ONYX-015 in combination with MAP chemotherapy is well tolerated with no significant toxicity due to ONYX-015 being encountered.

Cancer Hecht et al, 2003132 Mulvihill et al, 2001419 Trial (multiple groups) Completed N: 21

Age group: adults Unresectable pancreatic carcinoma Treatments enrollment: none Treatment requisite: ciprofloxacin, chemotherapy Follow-up: 36


Complete response, partial response, progressive disease, stable disease, survival

SAEs (patients): 2 sepsis, 2 duodenal perforation, 2 cystic fluid collection, 2 hyperlipasemia, 1 hyperamylasemia, 1 elevated liver tests, 1 fever, 6 leukopenia/neutropeni, 1 lymphopenia, 1 anemia, 1 increased partial thromboplastin time, 1 gemcitabine lung toxicity

This study indicates ONYX-015 injection via EUS into pancreatic carcinomas by the transgastic route with prophylactic antibiotics is feasible and generally well tolerated either alone or in combination with gemcitabine. Transgastric EUS-guided injection is a new and practical method of delivering biological agents to pancreatic tumors.






Cancer Lamont et al, 2000164 ID NR Single-arm trial N: 14

Age group: adults Recurrent squamous cell carcinoma of the head and neck Treatments enrollment: none Treatment requisite: intratumoral injection of the gene therapy with local anesthesia and/or intravenous sedation as needed for each injection (daily for 5 consecutive days, repeated every 3 weeks until tumor progression or adverse event); treatment cycles included cispla Follow-up: until death


Tumor size, necrosis induction of injected tumor (complete regression, partial regression, minor regression, stable disease, progressive disease)

Grade 3 mucositis (n = 2)

In patients with recurrent squamous cell carcinoma of the head and neck, ONYX-015 adenovirus plus chemotherapy (cisplatin and 5-fluorouracil) provided antitumor activity and local tumor control.






Cancer Makower et al, 2003133 Wadler, 2003420 ID NR, protocol reviewed by NIH Single-arm trial N: 20

Age group: adults Hepatobiliary tumors Treatments enrollment: none Treatment requisite: The first 8 patients treated received prophylactic antibiotic coverage with oral erythromycin (1 g every 6 hours) and kanamycin (1 g every 6 h), beginning on the day before ONYX- 015 administration and continuing for 24 hours after treatment.Also, patients received i.v. ticarcillin/clavulanate (3.1 g every 4 h) and gentamycin (80 mg every 8 h). Patients allergic to penicillin received vancomycin (1 g every 12 h), aztreonam (2 g every 8 h), and metronidazole (500 mg every 6 h). Antibiotics began on the day before ONYX-015 administration and continued for 1 week after treatment. Follow-up: 0


Toxicities, response to treatment, analysis of p53 status, correlation of p53 status with response, antiadenoviral antibody studies, analysis of viral shedding in body fluids

None Intralesional treatment with ONYX-015 in patients with hepatobiliary tumors is safe and well tolerated and some patients had evidence of an anticancer effect.






Cancer Nemunaitis et al, 2000131 Ganly et al, 2000421, Khuri et al, 2000422 ID NR (title describes study as trial) Trial (multiple groups) Completed N: 37

Age group: adults Advanced head and neck cancer Treatments enrollment: none Treatment requisite: none Follow-up: 4


Complete regression, partial regression, minor response, stable disease, progressive disease

None The findings suggest that belagenpumaucel-L improved survival for patients who were randomized within 12 weeks of completion of chemotherapy and in those who had received prior radiation. Further studies of belagenpumatucel-L in NSCLC are warranted.

Cancer Vasey et al, 2002175 ID NR Trial (multiple groups) N: 16

Age group: adults Recurrent or refractory epithelial ovarian cancer Treatments enrollment: had to have received platinum-containing chemotherapy with relapse within the previous 6 months Treatment requisite: laparoscopy or laparotomy for intraperitoneal catheter placement, baseline measurements of biomarkers and tumor Follow-up: unclear

ONYX-015 (d11520) No comparison group

Clinical response, survival time

Grade 3 events: pyrexia/sweats (n = 3), headaches (n = 2), myalgias (n = 1), malaise (n = 1), nausea (n = 3), vomiting (n = 2), diarrhea/ileitis (n = 1), abdominal pain (n = 1)

Patients generally tolerated the treatment but there was no clear clinical benefit: “There was no clear-cut evidence of clinical or radiologic response in any patient.”






Cancer Nemunaitis et al, 2006201 ID NR Trial (multiple groups) N: 13

Age group: adults Early stage (IB, IIA, IIB) non-small-cell lung cancer Treatments enrollment: none Treatment requisite: intramuscular need and syringe injections at weeks 0, 2, 4, and 8 Follow-up: until death

pVAX/L523S + Ad/L523S No comparison group

Relapse-free survival, overall survival

No patients developed grade 3 or 4 toxicity that was characterized as possibly, probably, or definitely related to the gene therapy or the procedure.

Results suggest a high level of safety. but evidence of L523S-directed immune activation was limited, suggesting a need for modification of dose, schedule, and site of vaccination with further clinical testing.

Cancer Kuball et al, 2002177 ID NR Single-arm trial Completed N: 6

Age group: adults Advanced stage cancer Treatments enrollment: none Treatment requisite: none Follow-up: 3

rAd/hup53 No comparison group

Tumor response None The treatment was well tolerated. To date, no evidence for objective tumor responses was observed. An amplification of humoral and cellular anti-adenoviral immune responses was demonstrated in all patients following rAd/hup53 vaccination.

Cancer Buller et al, 2002178 ID NR Trial (multiple groups) N: 41

Age group: adults Recurrent ovarian cancer Treatments enrollment: none Treatment requisite: none Follow-up: 3

rAd/p53; SCH 58500 Usual care: chemotherapy

Tumor sampling, toxicity, patient monitoring—ELISA Laboratory, data-serum, ascites sampling for pharmacokinetic studies, complete blood counts, fibrinogen, fibrin split products, PT, PTT, serum C3, C4, CH50, electrolytes including magnes

Fever (100%), hypotension (89%), variety of abdominal complaints (79%), hypertension (68%), nausea (63%), tachycardia (58%), vomiting (58%), fatigue (53%)

CT scans are not a valid measure of response to i.p. SCH 58500 due to extensive adenoviral-induced inflammatory changes. Intraperitoneal SCH 58500 is safe, well tolerated, and combined with platinum-based chemotherapy can be associated with a significant reduction of serum CA125 in heavily pretreated patients with recurrent ovarian, primary peritoneal, or fallopian tube cancer.






Cancer Lu et al, 2011224 ID NR RCT N: 45

Age group: adults Esophageal carcinoma Treatments enrollment: none Treatment requisite: none Follow-up: None

rAd2p53 Usual care

Toxic effects None This recombinant virus–RT combination is significantly more beneficial in palliation than RT alone, with minor side affects.

Cancer Dinney et al, 2013231 ID NR (but trial stated in title) Trial (multiple groups) N: 17

Age group: adults Non-muscle-invasive bladder cancer Treatments enrollment: Patients were required to have proven disease recurrence after 2 or more cycles of Bacillus Calmette-Guerin (BCG), with or without recombinant interferon-alpha (IFNα) protein, and at least 3 months since last treatment. Treatment requisite: Cystoscopy, biopsies, urinary cytology, and bladder capacity evaluation were performed 2 to 3 weeks before therapy. Patients were hospitalized for 48 hours post-therapy and monitored daily for 5 days for adverse events. Follow-up: 24

rAd-IFNalpha No comparison group

Tumor response (complete response), duration of response, progression-free survival

No significant treatment-related adverse events were observed. One patient was hospitalized for adverse events deemed not related to the study therapy.

Intravesical rAd-IFN alphaSyn3 therapy was well tolerated with no dose-limiting toxicity encountered. Efficient gene transfer and expression was confirmed by dose-dependent urinary interferon-alpha (IFNα) concentrations. Intravesical rAd-IFNα/Syn3 demonstrated promising clinical activity in non-muscle-invasive bladder cancer (NMIBC) recurring after BCG.






Cancer Shore et al, 2017248 NCT01687244 Trial (multiple groups) N: 43

Age group: adults High-grade, bacillus calmette-guerin-refractory or relapsed non-muscle-invasive bladder cancer Treatments enrollment: Patients were unable or unwilling to undergo radical cystectomy. Treatment requisite: none Follow-up: 12

rAd-IFNalpha/Syn3 No comparison group

High-grade disease recurrence

Nine patients (22%) reported a total of 19 grade 3 AEs: 12 in the low-dose arm (coronary artery occlusion, diarrhea, sepsis, arthralgia, renal neoplasm, transitional cell carcinoma, carotid artery occlusion, syncope, renal failure, nephroureterectomy, COPD, and hypotension) and 7 in the high-dose arm (abdominal pain, back pain, fracture, syncope, dysuria [n = 2]), and acute renal failure.

rAd-IFN alpha/Syn3 was well tolerated. It demonstrated promising efficacy for patients with HG NMIBC after BCG therapy who were unable or unwilling to undergo radical cystectomy.

Cancer Guan et al, 2011225 ID NR Controlled trial N: 82


rAd-p53 Usual care

Efficacy None The rAd-p53 gene therapy in combination with TACE is a safe and effective treatment modality for advanced HCC.

Cancer Chen et al, 2014236 ID NR RCT N: 48


rAd-p53 Usual care

Survival rate None Sequential therapy of p53 gene transcatheter arterial infusion was safe and could prolong the survival of the patients.






Cancer Deng et al, 2017152 NCT01574729 RCT N: 163

Age group: adults Non-small-cell lung cancer Treatments enrollment: none Treatment requisite: All patients had radical survery. Follow-up: minimum 36, median 43 (as of report)

rAd-p53 Usual care: radical surgery alone, other: radical surgery alone plus local injecton of vector

Progression-free survival, overall survival

Observed no serious adverse effect related to treatment thus far.

The wound surface injection of rAd-p53 showed efficacious effects in preventing recurrence or metastasis and improving PFS and OS after a radical surgery in patients with NSCLC.

Cancer Guan et al, 2009215 ID NR Controlled trial N: 12


rAd-p53 Usual care: therapy of bronchial arterial infusion (BAI)

Overall antitumor efficacy None The results show the combination of rAd-p53 and BAI was well tolerated in patients with NSCLC and may have improved the quality of life and delayed the disease progression.

Cancer Li et al, 2009217 Zhang et al, 2009423 ID NR (described as trial) Single-arm trial N: 22

Age group: adults Oral leukoplakia Treatments enrollment: none Treatment requisite: none Follow-up: 24

rAd-p53 No comparison group

Infection efficiency of rAd-GFP, cell morphology, growth inhibition ratio, apoptosis and cell cycle, messenger RNA and protein expression of p53, p21, bcl-2

Harms not reported Intraepithelial injections of recombinant human adenovirus-p53 were safe, feasible, and biologically active for patients with dysplastic oral leukoplakia.






Cancer Li et al, 2014237 ChiCTR-TRC-09000392 RCT Completed N: 99

Age group: adults Stage III or IV oral carcinoma Treatments enrollment: none Treatment requisite: chemotherapy Follow-up: 86

rAd-p53 Placebo

Complete response, partial response, stable disease, progressive disease, survival

None Intra-arterial infusion of combined rAd-p53 and chemotherapy significantly increased the survival rate of patients with stage III but not stage IV oral cancer, compared with intra-arterial chemotherapy. Intra-arterial infusion of combined rAd-p53 and chemotherapy may represent a promising alternative treatment for oral squamous cell carcinoma.

Cancer Liu et al, 2013232 Liu et al, 2012424 ID NR RCT Completed N: 107

Age group: adults Oral cancer Treatments enrollment: none Treatment requisite: radiotherapy (after gene therapy) Follow-up: 36

rAd-p53 No treatment

Local recurrent rate, 3-year disease-free survival, 3-year overall survival

SAEs (oral membrane burn and pain): 0 intervention, 2 placebo

The 3-year overall-survival (OS) rate and 3-year disease-free survival (DFS) rate of EG are 100% and 93%, respectively. The 3-year OS and DFS rates of CG are 94% and 68%, respectively. Mild or medium fever and flu-like symptoms were more frequently observed in EG and were considered to be associated with application of rAd-p53. Post-tumorectomy wound surface injection of rAd-p53 combined with radiotherapy is a safe and effective regimen for the patients with TGa or GCa.






Cancer Pan et al, 2009212 ID NR, but trial—including protocols and informed consent process—approved by the Chinese State Food and Drug Administration and Beijing Hospital Ethics Committee on September 12, 2001 RCT N: 82

Age group: adults Nasopharyngeal carcinoma Treatments enrollment: none Treatment requisite: none Follow-up: 61

rAd-p53 Placebo, usual care: radiotherapy

Overall survival rate, tumor control

None In patients with NPC, rAd-p53 was safe and biologically active. The results indicated rAd-p53 improves radiotherapeutic tumor control and survival rate in patients with NPC.

Cancer Su et al, 2016139 RCT Completed N: 104

Age group: adults Locally advanced cervical cancer Treatments enrollment: none Treatment requisite: radiotherapy Follow-up: 97

rAd-p53 Other: radiotherapy alone

Survival, complete response, partial response, stable disease, progressive disease

SAEs: late radiorectitis: 4 PRT, 3 RT; late radiocystitis: 1 PRT, 0 RT; fever: 18 both groups

The 5-year progress-free survival rate of the PRT group was 17.1% higher than that of the RT group (HR = 0.485; 95% CI, 0.234-1.006; p = 0.047). rAd-p53 administration did not increase the adverse events caused by radiotherapy, except for transient fever after rAd-p53 administration. rAd-p53 was safe and biologically active in improving radiotherapeutic survival rates in patients with cervical cancer.






Cancer Wang et al, 2016151 CH21010110 Trial (multiple groups) Completed N: 382

Age group: adults Renal cell carcinoma Treatments enrollment: none Treatment requisite: lenvatinib Follow-up: 42

rAd-p53 Other: lenvatinib

Complete response, partial response, stable disease, progressive disease, progression-free survival

SAEs (events): 5 hypertension, 4 proteinuria, 1 diarrhea, 2 rash, 1 fatigue, 2 pain in injection site

Taken together, lenvatinib and rAd-p53 are well tolerated at the indicated dose. Gene and target therapy for RCC could be further enhanced by synergistic effects of lenvatinib and rAd-p53.

Cancer Xiao et al, 2018155 ID NR. This study was approved by the Institutional Review Board of the authors’ hospital. Written informed consent was obtained from all patients. Controlled trial Completion date: 11/2014 N: 71

Age group: adults Unresectable advanced soft-tissue sarcomas Treatments enrollment: advanced unresectable STS Treatment requisite: none Follow-up: 6

rAd-p53 Usual care: recombinant adenovirus-p53 (rAd-p53) gene therapy combined with radiotherapy and hyperthermia for advanced STS

Disease control rate, progressive disease rate, progression-free survival, overall survival

No significant difference in all adverse events, except for transient fever, which occurred in 89% of patients

rAd-p53 combined with radiotherapy and hyperthermia can effectively improve the therapeutic efficacy and survival outcomes in patients with advanced unresectable STS, providing a new therapeutic strategy.






Cancer Kauczor et al, 1999157 ID NR Trial (multiple groups) N: 15

Age group: adults Incurable ((stage IIIb or IV) non-small-cell lung cancer Treatments enrollment: none Treatment requisite: spiral computed tomography (CT) performed prior to therapy start; dose levels 1 to 3 were delivered bronchoscopically and dose levels 3 to 4 were deilvered percutaneously under CT guidance; spiral CT was performed again at 28 days post-treatment Follow-up: 1

Replication-defective adenoviral expression vector encoding wild-type p53 No comparison group

Tumor progression (stable disease or progressive disease)

Not discussed After 28 days, 4 of the 6 patients showed stable disease at the treated tumor site, whereas other tumor sites progressed. Computed tomography–guided injections are a sufficient and easy-to-perform procedure for intratumoral gene therapy delivery.

Cancer Schuler et al, 1998156 Boulay et al, 2000425 ID NR, protocol approved by German and Swiss national reugulatory offices Single-arm trial N: 15


Replication-defective adenoviral expression vector encoding wild-type p53 No comparison group

None No clinically significant toxicity observed

Wild-type p53 gene therapy by intratumoral injection of a replication-defective adenoviral expression vector is safe, feasible, and biologically effective in patients with advanced non-small-cell lung cancer.

Cancer Dong et al, 2014239 Control group was from patients who received TACE along the same period Trial (multiple groups) N: 299

Age group: adults Unresectable hepatocellular carcinoma Treatments enrollment: none Treatment requisite: none Follow-up: 3

rhAd5 Usual care

Progression-free survival, overall survival

None This study suggests rhAd5 is a safe, effective gene therapy that prolongs the PFS and OS time of patients with unresectable HCC.






Cancer Xiao et al, 2017153 ID NR RCT N: 40

Age group: adults Locally advanced cervical cancer (LACC) Treatments enrollment: Patient had to have treatment for naïve cancer (ie, no prior chemotherapy and/or radiotherapy). Treatment requisite: All patients had chemotherapy (the gene therapy group was also adminsitered vector). Follow-up: Not discussed

rhAd-p53 Usual care PVB group (cisplatin + vincristine + bleomycin), other: The treatment group is the gene therapy + PVB group (cisplatin + vincristine + bleomycin).

Reduction in size of cancer foci, total efficacy rate (complete response, partial response, stable disease, progressive disease)

Bone marrow suppression (n = 1), elevated aminotransferase levels (n = 2), high fever (n = 5)

Intratumoral injection of rhAd‑p53 combined with neoadjuvant chemotherapy may have advantages over conventional chemotherapy for its high efficacy, safety, and synergism in the therapy for LACC.

Cancer Atencio et al, 2006197 ID NR Single-arm trial N: 29

Age group: adults Colorectal cancer metastatic to the liver Treatments enrollment: none Treatment requisite: none Follow-up: none

SCH 58500 No comparison group

Immune responses to SCH 58500, tissue-specific detection of SCH 58500 DNA and transgene p53 mRNA, distribution of SCH 58500 in liver, Ad transduction and pretreatment total or serum neutralizing Ad antibody levels, Ad transduction and CAR expression

None IHA administration of a replication defective adenovirus is a feasible mode of delivery, allowing for exogenous transfer of the p53 gene into target tissues, with evidence of functional p53. Limited and transient inflammatory responses to the drug occurred, but preexisting immunity to Ad did not preclude SCH 58500 delivery.

Cancer Schuler et al, 2001169 ID NR, protocol reviewed by national regulatory offices of each participating center Trial (multiple groups) N: 25

Age group: adults Advanced non-small-cell lung cancer Treatments enrollment: none Treatment requisite: none Follow-up: none

SCH 58500; rAd/p53 No comparison group

None None Intratumoral adenoviral p53 gene therapy appears to provide no additional benefit in patients receiving an effective first-line chemotherapy for advanced NSCLC.






Cancer Kuball et al, 2002173 ID NR Trial (multiple groups) N: 12

Age group: adults Bladder cancer Treatments enrollment: none Treatment requisite: cystoscopy or catheter placement Follow-up: 12

SCH 58500; rAd/p53 No comparison group

Toxicity and survival No observed dose-limiting toxicity

Intravesical instillation of SCH58500 combined with a transduction-enhancing agent is safe, feasible, and biologically active in patients with bladder cancer.

Cancer Westphal et al, 2013234 Trial (multiple groups) Completed N: 251

Age group: adults High-grade glioma Treatments enrollment: none Treatment requisite: none Follow-up: 43

Sitimagene ceradenovec Usual care: 2004-000464-28

Time to death or re-intervention


The findings suggest use of sitimagene ceradenovec and ganciclovir after resection can increase time to death or re-intervention in patients with newly diagnosed supratentorial glioblastoma multiforme, although the intervention did not improve overall survival. Locally delivered gene therapy for glioblastoma should be further developed, especially for patients who are unlikely to respond to standard chemotherapy.






Cancer Nemunaitis et al, 2010127 ID NR Single-arm trial N: 16

Age group: adults Solid tumors Treatments enrollment: XRT, carboplatin, docetaxel, anastrozole, interferon, dacarbazine lenalidomide, vinblastine, cisplatin, IL‑2, interferon, perifosine, cisplatin, doxorubicin, ifosfamide, gemcitabine, perifosine, irinotecan, topotecan, pemetrexed, CT 2103, paclitaxel, carbo Treatment requisite: none Follow-up: 0

Telomelysin No comparison group

Adverse events, clinical response, viral pharmacokinetics analysis, viral e1A, hexon expression in treated tumors, neutralizing antibody response, serum cytokines, peripheral blood lymphocyte immunophenotyping, htert mrnA

None Telomelysin was well tolerated. Evidence of antitumor activity was suggested.

Cancer Dummer et al, 2008210 ID NR, reviewed by Swiss and Belgium federal agencies Single-arm trial N: 35

Age group: adults Advanced solid tumors and melanoma Treatments enrollment: none Treatment requisite: none Follow-up: none

TG1024 No comparison group

Serum IL-2 levels None The results show intratumoral injections of TG1024 are safe and well tolerated.

Cancer Khorana et al, 2003182 ID NR Trial (multiple groups) N: 11

Age group: adults Malignant melanoma Treatments enrollment: Patients had cancer not treatable with current therapy. Treatment requisite: none Follow-up: until death


Size of tumor, time to disease progression, achievement of stable disease, survival rate

No patients died because of therapy administration and no grade 4 toxicities were observed. Two grade 3 toxicities were observed in one patient: high fever and deep venous thrombosis (both required hospitalization).

It is possible that a different dose schedule may enhance clinical efficacy of the study drug.






Cancer Dreno et al, 2014148 NCT00394693 Single-arm trial Completed N: 13

Age group: adults B-cell lymphomas Treatments enrollment: none Treatment requisite: none Follow-up: 53


Complete response, partial response, stable disease, duration of response, dermatology life quality index, time to disease progression

SAEs: 1 event The study showed treatment with TG1042 was associated with a clinical benefit in most of the patients with relapsing CBCL, including tumor regression, a clinically meaningful duration of response, and a good treatment tolerance.

Cancer Dummer et al, 2004190 ID NR, protocol reviewed by Swiss Agency for Therapeutic Products Single-arm trial N: 9

Age group: adults Advanced primary cutaneous T-cell lymphomas, multilesional cutaneous B-cell lymphomas Treatments enrollment: topical steroids, PUVA, IFN-, acitretin, bexarotene, imiquimod, radiotherapy, methotrexate, antibiotics, rituximab Treatment requisite: none Follow-up: 32


Clinical outcome, safety, immune response at injection site, systemic immune response

None The study shows intralesional injections of TG1042 are both safe and well tolerated.






Cancer Khammari et al, 2015241 NCT00720031 Single-arm trial N: 18

Age group: adults Metastatic melanoma Treatments enrollment: Patients had to have received at least one treatment with a chemotherapy or immunotherapy. Treatment requisite: blood draw 3 to 6 to generate T-cell clone(s), treatment with deticene while T-cell clones were being produced, TG1042 (adenovirus expressing interferon-alpha) and Interleukin-2 were infused after each T-cell clone infusion Follow-up: median: 30


Tumor response (complete regression, partial response, stable disease, disease progression), objective response, disease control rate, overall survival, lesion size and number

Grade 3 adverse events: flu-like symptoms (n = 1), asthenia (n = 3), nausea/vomiting (n = 1), axillary pain (n = 1)

Translational research on predictive markers did not significantly differ between responder and nonresponder patients. However, specifically regarding injected lesions, the clinical response correlated with CD3-/CD56+ NK cells that could be activated by TG1042. Further larger studies of this combined immunotherapy are needed to confirm these findings. Intralesional TG1042 combined with antigen-selected TILs should be discussed.

Cancer Chang et al, 2012146 GenVec, 2003426 NCT00051480 Trial (multiple groups) Completed N: 24

Age group: adults Advanced resectable esophageal cancer Treatments enrollment: none Treatment requisite: chemoradiation, esophagectomy Follow-up: 60

TNFerade No comparison group

Overall survival, disease-free survival

SAEs: 3 patients (unclear)

Preoperative TNFerade, in combination with chemoradiotherapy is biologically active and safe and is associated with long survival. This regimen warrants additional studies.

Cancer Herman et al, 2013230 NCT00051467 RCT Completed N: 304

Age group: adults Locally advanced pancreatic cancer Treatments enrollment: none Treatment requisite: standard of care Follow-up: 50.5

TNFerade No treatment

Death, progression-free survival, tumor response rates, surgical downstaging rates

SAEs (grades 3-4): 116 intervention, 50 placebo

Standard of care plus TNFerade is safe but not effective for prolonging survival in patients with LAPC.






Cancer Senzer et al, 2004123 Trial (multiple groups) N: 36

Age group: adults Solid tumors Treatments enrollment: exhausted all prior treatment options Treatment requisite: external beam radiation Follow-up: 3


Tumor response, safety No serious adverse events reported

This is the first human study with TNFerade and radiation. The combined treatment was well tolerated in patients with predominantly prior treatment-refractory solid tumors.

Cancer Antonia et al, 2002125 Trial (multiple groups) BB-MF7553 N: 15

Age group: adults Renal cell carcinoma Treatments enrollment: none Treatment requisite: interleukin 2, intradermal injection of unmodified irradiated autologous tumor cells Follow-up: 10

Ad.hB7-1 No comparison group

Toxicity, survival, tumor response

No treatment-related serious adverse events reported

The B7-1 modified autologous tumor cell vaccine is safe and can be combined with systemic IL-2 with acceptable toxicity. Immunological and clinical responses were observed in some patients.

Cardiovascular disease Creager et al, 2011265 NCT00117650 RCT N: 289

Age group: adults Intermittent claudication Treatments enrollment: none Treatment requisite: none Follow-up: none

Ad2/HIF-1alpha/VP16 No treatment

Claudication onset time, ankle-brachial index, quality of life

None Gene therapy with intramuscular administration of Ad2/HIF-1 was not an effective treatment for patients with intermittent claudication.

Cardiovascular disease Rajagopalan et al, 2007260 ID NR RCT N: 28

Age group: adults Critical limb ischemia Treatments enrollment: none Treatment requisite: none Follow-up: 12

Ad2/HIF-1alpha/VP16 Placebo

Deaths and amputations None HIF-1 therapy in patients with critical limb ischemia was well tolerated, supporting further, larger, randomized efficacy trials.






Cardiovascular disease Hammond et al, 2016270 Hammond, 2015427 NCT00787059 RCT N: 56

Age group: adults Heart failure Treatments enrollment: implanted cardiac defibrillator (ICD) and at least 1 major coronary artery or graft with less than 50% proximal obstruction Treatment requisite: intracoronary nitroprusside (50 μg/min) Follow-up: 3

Ad5.hAC6 Placebo

LVEF (echocardiography, before and during dobutamine infusion), LV peak +dP/dt and peak –dP/dt before and during dobutamine infusion, exercise capacity assessed by exercise treadmill testing, symptoms, ICD events, hemodynamic values obtained at catheteriz

SAE: 18 intervention, 5 control; HF admission: 4 intervention, 4 control; death: 1 intervention, 1 control

AC6 gene transfer safely increased LV function beyond standard heart failure therapy, attainable with one-time administration. Larger trials are warranted.

Cardiovascular disease Grines et al, 2003256 Cardium Therapeutics, 2016428; Kaski and Consuegra-Sanchez, 2013429 ID NR. The study was approved by the Food and Drug Administration, Recombinant DNA Advisory Committee, appropriate institutional review boards and biosafety committees, and was conducted in accordance with the International Conference on Harmonization and Good Clinical Practice Guidelines. All patients provided written informed consent. RCT Completed N: 53

Age group: adults Stable angina Treatments enrollment: antianginal drugs Treatment requisite: none Follow-up: 12

Ad5FGF-4 Placebo

Reversible perfusion defect size, perfusion defect size


Intracoronary injection of Ad5FGF-4 showed an encouraging trend for improved myocardial perfusion; however, further studies of therapeutic angiogenesis with Ad5FGF-4 will be necessary.






Cardiovascular disease Matya et al, 2005257 ID NR RCT Completed N: 13

Age group: adults Unreconstructable critical limb ischemia Treatments enrollment: none Treatment requisite: none Follow-up: 6

Ad5FGF-4 Placebo

Rest pain, use of analgesics, leg ulcer/gangrene, ABI and TBI, DSA, MRI, Tc-Scint

SAEs: 14 total Injections of Ad5FGF-4 were generally well tolerated and considered safe. Transfection efficacy at these concentrations may have been limited or local. The small sample size did not allow any firm conclusions regarding clinical efficacy, but a trend toward more and slightly larger blood vessels was observed in the angiograms. It is concluded that intramuscular injection of Ad5FGF-4 into CLI patients seemed safe, but transfection efficacy was limited at the assessed doses. Conclusions regarding clinical efficacy are impossible to draw from this small patient cohort.

Cardiovascular disease Grines et al, 2002251 ID NR RCT N: 79

Age group: adults Stable angina pectoris Treatments enrollment: none Treatment requisite: none Follow-up: 3

Ad5-FGF4 Placebo

None None Results show evidence of favorable anti-ischemic effects with Ad5-FGF4 compared with placebo, and it appears to be safe. Angiogenic gene transfer with Ad5-FGF4 shows promise as a new therapeutic approach to the treatment of angina pectoris.






Cardiovascular disease Mulder et al, 2009249 ID NR Trial (multiple groups) Completed N: 15

Age group: adults Nonhealing diabetic foot ulcers Treatments enrollment: none Treatment requisite: none Follow-up: 6

Ad-5PDGF-B No comparison group

Ulcer wound area, ulcer closure

SAEs (events): 3 osteomyelitis, 1 septic arthritis, 1 acute angle glaucoma, 1 proteinuria, 1 hypersomnolence, 1 increased ammonia, 1 increased transaminases, 1 myocardial infarction, 1 cardiogenic shock, 2 gastrointestinal disorders

In the 12 patients who completed the study, ulcer closure was observed by month 3 in 10 patients, 7 of whom received a single application of GAM501. In conclusion, GAM501 did not appear to have any toxicity at doses that showed biological activity. GAM501 holds promise as a potentially effective treatment for nonhealing diabetic foot ulcers.

Cardiovascular disease Blume et al, 2011264 NCT00493051 RCT Completed N: 124

Age group: adults Diabetic neuropathic foot ulcers Treatments enrollment: none Treatment requisite: formulated collagen gel Follow-up: 3

Ad5PDGF-B (GAM501) Usual care

Acetate wound size, wound healing rate

None Both GAM501 and FCG appeared to be safe and well tolerated, and alternate dosing schedules hold promise to improve overall complete wound closure in adequately powered trials.

Cardiovascular disease Meng et al, 2018250 NCT01925352 Controlled trial N: 30

Age group: adults Postinfarction heart failure Treatments enrollment: none Treatment requisite: none Follow-up: 6

Ad-HGF No treatment

Left ventricular end-diastolic dimension, left ventricular ejection fraction, summed rest score of single photon emission computed tomography

None Percutaneous endocardial administration of Ad-HGF is safe and potentially efficient in improving LVEF and lowering LVDd of patients with postinfarct failure.






Cardiovascular disease Yuan et al, 2008262 ID NR (described as trial in abstract) Single-arm trial N: 18

Age group: adults Coronary heart disease Treatments enrollment: coronary artery bypass surgery Treatment requisite: none Follow-up: 1

Ad-HGF No comparison group

Changes of vital symptoms, blood and urea routine analyses, myocardial profusion

None These preliminary clinical data indicate direct intramyocardial administration of Ad-HGF was well tolerated and could improve myocardial perfusion with a dose–effect relationship, encouraging larger and randomized efficacy trials.

Cardiovascular disease Yang et al, 2009261 Yang et al, 2009430 ID NR (title states trial) Single-arm trial N: 18

Age group: adults Severe and diffused triple-vessel coronary artery disease Treatments enrollment: none Treatment requisite: none Follow-up: 14

Ad-hHGF No comparison group

Supraventricular or ventricular arrhythmias, derum HGF levels, hepatocyte growth

None, safe The study demonstrates it is feasible to safely use an adenovirus gene-transfer vector to deliver the human hepatocyte growth factor gene to individuals with clinically significant coronary artery disease by direct intracoronary injection.

Cardiovascular disease Fuchs et al, 2006259 ID NR RCT Completed N: 10

Age group: adults Refractory advanced coronary artery disease Treatments enrollment: none Treatment requisite: none Follow-up: 12

AdVEGF121 Placebo

Exercise treadmill test (ETT), Canadian Cardiovascular Society Angina Classification, Seattle Angina Questionnaire


Percutaneous, catheter-based AdVEGF121 intramyocardial injection is a practical, feasible, and potentially safe approach for intramyocardial gene transfer. A larger randomized, phase II efficacy study is warranted.






Cardiovascular disease Rajagopalan et al, 2003255 Rajagopalan et al, 2003431 ID NR RCT Completed N: 105

Age group: adults Peripheral arterial disease Treatments enrollment: stable medication regimen Treatment requisite: none Follow-up: 6.5

AdVEGF121 Placebo

Change in peak walking time, claudication onset time, postexercise ankle-brachial index intreated limb, physical component summary scale of SF-36, health survey and walking impairment questionnaire


A single unilateral intramuscular administration of AdVEGF121 was not associated with improved exercise performance or quality of life in this study. This study does not support local delivery of single-dose VEGF121 as a treatment strategy in patients with unilateral PAD.

Cardiovascular disease Rosengart et al, 2013267; Rosengart et al, 1999432; Rosengart et al, 1999433 NCT01174095 Trial (multiple groups) N: 31

Age group: adults Coronary artery disease Treatments enrollment: none Treatment requisite: none Follow-up: 132

AdVEGF121 No comparison group

Survival, angina score Incidences of malignancy and retinopathy were no greater than expected for the age-matched general population.

Adenovirus-mediated VEGF direct myocardial administration is safe, and future larger trials to assess efficacy are warranted.

Cardiovascular disease Stewart et al, 2006258 ID NR RCT Completed N: 67

Age group: adults Nonrevascularizable ischemic heart disease Treatments enrollment: 2 of the 3 long-acting nitrates, calcium-channel blockers, and beta-blockers. Treatment requisite: none Follow-up: 6.5

AdVEGF121 Usual care

Total exercise time (ETT), onset of 1 mm additional ST-segment depression while exercising


Overall there was no significant difference in adverse events between the 2 groups, despite the fact that procedure-related events were seen only in the thoracotomy group. Therefore, administration of AdVEGF121 by direct intramyocardial injections resulted in objective improvement in exercise-induced ischemia in patients with refractory ischemic heart disease.






Cardiovascular disease Hartikainen et al, 2017272; Kuopio University, 2015434 NCT01002430, EudraCT 003295-22 RCT N: 30

Age group: adults Refractory angina Treatments enrollment: severe refractory angina Treatment requisite: none Follow-up: 12

AdVEGF-DDeltaNDeltaC (AdVEGF-D) Placebo

Myocardial perfusion, angina pectoris symptoms (stress and at rest), quality of life

Death (control n = 0, treated n = 3), ACS or MI (control n = 1, treated n = 3), stroke (control n = 0, treated n = 2)

AdVEGF-DeltaNDeltaC gene therapy was safe, feasible, and well tolerated. Myocardial perfusion increased at 1 year in the treated areas with impaired MPR at baseline. Plasma Lp(a) may be a potential biomarker to identify patients that may have the greatest benefit with this therapy.

Cardiovascular disease Kastrup et al, 2011263 ID NR RCT N: 17

Age group: adults Refractory advanced coronary artery disease Treatments enrollment: none Treatment requisite: intramyocardial injection of therapy or placebo. Follow-up: 12

BIOBYPASS (AdGVVEGF121.10NH) Placebo

Improvements in exercise capacity, time to ischemic threshold, myocardial perfusion

None Direct intramyocardial injection of BIOBYBASS (AdGVVEFG121.10NH) was safe but did not improve exercise capacity, time to ischemic threshold, or myocardial perfusion compared with placebo injection in refractory myocardial ischemia patients.

Cardiovascular disease Mohler et al, 2003254 ID NR Controlled trial N: 15

Age group: adults Critical limb ischemia Treatments enrollment: none Treatment requisite: none Follow-up: 12

CI-1023; Ad(GV)VEGF121.10 Placebo

Resting ankle-brachial indexes

1 death, 1 bladder neoplasm, 1 increased swelling

CI-1023 appears to be well tolerated and safe for single-dose administration in patients with critical limb ischemia due to peripheral arterial disease.






Cardiovascular disease Makinen et al, 2002252 ID NR RCT Completed N: 54

Age group: children and adults Lower-limb ischemia Treatments enrollment: none Treatment requisite: none Follow-up: 36

VEGF-Ad, VEGF-P/L Placebo

DSA analysis of vascularity, restenosis rate, Rutherford class, ABI

SAEs: 5 intervention (2 groups), 1 placebo

For the primary endpoint, follow-up DSA revealed increased vascularity in the VEGF-treated groups distally to the gene transfer site (VEGF-Ad P = 0.03, VEGF-P/L P = 0.02) and in the VEGF-Ad group in the region of the clinically most severe ischemia (P = 0.01). As for the secondary endpoints, mean Rutherford class and ABI showed statistically significant improvements in the VEGF-Ad and VEGF-P/L groups, but similar improvements were also seen in the control patients. Catheter-mediated VEGF gene therapy is safe and well tolerated. Angiography demonstrated that VEGF gene transfer increased vascularity after PTA in both VEGF-Ad-, and VEGF-P/L-treated groups.






Cardiovascular disease Hedman et al, 2003253 Hedman et al, 2009435 ID NR, protocol approved by the Finnish Board for Gene Technology and the Finnish Agency for Medicinal Products RCT N: 103

Age group: adults Catheter-based local intracoronary vascular endothelial growth factor gene transfer Treatments enrollment: none Treatment requisite: none Follow-up: 6

VEGF-Adv, VEGF-P/L Placebo

Minimal lumen diameter and percentage diameter stenosis, myocardial perfusion, exercise tolerance, incidence of new cardiac events, emergency or elective angiography or revascularization, functional class, working ability, need for peroral nitrates

1 death, 1 cancer, 1 sarcoidosal granulomas, 1 “no flow" phenomenon and cardiac arrest during control angiography, a aspiratory pneumonia and pseudomembranotic colitis, 1 stroke, fever, increase in anti-Adv antibodies, transient decrease in the platelet count, increase in LDH, serum IL-6 level increase

Gene transfer with VEGF-Adv or VEGF-P/L during PTCA and stenting shows intracoronary gene transfer can be performed safely (no major gene transfer–related adverse effects were detected), no differences in clinical restenosis rate or minimal lumen diameter were present after the 6-month follow-up, and a significant increase was detected in myocardial perfusion in the VEGF-Adv–treated patients.

Immune deficiency Baden et al, 2016279 NCT01215149 RCT N: 218

Age group: adults Prophylactic HIV-1 vaccine Treatments enrollment: none Treatment requisite: Patients had to be willing to undergo HIV testing and accept the HIV test results, undergo risk-reduction counselling, and commit to low-risk behavior for the duration of the trial. Follow-up: 12

Ad26.ENVA.01 and Ad35-ENV Placebo

Immunogenicity of vaccines, evaluation of anti-tumor immunity induced by vaccines

No vaccine-associated serious adverse events reported

Baseline vector immunity did not markedly affect responses, and a significant immune response by both vaccines was observed in all populations.







Age group: adults HIV Treatments enrollment: none Treatment requisite: none Follow-up:12

Ad26-EnvA Placebo

Safety and tolerability, immunogenicity

Safe This Ad26 vectored vaccine was generally safe and immunogenic at all doses tested. Reactogenicity was minimal with doses of 5 × 1010 vp or less. Ad26 is a promising new vaccine vector for HIV-1.

Immune deficiency Omosa-Manyonyi et al, 2015278 NCT01264445 RCT N: 146

Age group: adults HIV Treatments enrollment: none Treatment requisite: none Follow-up: 16

Ad35-GRIN Other: 4 regimens: heterologous prime-boost with 2 doses of F4/AS01E or F4/AS01B followed by Ad35-GRIN; Ad35-GRIN followed by 2 doses of F4/AS01B; or 3 coadministrations of Ad35-GRIN and F4/AS01B

Safety and tolerability None Coadministration of an adjuvanted protein and an adenovirus vector showed an acceptable safety and reactogenicity profile and resulted in strong, multifunctional, and complementary HIV-specific immune responses.



Ad5HVR48.ENVA.01 Placebo

Safety and tolerability, Ad5 nAb responses, Ad48 nAb responses, HIV-1 Env-specific antibody responses, HIV-1 EnvA-specific cellular immune responses

None Ad5HVR48.ENVA.01 was safe, well tolerated, and immunogenic at all doses tested.

Immune deficiency Churchyard et al, 2015282 NCT01017536 RCT Completed N: 26

Age group: adults HIV Treatments enrollment: Bacillus Calmette-Guérin vaccination Treatment requisite: none Follow-up: 12

AERAS-402/AD35.TB-S Placebo

CD4+ T-cell response, CD8+ T-cell response, antibody response

SAES (events/patients): 1 lower-respiratory tract infection; 1 joint injury

AERAS-402/AD35.TB-S was well tolerated, safe, and induced predominantly polyfunctional CD4+ and CD8+ T-cell responses to the vaccine.






Immune deficiency Koblin et al, 2011274 NCT00384787 Trial (multiple groups) N: 90


rAd5 No comparison group

Vaccine safety, immunogenicity

None The higher frequency of local reactions after ID and SC administration and the lack of sufficient evidence to show there were any differences in immunogenicity by route of administration do not support changing route of administration for the rAd5 boost.

Immune deficiency Koup et al, 2010281 NCT00102089 and NCT00108654 Trial (multiple groups) Completed N: 14

Age group: adults HIV Treatments enrollment: none Treatment requisite: 4 to 6 plasmid DNA Follow-up: 6

rAd5 No comparison group

CD4+ T-cell response, CD8+ T-cell response, antibody response

None Heterologous prime-boost using vector-based gene delivery of vaccine antigens is a potent immunization strategy for inducing antibody and T-cell responses.

Immune deficiency Li et al, 2011273 Schooley, 2010436 NCT00080106 RCT Completed N: 110

Age group: adults HIV Treatments enrollment: pre-antiretroviral therapy Treatment requisite: ART if needed Follow-up: 16

rAd5 Placebo

Analytic treatment interruption, plasma viral load

None Therapeutic vaccination with an rAd5-HIV gag vaccine was associated with lower ATI week 16 PVL even after controlling for viral and host genetic factors.

Immune deficiency Stephenson et al, 2018280 NCT02366013 RCT N: 33

Age group: adults HIV-1 Treatments enrollment: none Treatment requisite: none Follow-up: 8

rcAd26.MOS1.HIV-Env Placebo

Vaccine safety, vaccine-specific immune responses, viral shedding

None The highly attenuated rcAd26.MOS1.HIV-Env vaccine was well tolerated up to 10^11 VP in healthy, HIV-1-uninfected adults, though the single dose was poorly immunogenic, suggesting the replicative capacity of the vector was too attenuated.






Immune deficiency Achenbach et al, 2015277 NCT00976404 RCT N: 28

Age group: adults HIV Treatments enrollment: none Treatment requisite: oral raltegravir 400 mg and oral maraviroc 150 mg, 300 mg, or 600 mg Follow-up: 2

rAd5 Other: antiretroviral therapy intensification plus injections of HIV DNA prime vaccine

Change in total HIV DNA in the peripheral blood, adverse events

2 increase in creatine kinase, 1 acute coronary syndrome, 1 acute coronary syndrome

Antiretroviral therapy intensification followed by DNA prime and rAd5 boost vaccine did not significantly increase HIV expression or reduce the latent HIV reservoir.

Neurodegenerative disorders Zavalishin et al, 2008297 ID NR RCT N: 10

Age group: adults Amyotrophic lateral sclerosis Treatments enrollment: none Treatment requisite: none Follow-up: 24

Ad5-VEGF Placebo

Change in neurological deficit, change in vital lung capacity, change in muscle force of 36 muscles, improvement in survival

No serious undesirable events observed

The life span of patients under conditions of hypoxia increased after treatment with the test drug, which was probably related to improved resistance of motoneurons. The presence of virus-neutralizing antibodies decreases the effectiveness of adenoviral vectors, which necessitates a differential approach to the selection of patients and continuous monitoring of gene therapy.






Ocular disorders Campochiaro et al, 2006314 ID NR Trial (multiple groups) N: 28

Age group: adults Age-related macular degeneration Treatments enrollment: none Treatment requisite: topical anesthetic injection under the conjunctiva Follow-up: 12

AdPEDF.11 No comparison group

Safety, tolerability, visual acuity

Eye pain (n = 1) These data suggest the possibility of antiangiogenic activity that may last for several months after a single intravitreous injection of doses greater than 108 PU of AdPEDF.11. This study provides evidence that adenoviral vector-mediated ocular gene transfer is a viable approach for the treatment of ocular disorders and that further studies investigating the efficacy of AdPEDF.11 in patients with neovascular AMD should be performed.

Other: normal patients Harvey et al, 1999355 BB-IND 6950 Trial (multiple groups) N: 6

Age group: adults Healthy patients Treatments enrollment: none Treatment requisite: Each patient received one intradermal administration of the vector in each of 2 sites + skin biopsy. Follow-up: 1

Ad(GV)CD.10 No comparison group

Vector persistence, skin induration, systemic anti-adenovirus immunity against Ad5

Not reported Intradermal administration of an E12 E32 Ad vector to normal patients induces mild/moderate local cellular responses, even in Ad-immunized individuals, and these observations provide a baseline to determine if human anti-Ad vector host responses can be circumvented by using other means.






Other: healthy adults Creech et al, 2013342 NCT00371189 RCT N: 72

Age group: adults Malaria (vaccine) Treatments enrollment: none Treatment requisite: none Follow-up: 1

Ad35.CS.01 Placebo

Solicited local reactions, overview of serious adverse events and laboratory adverse events, unsolicited adverse events, immunogenicity (humoral response)

While the vaccine was generally well tolerated, adverse events were more frequent in the highest-dose groups (1010 and 1011 vp/mL). More robust humoral responses were also noted at the highest doses, with 73% developing a positive ELISA response after the 3-dose series of 1011 vp/mL.

The Ad35.CS.01 vaccine was most immunogenic at the highest dosages (1010 and 1011 vp/mL).

Other: healthy adults Gurwith et al, 2013341 NCT01006798 RCT N: 166

Age group: adults Influenza Treatments enrollment: none Treatment requisite: none Follow-up: 6

Ad4-H5-Vtn Placebo

Seroconversion by haemagglutination-inhibition

None Oral Ad4 vector priming might enhance the efficacy of poorly immunogenic vaccines such as H5N1.

Other: ebola vaccine Li et al, 2017348 Zhu et al, 2015437 NCT02326194 and NCT02533791 RCT N: 120

Age group: adults Ebola Treatments enrollment: none Treatment requisite: none Follow-up: 5

Ad-5 Placebo

Ebola glycoprotein-specific ELISA antibody responses 28 days post boost and the occurrences of adverse reactions post boost

Safe The adenovirus 5-vectored ebola vaccine of 1·6 × 1011 viral particles was highly immunogenic and safe.

Other: healthy adults Zhu et al, 2017347 PACTR201509001259869 RCT N: 500


Ad-5 Placebo

Adverse reactions, serious adverse events, HIV infection rate

Safe The recombinant adenovirus type 5 vector-based ebola vaccine was safe and highly immunogenic in healthy Sierra Leonean adults, and 8·0 × 1010 viral particles was the optimal dose.






Other: partial ornithine transcarbamylase deficiency Raper et al, 2002357 Raper et al, 2003438 ID NR, protocol reviewed by NIH-RAC and FDA Single-arm trial N: 18

Age group: adults Ornithine transcarbamylase deficiency Treatments enrollment: none Treatment requisite: none Follow-up: 18

Ad-OTC No comparison group

Toxicity Myalgia and flulike symptoms, fever, anemia, thrombocytopenia, 1 case of fatal systemic inflammatory response syndrome

The low levels of gene transfer detected in this trial suggest that at the doses tested, significant metabolic correction did not occur. However, substantial subject-to-subject variation in host responses is a limitation.

Other: healthy/infectious disease vaccine De Santis et al, 2016346 NCT02289027 RCT Completed N: 120

Age group: adults Health volunteers Treatments enrollment: none Treatment requisite: none Follow-up: 6

ChAd3-EBO-Z Placebo

CD4 T-cell response, CD8 T-cell response, antibody response

SAEs (events): deployed: 2 headache, 1 fever, 3 other; nondeployed: 0

ChAd3-EBO-Z was safe and well tolerated, although mild to moderate systemic adverse events were common. A single dose was immunogenic in almost all vaccine recipients. Antibody responses were still significantly present at 6 months. There was no significant difference between doses for safety and immunogenicity outcomes. This acceptable safety profile provides a reliable basis to proceed with phase II and phase III efficacy trials in Africa.

Other: uncertain Tapia et al, 2016345 NCT02231866 and NCT02267109 RCT N: 91


ChAd3-EBO-Z Placebo

Safety, measured with occurrence of adverse events

No AEs 1×1011 pu single-dose ChAd3-EBO-Z could suffice for phase III efficacy trials of ring-vaccination containment needing short-term, high-level protection to interrupt transmission.






Other: malaria vaccine Mensah et al, 2017350 NCT02083887 RCT N: 65

Age group: children Malaria (vaccine) Treatments enrollment: none Treatment requisite: none Follow-up: 0

ChAd63 Usual care

Safety No AEs The vaccines were well tolerated in all age groups, with no vaccine-related serious AEs.

Other: health/infectious disease vaccine Sheehy et al, 2012340 Controlled trial Completed N: 44

Age group: adults Healthy volunteers Treatments enrollment: none Treatment requisite: MVA MSP1 Follow-up: 2

ChAd63 Other: infected controls

Parasite concentration in blood, malaria diagnosis

No SAE reported in text (only in figures)

The results demonstrate immune interference whereby responses against merozoite surface protein 1 are dominant over apical membrane antigen 1 and ME-TRAP. The results show induction of strong cellular immunity against MSP1 and AMA1 is safe but does not impact on parasite growth rates in the blood. The data call into question the utility of T cell–inducing blood-stage malaria vaccines and suggest the focus should remain on high-titer antibody induction against susceptible antigen targets.

Other: malaria vaccine Venkatraman et al, 2017349 NCT01669512 Trial (multiple groups) N: 23

Age group: adults Malaria Treatments enrollment: none Treatment requisite: none Follow-up: 4

ChAd63 No comparison group

Adverse events, Immunogenicity

None reported The results demonstrate Matrix-M can be safely used in combination with ChAd63-MVA ME-TRAP heterologous prime-boost immunization without any reduction in cellular or humoral immunogenicity.






Other: none Osman et al, 2017354 ISRCTN 07766359 Trial (multiple groups) Completed N: 20

Age group: adults Healthy volunteers Treatments enrollment: none Treatment requisite: none Follow-up: 3

ChAd63-KH No comparison group

None None ChAd63-KH was safe, and whole-blood transcriptomic profiling indicated ChAd63-KH induced innate immune responses characterized by an interferon signature and the presence of activated dendritic cells. Broad and quantitatively robust CD8 + T-cell responses were induced by vaccination in 100% of vaccinated patients.

Other: influenza Antrobus et al, 2014344 Coughlan et al, 2012439 Trial (multiple groups) N: 15

Age group: adults Influenza Treatments enrollment: none Treatment requisite: none Follow-up: 4

ChAdOx1 No comparison group

Safety No treatment-related serious adverse events reported

ChAdOx1 NP + M1 appears to be safe and immunogenic and may be a promising vaccine vector that could be used to deliver vaccine antigens where strong cellular immune responses are required for protection.

Other: loosened hip prosthesis de Poorter et al, 2008358 de Poorter et al, 2008440 ID NR, protocol approved by the Central Committee on Research Involving Human Subjects (CCMO and Ministry of Housing, Spatial Planning, and the Environment (VROM, The Netherlands) Single-arm trial N: 12

Age group: adults Loosened hip prosthesis Treatments enrollment: arthrogram of the hip with aspiration of joint fluid to exclude bacterial infection Treatment requisite: hip synovial fluid aspiration, joint rinsed to remove neutralizing antibody Follow-up: 6

CTL 102 No comparison group

Safety, tolerability, walking distance, patient satisfaction

Two patients in the high-prodrug dose group had grade 2 rises in AST and ALT levels and 2 had diarrhea.

These data show this gene therapy approach targeted at the interface membrane around a loosened hip prosthesis is a feasible treatment option for elderly patients for whom surgical intervention is not appropriate.






Other: venous leg ulcer disease Margolis et al, 2009359 Margolis et al, 2004441 ID NR, protocol reviewed by FDA Single-arm trial N: 15

Age group: adults Venous leg ulcer disease Treatments enrollment: none Treatment requisite: none Follow-up: 6

H5.020CMV.PDGF-beta No comparison group

Wound response, routine blood testing, H5 adenovirus detection, PDGF antibody, detection of adenoviral DNA within wound bed, assessment of wound neovascularization, assessment of tissue inflammation, assessment of progenitor cell recruitment

The injections were well tolerated and patients were able to use a compression bandage during the 28 days of the initial study period.

The study demonstrated that H5.020CMV.PDGF-B was able to transfect cells in the wound.

Other: healthy/infectious disease vaccine Gray et al, 2014343 Gray et al, 2011442 RCT Completed N: 800


MRKAd5 Placebo

HIV infection None The increased HR of HIV-1 acquisition, irrespective of number of doses received, warrants further investigation to understand the biological mechanism. Further use of the Ad5 vector for HIV vaccines is not warranted.

Other: infectious disease Chuang et al, 2013352 NCT00870987 Controlled trial Completed N: 26

Age group: adults Malaria Treatments enrollment: none Treatment requisite: none Follow-up: 1

NMRC-M3V-D/AdPfCA (DNA plasmids + Ad vector) Other: infected with malaria

Development of parasitemia, antibody response

SAEs (events/patients): 1 pulmonary embolism

The DNA/Ad regimen provided the highest sterile immunity achieved against malaria following immunization with a gene-based subunit vaccine (27%). Protection was associated with cell-mediated immunity to AMA1, with CSP probably contributing. Substituting a low seroprevalence vector for Ad5 and supplementing CSP/AMA1 with additional antigens may improve protection.






Other: adults Ledgerwood et al, 2010339 NCT00374309 RCT N: 31


rAd5 Placebo

Vaccine safety, ebola GP-specific antibody responses, ebola GP-specific T-cell responses, adenovirus 5-specific antibody and T-cell responses

None The vaccine was well tolerated by patients in both dose groups regardless of preexisting Ad5 antibody status.

Other: healthy volunteers Walsh et al, 2016353 NCT01095224 Trial (multiple groups) Completed N: 180


VRC-HIVADV038-00-VP (rAd5-EnvA), VRC-HIVADV052-00-VP (rAd5-EnvB), and VRC-HIVADV027-00-VP (rAd35-EnvA) No comparison group

None SAEs (events/patients): 1 severe neutropenia, 1 upper UTI; among the AEs, the vast majority (93.7%) were judged to be not related to the study products; most AEs judged to be related to vaccination were local injection site reactions; 2 SAEs occurred during the study

Nonserious AEs were reported by patients during the study duration and coded for their relationship to the study product (related or not related).

Other: norovirus Kim et al, 2018351 NCT02868073 RCT N: 66

Age group: adults Norovirus Treatments enrollment: none Treatment requisite: none Follow-up: 12

VXA-G1.1-NN Placebo

Antibody responses to norovirus VP1, memory and antibody-secreting cell responses, activation properties of B cells

No grade 3 or 4 solicited adverse events

This vaccine was well tolerated and generated substantial immune responses, and these results represent a major step forward for development of a safe and novel norovirus vaccine.

Respiratory conditions Bellon et al, 1997327 Trial (multiple groups) N: 6

Age group: adults Cystic fibrosis Treatments enrollment: Confirmation of adenoviral Ela-like DNA sequences were in nasal or bronchial airway. Treatment requisite: none Follow-up: 15

Ad CFTR No comparison group

Toxicity, lung response, hematological, biochemical, inflammatory, immunological, virological parameters, safety

No treatment-related adverse events reported

No significant changes in immunological and inflammatory parameters were observed.






Respiratory conditions Harvey et al, 1999331 ID NR Trial (multiple groups) N: 14

Age group: children and adults Cystic fibrosis Treatments enrollment: none Treatment requisite: baseline biomarker assessment, biomarkers collected at various time points Follow-up: 8

Ad(GV)CFTR.10 No comparison group

Not discussed No significant adverse effects clearly attributable to therapy

This impressive level of expression is linked to the challenging fact that expression is limited in time. Although this can be initially overcome by repetitive administration, unknown mechanisms eventually limit this strategy, and further repetitive administration does not lead to repetitive expression.

Respiratory conditions Joseph et al, 2001333 Perricone et al, 2001443 ID NR Trial (multiple groups) N: 36

Age group: children and adults Cystic fibrosis Treatments enrollment: none Treatment requisite: bronchoscopic delivery (n = 20) or aerosol delivery (n = 16) of gene therapy Follow-up: 12

Ad2/CFTR No comparison group

Pulmonary function testing, reduction in bronchiectasis on CT scan (48 hours post-treatment compared with baseline)

No serious adverse reactions

Vector administration was tolerated but transfer of cystic fibrosis transmembrane conductance regulator (CFTR) cDNA was inefficient and transgene expression was transient for the doses and method of administration, as evidenced by no consistent change in pulmonary function.






Respiratory conditions Zabner et al, 1996330 Welsh et al, 1995444 ID NR Trial (multiple groups) N: 6

Age group: adults Cystic fibrosis Treatments enrollment: none Treatment requisite: vector applied to nasal epithelium with a modified Foley catheter placed beneath the inferior turbinate; measurements (with associated perfusions) were done with a rubber catheter telescopically introduced into the nostril Follow-up: 1

Ad2/CFTR-2 No comparison group

Measurement of serum chemistries and blood counts, pulmonary function tests, sputum cultures

No adverse events observed that could be attributed to vector

The vector partially corrected the defect in airway epithelial Cl- transport in some patients, with variability observed between patients and less correction with subsequent administration. Future work must focus on vectors with increased efficiency and with the ability to evade host defenses.

Respiratory conditions Knowles et al, 1995329 ID NR, approved by NIH-RAC and FDA Single-arm trial N: 12

Age group: adults Cystic fibrosis Treatments enrollment: none Treatment requisite: none Follow-up: 1

Ad5-CB-CFTR No comparison group

None Toxic effects (n = 2) In patients with cystic fibrosis, adenoviral vector–mediated transfer of the CFTR gene did not correct functional defects in nasal epithelium, and local inflammatory responses limited the dose of adenovirus that could be administered to overcome the inefficiency of gene transfer.






Respiratory conditions Crystal et al, 1994328 Hay et al, 1995445 ID NR Single-arm trial N: 4

Age group: adults Cystic fibrosis Treatments enrollment: none Treatment requisite: All patients underwent baseline (1 week), vehicle (1 week), and treatment. patients were isolated for 2 days prior to treatment, and vehicle/treatment was administered to the nasal epithelium by syringe and catheter on day 1 and on days 2 to 3, vehicle/treatment was administered by bronchoscope to the bronchial epithelium Follow-up: 12

AdCFTR No comparison group

Electric potential difference between nasal epithelium surface and subcutaneous tissues

No adverse effects were observed with AdCFTR administration to the nasal epithelium. One patient needed treatment after AdCFTR administration to the bronchial epithelium (2-4 weeks for complete recovery).

An adenovirus vector to transfer and express the CFTR cDNA in the respiratory epithelium of individuals with cystic fibrosis is feasible, and correction of the cystic fibrosis phenotype in the airway epithelium may be achieved with this strategy.

Respiratory conditions Harvey et al, 2001326 Trial (multiple groups) N: 6

Age group: adults Cystic fibrosis Treatments enrollment: fiber-optic bronchoscopy, atropin, meperidine, midazolam, lidocaine Treatment requisite: none Follow-up: 2

AdGVCD.10 No comparison group

Systemic and mucosal humoral and cellular immune responses, safety

No serious adverse events reported

These results suggest that, while adaptive anti-Ad immune responses likely play some role in the disappearance of the vector DNA following vector administration to the human lung, other mechanisms may also be involved in the response of humans to Ad gene transfer vectors.

Abbreviations: AAV, adeno-associated virus therapy; AEs, adverse events; ID, trial identification number; mL, milliliter; NR, not reported; RCT, randomized controlled trial; SAEs, serious adverse events.


Appendix Table A2. Published AAV Trials Indication Citations Design N




Blood disorders Mingozzi et al, 2009118 ID NR, protcol reviewed by NIH Single-arm trial N: 8

Age group: adults Lipoprotein lipase deficiency Treatments enrollment: none Treatment requisite: none Follow-up: 31

AAV-1-LPL(S447X) No comparison group

Transient elevation of CPK following vector administration, activation of capsid T-cell responses, MHC class I and II epitopes

None Four of 8 patients had detectable T-cell responses to capsid with dose-dependent kinetics of appearance. Patients with detectable T-cell responses to capsid also had higher anti-AAV-1 IgG3 antibody titer. No subject developed B- or T-cell responses to the LPL transgene product. These findings suggest that T-cell responses directed to the AAV-1 capsid are dose-dependent.

Blood disorders Jiang et al, 2006117 ID NR protcol reviewed by NIH Single-arm trial N: 8

Age group: adults Severe hemophilia B Treatments enrollment: none Treatment requisite: none Follow-up: 10

AAV2-FIX No comparison group

FIX expression Not reported These results demonstrate, for the first time, multiyear FIX expression by AAV2 vector in humans and suggest improved muscle delivery provides effective treatment for protein deficiencies or muscle-specific diseases.






Blood disorders Rangarajan et al, 2017121 BioMarin, 2022446 NCT02576795 Trial (multiple groups) N: 9

Age group: adults Hemophilia A Treatments enrollment: Eight patients had been receiving regular factor VIII prophylaxis before the study. One patient used on-demand factor VIII for bleeding episodes. Treatment requisite: glucocorticoids if the alanine aminotransferase level increased from the individual participant’s baseline level Follow-up: 12

AAV5-hFVIII-SQ No comparison group

Factor VIII use, number of bleeding episodes

Progression of chronic arthropathy in 1 patient

AAV5-hFVIII-SQ was associated with persistent normalization of factor VIII activity level over 1 year in 6 of 7 patients who received a high dose, with stabilization of hemostasis and a profound reduction in factor VIII use in all 7 patients.

Blood disorders Miesbach et al, 2018116 UniQure Biopharma, 2015447 NCT02396342; EudraCT 2013-005579-42 Single-arm trial N: 10

Age group: adults Hemophilia B Treatments enrollment: none Treatment requisite: none Follow-up: 12

AMT-060 No comparison group

Treatment-related adverse events, NAbs to AAV5, total immunoglobulin M (IgM) and IgG antibodies against AAV5, AAV5 capsid-specific T cells, antibodies to FIX (including inhibitors), shedding of AMT-060 vector, inflammatory markers

None A single infusion of AMT-060 had a positive safety profile and resulted in stable and clinically important increases in FIX activity, a marked reduction in spontaneous bleeds and FIX concentrate use, without detectable cellular immune responses against capsids.






Blood disorders Ultragenyx Pharmaceutical Inc, 2017115 NCT02618915 Trial (multiple groups) 11/2018 N: 6

Age group: adults Hemophilia B Treatments enrollment: none Treatment requisite: none Follow-up: 12

DTX101; AAVrh10FIX No comparison group

EuroQoL-5D-5 level questionnaire, haemophilia-specific quality of life questionnaire

SAEs: 1 patient (musculoskeletal and connective tissue disorders)

None

Blood disorders D’Avola et al, 2016120 Digna Biotech, 2014448 NCT02076763, NCT02082860 (experimental phase) Trial (multiple groups) N: 8

Age group: adults Acute intermittent porphyria Treatments enrollment: none Treatment requisite: none Follow-up: 12

rAAV2/5-PBGD No comparison group

Immune responses, viral shedding, aminolevulinic acid and porphobilinogen levels, requirement of AIP-specific therapies and hospitalizations, depression, anxiety, quality of life, liver transduction

Four severe adverse events observed in 2 patients: pilonidal cyst surgery, hospital admission for insulin-pump infusion placement, myocarditis, upper abdominal pain

RAAV2/5-PBGD administration is safe, but AIP metabolic correction was not achieved at the doses tested in the study. However, the treatment had a positive impact in clinical outcomes in most patients.

Blood disorders Nathwani et al, 2014119 Nathwani et al, 2011449 NCT00979238 Trial (multiple groups) N: 10

Age group: adults Severe hemophilia B Treatments enrollment: none Treatment requisite: none Follow-up: median = 38

scAAV2/8-LP1-hFIXco No comparison group

Increase in steady-state transgenic factor IX activity, reduction or elimination of use of factor IX concentrate, reduction in the number of bleeding episodes

Unlikely related: staphylococcus septic arthritis infection (grade 4, n = 1); supraventricular tachycardia (grade 4, n = 1); related to treatment: increase in alanine aminotransferase (grade 3, n = 1)

The infusion of a single dose of AAV8 vector resulted in long-term therapeutic factor IX expression associated with clinical improvement.






Blood disorders George et al, 201712 Pfizer, 2019450 NCT02484092 Single-arm trial N: 10

Age group: adults Hemophilia B Treatments enrollment: Patients were required to have ≥50 prior exposure days to any factor IX (FIX) protein products in their lifetime. Treatment requisite: Patients received a 100% correction dose of their FIX product immediately before transfusion of gene therapy. Follow-up: 12 (invited to enroll in long-term follow-up protocol after 12 months)

SPK-9001 No comparison group

Change in annualized bleeding rate, factor IX concentrate consumption, number of infusions

No serious adverse events observed

The study found sustained therapeutic expression of factor IX coagulant activity after gene transfer in 10 patients with hemophilia who received the same vector dose. Transgene derived factor IX coagulant activity enabled the termination of baseline prophylaxis and the near elimination of bleeding and factor use.

Cancer Di, 2012147 ID NR Single-arm trial Completed N: 27

Age group: adults Cancer Treatments enrollment: none Treatment requisite: none Follow-up: 9

rAAV-DC No comparison group

Complete remission, partial remission, minor remission, stable disease, progressive disease, progression-free survival

None These preliminary data suggest that the rAAV-DC immunotherapy is well tolerated and showed no severe adverse reactions in cancer patients.






Cancer Mundt et al, 2004122 Trial (multiple groups) N: 14

Age group: adults Soft tissue sarcoma Treatments enrollment: none Treatment requisite: external beam radiotherapy Follow-up: 2


Tumor response, safety Grade 4 wound infection and gangrenous necrosis (n = 2)

TNFerade and radiation therapy were well tolerated in the treatment of patients with soft-tissue sarcoma of the extremity. The number of objective responses observed warrants additional studies of this approach in a larger controlled prospective trial.

Cardiovascular disease Hulot et al, 2017271 None NCT01966887 RCT N: 9

Age group: adults Systolic heart failure Treatments enrollment: Patients had undergone visually complete resection of papillary lesions. Patients could not have received intravesical therapy within 3 months before beginning study treatment, with the exception of cytotoxic agents when administered as a single instillat Treatment requisite: none Follow-up: 12

AAV1/SERCA2a Placebo

LV end-systolic volumes, LV end-diastolic volume, ejection fraction, echocardiography, peak VO2 max, NT-proBNP

No safety issues noted At 6 months, LVESV was increased in both groups compared with baseline: median (interquartile range) in AAV1/SERCA2a vs placebo: 13 (13;14) mL vs 3.5 (−36;36) mL, P = 0.74, with a mean difference between groups of 11.4 mL in favor of placebo.






Cardiovascular disease Greenberg et al, 2016269 Greenberg et al, 2014451 NCT01643330 RCT Completed N: 250

Age group: adults Cardiac disease Treatments enrollment: receiving optimum tolerated stable medical treatment for at least 30 days Treatment requisite: none Follow-up: 12


Time to recurrent events (hospital admission because of heart failure or ambulatory treatment for worsening heart failure), time to first terminal event (all-cause death, heart transplantation, implantation of a durable mechanical circulatory support devi)

All-cause hospital admission: placebo: 240; intervention: 172 (100); heart failure-related hospital admission: placebo: 121; intervention: 99; ambulatory treatment for worsening heart failure: placebo: 7; intervention: 8; nonfatal myocardial infarctions: placebo: 5; intervention: 3; Non-fatal strokes: Placebo: 3; Intervention: 5; Heart transplantation Placebo: 4; Intervention: 7; Durable MCSD implant; Placebo: 8; Intervention: 7; Deaths: Placebo: 20; Intervention: 25

Despite promising results from previous studies, AAV1/SERCA2a at the dose tested did not improve the clinical course of patients with heart failure and reduced ejection fraction. Although the study did not find evidence of improved outcomes at the dose of AAV1/SERCA2a studied, the findings should stimulate further research.

Cardiovascular disease Zsebo et al, 2014268 Jessup et al, 2011452; Jaski et al, 2009453; Hjjar et al, 2008454; Celladon, 2010455; Celladon, 2015456 NCT00454818 RCT N: 39

Age group: adults Advanced heart failure Treatments enrollment: none Treatment requisite: none Follow-up: 24


Mortality, hospitalization, symptomatic efficacy

None After a single intracoronary infusion of AAV1/SERCA2a in patients with advanced heart failure, positive signals of cardiovascular events persist for years.






Cardiovascular disease Gaudet et al, 2013266 Stroes et al, 2008457 NCT01109498, CT-AMT-011–01 Trial (multiple groups) N: 14

Age group: adults Lipoprotein lipase deficiency Treatments enrollment: none Treatment requisite: controlled low-fat diet as part of preobservational study (low-fat diet continued during study) Follow-up: 24

Alipogene tiparvovec (AAV1-LPLS447X) No comparison group

Reduction in fasting median plasma triglyceride

High fever (39.9 ºC) postinjection (n = 1); long-term follow-up had 6 serious adverse events, including a patient who had a cardiac arrest leading to death but none of the serious AEs were related to alipogene tiparvovec administration

This is the first demonstration of a single gene therapy intervention leading to persistent transgene expression and sustained clinical benefit in a systemic metabolic disorder.

Immune deficiency Vardas et al, 2010283 Mehendale et al, 2010458; International AIDS Vaccine Initiative, 2007459 NCT00482027 (also NCT00888446) RCT N: 91

Age group: adults HIV-1 Treatments enrollment: none Treatment requisite: contraception (4 months), HIV testing, counseling (pre-HIV and post-HIV test, HIV risk reduction) Follow-up: 18

tgAAC09 Placebo

Change in immunogenicity

5 serious adverse events, all considered unrelated to the therapy (1 in the placebo group): malaria (n = 1), preeclampsia (n = 2), inguinal hernia (n = 1), anemia due to a bleeding ulcer (n = 1), death due to viral encephalitis (n = 1), occurred in the low dose group)

Two doses of tgAAC09 were well tolerated at the dosage levels given. Fewer than half the recipients of the highest vaccine dosage, 3 1012 DRP, had T-cell responses to HIV.






Inflammatory disorders Carpentier et al, 2012287 Ferreira et al, 2014460 NCT00891306 Single-arm trial N: 5

Age group: adults Lipoprotein lipase deficiency (LPLD) Treatments enrollment: none Treatment requisite: none Follow-up: 3

AAV1-LPL(S447X)) No comparison group

Effect on fasting plasma metabolites, hormones, and lipids; postprandial glucose, insulin, and C-peptide and total plasma and chylomicron TG levels; postprandial glucose, insulin, and C-peptide and total plasma and chylomicron TG levels; postprandial plasma NEFA and glycerol levels and appearance rates

None Intramuscular administration of alipogene tiparvovec resulted in a significant improvement of postprandial chylomicron metabolism in LPLD patients, without inducing large postprandial NEFA spillover.

Inflammatory disorders Mease et al, 2009285 Targeted Genetics, 2005461 NCT00617032 RCT N: 15

Age group: adults Inflammatory arthritis Treatments enrollment: Patients with rheumatoid arthritis had to have an adequate trial of at least 1 DMARD prior to screening and couldn't be taking a TNF-α antagonist. Treatment requisite: none Follow-up: 6

rAAV2-TNFR:Fc Placebo

Improvement in tender joint count (68 joints), improvement in swollen joint count (66 joints), improvement in patient’s self assessment of pain, improvement in patient and physician global assessment of disease activity, improvement in patient’s assessment

4 SAEs requiring hospitalization in the same participant: labyrinthitis, myocardial infarction, and 2 episodes of congestive heart failure; thought to be unrelated to treatment

It is feasible to proceed with larger trials to further test the safety and efficacy of local TNFR:Fc gene transfer as a therapeutic modality for patients with inflammatory arthritis.






Inflammatory disorders Mease et al, 2010286 ID NR RCT N: 127

Age group: adults Inflammatory arthritis with peripheral joint involvement Treatments enrollment: rheumatoid arthritis: failure or inadequate response to at least 1 disease-modifying antirheumatic drug Treatment requisite: none Follow-up: Unclear—likely at least 7 months but no median value is given

rAAV2-TNFR:Fc Placebo

Decrease in target joint swelling, decrease in target joint tenderness, improvement in target joint global visual analog scale, improvement in joint function visual analog scale, improvement in target joint pain

Ten patients in the gene therapy experienced 12 serious adverse events. Unrelated (n = 1 for each): degenerative joint disease requiring L knee replacement, infected incision after repair of traumatic ankle fracture, syncope from coronary artery disease. Unlikely related (n = 1 for each): abdominal pain from constipation, cellulitis and ulcer leg calf, acute pyelonephritis, myocardial infarction, massive pulmonary emboli (fatal), pneumonia, disseminated histoplasmosis + retroperitoneal hemorrhage (fatal). Probably related (n = 1 for each): septic arthritis of injected joint.

Patient-reported outcome measures of clinical response showed greater improvement in treated patients than in placebo patients.






Inflammatory disorders Targeted Genetics Corporation, 2008284 Frank et al, 200960 Heald et al, 2010462 NCT00126724 RCT 10/2008 N: 120

Age group: adults Inflammatory arthritis Treatments enrollment: none Treatment requisite: none Follow-up: 4

tgAAC94 Placebo, usual care

Serious adverse events, severe or very severe adverse events, study drug–related adverse events

1 reported death The case study reinforces the importance of considering infectious complications.

Muscular conditions Herson et al, 2012289 Genthon, 2010463 NCT01344798 Single-arm trial N: 9

Age group: children and adults Limb girdle muscular dystrophy type 2C Treatments enrollment: none Treatment requisite: none Follow-up: 6

AAV1.des.h(gamma) SGC No comparison group

Tolerability of AAV1.des.h

None The protein expression can be induced in patients with limb girdle muscular dystrophy type 2C by adeno-associated virus serotype 1 gene transfer with no serious adverse effects.

Muscular conditions Smith et al, 2017290 Smith et al, 2013362 Byrne et al, 2014464 Corti et al, 2017465 NCT00976352 Trial (multiple groups) N: 9

Age group: children Infantile-onset Pompe disease Treatments enrollment: had chronic respiratory insufficiency despite long-term use of enzyme-replacement therapy Treatment requisite: enzyme-replacement therapy (ERT) infusions every 1 to 2 weeks for >1 year and remained on ERT throughout study Follow-up: 12

AAV1-CMV-GAA No comparison group

Maximal inspiratory pressure, respiratory responses to inspiratory threshold loads (load compensation), physical evidence of diaphragm activity (descent on MRI, EMG activity)

1 slight increase in antiacid alpha-glucosidase, 1 right lung contusion with apical pneumothorax (resolved), 1 pleural effusion (determined to be unrelated)

Combined AAV1-CMV-GAA and exercise training conferred benefits to dynamic motor function of the diaphragm. Children with a higher baseline neuromuscular function may have greater potential for functional gains.






Muscular conditions Bowles et al, 2012288 Nationwide Children's Hospital, 2009466 NCT00428935 RCT N: 6

Age group: children Duchenne muscular dystrophy Treatments enrollment: none Treatment requisite: methylprednisolone Follow-up: 24

AAV2.5 Placebo

Muscle transduction Save and well tolerated This trial established that the rationally designed AAV2.5 vector was safe and well tolerated.

Neurodegenerative disorders Mendell et al, 2015306 Nationwide Children’s Hospital, 2017467 NCT01519349 Trial (multiple groups) N: 6

Age group: adults Becker muscular dystrophy Treatments enrollment: none Treatment requisite: treatment with prednisone for 1 month pre (and 1 month post) viral gene therapy injection Follow-up: 12

AAV1.CMV.FS344 No comparison group

Walk distance improvement (6-minute walk test), improvement in muscle strength

No significant adverse events observed in either arm

The results are encouraging for treatment of dystrophin-deficient muscle diseases.

Neurodegenerative disorders Worgall et al, 2008296 ID NR, protocol reviewed by NIH-RAC Single-arm trial N: 10

Age group: children Late infantile neuronal ceroid lipofuscinosis Treatments enrollment: none Treatment requisite: none Follow-up: none

AAV2CUhCLN2 No comparison group

Safety of administration of AAV2CUhCLN2, anti-AAV antibodies, disease progression assessed by CNS imaging, safety

None The data support the hypothesis that AAV-mediated CNS gene transfer can slow the rate of progression of the CNS manifestations of the disease and support the concept that additional studies using AAV-mediated CNS gene transfer to treat the CNS manifestations of LINCL are warranted.






Neurodegenerative disorders Souweidane et al, 2010300 Crystal et al, 2004468 ID NR, protocol reviewed by NIH-RAC Single-arm trial N: 10

Age group: children Late infantile neuronal ceroid lipofuscinosis disease Treatments enrollment: none Treatment requisite: none Follow-up: 1

AAV2(CU)hCLN2 No comparison group

Target site infusion None The neurosurgical considerations and results of this study are presented to offer guidance and a basis for the design of future gene therapy or other clinical trials in children that utilize direct therapeutic delivery.

Neurodegenerative disorders LeWitt et al, 2011302 NCT00643890 RCT Completed N: 45

Age group: adults Advanced Parkinson’s disease Treatments enrollment: levodopa Treatment requisite: none Follow-up: 6

AAV2-GAD Placebo

UPDRS motor ratings, clinical global impression of severity, consistent medication effects, on–off fluctuations, freezing gait

SAE: 1 intervention; 0 placebo

The efficacy and safety of bilateral infusion of AAV2-GAD in the subthalamic nucleus support its further development for Parkinson’s disease and show the promise for gene therapy for neurological disorders.

Neurodegenerative disorders Hwu et al, 2012304 ID NR Single-arm trial N: 4

Age group: children Aromatic L-amino acid decarboxylase (AADC) deficiency Treatments enrollment: none Treatment requisite: stereotactic surgical delivery of gene therapy and hospitalization for 1 week after therapy delivery Follow-up: max 24+, but still ongoing

AAV2-hAADC No comparison group

Improvement in weight, improvement in motor functions, improvement in cognitive functions, improvement in oculogyric crises symptoms, improvement in symptoms (ptosis, dyskinesia, head control, sitting, standing)

Orofacial dyskinesia (n = 2)

Gene therapy targeting primary AADC deficiency is well tolerated and leads to improved motor function.






Neurodegenerative disorders Mittermeyer et al, 2012303 ID NR Single-arm trial N: 10

Age group: adults Parkinson's disease Treatments enrollment: none Treatment requisite: none Follow-up: 48

AAV2-hAADC No comparison group

FMT uptake, clinical safety, efficacy

None This study showed AAV2-hAADC treatment was safe and that AADC gene expression was maintained at least 4 years after administration of therapy.

Neurodegenerative disorders Marks et al, 2010301 Ceregene, 2008469 NCT00400634 RCT Completed N: 58

Age group: adults Parkinson’s disease Treatments enrollment: levodopa Treatment requisite: none Follow-up: 18

AAV2-neurturin Placebo

UPDRS part 3 score in the off state, UPDRS score in the off state, UPDRS score in the on state, home diary assessment of motor state, timed walking test, Purdue pegboard test—most-affected hand, Purdue pegboard test—least-affected hand, Dyskinesia rating

SAEs (patients): 13 intervention, 4 placebo

Intraputaminal AAV2-neurturin is not superior to sham surgery when assessed using the UPDRS motor score at 12 months. However, the possibility of a benefit with additional targeting of the substantia nigra and longer-term follow-up should be investigated in further studies.

Neurodegenerative disorders Olanow et al, 2015307 Bartus et al, 2013470; Therapeutics Sangamo Therapeutics, 2018471; Marks et al, 2016472 NCT00985517 RCT Completed N: 51

Age group: adults Parkinson disease Treatments enrollment: stable doses of antiparkinsonian drugs for at least 6 weeks Treatment requisite: none Follow-up: 15

AAV2-neurturin Placebo

UPDRS motor component, total UPDRS, subject-completed home diary assessment of motor state, Clinical Global Impression, Patient Global Impression, Unified Dyskinesia Rating Scale, nonmotor symptom questionnaire, and Parkinson’s disease

SAEs: 5 patients intervention; 8 patients placebo; 2 patients had cerebral hemorrhages with transient symptoms. No clinically meaningful adverse events were attributed to AAV2-neurturin.

There was no significant difference between groups in the primary endpoint and in most secondary endpoints.






Neurodegenerative disorders Rafii et al, 2014305 Ceregene, 2010473 NCT00087789 Trial (multiple groups) N: 10

Age group: adults Alzheimer’s disease Treatments enrollment: none Treatment requisite: stereotactic neurosurgical administration of gene therapy under general anesthesia Follow-up: 24, invited to join long-term follow-up study after

AAV2-NGF No comparison group

Cognitive function (Alzheimer’s Disease Assessment Scale–Cognitive, Alzheimer’s Disease Cooperative Study Clinical Global Impression of Change , digit span backward, judgment of line orientation, category fluency), stabilization or improvement in glucose metabolism (PET scans) while taking the Snodgrass Picture Naming Activation Task

All adverse events were thought to be unelated or unlikely to be related to the study drug. Serious adverse events: abdominal pain (n = 1), cholecystitis (n = 1), pneumonia (n = 1), pelvic fracture (n = 1), failure to thrive resulting in death (n = 1)

This trial provides important evidence that bilateral stereotactic administration of AAV2-NGF is feasible, well tolerated, and able to produce long-term, biologically active NGF expression.

Neurodegenerative disorders Rafii et al, 2018293 Sangamo and Alzheimer’s Disease Cooperative, 2019474 NCT00876863 RCT Completed N: 49

Age group: adults Alzheimer’s disease Treatments enrollment: cholinesterase inhibitors, memantine Treatment requisite: none Follow-up: 24

AAV2-NGF Placebo

ADAS-Cog 11, clinical dementia rating—sum of boxes, Modified Clinical Global Impression of Change, MMSE, neuropsychiatric inventory, Alzheimer's disease cooperative study—activities of daily living


This multicenter randomized clinical trial demonstrated the feasibility of sham surgery—controlled stereotactic gene delivery studies in patients with AD. AAV2-NGF delivery was well-tolerated but did not affect clinical outcomes or selected AD biomarkers. Pathological confirmation of accurate gene targeting is needed.






Neurodegenerative disorders Kaplitt et al, 2007294 Neurologix Inc, 2008475 NCT00195143 Single-arm trial N: 12

Age group: adults Parkinson's disease Treatments enrollment: none Treatment requisite: surgery Follow-up: 12

AAV-GAD No comparison group

Clinical improvement in motor ratings

None AAV-GAD gene therapy of the subthalamic nucleus is safe and well tolerated by patients with advanced Parkinson’s disease, suggesting in vivo gene therapy in the adult brain might be safe for various neurodegenerative diseases.

Neurodegenerative disorders Christine et al, 2009298 Genzyme, 2013476 Valles et al, 2010477 NCT00229736 Single-arm trial N: 10

Age group: adults Parkinson disease Treatments enrollment: none Treatment requisite: none Follow-up: none

AAV-hAADC No comparison group

Unified Parkinson’s disease rating scale, imaging results

No direct adverse events were noted, but 2 patients sustained vascular complications distant from the infusion site.

This study provides class IV evidence that bilateral intrastriatal infusion of adeno-associated viral type 2 vector containing the human AADC gene improves mean scores on the Unified Parkinson’s disease rating scale by approximately 30% in the on and off states, but the surgical procedure may be associated with an increased risk of intracranial hemorrhage and self-limited headache






Neurodegenerative disorders Muramatsu et al, 2010299 ID NR Single-arm trial Completed N: 6

Age group: adults Parkinson's disease Treatments enrollment: at least 5 years of levodopa therapy Treatment requisite: none Follow-up: 12

AAV-hAADC-2 No comparison group

UPDRS, motor state diaries, MMSE, short form of the GDS, laboratory tests

None The findings provide class IV evidence regarding the safety and efficacy of AADC gene therapy and warrant further evaluation in a randomized controlled, phase II setting.

Neurodegenerative disorders Mendell et al, 201711 AveXis, 2017478 NCT02122952 Trial (multiple groups) N: 15

Age group: children Spinal muscular atrophy type 1 Treatments enrollment: Patients had genetically confirmed diagnosis of SMA1. Patients with the c.859G→C disease modifier in exon 7 of SMN2 were excluded. Treatment requisite: prednisolone Follow-up: 30

AVXS-101 No comparison group

Time until death or the need for permanent ventilatory assistance, Children’s Hospital of Philadelphia infant test of neuromuscular disorders

Patient 1 in cohort 1 had elevations in serum aminotransferase levels (31 times the upper limit of the reference range for alanine aminotransferase [ALT]). One patient in cohort 2 required additional prednisolone to attenuate elevated serum ALT and AST level.

In patients with SMA1, a single intravenous infusion of adeno-associated viral vector containing DNA coding for SMN resulted in longer survival, superior achievement of motor milestones, and better motor function than in historical cohorts.






Neurodegenerative disorders Marks et al, 2008295 Ceregene, 2007479 NCT00252850 Trial (multiple groups) N: 12

Age group: adults Parkinson's disease Treatments enrollment: Patients had to be on stable doses of antiparkinsonian drugs in the month preceding the trial. Treatment requisite: The therapy was administered bilaterally into the putamen in four needle tracks on each side. Follow-up: 12

CERE-120 No comparison group

Change in Unified Parkinson’s Disease Rating Scale 22 motor score (part III) (25% reduction is considered clinically meaningful); change in time spent in the on state without dyskinesia; change in complete UPDRS, change in patient-completed diary assessments of motor function, change in timed motor tests (e.g. timed walking test, Purdue Pegboard), change in dyskinesia rating scale, clinical global impression of severity, change in clinical global impression of improvement scales, and improvement in quality of life measures

No serious adverse events occurred in any patient.

The initial data support the safety, tolerability, and potential efficacy; however, these results must be viewed as preliminary until data from blinded, controlled clinical trials are available.






Neurodegenerative disorders Mendell at al, 2017292 Mendell et al, 2017480 NCT02354781, IND 14845 Controlled trial N: 14

Age group: adults Sporadic inclusion body myositis Treatments enrollment: none Treatment requisite: pretreatment muscle biopsy, prednisone treatment for 1 month prior to and after vector administration Follow-up: 2 to 24 (range)

rAAV1.CMV.huFS344 No treatment

Improvements in 6-minute walk test, exercise tolerance, activities of living

No observed therapy-related serious adverse events (fall, n = 2; biking accident, n = 1)

The findings show promise for follistatin gene therapy for mild to moderately affected, ambulatory sporadic inclusion body myositis patients.

Neurodegenerative disorders Mendell et al, 2009291 Mendell et al, 2010481 Nationwide Children's Hospital, 2011482 NCT00494195 RCT N: 6

Age group: children Muscular dystrophy (limb-girdle muscular dystrophy type 2D) Treatments enrollment: Patients had to be treatment-free for 3 months prior to enrollment. Treatment requisite: methylprednisolone at 4, 24, and 48 hours post gene therapy injection Follow-up: 6

rAAV1.tMCK.hSGCA Placebo

Improvement in gene expression, improvement in muscle size

None observed We observed sustained gene expression but studies over longer time periods without immunotherapy will be required for design of vascular delivery gene therapy trials.






Neurodegenerative disorders Tardieu et al, 2017308 Lysogene, 2017483 SRCTN19853672 Single-arm trial N: 4

Age group: children Mucopolysaccharidosis type IIIB syndrome (Sanfilippo type B syndrome) Treatments enrollment: none Treatment requisite: Immunosuppression was started 14 days before surgery with 0·2 mg/kg oral tacrolimus per day and 1200 mg/m² oral mycophenolate mofetil per day. A 4-hour pharmacokinetic profile was determined when steady state was achieved and 7 days after. Follow-up: 30

rAAV2/5_NAGLU No comparison group

Brain cells showed sustained enzyme production that led to improved cognitive outcomes in all patients compared with the natural history of mucopolysaccharidosis type III syndromes, with the outcomes being best in the youngest patient. We saw an initial specific immune response to the therapeutic enzyme that later subsided, which indicated acquired immunological tolerance for three patients. The treatment had a good safety profile within the follow-up period in all patients.

All adverse events were mild, chiefly diarrhea or anesthesia related.

Intracerebral rAVV2/5 was well tolerated and induced sustained enzyme production in the brain. The initial specific anti-NAGLU immune response that later subsided suggested acquired immunological tolerance. The best results being obtained in the youngest patient implies a potential window of opportunity. Longer follow-up is needed to further assess safety outcomes and persistence of improved cognitive development.

Ocular disorders MacLaren et al, 2014318 Chen et al, 2000484 University of Oxford, 2017485 Xue et al, 2016486 Simunovic et al, 2016487 Xue et al, 2018488 Simunovic et al, 2017489 NCT01461213 Single-arm trial N: 6

Age group: adults Choroideremia Treatments enrollment: none Treatment requisite: surgery Follow-up: 6

AAV.REP1 No comparison group

Retinal sensitivity, vision change

Complications in 2 patients

The initial results of this retinal gene therapy trial are consistent with improved rod and cone function that overcome any negative effects of retinal detachment.






Ocular disorders Maguire et al, 200875 Maguire et al, 200976 Simonelli et al, 2010490 Ashtari et al, 2011491 Spark Therapeutic, 2024492 Bennett et al, 2012493 Spark Therapeutics, 2026494 Bennett et al, 201677 Testa et al, 2013495 Ashtari et al, 2017496 NCT00516477, NCT01208389 (follow-up) Single-arm trial N: 3

Age group: adults Leber's congenital amaurosis type 2 Treatments enrollment: none Treatment requisite: none Follow-up: 20

AAV2.hRPE65v2 No comparison group

Visual acuity No serious adverse events related to the vector

Although normal vision was not achieved, this study provides the basis for further gene therapy studies in patients with Leber's congenital amaurosis.

Ocular disorders Fischer et al, 2018309 study eye RCT N: 6

Age group: adults Choroideremia Treatments enrollment: confirmed REP gene mutation Treatment requisite: none Follow-up: 12

AAV2-REP1 No treatment

Best-corrected visual acuity


AAV2-REP1 can maintain and, in some cases, improve visual acuity in choroideremia. Longer-term follow-up is necessary to establish whether these benefits are maintained.






Ocular disorders Lam et al, 2018310 Byron Lam and University of Miami, 2018497 NCT02553135 Trial (multiple groups) N: 6

Age group: adults Advanced choroideremia Treatments enrollment: none Treatment requisite: oral corticosteroid (prednisone) for a total of 21 days, starting 2 days before surgical procedure; surgical procedure: 3-port pars plana vitrectomy performed under general anesthesia and an automated injection system for the vector was used to deliver treatment to the subretinal space Follow-up: 24

AAV2-REP1 (10(11) No comparison group

Early treatment diabetic retinopathy study letters best-corrected visual acuity in treated versus untreated eye, intraocular pressure, change from baseline in microperimetry, change from baseline in fundus autofluorescence, change from base


Sustained improvement or maintenance of best-correct visual acuity can be achieved in patients with choroideremia with high-dose AAV2-REP1, and the therapy can be delivered with intraoperative OCT with a good safety profile.






Ocular disorders Heier et al, 2017325 Genzyme, 2014498 NCT01024998 Trial (multiple groups) N: 19

Age group: adults Advanced neovascular age-related macular degeneration Treatments enrollment: Patients had best corrected visual acuity of 20/100 or worse in the study eye and 20/400 or better in fellow eye; showed intraretinal or subretinal fluid in macula; and had adequate pupillary dilation. Treatment requisite: broad-spectrum topical antibiotic solution in the study eye for 3 days before the injection Follow-up: 12

AAV2-sFLT01 No comparison group

Best-corrected visual acuity

1 death of a 91-year-old patient 1 year after study completion and 2 years after vector injection. The patient chose not to enter the extended follow-up study, and information regarding the cause of death was unobtainable.

Intravitreous injection of AAV2-sFLT01 seemed to be safe and well tolerated at all doses.

Ocular disorders Cukras et al, 2018312 NCT02317887 Trial (multiple groups) N: 9

Age group: adults X-linked retinoschisis Treatments enrollment: none Treatment requisite: none Follow-up: 6

AAV8-RS1 No comparison group

Visual acuity, retinal sensitivity on MP1 testing, ocular CT, electroretinogram

The investigational product was generally well tolerated in all but 1 individual.

This study showed the feasibility of this approach for delivery of an AAV8 vector into the eye. As found in other trials, a dose-dependent increase in ocular inflammation that resolved with topical and systemic steroids was also observed. Cavity closure in one participant provided the first signal of possible efficacy.






Ocular disorders Constable et al, 2016324 Rakoczy et al, 2015499; Constable et al, 2016500; Constable et al, 2017501; Perth Western Australia Lions Eye Institute, 2017502 NCT01494805 Controlled trial N: 40

Age group: adults Wet age-related macular degeneration Treatments enrollment: Most patients had previous anti-VEGF therapy and no washout period was required. Treatment requisite: none Follow-up: 36

rAAV.sFlt-1 No treatment, other: all patients received 0.5 mg ranibizumab (RBZ) at baseline and week 4; patients were randomized to no additional treatment, high dose, or low dose

Phase I: reduced number of subsequent RBZ retreatments during the first year, improvement and maintenance of center-point thickness, vision improvement, BCVA change from baseline Phase II: data not yet available

Subconjunctival hemorrhage; subretinal hemorrhage; mild cell debris in the vitreous; 2 phakic patients required cataract surgery

rAAV.sFlt-1 gene therapy may prove to be a potential adjunct or alternative to conventional intravitreal injection for patients with wet AMD by providing extended delivery of sFlt-1.

Ocular disorders Jacobson et al, 2012317 Cideciyan et al, 2009503; Cideciyan et al, 2014504 NCT00481546 Single-arm trial N: 15

Age group: adults Leber congenital amaurosis Treatments enrollment: none Treatment requisite: none Follow-up: 36

rAAV2-RPE65 No comparison group

Systemic and ocular safety

None Gene therapy for Leber congenital amaurosis caused by RPE65 mutations is sufficiently safe and substantially efficacious in the extrafoveal retina.






Ocular disorders Dimopoulos et al, 2018311 Ian et al, 2017505 NCT02077361 Single-arm trial N: 6

Age group: adults Choroideremia Treatments enrollment: none Treatment requisite: pretreatment with oral prednisone Follow-up: 24

rAAV2.REP1 No comparison group

Safety, best-corrected visual acuity, fundus autofluorescence, spectral-domain optical coherence tomography, microperimetry, quality of life

1 localized intraretinal immune response

One serious adverse event was experienced in 6 patients treated with a subfoveal injection of AAV2.REP1. The area of remaining functional RPE in the treated eye and untreated eye declined at the same rate during a 2-year period. Fundus autofluorescence area is a remarkably predictive biomarker and objective outcome measure for future studies of ocular gene therapy in CHM patients.

Ocular disorders Bainbridge et al, 2015319 Bainbridge et al, 2008506; Ripamonti et al, 2015507; University College London, 2014508 NCT00643747 Single-arm trial N: 12

Age group: adults Leber's congenital amaurosis Treatments enrollment: none Treatment requisite: none Follow-up: 36

rAAV2/2 RPE65 No comparison group

Visual acuity, contrast sensitivity, color vision, spectral sensitivities

None Gene therapy with rAAV2/2 RPE65 vector improved retinal sensitivity, albeit modestly and temporarily.






Ocular disorders Le Meur et al, 2018313 NCT01496040 Trial (multiple groups) N: 9

Age group: children and adults Leber congenital amaurosis Treatments enrollment: none Treatment requisite: 3-way 20G vitrectomy to inject vector; prednisolone daily treatment for 1 week prior to injection and continued for 1 month post injection; dexamethasone-tobramycin eye drops for 1 month post injection; atropine eye drops for 7 days post injection Follow-up: maximum 42

rAAV2/4.RPE65.RPE65 No comparison group

Improvement in perception of detail, fixation, color vision; reduction in photophobia, visual fatigue

Observed no local or systemic adverse effects related to treatment: thyroidectomy (n = 1), supraventricular tachycardia (n = 1) were deemed serious adverse events not related to treatment

The therapy is well tolerated but the efficacy varies depending on the patient.

Ocular disorders Weleber et al, 2016323 Applied Genetic Technologies, 2014509 NCT00749957 Trial (multiple groups) N: 12

Age group: children and adults Leber congenital amaurosis, severe early childhood-onset retinal degeneration Treatments enrollment: none Treatment requisite: vitrectomy (for subretinal injection of therapy), postoperative treatment (local corticosteroids, antibiotics) Follow-up: 24

rAAV2-CB-hRPE65 No comparison group

Improvements in visual acuity, optical coherence tomography, perimetry (static, kinetic), electroretinography, quality of life

Serious adverse event not considered to be due to therapy: noncardiac chest pain and hypertension (n = 1)

Treatment with rAAV2-CB-hRPE65 was not associated with serious adverse events, and improvement in 1 or more measures of visual function was observed in 9 of 12 patients. The greatest improvements in visual acuity were observed in younger patients with better baseline visual acuity.






Ocular disorders Hauswirth et al, 2008315 Cideciyan et al, 2008510 ID NR Single-arm trial N: 3

Age group: adults Leber congenital amaurosis Treatments enrollment: none Treatment requisite: none Follow-up: 3

rAAV2-CBSB-hRPE65 No comparison group

Ocular safety, visual function, central retinal structure

None No positive result was evident.

Ocular disorders Banin et al, 2010316 Hadassah Medical, 2016511 NCT00821340 Single-arm trial N: 208

Age group: children and adults Leber congenital amaurosis Treatments enrollment: none Treatment requisite: none Follow-up: none

rAAV2-hRPE65 No comparison group

Visual function, ocular safety

None The investigated process of genetically analyzing affected isolated populations as a screen for gene-based therapy suggests a new paradigm for disease diagnosis and treatment.

Ocular disorders Wan et al, 2016322 Yang et al, 2016512 Yang et al, 2016513 NCT01267422 Trial (multiple groups) N: 9

Age group: adults Leber’s hereditary optic neuropathy Treatments enrollment: none Treatment requisite: none Follow-up: 9

rAAV2-ND4 No comparison group

Visual acuity, vision field, VEP, OCT, blood and urine, liver, kidney, immune function

None Findings support the feasible use of gene therapy for Leber’s hereditary optic neuropathy.






Ocular disorders Ghazi et al, 2016321 NCT01482195 Trial (multiple groups) N: 6

Age group: children and adults Retinitis pigmentosa Treatments enrollment: none Treatment requisite: vitrectomy and subretinal injection of therapy, subconjunctival antibiotics and steroids Follow-up: 180

rAAV2-VMD2-hMERTK No comparison group

Improvements in visual function: visual acuity, retinal function, central macular and foveal thickness

None listed as serious Gene therapy for MERTK-related RP using careful subretinal injection of rAAV2-VMD2-hMERTK is not associated with major side effects and may result in clinical improvement in a subset of patients.

Ocular disorders Feuer et al, 2016320 NCT02161380 Trial (multiple groups) N: 5

Age group: adults Leber hereditary optic neuropathy Treatments enrollment: none Treatment requisite: intravitreal injection Follow-up: 36

scAAV2(Y444,500,730F)-P1ND4v2 No comparison group

Loss of visual acuity to no light perception

No observed serious ocular or systemic adverse events

No serious safety problems were observed in the first 5 patients enrolled in this phase I trial of virus-based gene transfer in this mitochondrial disorder. Additional study follow-up of these and additional patients planned for the next 4 years is needed to confirm these preliminary observations.

Ocular disorders Russell et al, 201774 Spark et al, 2015514 NCT00999609 RCT Completed N: 31

Age group: children and adults Inherited retinal dystrophy Treatments enrollment: none Treatment requisite: none Follow-up: 12

Voretigene neparvovec; AAV2-hRPE65v2 Placebo

Multiluminance mobility test score (bilateral), multiluminance mobility test score (first injected eye), full-field light sensitivity threshold (2 eye average), best-corrected visual acuity (2 eye average)

No product-related serious adverse events or deleterious immune responses occurred.

Treatment with Voretigene neparvovec gene replacement improved functional vision in RPE65-mediated inherited retinal dystrophy that was previously medically untreatable.






Other: prophylactic AIDS vaccine candidate Mehendale et al, 2008356 ID NR, approved by ethical, scientific, and regulatory authorities in Europe and India RCT N: 80


tgAAC09 Placebo

HIV test No vaccine-related serious adverse events reported

All responses were to gag epitopes. tgAAC09 appears to be safe, well tolerated, and modestly immunogenic.

Respiratory conditions Wagner et al, 1999332 Wagner et al, 1999515 ID NR, reviwed by FDA, NIH-RAC Single-arm trial N: 10

Age group: adults Cystic fibrosis Treatments enrollment: none Treatment requisite: none Follow-up: none

AAV-CFTR No comparison group

None Little or no inflammatory or immune responses observed

AAV-CFTR administration to the maxillary sinus results in successful, dose-dependent gene transfer to the maxillary sinus and alterations in sinus TEPD suggestive of a functional effect, with little or no cytopathic or host immune response.






Respiratory conditions Moss et al, 2007337 Moss et al, 2004516 ID NR, protocol reviewed by NIH-RAC and FDA RCT Completed N: 109

Age group: children and adults Cystic fibrosis Treatments enrollment: none Treatment requisite: none Follow-up: 7

AAV-CFTR (tgAAVCF) Placebo

Absolute FEV1, change in FEV1, FEV1 percentage predicted, forced vital capacity, mid-maximal expiratory flow rate (FEF25-75)

SAEs (patients): 13 intervention, 11 placebo

Repeated doses of aerosolized tgAAVCF were safe and well tolerated but did not result in significant improvement in lung function over time. Because gene transfer is the simplest, most basic way to correct the underlying genetic defect that leads to disease in CF, further research is warranted to develop an effective gene transfer agent for the treatment of CF.

Respiratory conditions Brantly et al, 2009338 Flotte et al, 2011517; Brantly et al, 2006518 University of Massachusetts Worcester, 2015519; Mueller et al, 2013520; Applied Genetic Technologies, 2011521 NCT00430768 Trial (multiple groups) N: 9

Age group: adults Alpha-1 antitrypsin deficiency Treatments enrollment: none Treatment requisite: AAT protein augmentation Follow-up: none

rAAV1-AAT No comparison group

Hematology or clinical chemistry parameters

No SAEs were reported during the study. Potentially related AEs included mild erythema near the injection site. There was no indication of muscle toxicity or inflammation.

These findings suggest immune responses to AAV capsid that develop after intramuscular injection of a serotype 1 rAAV vector expressing AAT do not completely eliminate transduced cells in this context.






Respiratory conditions Flotte et al, 2003336 National Institute of Diabetes, 2002522 NCT00004533 Trial (multiple groups) N: 25

Age group: children and adults Cystic fibrosis Treatments enrollment: none Treatment requisite: none Follow-up: 24

rAAV2-CFTR (tgAAVCF) No comparison group

Safety outcomes, vector viremia, shedding, immune response, DNA transfer outcomes

All patients experienced at least 1 AE, most of which were clearly unrelated to vector administration. None resulted in death or withdrawal

The current study provides clear evidence of the safety of upper- and lower-respiratory tract delivery of tgAAVCF within a dose range resulting in measurable DNA transfer, which supports its continued development as a clinical agent for CFTR gene transfer in the context of CF lung disease.

Respiratory conditions Aitken et al, 2001334 ID NR, protocol reviewed by NIH-RAC and FDA Single-arm trial N: 12

Age group: adults Cystic fibrosis Treatments enrollment: none Treatment requisite: none Follow-up: 3

tgAAVCF No comparison group

None 242 adverse events total, 6 serious and 3 possibly related to the study drug

This phase I trial shows aerosolized tgAAVCF is safe and widely delivered to the proximal airways of CF patients by nebulization.

Respiratory conditions Wagner et al, 2002335 ID NR RCT Completed N: 23

Age group: children and adults Cystic fibrosis with antrostomies Treatments enrollment: none Treatment requisite: none Follow-up: 3

tgAAVCF Placebo

Recurrent sinusitis, imaging, histopathology

The tgAAVCF administration was well tolerated, without adverse respiratory events, and there was no evidence of enhanced inflammation in sinus histopathology or alterations in serum-neutralizing antibody titer to AAV capsid protein.

This phase II trial confirms the safety of tgAAVCF but provides little support of its efficacy in the within-patient controlled sinus study.

Abbreviations: AAV, adeno-associated virus therapy; AEs, adverse events; ID, trial identification number; mL, milliliter; NR, not reported; RCT, randomized controlled trial; SAEs, serious adverse events.

emerging technologies and therapeutics report 1 · 2020-02-27 · emerging technologies and...

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