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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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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
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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
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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
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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
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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
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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
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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
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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;
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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.
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GT May Be Inflecting in Value, But Has Yet To Produce a
Commercially Viable Product
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Old and New GT Companies Advancing Diverse PlatformsAdvancing
Diverse Platforms
Gene EditingGene AugmentationAAV
AdV
Adoptive Cellular I/OLenti p /Lenti-Retro
Plasmid
Other
Partners
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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
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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
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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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Recent Gene Therapy News Highlights Progress and Remaining
IssuesProgress and Remaining Issues
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
27
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Recent Gene Therapy News Highlights Progress and Remaining
IssuesProgress and Remaining Issues
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
28
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Recent Gene Therapy News Highlights Progress and Remaining
IssuesProgress and Remaining Issues
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
29
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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
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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
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C ll l Th tiCellular Therapeutics
Gene Therapies for Rare Diseases
Stewart Abbot
20May 2015NON-CONFIDENTIAL
-
Celgene Cellular Therapeutics (CCT)
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
33
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Celgene Cellular Therapeutics (CCT)
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.
34
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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
35
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Pharma Approaches to Individualized Treatments
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.
36
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Pharma Approaches to Individualized Treatments
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
37
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Pharma Approaches to Individualized Treatments
• 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
38
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Pharma Approaches to Individualized Treatments
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
39
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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?
40
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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
41
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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
42
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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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