Download GS010 - Gensight

Investors Presentation
A leading gene therapy biotechnology company
www.gensight-biologics.com
A leading gene therapy biotechnology
company
Today’s speakers
Thomas Gidoin
Jean-Philippe Combal
Bernard Gilly
Chief Executive Officer
Chief Financial Officer
Chief Operating Officer
•
PIXIUM VISION (Since 2011) Chairman
of the Board, Founder
•
GALDERMA INTERNATIONAL
(2011-2014)
•
DBV TECHNOLOGIES (2012-2015) - VP
Finance
•
FOVEA PHARMA (2005-2009)
Chairman & CEO - sold to Sanofi
•
SANOFI (2010-2011) VP, Strategic
Marketing Ophthalmic Division
•
•
SOFINNOVA PARTNERS (2000-2005)
Managing Partner
•
FOVEA (2006-2011) VP, Director of
Development
IPSEN (2008-2011) – UK Operations
Controller (London) Senior Financial
Analyst (Paris)
•
ERNST & YOUNG (2007-2008) - Auditor
•
TRANSGENE (1992-2000) Chairman &
•
Pharm.D and Ph.D.
•
Ph.D. in biology and bio-economics
CEO
SEPT 2016 │ Non Confidential
Page 3
GenSight: two disruptive proprietary gene therapy technology platforms
Innovative gene therapy
approaches for severe retinal
degenerative pathologies leading
to blindness as well as diseases of
the central nervous system
MTS
GS010: ongoing Phase
III for lead product
candidate dedicated to
Leber Hereditary Optic
Neuropathy (LHON)
2 DISRUPTIVE TECHNOLOGY
PLATFORMS
FOR 2 PRODUCTS
Well positioned to advance
disruptive gene therapy
technologies in ophthalmology to
commercialization
SEPT 2016 │ Non Confidential
OPTOGENETICS
GS030: second lead
product candidate
targeting photoreceptor
degenerative diseases
(RP/AMD)
Page 4
Advanced solutions for severe ophthalmologic diseases
2012
2013
2014
2015
GS010 - LHON
CORPORATE
CLINICAL
PRECLINICAL
2016
2017
2018
FIRST SALES
Phase III start
CLINICAL
GS030 - RP / AMD
PRECLINICAL
Creation
Series A: c. €20m
March 2013
Series B: c. €32m
July 2015
CLINICAL
IPO: c. €45m
July 2016
Euronext Paris
Ticker: SIGHT
First lead product candidate GS010 two years away from BLA submission
SEPT 2016 │ Non Confidential
Page 5
Disruptive gene therapy approaches for
severe retinal degenerative pathologies
leading to blindness
Degenerative retinal diseases
•
The eye transforms light into electric signals
•
Photoreceptor cells are responsible for this conversion
•
Electric signals are sent to the visual cortex of the brain
via the ganglion cells forming the optic nerve
RETINITIS
PIGMENTOSA
(RP)
GEOGRAPHIC
ATROPHY
(Late stage form
of Age-Related
Degeneration AMD)
LEBER’S HEREDITARY OPTIC
NEUROPATHY (LHON)
Degeneration of
retinal ganglion cells
Degeneration
of PRs
Targeting 3 types of uncured diseases : LHON and RP/AMD
Source: Company
SEPT 2016 │ Non Confidential
Page 7
Gene therapy approach to treat vision loss due to retinal disease
1
Genetic disorders or
aging are responsible
for retinal
degenerative diseases
that lead to blindness.
Therapeutic gene is
packaged in a virus
vector (AAV)
2
AAV which contains
the therapeutic gene is
injected into the eye
(intravitreal or
subretinal)
3
AAV vector enters
retinal cells where it
expresses a
therapeutic protein,
that enables the retina
to regain lost function
Source: Company
SEPT 2016 │ Non Confidential
Page 8
Advantages of gene therapy in ophthalmology
THE EYE:
STRATEGIC
TARGET
•
•
•
•
No approved curative treatments for retinal degenerative diseases
Immune privilege, closed system
Easy access
Long-term expression of transduced gene due to low turnover rate of
retinal cells
AAV
SUCCESSFUL
FOR RETINA
• Proven safety and proof of effect in humans
NO OTHER
APPROVED
THERAPEUTIC
APPROACHES
• Genetic replacement therapy for diseases caused by single gene mutations
(LHON)
• Efficient transduction of retinal cells
• Validated manufacturing process
• In-situ insertion of therapeutic gene to stimulate sight in patients with
severe vision loss due to multiple causes, such as RP and AMD
Source: Company
SEPT 2016 │ Non Confidential
Page 9
OPTOGENETICS
MTS PLATFORM
GenSight: solid and advanced product portfolio in ophthalmic gene therapy
RESEARCH
PRECL.
PHASE
I/II
PHASE
III
LAUNCH
Status
Product
Technology
Indication
GS010
MTS
LHON ND4
GS011
MTS
LHON ND1
Undisclosed
mitochondrial
target
MTS
Undisclosed
GS030
Optogenetics
RP
GLP toxicity trials Q3 2016
GS030
Optogenetics
AMD
Enter into Phase I/II with a
delay of 8-12 months
following RP
(Geographic
Atrophy)
FDA & EMA Orphan Drug designation
Phase III trials (RESCUE and
REVERSE) ongoing
Initiate regulatory preclinical
studies as soon as GS010
clinical data are received
Leveraging two high potential technology platforms in several indications
SEPT 2016 │ Non Confidential
Page 10
Ongoing Phase III for our lead product
candidate dedicated to Leber Hereditary
Optic Neuropathy (LHON): GS010
LHON: neuro-degenerative mitochondrial disease characterized by
sudden loss of sight
Evolution of vision from onset
ONSET
3M
6M
Retinal nerve fiber layer thickness average change
12M
30
20
10
2nd EYE
0
Blindness
occurs
sequentially
within 12
months of
onset
-10
-20
-30
TIME
Image source: illustrated from Newamn NJ et al., Am J Ophthalmom. 141(6), 1061-1067,2006
Incidence
0.15/100,000
Prevalence 1/31k-40k
Blindness
15-35y
-40
-50
% change vs. baseline
VISION
1st EYE
PRE-ONSET
ONSET
3M
6M
9M
Image source: illustrated from Barboni et al Natural History of Leber’s
Hereditary Optic Neuropathy: An OCT Study
TIME
• Orphan maternally inherited mitochondrial disease
• Painless sudden loss of central vision in the 1st eye with 2nd eye sequentially impaired: symmetric
disease with poor functional visual recovery
• 97% of patients have bilateral involvement <1 year / 25% of cases are simultaneous
• Targets ND4 which accounts for ~75% of LHON in North America & Europe
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Page 12
GenSight’s proprietary gene sequencing encapsulated in AAV
1
Transduction of
retinal cell with
replacement
mitochondrial gene
2
Transcription of
replacement
mitochondrial gene
in the nucleus
3
Delivery of
replacement gene
mRNA to polysomes
located at the
mitochondrial
surface
4
Synthesis,
translocation and
proper localization
of replacement
mitochondrial
protein
The only technology that permits missing mitochondrial proteins to be
shuttled into the mitochondrion to restore energy production
SEPT 2016 │ Non Confidential
Page 13
Phase I/II efficacy results at week 48: very promising data (1/4)
Study design
Results
•
First-in-man, dose-escalation safety study,
single center, Paris XV-XX
•
Four dose levels : 9E9; 3E10; 9E10 and 1.8E11
vg/eye = 4 cohorts ; one additional cohort at
MTD (9E10 ; n=3)
 Excellent systemic safety
•
Each dose tested in three patients, at least 4w
delay between patient 1 & 2
•
Decision to increase the dose taken by a DSMB
 Mostly mild, well tolerated, ocular
side effects that are responsive to
standard therapy
•
Chronic LHON ND4 patients with <20/200
 Typical immune responses
•
Single intra-vitreal injection in the worst
affected eye
 No dose-related toxicity
The primary objectives were successfully met:
GS010 appears to be well tolerated with a good safety profile
Source: Company
SEPT 2016 │ Non Confidential
Page 14
Phase I/II efficacy results at week 48: very promising data (2/4)
ETDRS letters (LogMAR) visual
acuity change from baseline to
week 48
Treated Eye (TE)
LogMAR
Untreated Fellow Eye (UTE)
LogMAR
Outcomes in visual acuity
TE vs UTE (LogMAR)
Patients with ≤ 2y disease
duration (n=5)*
+30 letters
(-0.59)
+13 letters
(-0.25)
+17 letters
Patients with > 2y disease
duration (n=7)
- 4 letters
(0.08)
-3 letters
(0.06)
(-0.338)
No difference
Trends of Improved Visual Acuity
Note (*): excluding as per phase III inclusion criteria with Hand Motion
SEPT 2016 │ Non Confidential
Page 15
Phase I/II efficacy results at week 48: very promising data (3/4)
Mean change from Baseline
Week 0
Week 24
Week 36
Illustration of visual benefit for patient
SHAM
Week 48
GS010
30
Patients <2 years treated
Patients <2 years untreated
Patients >2 years treated
Patients >2 years untreated
10
4
3
0
1
Week 0
17
+11 letters
+17 letters
13
Week 36
6
-3
-5
-6
-4
Sustained and increased improvement over time
in visual acuity for treated eyes in patients with
less than 2 years from onset
Week 48
Source: Company
SEPT 2016 │ Non Confidential
Page 16
Phase I/II efficacy results at week 48: very promising data (4/4)
 Symptom duration impacts magnitude of treatment effect
— VA beneficial trends at week 48 in patients ≤ 2y symptom
duration
— Color vision beneficial trends at week 48 in patients with ≤ 2y
symptom duration, confirmed with subjective outcome from
patients
 Baseline vision status at treatment impacts magnitude of
treatment effect
— Observed in visual field & color vision tests
 Analysis supports protocol strategy for phase III
— Population divided by time from onset
— Effect analyzed on better seeing eye
“Now I can see if
a traffic light is
red or green.
In the subway, I
can read the
names of
stations with
large letters.
I have better
autonomy”
« Phase 1 Patient »
Strong Phase I/II results trends that validate Phase III design
SEPT 2016 │ Non Confidential
Page 17
Two ongoing Phase III trials: time based strategy
One eye of each patient randomized to GS010 or sham
Right Eye
Group #1
Right Eye
Group #2
Primary Comparison: eyes receiving
GS010 vs. eyes receiving sham
GS010
sham
sham
Design
RESCUE
Onset of disease:
≤ 6 months
REVERSE
Onset of disease:
6 months to ≤ 1
year
• Initiation: Q4 2015
• 36 patients in each
• Randomized (one eye
treated vs. sham),
double-masked, shamcontrolled, multi-center
• 21 patients injected as
of June 21, 2016
GS010
Primary outcome
at 48 weeks
• Mean
Difference
in ETDRS/
compared
to eyes
receiving
SHAM
treatment
Secondary outcome at 48 weeks
•
Measure vision gain, vision stabilization, or
reduction in vision decline
•
Best or worst eyes vs. sham
•
Responders analysis:
—
Gain from baseline of 15 or more ETDRS
letters
OR
—
Snellen acuity >20/200
Source: Company
SEPT 2016 │ Non Confidential
Page 18
Numerous development milestones for GS010 through
Phase I/II
48W data
IND
Phase I/II
72W data
Phase I/II
96W data
US
SIV
CTA
Q4 2015
FPFV
PHASE III
2017
2016
RESCUE
REVERSE
LPFV
LPFV
LPLV
RESCUE
REVERSE
LPLV
RESCUE
REVERSE
48W
DATA
START
IND: Investigational New Drug
CTA: Clinical Trial Application
US SIV: US Secondary Investigation
2018
FPFV: First Patient First Visit
LPFV: Last Patient First Visit
LPLV: Last Patient Last Visit
BLA
Submission
Expected
Approval
Initiation of Asian Strategic
Partnership
Objective: obtain the marketing authorization for GS010 within 24 months
An accelerated path to market
SEPT 2016 │ Non Confidential
Page 19
Second lead product candidate
targeting photoreceptor degenerative
diseases (RP/AMD): GS030
RP / AMD: degenerative diseases of photoreceptors leading to blindness
Retinitis Pigmentosa (RP)
•
•
•
Blinding genetic disease with multiple mutations (+100
genes)
Sequential photoreceptor degeneration
Slow & irreversible evolution leading to blindness
Age-Related Macular Degeneration (AMD)
•
•
•
—
—
•
Incidence
15K-20K / year
Prevalence
350K-400K
(1.5 M worldwide)
Blindness Occurence
40-45 years old
Onset of AMD: 55 to 60 years of age
Early form: dry-AMD that evolves with aging to late AMD
Late AMD can either be:
Neovascular form (wet-AMD)
Geographic atrophy
Prevalence of geographic atrophy increases with age
from 3.5% over 75 years to 22% over 90 years
Incidence of AMD
350k - 400k / year
Prevalence of Late
AMD
1.47% with 0.81% geographic
atrophy in at least one eye
Blindness Occurrence
from Late AMD
250 000 with geographic atrophy
accounting from 10 to 20% of
blind patients
Source: Company
SEPT 2016 │ Non Confidential
Page 21
Optogenetics: gene therapy with photosensitive protein
Transferring a gene
encoding lightsensitive protein to
retinal ganglion cells
to restore
photoreceptor
function in cells that
are still wired to the
visual cortex
Restore photoreceptor function in cells
SEPT 2016 │ Non Confidential
Page 22
GS030: stimulating the eye with light through gene therapy
1
3
2
AAV2.7m8
+
+ ChrimsonR
Gene therapy
transfer of
light
sensitive
protein
Expression in
retinal cells
Stimulation with optoelectronic device
External visual interface transforms
external light stimuli into signal that
activates the transduced retinal cells
Source: Company
SEPT 2016 │ Non Confidential
Page 23
GS030: activation and stimulation of photoreceptors
GS030 proof of concept in non-human primates at 2 months post-injection
1.
GS030 injected
intravitreally in normal
primates
2.
Retina is isolated at week
8 and placed on multielectrode array
3.
Retinal ganglion cells are
stimulated with red light
at 600 nm
4.
Firing of RGCs is
measured in response to
different light levels
whilst photoreceptor
signaling is chemically
blocked
5.
GS030-engineered RGCs
fire in response to light
Bilateral IVT administration with 5x1011 VG/eye (in 100 µL)
* Partial data; experiments still ongoing
Solid results to enter into clinical phase I in 2017
SEPT 2016 │ Non Confidential
Page 24
No adverse effect associated with GS030 in non-human primates
Bilateral IVT administration with 5x1011 VG/eye (in 100 µL)
Ophthalmology examinations
(n=8 or 4 eyes)
•
•
Normal in all animals at 2 months (n=8 eyes)
Normal in all animals at 3 & 6 months (n=4 eyes)
Histopathology
(n=2 eyes/ timepoint)
•
Eye tissues: no ocular inflammation
•
Other tissues: no histological findings
Retina structural modifications
(n=2 eyes/ timepoint)
•
No apparent structural modifications of the retina (layer
thickness and structures)
No retinal cell degeneration or necrosis
•
• Very mild increase in humoral immune response (NAb) in serum at 2 months, none at 6 months
• No NAb in aqueous humor from both eyes at 2 & 6 months
GS030 expression does not lead to retinal inflammation nor pathological
modifications of the retina
Source: Company
SEPT 2016 │ Non Confidential
Page 25
Key development milestones for GS030
Initiation of
Pivotal Trials
2016
ODD
2017
SA
EMA
CTA
2018
PreIDE
Early data
from Phase I/II
Patients
GMP like
Batches
GLP Regulatory
Tox Study in Monkeys
2019
48 w data
from Phase
I/II
Initiation of Phase I/II in RP
Patients subject to tox results
ODD: Orphan Drug Designation
CTA: Clinical Trial Application
EMA: European Medicines Agency
IDE: Investigational Device Exemption
SEPT 2016 │ Non Confidential
Page 26
Building a high strategic value
Curing blindness represents major market opportunity
Geographical Split - Blind people in major markets
285m people
visually impaired
North
America
3.2m
Europe
3.0m
Asia
16m
39m
totally blind
Blindness
6M BLIND
PEOPLE IN
NORTH AMERICA
AND EU
RP and AMD are the main
causes of blindness in
Europe and in the US
Total blindness costs
exceed tens of billions
of USD per annum
No curative treatment exists for blind patients
Source: WHO, IAPB-VISION2020, NORC-Univ. of Chicago / The Economic Burden of Vision Loss and Eye Disorders in the United States, 2014
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Page 28
Favorable reimbursement conditions
Gene therapy in ophthalmology for rare diseases could be
considered similar to organ transplants for payers
Blindness represents a high burden to health systems
(direct medical costs and long term care)
Increasing pressure from patients and patients associations
due to the absence of curative treatments
SEPT 2016 │ Non Confidential
Page 29
Pricing and prevalence: organ transplant / gene therapy
Orphan Therapy Annual
Cost per Patient ($)
$600 000
Transplant cost per patient
to 180 days
$1 500 000
INTESTINE
$550 000
$1 350 000
CARBAGLU
$500 000
HEART
$450 000
$1 200 000
ELAPRASE
$400 000
$1 050 000
CINRYSZ
LUNG
SOLIRIS
ORFADIN
NAGLAZYME
$350 000
$300 000
ARCALYST
$250 000
ALLOGENEIC BONE MARROW
$200 000
$150 000
$750 000
MYOZYME
ALDURAZYME
FABRAZYME
PANCREAS
$600 000
LIVER
CEREZYME
AUTOLOGOUS BONE MARROW
REMODULIN ZAVESCA
$100 000
$900 000
$450 000
KIDNEY
$300 000
ILARIS
KUVAN
$150 000
TRACLEER
$50 000
$0
$0
0
2 000
4 000
6 000
8 000
10 000
12 000
Addressable market (patients)
14 000
16 000
Transplant
18 000
Drug
Orphan therapies and transplants: a relevant pricing benchmark
Source: Nature Biotechnology, Volume 33, Number 9, September 2015: The payers’ perspective on gene therapy
SEPT 2016 │ Non Confidential
Page 30
Potential applications of GenSight technology platforms
Current focus
Potential applications
MTS
PLATFORM
Other LHON
NARP
Leigh Syndrome
Dominant Optic
Atrophy
Amyotrophic Lateral
Sclerosis
Parkinson’s
LHON
RP
AMD
OPTOGENETICS
PLATFORM
SENSORIAL
NON-SENSORIAL
Dry-AMD
Vagus Nerve
Stimulation
Congenital Deafness
Rare Diseases
Ability to leverage technology platforms and significant expertise to expand
the pipeline in ophthalmology and other neurodegenerative disorders
SEPT 2016 │ Non Confidential
Page 31
Appendix
Strong support from eminent Key Opinion Leaders
Alfredo Sadun, M.D., Ph.D.
Doheny Eye Institute, University of California, Los Angeles
Patrick Yu-Wai-Man, M.D., Ph.D., FRCOpth
Moorfields Eye Hospital NHS Foundation Trust, London
Pr. José-Alain Sahel, M.D., Ph.D.
Nancy J Newman, M.D.
Vision Institute, Paris
Emory University School of Medicine, Atlanta, Georgia
Pr. Ernst Bamberg, Ph.D.
Pr. Jean Bennett, M.D., Ph.D.
F. M. Kirby Center for Molecular Ophthalmology,
University Of Pennsylvania School Of Medicine
Center for Cellular and Molecular Therapeutics, The
Children’s Hospital of Philadelphia (CHOP)
University of Frankfurt, Germany
Max Planck Institute of Biophysics, Frankfurt
Thomas Klopstock, M.D.
Department of Neurology, University of
Munich, Friedrich-Baur-Institute, Munich
Dr. Luk H. Vandenberghe, Ph.D.
Ocular Genomics Institute, Harvard Medical School
Mark Moster, M.D.
Wills Eye Hospital, Thomas Jefferson University, Philadelphia
Pr. Connie Cepko, Ph.D.
Department of Genetics, Harvard Medical
School
SEPT 2016 │ Non Confidential
Dr. Botond Roska, M.D., Ph.D.
University of Basel
Friedrich Miescher Institute for Biomedical
Research
Valerio Carelli, M.D., Ph.D.
Istituto delle Scienze Neurologiche di Bologna,
Ospedale Bellaria, Bologna
Clinical investigators
Members of the Scientific Advisory Board / Founders
Page 33
Manufacturing agreements with top tier players
GS030
GS030
GS010
GS010
•
Transient triple transfection
•
Transient triple transfection
•
Baculovirus production
•
Preclinical and clinical trials
products
•
Clinical trials and commercial
products
•
•
QA documentation
•
•
Quality control tests
performed at different steps
of production process to
assess product strength,
quality, purity and safety
Full QA & QC documentation
with EMA/FDA GMP
qualification capabilities for
commercial purpose
Non-clinical safety evaluation,
clinical trials and potentially
commercial products
•
Full GMP compliance
•
FDA inspected
SEPT 2016 │ Non Confidential
•
Extensive experience for
commercial QA structure and
agencies’ inspection
management
Page 34
Our MTS Sequence enhances growth and ATP synthesis in LHON Fibroblasts
Survival rate on galactose
Rate of ATP synthesis on galactose
100%
100%
8%
14%
LHON + MTS1
12.7%
56%
LHON + MTS1 & MTS2
54.3%
84%
Fibroblasts
Control
LHON (mutated ND4)
Both MTS1 and MTS2 sequences are necessary for an
efficient transfer of the mitochondrial protein
From patent WO 2006/117250 A2
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Page 35
GS010 / GS030: IP and market exclusivity timelines
Products
Components
Licenses
Associated IP
Patent Term
GS010
Mitochondrial Targeting
Sequence
Worldwide exclusive
license in ophthalmology
MTS/3’UTR mitochondrial
trafficking IP
2026 + PTE/SPC *of 5 years
Non exclusive license
outside of ophthalmology
ORPHAN STATUS - MARKET EXCLUSIVITY
EU: 10 YEARS + 2 YEARS FOR PEDIATRIC
US: 7 YEARS IN THE US + 6 MONTHS FOR PEDIATRIC
Light Sensitive Protein
Worldwide exclusive license in
ophthalmology and nonexclusive license outside of
ophthalmology
ChrimsonR IP
2032 + PTE/SPC*
of 5 years
Engineered AAV
Worldwide exclusive license in
Optogenetics
Vector AAV2 7m8 IP
2032
GS030
ORPHAN STATUS - MARKET EXCLUSIVITY
EU: 10 YEARS + 2 YEARS FOR PEDIATRIC
US: 7 YEARS IN THE US + 6 MONTHS FOR PEDIATRIC
Note: *Patent Term Extension/Supplementary Protection Certificate
SEPT 2016 │ Non Confidential
Page 36
2015 Financial Statements – P&L
In million euros (IFRS)
31/12/2014
31/12/2015
Operating income
1.1
3.6
Research & Development
(6.2)
(10.7)
General & Administration
(1.6)
(6.5) (1)
Operating income (loss)
(6.7)
(13.7)
Financial income (loss)
0.1
0.0
Net income (loss)
(6.7)
(13.7)
Excluding non-recurring items
(6.7)
(10.7) (1)
Note (1): 3.0m of NASDAQ IPO related costs expensed in 2015
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Page 37
2015 Financial Statements – Balance Sheet
In million euros (IFRS)
31/12/2014
31/12/2015
Non-current assets
0.5
1.2
Cash and cash equivalents
10.7
30.1
Short term investments
1.4
-
Other current assets
2.2
5.0
TOTAL ASSETS
14.8
36.3
Shareholders’ equity
10.6
29.3
Non-current liabilities
0.7
0.7
Current liabilities
3.6
6.3
Total liabilities
4.2
7.0
TOTAL LIABILITIES & SHAREHOLDERS’ EQUITY
14.8
36.3
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Page 38
2015 Financial Statements – Cash Flow Statement
In million euros (IFRS)
31/12/2014
31/12/2015
Net cash flows from operating activities
(5.5)
(12.1)
Net cash flows from investment activities
(1.6)
0.6
Net cash flows from financing activities
0.7
30.9 (1)
(Decrease)/Increase in cash and cash equivalents
(6.4)
19.4
CLOSING CASH AND CASH EQUIVALENTS
10.7
30.1
Note (1): Mainly €30.8m net proceeds from our Series B in July 2015
SEPT 2016 │ Non Confidential
Page 39