What's Hot & What's Not

in Gene Therapies
p
for Rare Diseases
May 6, 2015
M d
Moderator:
t
Mike Rice, MS, MBA
Senior Consultant, Defined Health

Panelists:
Matthew Porteus, MD, PhD
Associate Professor of Pediatrics
(Cancer Biology), Stanford University
Stewart Abbot, PhD
Executive Director, Integrative Research at
Celgene Cellular Therapeutics (CCT)
Paul Gallagher, MBA
President, Compass Strategic Consulting
`

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y Web Panel Discussion
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p
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gy
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and biotech.

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Logistics

The web panel discussion will last 75 minutes

(until 12:15 PDT / 3:15 EDT).
EDT)

Contribute questions via the Q&A GoToWebinar

interface.

We will address the questions intermittently or at the

end. If we dont get to your question, we will respond
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.

Mike Rice
MS, MBA

Senior Consultant
Defined Health

Mike Rice

Pharma Has Benefitted Significantly

by
y Investing
g in Biologics
g
Top-Selling Products (WW Sales $M) 2004 vs. 2014
(coded by conventional vs. biologics)
C
Conventional
ti
l

2004

2014

Lipitor (atorvastatin) - Pfizer

Humira (adalimumab) AbbVie

Z
Zocor
(simvastatin)
( i
t ti ) - MRK

Sovaldi (sofosbuvir) - Gilead

Seretide/Advair (fluticasone;
salmeterol) - GSK

Lantus (insulin glargine

recombinant) - Sanofi

Norvasc (amlodipine) - Pfizer

Rituxan (rituximab) - Roche

Zyprexa
yp
((olanzapine)
p ) - Lillyy

Seretide/Advair (fluticasone,
salmetero)
l t ) - GSK
Avastin (bevacizumab) Roche
Herceptin (trastuzumab) Roche

Nexium (esomeprazole) - AZN

Procrit (epoetin alfa) - J&J
Zoloft (sertraline) - Pfizer

Remicade (infliximab) - J&J

Effexor (venlafaxine) - Wyeth

Crestor (rosuvastatin) - AZN

Plavix (clopidogrel) - BMS

Lyrica (pregabalin) - Pfizer

0
EvaluatePharma

Bi l i
Biologic

5,000

10,000 15,000

5,000 10,000 15,000

Gene and Cell Therapies Next

Advancement Beyond
y
Biologics
g
Therapeutic
Interventions
SmallMolecule
Modulators
Immune
Modulators

Protein
Augmentation
Plasma/tissue
derived
proteins

SMIs
Chaperones
Substrate
Reduction
Transcription /
Translation
enhancers
Epigenetics
E i
i

Recombinant
Recombinant
Proteins
Clotting
factors
Cytokines
Hormones
H
Growth
factors
Enzyme
R l
Replacement

Antibodies

Peptidesand
NucleicAcids

Plasmaderived
Polyclonal Igs

Immune
Modulators

Monoclonal
antibodies

Exon skipping

GeneCorrection
& Augmentation
Viralvectors
Retro/
Lentiviral
AdV
AAV

Antisense
mAB fragments
RNAi /miRNA
Scaffolds
Intrabodies

A
Aptamers/
t
/
Ribozyme

Nonviral
Plasmids/
Fragments
Geneediting
with
Meganucleases
ZincFingers
TALENS
CRISPR/Cas9

CellTherapy/
Regen Med
Autologous
andallogeneic
BMT/Cell
therapy
Othercell
sources: e.g.
ES,iPS
D
Devices
i
Encapsulation
Scaffolds
Implants
Microorgans
Aphaeresis
A h
i

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 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

Components of Gene Transfer Platforms:

Clinical Need, Intervention, Delivery Vector
Adenovirus
AAV

Gene Transfer
Vectors

Retro/Lentiviral
HSV, VACV, SV40
Plasmid/Fragment
Liposome, Other?
Vaccines

Gene
Therapy

Clinical
Need

Monogenic Disease
Infectious Disease
Polygenic Diseases
Oncology
Suicide Gene
Gene Augmentation
Antisense, RNAi

Therapeutic
Intervention

ZFs, CRISPR, TALENs

Ribozymes
Other?

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

Gene Therapies by All Therapeutic Areas

n = 574, individual products counted multiple times

14

13 6

28
203

28
28

29

33
39
Adis R&D Insight,
Thomson Reuters Cortellis

69
56

Oncology
Sensory Disorders
M t b li Disorders
Metabolic
Di d
Cardiovascular Disorders
Neuromuscular Disorders
Hematological Disorders
Neurological Disorders
Neurodegenerative Disorders
Infectious Disease
Immunological Disorders
Musculoskeletal Disorders
Other
Gastrointestinal Disorders
Liver Disorders
Skin Disorders
Genitourinary Disorders
Congenital Disorders
Lung Disorders
Accidents & Injury
Respiratory Disorders
Lymphatic Disorders

Gene Transfer Vectors:

Viral-Based Vectors Used in Majority of Pipeline

Most Advanced in Clinical Development
Gene Therapies in Development by Approach
n=394

13

Adeno-associated virus (AAV)

5
9 7

Other gene therapy

14

Adenovirus

15

122

Lentiviral vector
Plasmid

15

Cancer vaccine
16

Fragment/DNA
R
Retroviral
i l

23

T cell therapy
Cell therapy
Other viral vector

38

Oncolytic virus
65
49

Adis R&D Insight,

Thomson Reuters Cortellis

10

ZF
Transposon
TALEN/CRISPR

Therapeutic Intervention:

GT Originated as Functional Genomics Tools May

T
Transform
f
IInherited
h it d Di
Disorders
d
and
d Oth
Other Di
Diseases
Inherited Disorders

Transient

Stable

Enzyme (ERT)

Autologous Cell
Correction

mRNA
ASO / RNAi

Random

Directed

Exon Skipping

Plasmid Transfection

Recombination

mRNA

Viral Integration

Gene Activation

Viral Episomal?

Gene Editing

Triplex
Other epigenetic

11

Allo SCT

Transposons

Meganucleases, ZF,
CRISPR, TALENs,
CRISPR
TALENs SSODN

Cross-Comparison of
Gene
Ge
e Therapy
e apy Platforms
at o s
Technology
Adenovirus
(AdV)
AdenoAssociated
Vi
Virus
(AAV)

Retrovirus

Lentivirus

Gene
Editing

Capacity
< 8kB

< 5kB

< 8kB

8-10kB

n/a

Delivery*

I vivo
In
i

In vivo

Ex vivo

Ex vivo

Ex vivo

Integration

Pros/Cons

E i
Episomal
l

P: high packaging capacity

C elicits
C:
li it a potent
t t immune
i
response;
transiently expressed transgene

Episomal

P: non-pathogenic; infects dividing or

non-dividing cells
C: Prior exposure immune rejection;
DNA lost through cell division

Integrating

P: stable integration into host genome

C: random insertion tumorigenesis risk;
only infects dividing cell types

Integrating

P: infects dividing or non-dividing cells;

reduced tendency to cause cancer
C: theoretical tumorigenesis risk

Integrating

P: Ability to add, delete or correct genes

at the single nucleotide level
C: complexity vs. gene addition; <1x
amplification; limited clinical history

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

Emerging Genome-Editing Platforms

Facilitate Specific DNA Alterations

Gene editing refers to methods that target a

double-stranded break in the genome, then directs
a specific
p
DNA sequence
q
alteration.

ZFN, TALEN, and

CRISPR/Cas9 genome-editing
tools

Four families of engineered nucleases used:

Meganucleases (MEGAs): highly specific due to large
recognition site (dsDNA sequences of 12 to 40 base
pairs).
i )
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 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
Proc
Natl
N tl A
Acad
dS
Scii USA 93 (3)
(3): 1156
115660.;
60 Nature
N t
Bi t h l
Biotechnology
29 (2)
(2): 135
1356.;
6 N
Nature
t
R
Reviews
i
G
Genetics
ti 11 (3)
(3): 181
181190.
190

GT May Be Inflecting in Value,

But Has Yet To Produce a
Commercially Viable Product

14

Old and New GT Companies

Advancing Diverse Platforms
Gene Augmentation

Gene Editing

AAV

AdV

LentiLenti
Retro

Plasmid

Other
Partners

15

Adoptive
p
Cellular I/O
/

Indicator of Maturity of GT Platforms:

Peer Reviewed Publications
Peer-Reviewed

Numberr of Papers P
Published E
Each Year

Counts of Papers Published on PubMed Per Year

g Each Gene Therapy
py Approach
pp
Mentioning
2,000
1,800
1,600
,

Adeno-Associated Virus
Retroviral
CRISPR
ZZN/ZFPs

Adenoviral
Lentiviral
TALEN
Meganucleases

1,400
1,200
1,000
800
600
400
200
1985 1987 1989 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011 2013

PubMed

16

Indicator of Maturity of GT Platforms:

>200 Programs Advancing in Clinical Trials
S
Several
l with
ith Convincing
C
i i
PoC
P C

Broadly Applicable, Cancer is By Far the Most Active Area for Clinical Trials
Monogenetic Diseases May Be Most Tractable
Gene Therapies by All Phases of Development
n = 574, individual products counted multiple times
13
68

Preclinical
Phase 1/2
Phase 2
Phase 3

158

329

Registered
Marketed

Adis R&D Insight; Cortellis

17

Indicator of Maturity of GT Platforms:

IPOs Approaching Historic Highs

Thecombinedregenerativemedicinefield,includingcell,gene,
andgenemodifiedcelltherapies,generated$4.74Bthrough
partnering deals acquisitions and public and private
partneringdeals,acquisitions,andpublicandprivate
investmentsfromMarch2013toMarch2014.
Therearecloseto700clinicaltrialscurrentlyunderwaywiththe
largest areas of focus in oncology CNS disorders and
largestareasoffocusinoncology,CNSdisorders,and
cardiovasculardiseases.And,theclinicalpipelineismaturing
withoveronethirdofthosetrialsinlaterstages(P2orP3).The
rateofgrowthisreflectedinthepublicmarkets:25%ofthe
biotechIPOsinthesecondhalfof2013wereregenerative
medicinecompanies.
http://www.biospace.com/News/biotech-ipos-up-22-since-bubble-year-of-2000-shows/361523; http://www.poliwogg.com/news/125-sectors-to-watchin-biotech-and-healthcare-investing

18

Indicator of Maturity of GT Platforms:

Gene Therapy
py IPOs & VC Financing
g
IPO

VC Financing
2015

Apr 2015: $64M Series A ;

$29 M Series B

Dec 2014: $185 M

Jun 2014: $117 M
May 2014: $20 M

2014

Apr 2014: $55M

Series B

Jan 2014: $50 M

Nov2013: $47M Series A

Oct 2013: $44 M

Jul 2013: $184 M

Oct 2013: $50M Series A

2013

July 2013: $18M Seed Capital

May 2013: $18.4M Conv. Issue
May 2013: $150M Series F
Nov 2012: $37.5M
$37 5M Series B

EvaluatePharma

19

2012

May 2012: $10M Series D

Feb 2012: $43M Series D

2011

May 2011: $100M Series E

Indicator of Maturity of GT Platforms:

Pharma Investment
Gene Therapy Deal Timeline 2012-2015
Oct 2013
$1M
Acquisition

June 2014
$44M
Acquisition

2013

July 2013
$40M
Familial lipoprotein
lipase deficiency
EvaluatePharma, Company Website

20

June 2014
Aug 2014
Dec 2014
Jan 2015
$252M
$4M
$280M
$6M
Hemophilia A Acquisition Hemophilia B Hemophilia A&B

2014

July 2014
$1M
CV

Apr 2015
$64M
VC Funding

2015

Jan2015
$11M+
$
CRISPR
platform

Feb 2015
$845M
Parkinsonss
Parkinson
Disease

April 2015
$1B
S100A1
CV

Gene Therapy Innovator Market Caps

Company Market Cap
Sangamo
Bluebird

$5.7B

6,000

ZioPharm
5,000

GenVec

IPO Amo
ounts ($M)

$4.3 B

AmpliPhi Biosciences

4,000

Intrexon

$3.07B

3,000

Celladon
AGTC

2,000

UniQure
$897M

1 000
1,000

A l
Avalanche
h
Spark

0
AAV
Bloomberg.com
oo be g co

21

AdV

Lenti

ZF

T-Cell Therapy Deal Timeline

2014 2015
2014-2015

Feb2014
$150M
CART

June2014
$350M
TCR

Sept2014
$350M
Dec2014
TargetedTcells $20M
CART

Jan2015
$525M
CART

Jan2015
$60M
CART

Jan2015
$150M
CART

Mar2015
CART

Opus Bio

2014

Jan2014
$13.5M
Acquisition

June2014
$265M
CART

EvaluatePharma, Company Website

22

Sept2014
CART

2015

Oct2014
TCRms

Dec2014
$11m
CART

Feb2015
CART,TCR

Mar2015
CART

Apr2015
CART

T-Cell Therapy Market Caps

Market Cap of Leading Biotechs
in T-Cell Space by Technology

ZioPharm

20,000

Takara Bio

18,000

Sangamo Biosciences

$17B

MolMed

16,000

MacroGenics

Marrket Cap ($M)

14,000

Lion Biotechnology
Kite Pharma

12,000

Juno Therapeutics

10,000

Emergent Biosolutions

$8.6B

8,000

Cellular Biomedicine Grp

Cellectis

6,000

Bluebird Bio
4,000

Bellicum

$2 3B
$2.3B

2,000

$1.2B

$797M

Atara Biotherapeutics
$536M

0
Bi-specific
Bloomberg.com
Bl
b

23

CAR T

TCR

CTL

Other T cell
therapy

TIL

Affimed Therapeutics

Pharmas Have Renewed Interest in

Gene Therapies;
p ;
However, Issues Remain

24

Translation of p
preclinical results into man

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
Manufacturing:
f t i
R
Reproducibility,
d ibilit Scalability,
S l bilit High
Hi h costt off goods
d

Market Access: Value-based pricing in different payer systems

Bioethics: Boundaries of use, Testing in vulnerable populations

Recent Gene Therapy News Highlights

Progress 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 member
of the panel.
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
response--a
a kind of one
one-two
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 Biotech's
Big
Bi t h' development
d
l
t strategy
t t
and
d heavy
h
research
h costs.
t The
Th day
d started
t t d with
ith FDA reviewers
i
offering
ff i some skeptical
k ti l
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. []
ttp //
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
http://www.fiercebiotech.com/story/fda-panel-gives-amgen-thumbs-t-vec-melanoma/2015-04-29

25

Recent Gene Therapy News Highlights

Progress and Remaining Issues
GlaxoSmithKline files for gene therapy OK as
a case of the jitters sets in
M 5,
May
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
ADA-SCID.
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
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. 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

26

Recent Gene Therapy News Highlights

P
Progress
and
dR
Remaining
i i
IIssues
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 Heart
York
H tA
Association
i ti classification,
l ifi ti
6 Minute
Mi t Walk
W lk Test,
T t and
d Quality
Q lit off Life)
Lif ) were also
l inconsistent
i
i t t with
ith a treatment
t t
t effect.
ff t No
N
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 to
our 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.
"This ttrial
"Thi
i l was extremely
t
l wellll executed
t d and
d adequately
d
t l ttested
t d th
the h
hypothesis,
th i b
butt th
the therapy
th
failed
f il d to
t achieve
hi
the
th primary
i
and
d
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

Recent Gene Therapy News Highlights

Progress and Remaining Issues
A Gene Therapy 'Cure' For Blindness Starts to Fade Within a Few Years
May 4, 2014
Th two
The
t
kkey reasons why
h gene therapies
th
i command
d such
h avid
id attention
tt ti these
th
days
d
center
t on their
th i promise
i off providing
idi a cure for
f
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
y to begin
g producing
p
g healthyy copies
p
of the RPE65 gene
g
needed to spur
p production
p
that uses a virus to deliver instructions to the eye
of 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.
photoreceptors
p
continued to die at the same rate as theyy do in the
"Our earlier results and these new measurements showed that p
natural 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
patients. And to be fair to the biotechs in this first wave of developers,
p , the limitations of Penn's treatment
Phase III studyy with 28 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

Recent Gene Therapy News Highlights

Progress and Remaining Issues
NIH Places Human Germline out of Bounds for
Genome Editing
g Funding
g
April 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
published
bli h d on the
th NIH website
b it
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
scientists
i ti t were using
i the
th technology
t h l
to
t alter
lt the
th human
h
germline
li and
d precipitated
i it t d widespread
id
d backlash
b kl h in
i the
th US scientific
i tifi
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
g Administration to regulate
g
gene
g
therapy
py products
p
under the Public Health Service Act and the Federal Food,, Drug,
g, and
Drug
Cosmetic Act
"NIH will continue to support a wide range of innovations in biomedical research, but will do so in a fashion that reflects wellestablished scientific and ethical principles," Collins said.

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

29

Matthew Porteus, MD, PhD

Introduction:

Associate Professor of Pediatrics

(Cancer Biology), Stanford University

Areas of interest in research

What is state of the art?

Involvement with CRISPR

Therapeutics

30

Gene Augmentation vs. Gene Editing

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 likely

to impact which disease first?

Whats down the road?

Matthew Porteus

Stewart Abbot, PhD

Introduction

What is Going on at CCT

How is Celgene employing gene

t
transfer
f and
d cellular
ll l therapies
th
i
across therapeutic areas?

How is a large pharma company

approaching making a business out
of individualized, potentially onetime treatments?

31

Executive Director, Integrative Research at

Celgene Cellular Therapeutics (CCT)

Infrastructure, logistics, manufacturing,

clinical development/regulatory expertise,
scalability, patient access

Stewart Abbot

C ll l Therapeutics
Cellular
Th
ti

Gene Therapies for Rare Diseases

Stewart Abbot
May 2015
20
NON-CONFIDENTIAL

Celgene Cellular Therapeutics (CCT)

Whats 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 capabilities

D
Developing
l i cell,
ll gene-modified
difi d cellll and
d tissue
ti
therapeutics
th
ti

Clinical-stage candidates including PDA-002

33

Primary focus on indications with high unmet clinical needs

(rare and not-so-rare)
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)

Partnered BiovanceTM and other biomaterial products with Alliqua

Biomedical

Celgene Cellular Therapeutics (CCT)

How are we employing gene transfer and cellular therapies

Mechanistic studies

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

Medium throughput RNA-silencing studies to define PDAC (MSC-like) cell MoA

Utilize detailed MoA findings

g to further augment
g
cell function byy engineering
g
g in or
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,

(HSC T-cells
T cells &
oncology)

Gene modified HSC-derived RBC (DARPA and other partners)

Chimeric antigen modified T-cell candidates

34

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.

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
p p in the United
States are living with rare diseases

Potential for precision medicine initiatives to define individualized treatment

subsets within highly common single disorders

35

Pharma Approaches to
Individualized Treatments
CCTs 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

Potentiall for
f rationally-designed
ll d
d therapeutics
h
to be
b curative

or at least
l
transformative

Assumption that high treatment effects can facilitate smaller clinical trials

Leveraging academic clinical experiences

Organizational structures evolving to embrace modality diversity

CCT organized as semi-autonomous unit within Celgene to develop modalityspecific knowledge

knowledge, regulatory infrastructures etc.

36

Pharma Approaches to
Individualized Treatments
CCTs Experience (continued)

Rapidly adapt to evolving scientific, regulatory and commercial

landscapes unencumbered by the potential for large organization
bureaucracy

37

Understand, and potentially embrace, initiatives such as Japans 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

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

Pharma Approaches to
Individualized Treatments
Summary

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

Current clinical success is supporting high levels of investment,

e g CART
e.g.

Current investment should support appropriate basic and clinical

R&D to ensure some the approaches change the near-future
practice of medicine

39

Paul Gallagher, MBA

Introduction:

40

President,
Compass Strategic Consulting, Inc.

Will payers carve out gene

therapies in health technology
assessments, pricing and coverage
decisions?

In planning will innovative

paymentt schemes,
h
such
h as
annuities, apply?

What should developers of gene

ttherapies
e ap es do to optimize
opt
e the
t e value
a ue
of innovations?

Paul Gallagher

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
regenerative medicine

Generally off the radar of

payerss
paye

Advocacy groups beginning

to look at reimbursement
issues

41

Alliance for Regenerative

Medicine

Calls for innovative payment

Pricing and budget impact

not value are issues in the
public domain

There is not just one business model for all gene therapies.
Different diseases will find different models
Jorn Aldag, CEO, UniQure

I dont know that this is on anybodys radar screen, thats the

other issue, I dont think a lot of senior leaders of our business
units really understand.
Member of formulary of major US payer, Dec 2014

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
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 its very difficult to amortize payments...the business

side of this is very much pre-determinedvery
pre determined very highly
regulated industryfor fully insured products there are specific
rules reserve requirements
Member of formulary of major US payer, Dec 2014

In your planning, assume current payment

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

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 be
specific for product and country / payer within country

42

Start early to understand the needs in markets

meet with payers
p y

If new payment mechanisms are necessary

for some curative therapies, change will
require a collaborative effort among
numerous stakeholders

43

Prioritize developing strong clinical, economic and longterm 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 makersuse strength in

numbersform a working group and explore options with
the budget holders

Build bridges to patient advocacy groups

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

44

What's Hot & What's Not

in Gene Therapies
p
for Rare Diseases
May 6, 2015
M d t
Moderator:
Mike Rice, MS, MBA
Senior Consultant, Defined Health

Panelists:
Matthew Porteus, MD, PhD
Associate Professor of Pediatrics
(Cancer Biology), Stanford University
Stewart Abbot, PhD
Executive Director, Integrative Research at
Celgene Cellular Therapeutics (CCT)
Paul Gallagher, MBA
President, Compass Strategic Consulting
`

45

Thank you for

joining us!

46