2015-05-06-web panel gene therapies for rare diseases...

What's Hot & What's Not in Gene Therapies for Rare Diseasesp

May 6, 2015

M d tModerator:

– Mike Rice, MS, MBASenior Consultant, Defined Health

Panelists:

– Matthew Porteus, MD, PhDAssociate Professor of PediatricsAssociate Professor of Pediatrics (Cancer Biology), Stanford University

– Stewart Abbot, PhDExecutive Director, Integrative Research at Celgene Cellular Therapeutics (CCT)Celgene Cellular Therapeutics (CCT)

– Paul Gallagher, MBAPresident, Compass Strategic Consulting

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Today’s Web Panel Discussion yIs Co-Hosted by:

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Defined Health is a leading knowledge-

based business development strategy

BIO is the world's largest trade

association representing biotechnology

allows organizations to simply and securely share

sensitive documents with external parties

p gyconsultancy to pharma

and biotech.

gyorganizations

across the world. BIO also organizes the BIO International

Convention which will with external partiesin the cloud.

Convention, which will be held in Philadelphia from June 15-18.

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Logistics

• The web panel discussion will last 75 minutes (until 12:15 PDT / 3:15 EDT)(until 12:15 PDT / 3:15 EDT).

• Contribute questions via the Q&A GoToWebinar interface.

• We will address the questions intermittently or at the end. If we don’t get to your question, we will respond to you after the web panel.to you after the web panel.

• The web panel discussion is being recorded, and we will contact you when it becomes available.

• We welcome your feedback after the web panel so we can improve others in the future.

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Mike RiceMS, MBA

Senior ConsultantDefined HealthDefined Health

Mike RiceMike Rice

4

Pharma Has Benefitted Significantly by Investing in Biologicsy g g

Top-Selling Products (WW Sales $M) 2004 vs. 2014(coded by conventional vs. biologics)

Bi l iC ti l

Z ( i t ti ) MRK

Lipitor (atorvastatin) - Pfizer Humira (adalimumab) -AbbVie

2004 2014

BiologicConventional

Zyprexa (olanzapine) - Lilly

Norvasc (amlodipine) - Pfizer

Seretide/Advair (fluticasone; salmeterol) - GSK

Zocor (simvastatin) - MRK

Seretide/Advair (fluticasone, l t ) GSK

Rituxan (rituximab) - Roche

Lantus (insulin glargine recombinant) - Sanofi

Sovaldi (sofosbuvir) - Gilead

Zoloft (sertraline) - Pfizer

Procrit (epoetin alfa) - J&J

Nexium (esomeprazole) - AZN

yp ( p ) y

Remicade (infliximab) - J&J

Herceptin (trastuzumab) -Roche

Avastin (bevacizumab) -Roche

salmetero) - GSK

0 5,000 10,000 15,000

Plavix (clopidogrel) - BMS

Effexor (venlafaxine) - Wyeth

0 5,000 10,000 15,000

Lyrica (pregabalin) - Pfizer

Crestor (rosuvastatin) - AZN

EvaluatePharma

5

Gene and Cell Therapies Next Advancement Beyond Biologicsy g

Therapeutic Interventions

Small Molecule Modulators

Protein Augmentation Antibodies

Peptides and Nucleic Acids

Gene Correction & Augmentation

Cell Therapy / Regen Med

• ImmuneModulators

• SMIs

• Plasma/tissue derived proteins

Recombinant

• Plasma derivedPolyclonal Igs

• Monoclonal antibodies

• ImmuneModulators

• Exon skipping

• Viral vectors‒ Retro/‒ Lentiviral‒ AdVAAV

• Autologousand allogeneicBMT/Cell therapy

• Chaperones

• Substrate Reduction

• Recombinant Proteins– Clotting factors

– CytokinesH

antibodies

• mAB fragments

• Scaffolds

• Antisense

• RNAi /miRNA

A t /

‒ AAV

• Non‐viral‒ Plasmids/‒ Fragments

• Other cell sources: e.g. ES, iPS

D i• Transcription / Translation enhancers

E i i

– Hormones– Growth factors

• EnzymeR l

• Intrabodies• Aptamers/ Ribozyme • Gene editing

with Meganucleases‒ Zinc FingersTALENS

• Devices‒ Encapsulation‒ Scaffolds‒ Implants‒Micro‐organsA h i• Epigenetics Replacement ‒ TALENS

‒ CRISPR/Cas9‒ Aphaeresis

Gene Therapy Defined

According to the FDA, gene therapy products are all 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 nucleichost 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.

FDA.gov

7

Components of Gene Transfer Platforms: Clinical Need, Intervention, Delivery Vector

AAV

Adenovirus

Retro/LentiviralGene Transfer Vectors

Vaccines

HSV, VACV, SV40

Plasmid/Fragment

Vectors

Liposome, Other?

Vaccines

Polygenic Diseases

Monogenic DiseaseClinical Need Infectious DiseaseGene

TherapyOncology

Suicide Gene

Gene Augmentation

Antisense, RNAi

Therapeutic Intervention

ZFs, CRISPR, TALENs

RibozymesOther?Other?

8

Clinical Need: Today There Are Over 500 Active Gene Therapy Programs

• Broadly Applicable: Investigated in >1,600 clinical trials• Cancer is By Far the Most Active Area for Clinical Trials –

Monogenetic Diseases May Be Most Tractable

13 65

Gene Therapies by All Therapeutic Areasn = 574, individual products counted multiple times

OncologySensory DisordersM t b li Di d

20328

28

1413 6 Metabolic Disorders

Cardiovascular DisordersNeuromuscular DisordersHematological DisordersNeurological DisordersNeurodegenerative DisordersInfectious Disease

29

28Infectious DiseaseImmunological DisordersMusculoskeletal DisordersOtherGastrointestinal DisordersLiver DisordersSkin Disorders

6956

39

33 Skin DisordersGenitourinary DisordersCongenital DisordersLung DisordersAccidents & InjuryRespiratory DisordersLymphatic Disorders

Adis R&D Insight,Thomson Reuters Cortellis Lymphatic DisordersThomson Reuters Cortellis

9

Gene Transfer Vectors: Viral-Based Vectors Used in Majority of Pipeline –

Most Advanced in Clinical DevelopmentMost Advanced in Clinical Development

Gene Therapies in Development by Approachn = 394

1413

9 7 5Adeno-associated virus (AAV)

Other gene therapy

Adenovirus

122

16

15

15 Lentiviral vector

Plasmid

Cancer vaccine

Fragment/DNA

R i l

38

23Retroviral

T cell therapy

Cell therapy

Other viral vector

Oncolytic virus65

49

Oncolytic virus

ZF

Transposon

TALEN/CRISPRAdis R&D Insight, Thomson Reuters Cortellis

10

Therapeutic Intervention:GT Originated as Functional Genomics Tools – May T f I h it d Di d d Oth DiTransform Inherited Disorders and Other Diseases

Inherited Disorders

StableTransient

Enzyme (ERT)

mRNA

ASO / RNAi

Allo SCT

Random

Autologous Cell Correction

Directed

mRNA

ASO / RNAi

Exon Skipping

Random

Plasmid Transfection

Viral Integration

Directed

Recombination

Gene Activation

Triplex

Other epigeneticTransposons

Meganucleases, ZF, CRISPR TALENs SSODN

Viral Episomal? Gene Editing

CRISPR, TALENs, SSODN

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Cross-Comparison of Gene Therapy PlatformsGe e e apy at o s

Technology Capacity Delivery* Integration Pros/Cons

Adenovirus 8kB I i E i lP: high packaging capacityC li it t t iAdenovirus (AdV) < 8kB In vivo Episomal C: elicits a potent immune response; transiently expressed transgene

Adeno-Associated Vi (AAV)

< 5kB In vivo Episomal

P: non-pathogenic; infects dividing or non-dividing cells

C: Prior exposure immune rejection;Virus (AAV) C: Prior exposure immune rejection; DNA lost through cell division

Retrovirus < 8kB Ex vivo IntegratingP: stable integration into host genomeC: random insertion tumorigenesis risk;

only infects dividing cell types

Lentivirus 8-10kB Ex vivo IntegratingP: infects dividing or non-dividing cells;

reduced tendency to cause cancerC: theoretical tumorigenesis risk

*Indicates how a technology is being used in its current format

Gene Editing n/a Ex vivo Integrating

P: Ability to add, delete or correct genes at the single nucleotide level

C: ↑complexity vs. gene addition;

Emerging Genome-Editing Platforms Facilitate Specific DNA AlterationsFacilitate Specific DNA Alterations

• Gene editing refers to methods that target a double-stranded break in the genome, then directs a specific DNA sequence alteration.

ZFN, TALEN, and CRISPR/Cas9 genome-editing p q

• Four families of engineered nucleases used:– Meganucleases (MEGAs): highly specific due to large

recognition site (dsDNA sequences of 12 to 40 base i )

tools

pairs).

– Zinc finger nucleases (ZFNs): fusion of a zinc finger DNA-binding domain to a DNA-cleavage domain.

– Transcription activator-like effector nucleases (TALENs): fusion of TALE DNA binding domain to a DNA cleavage domain.

– Clustered regularly interspersed shortClustered regularly interspersed short palindromic repeats (CRISPRs): Delivery of Cas9 (an RNA-guided DNA endonuclease enzyme) and appropriate guide RNAs into a cell used to cut the genome at a desired location.

P N tl A d S i USA 93 (3) 1156 60 N t Bi t h l 29 (2) 135 6 N t R i G ti 11 (3) 181 190Proc Natl Acad Sci USA 93 (3): 1156–60.; Nature Biotechnology 29 (2): 135–6.; Nature Reviews Genetics 11 (3): 181–190.

GT May Be Inflecting in Value, But Has Yet To Produce a

Commercially Viable Product

14

Old and New GT Companies Advancing Diverse PlatformsAdvancing Diverse Platforms

Gene EditingGene AugmentationAAV

AdV

Adoptive Cellular I/OLenti p /Lenti-Retro

Plasmid

Other

Partners

15

Indicator of Maturity of GT Platforms: Peer Reviewed PublicationsPeer-Reviewed Publications

Counts of Papers Published on PubMed Per Year Mentioning Each Gene Therapy Approach

1,600

1,800

2,000 Ea

ch Y

ear

g py pp

Adeno-Associated Virus AdenoviralRetroviral LentiviralCRISPR TALENZZN/ZFPs Meganucleases

1,000

1,200

1,400

,

Pub

lishe

d E ZZN/ZFPs Meganucleases

400

600

800

1,000

r of

Pap

ers

P

-

200

400

1985 1987 1989 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011 2013

Num

ber

PubMed

16

Indicator of Maturity of GT Platforms: >200 Programs Advancing in Clinical Trials –

S l ith C i i P CSeveral with Convincing PoC

• Broadly Applicable, Cancer is By Far the Most Active Area for Clinical Trials –Monogenetic Diseases May Be Most Tractable

13

Gene Therapies by All Phases of Developmentn = 574, individual products counted multiple times

68Preclinical

Phase 1/2

Phase 2

329158

Phase 3

Registered

Marketed

Adis R&D Insight; Cortellis

Marketed

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Indicator of Maturity of GT Platforms: IPOs Approaching Historic HighsIPOs Approaching Historic Highs

The combined regenerative medicine field, including cell, gene, and gene‐modified cell therapies, generated $4.74B through partnering deals acquisitions and public and privatepartnering deals, acquisitions, and public and private investments from March 2013 to March 2014.

There are close to 700 clinical trials currently underway with the largest areas of focus in oncology CNS disorders andlargest areas of focus in oncology, CNS disorders, and cardiovascular diseases. And, the clinical pipeline is maturing with over one‐third of those trials in later stages (P2 or P3). The rate of growth is reflected in the public markets: 25% of the biotech IPOs in the second half of 2013 were regenerative medicine companies.

http://www.biospace.com/News/biotech-ipos-up-22-since-bubble-year-of-2000-shows/361523; http://www.poliwogg.com/news/125-sectors-to-watch-in-biotech-and-healthcare-investing

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Indicator of Maturity of GT Platforms: Gene Therapy IPOs & VC Financingpy g

2015

IPO VC Financing

Apr 2015: $64M Series A ;

2014

Apr 2015: $64M Series A ; $29 M Series B

Dec 2014: $185 M

Jun 2014: $117 M

2014

Oct 2013: $50M Series A

Apr 2014: $55M Series B

May 2014: $20 M

Jan 2014: $50 M

Oct 2013: $44 MNov2013: $47M Series A

2013

Oct 2013: $50M Series A

July 2013: $18M Seed CapitalMay 2013: $18.4M Conv. Issue

May 2013: $150M Series F

Jul 2013: $184 M

Nov 2012: $37 5M Series B

2012

2011

Nov 2012: $37.5M Series B

May 2012: $10M Series D Feb 2012: $43M Series D

May 2011: $100M Series E2011EvaluatePharma

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Indicator of Maturity of GT Platforms: Pharma Investment

Gene Therapy Deal Timeline 2012-2015

Jan 2015$6M

Hemophilia A&B

Dec 2014$280M

Hemophilia B

June 2014$252M

Hemophilia A

Aug 2014$4M

Acquisition

June 2014$44M

Acquisition

Oct 2013$1M

Acquisition

Apr 2015$64M

VC Funding

2013 2014 2015

Feb 2015$845M

Parkinson’s

July 2014$1MCV

July 2013$40M

Familial lipoprotein lipase deficiency Jan2015$11M+

April 2015$1B

S100A1CVParkinson s

Disease$CRISPR platform

EvaluatePharma, Company Website

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Gene Therapy Innovator Market Caps

Company Market CapSangamo

5,000

6,000Bluebird

ZioPharm

GenVec

$5.7B

3,000

4,000

ount

s ($

M) AmpliPhi Biosciences

Intrexon

Celladon

$3.07B

$4.3 B

1 000

2,000IPO

Am

o Celladon

AGTC

UniQure

A l h$897M

Bloomberg.com

0

1,000

AAV AdV Lenti ZF

Avalanche

Spark

oo be g co

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T-Cell Therapy Deal Timeline 2014 20152014-2015

Feb 2014$150MCAR‐T

June 2014$350MTCR

Sept 2014$350M

Targeted T‐cells

Opus Bio

Dec 2014$20MCAR‐T

Jan 2015$525MCAR‐T

Jan 2015$150MCAR‐T Mar 2015

CAR‐T

Jan 2015$60MCAR‐T

2014 2015

Jan 2014$13.5M

Acquisition

June 2014$265MCAR‐T

Sept 2014CAR‐T

Oct 2014TCRms

Dec 2014$11mCAR‐T

Mar 2015CAR‐T

Apr 2015CAR‐T

Feb 2015CAR‐T, TCR

EvaluatePharma, Company Website

22

T-Cell Therapy Market Caps

20,000

Market Cap of Leading Biotechsin T-Cell Space by Technology

ZioPharm

Takara Bio

14,000

16,000

18,000 Sangamo Biosciences

MolMed

MacroGenics

Lion Biotechnology

$17B

10,000

12,000

rket

Cap

($M

)

Lion Biotechnology

Kite Pharma

Juno Therapeutics

Emergent Biosolutions$8.6B

4,000

6,000

8,000

Mar Cellular Biomedicine Grp

Cellectis

Bluebird Bio

Bellicum$2 3B

0

2,000

Bi-specific CAR T TCR CTL Other T celltherapy

TIL

Atara Biotherapeutics

Affimed Therapeutics

$2.3B

$1.2B $797M$536M

Bl bBloomberg.com

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Pharmas Have Renewed Interest in Gene Therapies;p ;

However, Issues Remain

• Translation of preclinical results into manp– Delivery, Stability, Immunogenicity– Safety – e.g. anaphylaxis, insertional mutagenesis, cytokine storm

• Higher regulatory scrutiny – Innovative clinical endpoints necessary– RAC review

• Does not fit nicely into Pharma scalability model– Complicated IP and stacking royalties– Individualized vs. one-size fits all– Involves devices and process

M f t i R d ibilit S l bilit Hi h t f d• Manufacturing: Reproducibility, Scalability, High cost of goods• Market Access: Value-based pricing in different payer systems• Bioethics: Boundaries of use, Testing in vulnerable populations

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Recent Gene Therapy News Highlights Progress and Remaining IssuesProgress and Remaining Issues

FDA Panel Gives a Thumbs Up to Amgen's T-Vec For Melanoma

April 29, 2015

Amgen's regulatory team for talimogene laherparepvec (T-Vec) was grilled by a group of outside FDA experts who picked up on some major questions regarding the Phase III melanoma study that was used to back its new drug application. A vigorous defense of the drug, though, helped make a winning case for the therapy, which was ultimately supported by all but one memberof the panelof the panel.

There was considerable sentiment in favor of restricting the drug to certain patient groups, with some of the panelists expressing their frustration that they couldn't register a vote regarding the low likelihood that the drug would work for visceral (internal) tumors or later-stage patients.

At the end of the day, though, the expanded panel voted 22 to 1 that the drug has a favorable risk/benefit profile. T-Vec is injected directly into tumors, where it replicates and then ideally ruptures the tumor cells. The rupture causes the release of antigens which in turn spur the immune system response--a kind of one-two punch that represents a different approach toantigens which in turn spur the immune system response a kind of one two punch that represents a different approach to treating melanoma.

"There are clearly patients in my clinic I'd like to use this for," noted Patrick Hwu, a professor in the department of Melanoma Medical Oncology at the University of Texas MD Anderson Cancer Center who voted to support T-Vec. A number of the experts noted that the more "arrows" they had in their therapeutic quiver, the better off patients would be. The final decision is being left in the hands of the FDA, though today's vote would make T-Vec an odds-on favorite for approval. If so, Amgen ($AMGN) is on track to score several possible approvals this year, marking some advances after analysts like Geoffrey Porges have criticized the Bi Bi t h' d l t t t d h h t Th d t t d ith FDA i ff i k ti lBig Biotech's development strategy and heavy research costs. The day started with FDA reviewers offering some skeptical remarks about their interpretation of the late-stage data. "The evidence that talimogene has a systemic effect was limited and difficult to calculate," FDA reviewer Robert Le told the committee. In particular, committee members noted that there were widely different response rates among different subgroups in the study. For Le, "first line or less advanced patients may have responded better.” “Subjects with small lesions may be more likely to respond," he added, "larger lesions less likely.” […]

http://www.fiercebiotech.com/story/fda-panel-gives-amgen-thumbs-t-vec-melanoma/2015-04-29ttp // e ceb otec co /sto y/ da pa e g es a ge t u bs t ec e a o a/ 0 5 0 9

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GlaxoSmithKline files for gene therapy OK as a case of the jitters sets inM 5 2015May 5, 2015

By John Carroll

GSK CEO Andrew Witty

Close to 5 years after GlaxoSmithKline ($GSK) signed on to collaborate with the San Raffaele Telethon Institute for Gene Therapy in Italy, the partners have stepped up with a European application to start marketing a gene therapy for extraordinarily rare cases of immune deficiency triggered by ADA-SCID. And its delivery into regulatory hands comes as the gene therapy field has beenimmune deficiency triggered by ADA SCID. And its delivery into regulatory hands comes as the gene therapy field has been recoiling from some notable setbacks that have begun to cloud what has been a bullish sector in biotech.

The drug is the rarely mentioned GSK2696273, a gene therapy which uses a viral vector to insert working copies of the ADA gene into stem cells extracted from the bone marrow of patients. The cells are then reintroduced to the patient, who can expect to start making the gene on their own, repairing their immune system.

The Europeans will be reviewing an application built on data from 18 patients, with the first treatment dating back 13 years. All are alive, though three had to have follow-up enzyme replacement therapy or a bone marrow transplant, which is what most of thesealive, though three had to have follow up enzyme replacement therapy or a bone marrow transplant, which is what most of these patients rely on today.

An approval for GlaxoSmithKline in Europe would have wide implications. With so few patients, the center in Italy may well become a Mecca for patients around the world, including the U.S.

"This is an important landmark for clinicians, researchers and all the staff at TIGET who have been working side by side with GSK towards approval of this gene therapy," says Alessandro Aiuti, the clinical research coordinator at TIGET. "In the past years we have witnessed how a single infusion of gene modified stem cells has changed the lives of these children and their families. Ifhave witnessed how a single infusion of gene modified stem cells has changed the lives of these children and their families. If authorized, we will be ready to offer gene therapy at our center to ADA-SCID patients in need from Europe and other countries.

https://www.genomeweb.com/research-funding/nih-places-human-germline-out-bounds-genome-editing-funding

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Recent Gene Therapy News Highlights P d R i i IProgress and Remaining Issues

Celladon Reports Negative Results for CUPID2 Trial of MYDICAR(R) in Advanced Heart Failure

April 26, 2015

- Investigational gene therapy fails to meet primary and secondary endpoints

Celladon Corporation today announced that its Phase 2b CUPID2 trial did not meet its primary and secondary endpoints. CUPID2 is a randomized, double-blind, placebo-controlled, multinational trial evaluating a single, one-time, intracoronary infusion of the cardiovascular gene therapy agent MYDICAR® (AAV1/SERCA2a) versus placebo added to a maximal, optimized heart failure drug and device regimen. In the study, the primary endpoint comparison of MYDICAR to placebo resulted in a hazard ratio of 0.93 (0.53, 1.65 95%CI) (p=0.81), defined as heart failure-related hospitalizations or ambulatory treatment for worsening heart failure. The secondary endpoint comparison of MYDICAR to placebo, defined as all-cause death, need for a mechanical circulatory support device, or heart transplant, likewise failed to show a significant treatment effect. The efficacy endpoint analyses were performed on the (n=243) modified intent to treat population (mITT), which excludes clinical events that occurred in patients who did not receive MYDICAR or placebo, or which occurred prior to dosing. All other exploratory efficacy endpoints (improvement in New Y k H t A i ti l ifi ti 6 Mi t W lk T t d Q lit f Lif ) l i i t t ith t t t ff t NYork Heart Association classification, 6 Minute Walk Test, and Quality of Life) were also inconsistent with a treatment effect. No safety issues were noted.

"We are surprised and very disappointed that MYDICAR failed to meet the endpoints in the CUPID2 trial, and we are rigorously analyzing the data in an attempt to better understand the observed outcome. We would like to express our sincere gratitude toour investigators and patients who participated in the study," said Krisztina Zsebo, Ph.D., CEO of Celladon. "At the same time we are evaluating our other programs in order to determine the best path forward to maximize shareholder value.“

"Thi t i l t l ll t d d d t l t t d th h th i b t th th f il d t hi th i d"This trial was extremely well executed and adequately tested the hypothesis, but the therapy failed to achieve the primary and secondary endpoints. However, there were no safety issues," said Barry Greenberg, M.D., FACC, Director, Advanced Heart Failure Treatment Program; Distinguished Professor of Medicine, University of California, San Diego, and the Chairman of the Executive Clinical Steering Committee of the CUPID2 trial.

http://ir.celladon.com/releasedetail.cfm?releaseid=908592

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A Gene Therapy 'Cure' For Blindness Starts to Fade Within a Few YearsMay 4, 2014

Th t k h th i d h id tt ti th d t th i i f idi fThe two key reasons why gene therapies command such avid attention these days center on their promise of providing a cure for some terrible conditions along with the prospect of a 7-figure price tag. But some prominent investigators at the University of Pennsylvania raised a cautionary note over the weekend, reporting that their "cure" for blindness only worked for one to three years before patients' vision began to fade again. And their decline clearly rattled investors' faith in a hot biotech involved in the same field.

The team, led by Samuel Jacobson, followed up on the experiences of three long-term patients who had received a gene therapy that uses a virus to deliver instructions to the eye to begin producing healthy copies of the RPE65 gene needed to spur production y g p g y p g p pof a vital protein. Mutations in the gene are linked to about 10% of all cases of Leber congenital amaurosis (LCA), an inherited disease.

A number of patients in the group of 15 in the study demonstrated rapid improvement in vision, including the three long-term patients studied in the follow-up. This was one of several small human studies that helped revive expectations for gene therapies. But instead of the permanent cure everyone was hoping for, their vision peaked and then began to decline.

"Our earlier results and these new measurements showed that photoreceptors continued to die at the same rate as they do in the p p ynatural course of the disease, regardless of treatment," said Jacobson in a statement.

But the setback doesn't spell the end of their work. Jacobson concluded that a follow-up treatment could be used to maintain vision, combination therapies could be developed to amp up efficacy and patients could be evaluated to determine which would most likely benefit the most from these therapies.

Spark Therapeutics’ lead therapy delivers a functional copy of the RPE65 gene for LCA patients. The treatment is currently in a Phase III study with 28 patients. And to be fair to the biotechs in this first wave of developers, the limitations of Penn's treatment y p p ,could be limited to the disease or the particular technology it uses to reintroduce the RPE65 gene.

Shares for Spark slipped close to 16% in premarket trading on Monday, wiping out about $200 million in value.

Those are all important considerations as analysts and insiders in this field speculate how payers could afford gene therapies that may come with a price tag of $1 million or more. Figuring out how to price a therapy with no guarantee of a cure can only complicate matter.

http://www.fiercebiotech.com/story/gene-therapy-cure-blindness-starts-fade-within-few-years/2015-05-04

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NIH Places Human Germline out of Bounds for Genome Editing Fundingg gApril 29, 2015

NEW YORK (GenomeWeb) – Reacting to research published last week in which Chinese scientists conducted germline editing on a non-viable human zygote, the National Institutes of Health today firmly came down in opposition to the use of gene editing technologies in the human germline.

"NIH will not fund any use of gene-editing technologies in human embryos," NIH Director Francis Collins wrote in a statement bli h d th NIH b itpublished on the NIH website

While technologies like CRISPR/Cas9 provide an "elegant" way of editing the genome, Collins said safety and ethical issues outweighed any potential benefits and added that germline editing “has been viewed almost universally as a line that should not be crossed.”

NIH's stand comes a week after scientists from Sun-yat Sen University in China published a study reporting CRISPR/Cas9 gene editing of the beta-thalassemia gene in nonviable tripronuclear human zygotes. The study confirmed rumors that

i ti t i th t h l t lt th h li d i it t d id d b kl h i th US i tifiscientists were using the technology to alter the human germline and precipitated widespread backlash in the US scientific and popular press.

In his statement, Collins mentioned several legal and regulatory barriers to conducting such research in the US, including the Dickey-Wicker amendment, which forbids federal funding for the creation of human embryos for research, as well as research in which human embryos are destroyed; NIH Guidelines pertaining to the Recombinant DNA Advisory Committee, which states that research proposals for germline changes will not even be considered; and the authority given to the US Food and Drug Administration to regulate gene therapy products under the Public Health Service Act and the Federal Food, Drug, and g g g py p , g,Cosmetic Act

"NIH will continue to support a wide range of innovations in biomedical research, but will do so in a fashion that reflects well-established scientific and ethical principles," Collins said.

https://www.genomeweb.com/research-funding/nih-places-human-germline-out-bounds-genome-editing-fundingttps // ge o e eb co / esea c u d g/ p aces u a ge e out bou ds ge o e ed t g u d g

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Matthew Porteus, MD, PhD

• Introduction:

– Associate Professor of PediatricsAssociate Professor of Pediatrics (Cancer Biology), Stanford University

– Areas of interest in research

• What is state of the art?

– Gene Augmentation vs. Gene Editing

• Involvement with CRISPR Therapeutics Matthew PorteusMatthew Porteus

– How is the ability to raise significant capital in a biotech company changing the advancement of the field compared to the academic setting?

• What specific technologies are likelyWhat specific technologies are likely to impact which disease first?

• What’s down the road?

30

Stewart Abbot, PhD

• Introduction– Executive Director, Integrative Research at

Celgene Cellular Therapeutics (CCT)

• What is Going on at CCT

• How is Celgene employing gene t f d ll l th i

Stewart AbbotStewart Abbot

transfer and cellular therapies across therapeutic areas?

• How is a large pharma company approaching making a business outapproaching making a business out of individualized, potentially one-time treatments?

– Infrastructure, logistics, manufacturing, clinical development/regulatory expertise,clinical development/regulatory expertise, scalability, patient access

31

C ll l Th tiCellular Therapeutics

Gene Therapies for Rare Diseases

Stewart Abbot

20May 2015NON-CONFIDENTIAL


What’s going on at CCT• CCT is a wholly owned subsidiary of Celgene Corporation• Established in 2003 as semi-autonomous group within Celgene• Longstanding interest in human-placental cells (HSC and MSC)• Internal R&D, regulatory, clinical and cell and tissue product

manufacturing capabilitiesD l i ll difi d ll d ti th ti• Developing cell, gene-modified cell and tissue therapeutics

– Primary focus on indications with high unmet clinical needs (rare and not-so-rare)

• Clinical-stage candidates including PDA-002– Diabetic foot ulcers and PAD

• Support chimeric antigen receptor-modified T cell collaborations• Revenue generating activities including biomaterial products and private

tissue and HSC banking (LifebankUSA)tissue and HSC banking (LifebankUSA)• Partnered BiovanceTM and other biomaterial products with Alliqua

Biomedical

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How are we employing gene transfer and cellular therapies• Mechanistic studies

– Medium throughput RNA-silencing studies to define PDAC (MSC-like) cell MoA• Transfection protocols for “whole genome” siRNA and miRNA• Viral transduction – stable cell lines for in vitro and in vivo functional studies

• Potential for product life cycle management– Utilize detailed MoA findings to further augment cell function by engineering in or g g y g g

out CTQ functionality

• Gene-modified cellular candidates– Embracing technology convergences between cell and gene-therapy platforms

Applying platform technologies in areas of high domain knowledge (HSC T cells &– Applying platform technologies in areas of high domain knowledge (HSC, T-cells & oncology)

– Gene modified HSC-derived RBC (DARPA and other partners)– Chimeric antigen modified T-cell candidates

• Celgene collaborations with bluebirdbio and BCM-CAGT leveraging CCT manufacturing and• Celgene collaborations with bluebirdbio and BCM-CAGT leveraging CCT manufacturing and R&D capabilities

• Focus on scientifically-driven product development and practicality of production, distribution etc.

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Pharma Approaches to Individualized Treatments

Rare Disorders

• The individual treatment MarmiteTM analogy:

– “You either love it or you hate it. ”

• Precision medicine versus rare diseases– 7,000 different rare diseases and disorders, 30 million people in the United , , p p

States are living with rare diseases

– Potential for precision medicine initiatives to define individualized treatment subsets within highly common “single” disorders

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CCT’s Experience• Initial focus on expanded allogeneic cell therapies for common disorders

– Immuno-evasive cells, scalable production, lower COGS

• Business models evolving to embrace individualized treatments for orphan indications

– Reimbursement and margins dependent on magnitude of treatment effects

– Ex vivo gene-modification of cellular therapies can overcome PK issues with gene-therapies

l f ll d d h b “ ” l– Potential for rationally-designed therapeutics to be “curative” or at least transformative

– Assumption that high treatment effects can facilitate smaller clinical trials

Leveraging academic clinical experiences– Leveraging academic clinical experiences

• Organizational structures evolving to embrace modality diversity

– CCT organized as semi-autonomous unit within Celgene to develop modality-specific knowledge regulatory infrastructures etcspecific knowledge, regulatory infrastructures etc.

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CCT’s Experience (continued)• Rapidly adapt to evolving scientific, regulatory and commercial

landscapes unencumbered by the potential for large organizationlandscapes unencumbered by the potential for large organization bureaucracy

– Understand, and potentially embrace, initiatives such as Japan’s Pharmaceutical and Medical Device (PMD) Act, Safety of Regenerative Medicine Act

• Focus on making the possible practical– Develop solid understanding of CTQ attributes for each product (non-modified or

gene-modified)– Consider duration of cell and gene-modified manufacturing cell processing and

infrastructure requirements (clean room suites, incubators etc.)– Time in culture = risk & cost in production– Develop robust, comparable and scalable manufacturing and distribution solutions– Leverage expertise in allogeneic cell process development and manufacturing

scale-up approaches to develop autologous cell manufacturing scale-out approaches

– Distribution logistics for frozen and non-frozen products and feedstock– Requirement for JIT processing and rapid release tests

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• Internal or external partnering to rapidly fill capability gaps– Novartis / U. Penn – GSK / Adaptimmune– CCT / Alliqua biomedical

• Embrace new technology developments – CCT / miRNA-based screening– Novartis / Intellia / Caribou– GSK / Celgene / CRISPR Therapeutics

• Check the business model is practical– Orphan versus ultra-orphan

• Patient access for trials• Patient available and reimbursement

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Summary

• Large-pharma increasing comfortable with advanced gene-basedLarge pharma increasing comfortable with advanced gene based therapeutics

• Current clinical success is supporting high levels of investment,e g CARTe.g. CART

• Current investment should support appropriate basic and clinical R&D to ensure some the approaches change the near-future practice of medicinepractice of medicine

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Paul Gallagher, MBA

• Introduction:– President,

Compass Strategic Consulting, Inc.

• Will payers carve out gene therapies in health technologytherapies in health technology assessments, pricing and coverage decisions?

• In planning will innovative t h h

Paul GallagherPaul Gallagher

payment schemes, such as annuities, apply?

• What should developers of gene therapies do to optimize the value t e ap es do to opt e t e a ueof innovations?

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Pricing and market access issues of gene therapies are just beginning to be addressed

• Glybera registered and priced in Germany at €877,400

• No country has carved out specific HTA process to cover

“There is not just one business model for all gene therapies. Different diseases will find different models”

Jorn Aldag, CEO, UniQure

regenerative medicine

• Generally off the radar of payers

I don’t know that this is on anybody’s radar screen, that’s the other issue, I don’t think a lot of senior leaders of our business units really understand.

Member of formulary of major US payer, Dec 2014paye s

• Advocacy groups beginning to look at reimbursement issues

– Alliance for Regenerative

The original annuity payment could … be set with certain types of 're-opener' clauses, such as with patent expiration [death], or if a less expensive new therapy came on line --thus subjecting the gene therapy annuity to the same vagaries Alliance for Regenerative

Medicine

• Calls for innovative payment

of market competition that standard pharmaceuticals face The special case of gene therapy pricing, Troyen A Brennan, James M Wilson, Nature Biotech, Sep 2014

I think it’s very difficult to amortize payments...the business side of this is very much pre determined very highly• Pricing and budget impact

not value are issues in the public domain

side of this is very much pre-determined…very highly regulated industry…for fully insured products there are specific rules – reserve requirements

Member of formulary of major US payer, Dec 2014

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In your planning, assume current payment mechanisms — generally one-time —mechanisms — generally one-time —

until health systems show willingness to carve out some gene therapies

• Remember affordability is a major issue in ex-US markets and coming to the US

• Consider that a new payment mechanism for gene• Consider that a new payment mechanism for gene therapies is asking for special treatment in HTAs and off the radar in the US, less so in the EU

– Innovative payment mechanisms need to beInnovative payment mechanisms need to be specific for product and country / payer within country

• Start early to understand the needs in markets —meet with payersp y

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If new payment mechanisms are necessary for some curative therapies, change will

require a collaborative effort among numerous stakeholders

• Prioritize developing strong clinical, economic and long-term follow-up data based on early analysis of gene therapy HTAs

• Focus on value, start with crystalizing the burden of illness

• Monitor health system structure / policy since they are likely to change based on recent history

• Educate payers, payer influencers and policy makers

• Collaborate with decision makers—use strength in numbers—form a working group and explore options with the budget holders

• Build bridges to patient advocacy groups

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Discussion andQ&AQ&A

Listeners, please type your questions into the Q&A interface in GoToWebinarQ&A interface in GoToWebinar.

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What's Hot & What's Not in Gene Therapies for Rare Diseasesp

May 6, 2015

M d tModerator:

– Mike Rice, MS, MBASenior Consultant, Defined Health

Panelists:

– Matthew Porteus, MD, PhDAssociate Professor of PediatricsAssociate Professor of Pediatrics (Cancer Biology), Stanford University

– Stewart Abbot, PhDExecutive Director, Integrative Research at Celgene Cellular Therapeutics (CCT)Celgene Cellular Therapeutics (CCT)

– Paul Gallagher, MBAPresident, Compass Strategic Consulting

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Thank you forThank you for joining us!

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2015-05-06-web panel gene therapies for rare diseases...

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