safety and immunogenicity for gene therapy medicinal products and therapeutic vaccines ·...
TRANSCRIPT
Dr. Nadine Kirsch-StefanDr. Mark Goldammer
Paul-Ehrlich-Institut
Safety and Immunogenicity for Gene Therapy Medicinal Products and Therapeutic Vaccines
Dr. Nadine Kirsch-Stefan and Dr. Mark Goldammer
27th AGAH Annual Meeting26.-27.04.2018, Munich
Nadine Kirsch-Stefan, Mark Goldammer
Gene Therapy Medicinal Products (GTMP)
Source: EMA and NIH https://stemcells.nih.gov/info/Regenerative_Medicine/2006Chapter4.
“…contain genes that lead to a therapeutic, prophylactic or diagnostic effect. Theywork by inserting 'recombinant' genes into the body, usually to treat a variety ofdiseases, including genetic disorders, cancer or chronic diseases.”
Nadine Kirsch-Stefan, Mark Goldammer
Vectors used for Gene Therapy
Vectors
Non-viral Viral
integrating non-integrating
Key requirements for a viral vector:
• Safety• Low toxicity• Stability• Cell type specificity
Nadine Kirsch-Stefan, Mark Goldammer
Vectors used for Gene Therapy based on Scientific Advice (PEI)
Retrovirus (30,2%)
Adeno-associated virus (24%)
Lentivirus (21,9%)
recombinant bacterium (10,4%)
RNA (9,4%)
Adenovirus (8,3%)
Source: PEI, only data > 8%
Cumulative data 2012 – 11/2017
Nadine Kirsch-Stefan, Mark Goldammer
Retroviral and lentiviral vectors
Safety and immunogenicity:
• Humoral immune response rather low• Integration into host cell genome raises the possibility of
insertional mutagenesis and oncogene activation• Generation of a replication competent virus
Technological approaches:
• Development of self-inactivating (SIN) vectors • Use of tissue specific promoters• Clonal analysis
Vector Transduction Genome Advantage
Retroviral Only dividing cells Integrated • Persistent gene transfer (stem cells)• High transduction efficiency
Lentiviral Dividing andnon-dividing cells
Integrated • Transduction of non-diving cells• Receptive to pseudotyping
Retrovirus7-10 kb genome
Source: Kaufmann JK & Nettelbeck DM (2012) Trends Mol Med
Nadine Kirsch-Stefan, Mark Goldammer
Adenoviral vectors
Safety and immunogenicity:
• Strongly immunogenic
• Vector can trigger an inflammatory response leading to
multiorgan failure (OTC clinical trial, 1999)
Advantage:
• Extremely efficient transduction of most tissues
Technological approaches:
• Extensive engineering to reduce immunogenicity
Today mainly used as vaccine and oncolytic virus Adenovirus~36 kb genome
Source: Kaufmann JK & Nettelbeck DM (2012) Trends Mol Med
Nadine Kirsch-Stefan, Mark Goldammer
Adeno-associated viral (AAV) vectors
Safety and immunogenicity:
• Reduced transduction efficiency due to pre-existing humoral immunity• Loss of transgene expression due to induction of cellular immune
response against the viral capsid• Repeated dosing not possible due to neutralizing antibodies
Advantage:• Non-pathogenic• Excellent safety profile • Wide tissue tropism
Countermeasures:• Use of serotypes with low pre-existing immunity• Immunosuppression • Optimization of transduction efficiency and transgene expression• Monitoring of immune responses
Source: Kaufmann JK & Nettelbeck DM (2012) Trends Mol Med
Adeno-associated virus4,7 kb genome
Nadine Kirsch-Stefan, Mark Goldammer
Chimeric Antigen Receptor (CAR) T cells
Safety and immunogenicity:
• Neurotoxicity• Cytokine release syndrome (CRS)• Tumor-lysis syndrome (TLS)• Immune reactions against mouse scFv• Off-target toxicities (i.e. B-cell aplasia and tissue damage)
Advantage:• Specific targeting of T cells via CAR• Clinical benefit in B cell malignancies (CD19-CAR T cells)
Countermeasures:• Use of humanized scFv• Identify biomarkers to predict common toxicities• 4th generation CARs and smart CARs
Source: Lawrence J (2016) The Pharmaceutical Journal
Nadine Kirsch-Stefan, Mark Goldammer
Addressing safety of GTMPs in NC studies
• Human specificity of the GTMP• Selection of a relevant animal model • Often single administration to induce long lasting effect• Translation of dose-response from animal models to humans
Challenges:
• Biodistribution is fundamental to identify target organs• Correlation of dose and expression of transgene (systemic and local)• Pharmacokinetics should be known before planning relevant studies• Specific aspects related to nature of GTMP should be considered
Addressing safety in non-clinical studies:
Nadine Kirsch-Stefan, Mark Goldammer
Scientific Advice in preparation for a Clinical Trial
• Receive procedural and regulatory advice• Discuss specific project and product related aspects• Get answers on quality, non-clinical and/or clinical issues
National Scientific Advice
Nadine Kirsch-Stefan, Mark Goldammer
Safety and Immunogenicity for Gene Therapy Medicinal Products and Therapeutic Vaccines
Therapeutic Vaccines
Nadine Kirsch-Stefan, Mark Goldammer
Therapeutic Vaccines
Other antigen delivering principles:
• RNAs• Virus like particles
Peptides [non biotechnology-derived] - examples:
• Cancer Preferentially expressed in tumour cells, such as Tyrosinase, MAGE or PRAME Neo-antigens
• Neurodegenerative diseases
α-synuclein, tau and amyloid-β
Cell therapies:
• Antigen dendritic cells (DCs)• Natural killer cells (NKs)• CMV or EBV specific T-cells
…etc
Nadine Kirsch-Stefan, Mark Goldammer
Development of Therapeutic Vaccines in Germany (PEI)
6 6
89 9
5
109
1112 12
16
10
7
10
7
0
2
4
6
8
10
12
14
16
18
2010 2011 2012 2013 2014 2015 2016 2017
Num
ber
National Scientific Advice
Clinical Trial Applications
Source: PEI
Nadine Kirsch-Stefan, Mark Goldammer
Safety & Immunogenicity – Therapeutic Vaccines
Immunotoxicity is defined as unintended immunosuppression or enhancement:
1) Drugs intended to modulate immune function for therapeutic purposes (e.g. to prevent organ transplant rejection) where adverse immunosuppression can be considered as exaggerated pharmacodynamics[also → Cytokine release syndrome]
2) Drugs not intended to affect immune function… → does not apply for therapeutic vaccines
ICH S8… does not apply to biotechnology-derived pharmaceutical products covered by ICH S6
Nadine Kirsch-Stefan, Mark Goldammer
Safety & Immunogenicity – Therapeutic Vaccines
4.5. Immunotoxicity studies
…standard testing batteries, however, are not recommended ...
3.6. Immunogenicity [Foreign Antigens]
…Many biotechnology-derived pharmaceuticals intended for human are immunogenic in animals. Therefore, measurement of antibodies associated with administration of these types of products should be performed when conducting repeated dose toxicity studies in order to aid in the interpretation of these studies…
… The induction of antibody formation in animals is not predictive of a potential for antibody formation in humans …
Nadine Kirsch-Stefan, Mark Goldammer
Safety & Immunogenicity – Therapeutic Vaccines
2. Species selection2.1. General principles…Comparisons of target sequence homology between species can be an appropriate starting point…
…when no relevant species can be identified because the biopharmaceutical does not interact with the orthologous target in any species, use of homologous molecules or transgenic models can be considered...
Nadine Kirsch-Stefan, Mark Goldammer
Safety & Immunogenicity – Therapeutic Vaccines
→ refers directly to tumour vaccines:
6.3.2. Immune-modulating compounds including tumour vaccines…Monitoring the immune response… to determine appropriate dose and schedule…
6.4.2. Combinations involving a non-cytotoxic drug…Co-enhancement is considered when both combination partners demonstrate (modest) anti-tumour activity per se and the anti-tumour activity of the combination is considerably increased. In phase II, the new combination should …
Applicants should also refer to:
Nadine Kirsch-Stefan, Mark Goldammer
Safety & Immunogenicity – Therapeutic Vaccines
In general:
• The pre-clinical programme should address the product-specific& all relevant safety concerns to the best extent
• A robust rational justifying the selected starting dose for a FIH must be provided → based on pre-clinical data
• Limitations of the available pre-clinical data have to be addressed appropriately for the planning, design and conduct of a FIH study
You may consider:
• Testing cytokine induction/inhibition → multiplex assays available• In relevant animal models – e.g. using homologous molecules
Haematology Organ toxicity – histology …
Nadine Kirsch-Stefan, Mark Goldammer
Safety & Immunogenicity – Experiences(neither comprehensive nor complete analysis - indications)
• Provenge®: Antigen-presenting cells loaded with recombinant fusion protein antigen, which contains both PAP (prostatic acid phosphatase) and GM–CSF (granulocyte-macrophage colony-stimulating factor) demonstrated improve overall survival in patients with androgen-dependent prostate cancer (ADPC) -achieved marketing authorisation in the EU and USA
Successful:
• Cancer: A trend towards using Neo-epitopes → specificity ↑• Combining therapeutic vaccine approaches + e.g. innovative adjuvants such as
cytokines or toll-like receptor agonists, check-point inhibition, etc.
Due to current experience, clearly related, severe adverse effects (other than injection side reactions) are relatively uncommon
Clinical studies demonstrate more and more targeted immunogenicity in humans
However - do not necessarily translate into clinical effects
Trends:
In general:
Nadine Kirsch-Stefan, Mark Goldammer
Safety & Immunogenicity – Immune Response & Clinical Effects
Tox/Safety Pharmacology
Immunogenicity
Pharmacology
Translation
inHumansinHumans
Pre-ClinicalProgrammePre-ClinicalProgramme
Nadine Kirsch-Stefan, Mark Goldammer
Tox/Safety Pharmacology
Immunogenicity
Pharmacology
Translation
inHumansinHumans
Pre-ClinicalProgrammePre-ClinicalProgramme
?
???
Safety & Immunogenicity – Immune Response & Clinical Effects
Nadine Kirsch-Stefan, Mark Goldammer
Tox/Safety Pharmacology
Immunogenicity
Pharmacology
Pre-ClinicalProgrammePre-ClinicalProgramme
inHumansinHumans
Translation
Safety & Immunogenicity – Immune Response & Clinical Effects
Nadine Kirsch-Stefan, Mark Goldammer
Safety & Immunogenicity – Therapeutic Vaccines
• Establishing product specific → predictive (animal) models No standard testing batteries recommended – however, guidelines give indications which relevant / critical safety aspects have to be addressed
Understanding of immunogenicity and prediction of immune answer and (extent) of clinical effects in humans[Tumour environment? Tumour escape? …]
Challenges:
• Early initiation of comprehensive product specific development plans
• Establishing a good understanding of mode of action → Prediction of (extent) of clinical effects (Safety & Efficacy)
• Early communication with regulatory agencies
Recommendation:
Nadine Kirsch-Stefan, Mark Goldammer
Thank you for your attention.
Further information on national Scientific Advice is available on the website of the Paul-Ehrlich-Institut: www.pei.de/innovation-office
Nadine Kirsch-Stefan, Mark Goldammer
Development of Gene Therapies in Germany (PEI)
10
4
21
9
14
22
34
27
4
9
6
3
8
18 18
30
0
5
10
15
20
25
30
35
40
2010 2011 2012 2013 2014 2015 2016 2017
Num
ber
National Scientific Advice
Clinical Trial Applications
Source: PEI
Nadine Kirsch-Stefan, Mark Goldammer
Vectors used for Gene Therapy worldwide
Retrovirus (14,5%)
Lentivirus (18,5%)
Adenovirus (16%)
Adeno-associated virus (14,4%)
Naked/Plasmid DNA (14,4%)
Source: Adapted from Wiley, The Journal of Gene Medicine, only data > 8%
Cumulative data 2012 – 11/2017
Nadine Kirsch-Stefan, Mark Goldammer
Gene Therapy Clinical Trials in Europe
UK (n=221)
Germany (n=92)
France (n=59)
Netherlands (n=37)
Spain (n=37)
Italy (n=28)
Belgium (n=22)
Sweden (n=13)
Source: Adapted from Wiley, The Journal of Gene Medicine, only European countries with n>10
Cumulative data 1989 – 11/2017
Nadine Kirsch-Stefan, Mark Goldammer
Gene Therapy Clinical Trials in Europe vs. US
US (n=1643)
Europe (n=527)
Source: Adapted from Wiley, The Journal of Gene Medicine
Cumulative data 1989 – 11/2017