Developing breakthrough therapies in NASH and...
Transcript of Developing breakthrough therapies in NASH and...
Developing breakthrough therapies inNASH and mucopolysaccharidosis
Corporate PresentationMay 2019
Non-confidential – Property of Inventiva │ 2
DISCLAIMER
This document has been prepared by Inventiva (the "Company") solely for the purpose of this presentation. This presentation includes only summary information and does not purport to be comprehensive. Any information in this presentation, whether from internal or from external sources, is purely indicative and has no contractual value. The information contained in this presentation are provided as at the date of this presentation. Certain information included in this presentation and other statements or materials published or to be published by the Company are not historical facts but are forward-looking statements. The forward-looking statements are based on current beliefs, expectations and assumptions, including, without limitation, assumptions regarding present and future business strategies and market in which the Company operates, and involve known and unknown risk, uncertainties and other factors, which may cause actual results, performance or achievements, or industry results or other events, to be materially different from those expressed or implied by these forward-looking statements. These risks and uncertainties include those discussed or identified under Chapter “Risk factors” in the Company’s registration document (document de reference) filed with the French Financial markets authority (AMF – Autorité des marchésfinanciers), available on the Company’s website (www.inventivapharma.com) and on the website of the AMF. The Company may not actually achieve the plans, intents or expectations disclosed in its forward-looking statements and you should not place undue reliance on the forward-looking statements contained herein. There can be no assurance that the actual results of the Company’s development activities and results of operations will not differ materially from the Company’s expectations. Factors that could cause actual results to differ from expectations include, among others, the Company’s ability to develop safe and effective products, to achieve positive results in clinical trials, to obtain marketing approval and market acceptance for its products, and to enter into and maintain collaborations; as well as the impact of competition and technological change; existing and future regulations affecting the Company’s business; and the future scope of the Company’s patent coverage or that of third parties.
The information contained in this presentation has not been subject to independent verification. No representation or warranty, express or implied, is made by the Company or any of its affiliates, advisors, representatives, agents or employees as to, and no reliance should be placed on, the fairness, accuracy, completeness or correctness of the information, or opinions contained herein. Neither the Company, nor any of its respective affiliates, advisors, representatives, agents or employees, shall bear any responsibility or liability whatsoever (for negligence or otherwise) for any loss howsoever arising from any use of this presentation or its contents or otherwise arising in connection with this presentation. Such information is subject to modification at any time, including without limitation as a result of regulatory changes or changes with respect to market conditions, and neither the Company, nor any of its affiliates, advisors, representatives, agents or employees, shall, nor has any duty to, update you.
Corporate Presentation | 2019
Non-confidential – Property of Inventiva │ 3Corporate Presentation | 2019
Inventiva investment highlights
Clinical stage biotech with focus on oral small molecules for high unmet need in fibrosis, lysosomal storage disorders and oncology
Two unencumbered late stage assets in two high value indications– Lanifibranor – only pan-PPAR agonist in clinical development for NASH, Phase IIb data
due H1 2020– Odiparcil – first orally available therapy for MPS, Phase IIa data due H2 2019
State of the art R&D capabilities including wholly owned ‘pharma scale’ discovery facilities
Portfolio underpinned by discovery engine focused on nuclear receptors, transcription factors and epigenetic targets with a 240,000 compound library, 60% of which are proprietary
Compelling early stage pipeline leveraging power of discovery engine in fibrotic disease and oncology, supported by validating partnerships with AbbVie and Boehringer Ingelheim
– ABBV-157 ROR program: first phase I completed and second one in 60 healthy volunteers and patients with chronic plaque psoriasis due to start in May 2019
– YAP-TEAD program in late pre-clinical stage, clinical candidate selection expected in 2019
Strong US and European shareholder base and experienced senior management team with a track record of operational and scientific excellence
Non-confidential – Property of Inventiva │ 4
Management team with extensive experience across all stages of drug development and commercialization
Corporate Presentation | 2019
Frédéric Cren, MA/MBA, CEO and Co-Founder Wide expertise within the areas of research, development, marketing, strategy and commercial
operations Held senior positions at Abbott, Fournier, Solvay Pharma and The Boston Consulting Group Former member of both Fournier and Solvay Pharma Executive Committees
Jean Volatier, MA, CFO Started his career with PwC in Paris and Philadelphia Former Head of controlling at URGO & Financial Director International Operations of Fournier Held various positions as CFO with Soufflet and Naos groups
Pierre Broqua, Ph.D., CSO and Co-Founder Has successfully managed numerous research programs leading to the discovery,
development and commercialization of innovative compounds, including lanifibranor and Ferring’s GnRH antagonist Degarelix/ Firmagon®
Held several senior research positions at Fournier, Solvay Pharma and Abbott
Marie-Paule Richard, MD, CMO Long and diverse international experience acquired with large pharmaceutical organizations
such as GSK, Aventis, Sanofi Pasteur as well as biotech in CMO roles Former CMO of Belgium biotech Tigenix, recently acquired by Takeda
Non-confidential – Property of Inventiva │ 5
Validated oral small molecule-focused discovery engine targeting nuclear receptors, transcription factors and epigenetic modulation
Corporate Presentation | 2019
Power of discovery engine underpins deep pipeline of clinical and discovery stage assets
Library of ~240,000 compounds of which 60% proprietary
Wholly-owned 129,000 square foot pharma-like R&D facilities
Expertise: nuclear receptors, transcription factors, epigenetic targets
Strong scientific team of ~90 people
Non-confidential – Property of Inventiva │ 6
Deep pipeline approaching major near term value inflection points
Corporate Presentation | 2019
Candidate / Program Indication Discovery IND
Enabling Phase I Phase II Phase III Commercial Rights
Lanifibranor NASHPhase IIb
results: H1 2020
Odiparcil MPS VIPhase IIa
results: H2 2019
ABBV-157 Moderate to severe psoriasis
SAD phase I completed(1)
Hippo Non-small cell lung cancer and mesothelioma
Candidate Selection: 2019
TGF-β Idiopathic pulmonary fibrosis (IPF)
Lead Op(2)
GAG clearance
ROR
pan-PPAR
YAP/TEAD
(1) SAD: Single Ascending Dose; (2) Lead optimization means refining molecules in advance of selecting candidates
Non-confidential – Property of Inventiva │ 7
Key financials and shareholder base
ISIN code FR0013233012
Market Euronext Paris
Shares outstanding 22.294.677Market cap(April 29 2019)
€57m
Cash position(December 31 2018)
€56,7m compared to €59.1m as of December 2017.Successful €48.5m Euronext IPO (February 2017) and €35.5m private placement (April 2018)
Revenues(December 31 2018)
€3.2m compared to €4.8m in 2017
R&D expenditures(December 31 2018)
€31,6m compared to €26,7m in 2017
Key financials Shareholder base
Analyst coverage
HC WainwrightLifeSci CapitalJefferiesKBCSociété GénéraleGilbert DupontKepler Chevreux
Ed ArcePatrick DolezalPeter WelfordLenny Van SteenhuyseDelphine Le LouëtJamila El BougriniArsene Guekam
Corporate Presentation | 2019
Free float*22.1%
BVF15,0%
Novo 8,8%
Sofinnova 7,1%Employees & Others
3,1%
Founders43,9%
*Including Perceptive Advisors
Lanifibranor in NonalcoholicSteatohepatitis (NASH)
Non-confidential – Property of Inventiva │ 9
Lanifibranor: only pan-PPAR agonist in clinical development for the treatment of NASH
Corporate Presentation | 2019
(1) Conducted by Abbott prior to our funding (2) LOE: Loss of exclusivity
Activity
Differentiated chemical structure with moderate and balanced pan-PPAR agonist activity (PPAR, PPAR and PPAR
Oral administration Anti-fibrotic, anti-inflammatory and beneficial metabolic effects observed in preclinical
models Phase IIa(1) trial demonstrated pan-PPAR agonist activity, supporting dose selection for
NASH clinical trial
Safety
Favorable safety profile demonstrated in:• 24-months rodent and 12-month monkey studies, highly differentiated from other PPAR
compounds; first PPAR drug to receive EMA authorization to perform 12 month study in humans in parallel with long-term toxicological studies
• Phase I trials with 125 healthy volunteers and Phase IIa study with 47 TD2M patients• NASH Phase IIb trials with ~75 patients treated for at least 24 weeks with 2 positive
DSMB reviews completed• Systemic sclerosis Phase IIb trial with 97 patients treated for 48 weeks
IP
Composition of matter patent granted in 53 countries: LOE(2) August 2031 including 5-year extension
Use patent granted in US covering several fibrotic diseases including NASH and SSc: LOE(1) 2035
Non-confidential – Property of Inventiva │ 10
Lanifibranor is a differentiated pan-PPAR agonist with moderate and well balanced activity on the 3 PPAR isoforms
Corporate Presentation | 2019
Compound PPAREC50 (nM)
PPAREC50 (nM)
PPAREC50 (nM)
Lanifibranor(1) 1630 850 230
Fenofibrate 2400 - -
Pioglitazone - - 263
Rosiglitazone - - 13
Elafibranor(2) 10 100 -
Seladelpar(3) - 2 -
Lanifibranor human dose response curves and EC50s for various PPAR agonists
-10 -8 -6 -40
25
50
75
100
125
150
%A
ctiv
atio
n
hPPARhPPARhPPAR
Lanifibranor (M)
Potency scale: red 10 nM; grey: 500 nM; green 5 000 nM
Lanifibranor binds differently than rosiglitazone to PPARγ inducing different coactivator recruitment(4)
Source: (1) Company data (2) Hanf R et al, Diabetes & Vascular Dis Res 2014 (3) Cymabay company presentation (4) J Med Chem. 2018 Feb 15. doi: 10.1021/acs.jmedchem.7b01285
Non-confidential – Property of Inventiva │ 11
Favorable safety profile differing from previously developed PPARs
Corporate Presentation | 2019
Organ PPAR isoforms activated
ReportedPPAR liabilities
Lanifibranoreffects
Heart PPAR Fluid retention Cardiac hypertrophy Not observed
Skeletal muscle PPAR Myofiber degeneration Not observed
Kidney PPAR > 50% increases in
creatinine, degenerative changes in renal tubules
Not observed
Urinary bladder PPAR Proliferative changes in bladder epithelium Not observed
Plasma volume and heart weight after administration of PPAR agonists
Source: Company data
Plasma Volume Heart Weight
0
20
40
60
* *
**
Rosi Mura IVA337 Tesa
Plas
ma
volu
me
(mL)
0.0
0.2
0.4
0.6
* * **
Rosi Mura IVA337 Tesa
Hea
rt w
eigh
t (%
BW
) ControlRosi (3 mg/kg/d)Rosi (10 mg/kg/d)Mura (10 mg/kg/d)Mura (100 mg/kg/d)IVA337 (100 mg/kg/d)IVA337 (1000 mg/kg/d)Tesa (1 mg/kg/d)Tesa (10 mg/kg/d)
Lani Lani
LaniLani
mg/kg/day; 9 W rat studySinglePPAR
DualPPAR
DualPPAR
PanPPAR
SinglePPAR
DualPPAR
DualPPAR
PanPPAR
Lanifibranor not associated with plasma volume expansion or heart weight increase
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Phase IIb study in systemic sclerosis confirmed favorable safety profile of lanifibranor
Well conducted 48 week phase IIb clinical trial in early diffuse systemic sclerosis adult patients
The primary endpoint on skin score was not met, nor secondary efficacy endpoints
Lanifibranor showed a favorable trend in patients’ global assessment of disease activity indicating a perceived benefit by patients
Within this fragile and poly-medicated population, lanifibranor was observed to be associated with a favorable safety profile without apparent adverse interactions with immunosuppressive background therapies, and no cardiac or renal safety concerns
Presence of mostly mild or moderate edema maybe due to twice daily administration of lanifibranor possibly leading to higher PPAR pathway activation reflected by high adiponectin levels in a systemic sclerosis population prone to present edema
Adiponectin levels in NATIVE NASH patients significantly lower compared to FASST systemic sclerosis patients
Corporate Presentation | 2019
Non-confidential – Property of Inventiva │ 13
No cardiac or renal safety concern observed in the phase IIb study in systemic sclerosis study after one year of treatment
Corporate Presentation | 2019
Description of fold in creatinine over time – observed cases under treatment - mITT
population
Description of fold in NT-ProBNP over time– observed cases under treatment -
mITT population
Valu
e (M
ean
±95
% C
I)
Week 12 Week 24 Week 48 Week 12 Week 24 Week 48
Valu
e (M
ean
±95
% C
I)Baseline Value (median)Placebo:Lanifibranor 800 mg:Lanifibranor 1200 mg:
71.087.089.0
Baseline Value (median)Placebo:Lanifibranor 800 mg:Lanifibranor 1200 mg:
60.154.857.5
Non-confidential – Property of Inventiva │ 14
Phase I and Phase IIa clinical studies(1) demonstrated beneficial effects on key metabolic markers
Corporate Presentation | 2019
Insulin resistance (HOMA-IR, adiponectin)
Dyslipidemia (increase in HDL-C, reduction of TG)
Lanifibranor metabolic markers in type II diabetic patients
Good overall tolerance and no major safety findings
No increases of creatinine, LFTs, or CPK
No changes in blood pressure
No signal of fluid overload or hemodilution
No clinically relevant weight gain
Clinical findings underline the favorable tolerability of lanifibranor
Source: Company data and * Ohashi, Endocr Metab Immune Disord Drug Targets. 2015. Note: (1) Conducted by Abbott
Placebo 400 mg 800 mg 1400 mg 0
100
200
300
IVA337 IVA337IVA337
p=0.08
p=0.05
p=0.05
Perc
ent c
hang
e of
bas
elin
e
Adiponectin (PPAR)
Perc
ent c
hang
e fr
om b
asel
ine
lanifibranor lanifibranor lanifibranorPlacebo 400 mg 800 mg 1400 mg
0
10
20
30
40
IVA337 IVA337IVA337
p=0.13
p<0.05
p<0.05
Perc
ent c
hang
e of
bas
elin
e
HDL Cholesterol (PPAR)
Perc
ent c
hang
e fr
om b
asel
ine
lanifibranor lanifibranor lanifibranorPlacebo 400 mg 800 mg 1400 mg
-50
-40
-30
-20
-10
0
IVA337 IVA337IVA337
p=0.08
p<0.05p<0.05
Perc
ent c
hang
e of
bas
elin
e
Triglycerides (PPAR)
Perc
ent c
hang
e fr
om b
asel
ine
lanifibranor lanifibranor lanifibranor
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NASH overview
Source: NASH Market, Allied Market Research 2016 ; Deutsche Bank Markets Research; Intercept website.; Epidemiology and natural history of non-alcoholic steatohepatitis.Clinical Liver Disease.2009 Nov;13(4):511-31.
Corporate Presentation | 2019
The overall NASH prevalence in the adult population of the United States is believed to be approximately 12%
A severe disease with no currently approved treatment
Hepato-carcinoma Death
Liver transplant
Reversible40-50%
15-20%
Severe liverdamage
HealthyLiver
NASHNAFLD
Cirrhosis
NASHwith
fibrosis 2-3% per year 30-40%
Non-confidential – Property of Inventiva │ 16
Lanifibranor’s mechanism of action addresses all the key features of NASH
Corporate Presentation | 2019
Insulin sensitivity
HDLc
TG
PPAR
Metabolism
FA uptake
FA catabolism
Lipogenesis
PPAR,
Steatosis
Inflammation and Ballooning
NFkB-dependent gene activation
Inflammasome
Ballooning
PPAR
Stellate cell proliferation and activation
Collagen and fibronectin production
PPAR
Fibrosis
Non-confidential – Property of Inventiva │ 17
Lanifibranor: differentiated potential to address all features of NASH in safe and efficacious manner
Corporate Presentation | 2019
Lanifibranor Ocaliva Elafibranor Cenicriviroc MGL-3196
Metabolism
Steato-hepatitis
Necro-inflammation Unclear
Fibrosis Unclear
Non-confidential – Property of Inventiva │ 18
PPAR efficacy is well established in NASH
Corporate Presentation | 2019
PPAR activation by pioglitazone significantly improves steatosis, ballooning and inflammation as well as metabolic markers in NASH patients after 6 months or 18 months of treatment:
Pioglitazone (PPAR) Belfort NASH study6 month treatment
Cusi NASH study18 month treatment
Placebo Pio P Placebo Pio P
Steatosis (% patients improved) 38% 65% 0.001 26% 71% < 0.001
Inflammation (% patients improved) 29% 65% 0.001 22% 49% < 0.001
Ballooning (% patients improved) 24% 54% 0.001 24% 51% < 0.001
NASH resolution (% patients) - NA - 19% 51% < 0.001
Fibrosis (mean change in score) - NS - 0 - 0.5 = 0.039
Pioglitazone improves advanced fibrosis(stage F3-F4) as indicated by an increasein the number of NASH patients whosefibrosis stage changed from F3-F4 to F0-F2 at the end of treatment
Source: Corey KE and Malhi H, Hepatology 2016. Note: clinical trial not conducted by Inventiva
Non-confidential – Property of Inventiva │ 19
Pioglitazone PPAR NASH resolution efficacy results are still unmatched
Corporate Presentation | 2019
Pioglitazone Cusi study (45 mg, 18 month), Annals of Internal Medicine, 2016 ; Ocaliva Regenerate Phase III study (25 mg, 18 months), press release Feb. 19, 2019
CVC Centaur Phase II study (150 mg, 12 months), Hepatology 2017 ; Elafibranor Golden 505 Phase II study (120 mg, 12 months), Gastroenterology. 2016
MGL-3196 Phase II study (100mg, 8 months), press release May 31, 2018 ; Aramchol Arrest Phase II study (600 mg, 12 months) – press release June 12, 2018
pbo19%
pbo8%
pbo12% pbo
6%pbo6%
pbo7%
51%
12%19%
8%
27%
19%
0%
10%
20%
30%
40%
50%
60%
Pioglitazone Ocaliva Elafibranor CVC MGL-3196 Aramchol
Patie
nts
with
impr
ovem
ent,
%
Resolution of NASH without worsening of fibrosis
Non-confidential – Property of Inventiva │ 20
PPAR activity can also be completed by PPARand efficacy
Corporate Presentation | 2019
Source: Ratziu V, et al. Gastroenterology 2016. Note: (1) GOLDEN 505 study conducted by Genfit
PPAR/ activation by elafibranor leads to significant improvement of ballooning and inflammation as well as metabolic markers in NASH patients after 12 months of treatment(1):
NASH resolution in ITT: 19% vs 12%, p = 0.045
Steatosis in patients with bNAS>4 (% patients improved ): 35% vs 18%, NS
Inflammation in patients with bNAS>4 (% patients improved ): 55% vs 33%, p < 0.05
Ballooning in patients with bNAS>4 (% patients improved ): 45% vs 23%, p = 0.02
Patients with resolved NASH showed significant reduction in liver fibrosis while non-responders did not show any change from baseline
Non-confidential – Property of Inventiva │ 21
Lanifibranor significantly reduces steatosis, inflammation, ballooning and fibrosis in preclinical models
Corporate Presentation | 2019
Source: Company data; The new-generation Pan-Peroxisome Proliferator-Activated Receptor Agonist IVA337 Protects the Liver From Metabolic Disorders and Fibrosis; Hepatology Communications, June 2017
Lanifibranor associated with beneficial effects on all NASH-relevant liver features
Oil + vehicleCCL4 + vehicleCCL4 + Lanifibranor 15 mg/kgCCL4 + Lanifibranor 30 mg/kg
0
1
2
3
*** ******
**
% o
f are
a
3 weeks 3 + 3 weeks
NAS-ballooning
0.0
0.5
1.0
1.5
2.0
*** ******ba
lloon
ing
scor
e
HFD(High Fat
Diet)
ND(Normal
Diet)
HFD + Lanifibranor 10 mg/kg
HFD + Lanifibranor 30 mg/kg
0
1
2
3
Aver
age
infla
mm
ator
y sc
ore
(His
tolo
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Vehicle Lanifibranor10mg/kg
Lanifibranor30mg/kg
******
Inflammation
Ballooning
0
100
200
300
400
Aver
age
num
ber o
f lip
id d
ropl
ets/
HPF
Vehicle Lanifibranor10mg/kg
Lanifibranor30mg/kg
*** ***
NAS score
High Fa
t Diet
IVA337 1
0 mg/k
gIVA33
7 30 m
g/kg
Contro
l Diet
0
2
4
6
8
10**
******
NAS Score
Lanifibranor inhibits steatosis and inflammation in the MCD model
Lanifibranor reverses established liver fibrosis in CCL4 models
Lanifibranor significantly reduces ballooning and the NAS score in the foz/foz model
Steatosis
CCl4 model
HFD(High Fat
Diet)
ND(Normal
Diet)
HFD + Lanifibranor 10 mg/kg
HFD + Lanifibranor 30 mg/kg
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Lanifibranor potently reverses NASH in an established preclinical model
Corporate Presentation | 2019
Source: EASL 2019 presentation: Differential therapeutic effects of single and pan-PPAR agonists on steatosis, inflammation, macrophage composition and fibrosis in a murine model of non-alcoholic steatohepatitis
Control Diet CDAA + Vehicle
CDAA + Lanifibranor(Pan-PPAR)
CDAA + Fenofibrate(PPAR)
CDAA + GW501516 (PPAR)
CDAA + Pioglitazone (PPAR)
The pan-PPAR agonist lanifibranor ameliorates hepatic steatosis, inflammation and fibrosis.Lanifibranor shows stronger effect than single-PPAR approaches
CDAA-HFD: choline-deficient, L-amino acid-defined plus high fat diet* denotes the level of significance compared to CDAA + Vehicle# denotes the level of significance compared to CDAA + Lanifibranor
Steatosis Inflammation Ballooning NAFLD Activity Score
• pan-PPAR Lanifibranor, 30mg/kg/day• PPARα Fenofibrate, 100mg/kg/day
n = 6 for Control, n = 8 for CDAA-HFD groups; 12W treatment (6W CDAA-HFD + 6W CDAA-HFD + selected PPAR or vehicle)
• PPARγ Pioglitazone, 30mg/kg/day• PPARδ GW501516, 10mg/kg/day
Non-confidential – Property of Inventiva │ 23
Overview of NATIVE trial design (I/II)
Corporate Presentation | 2019
More information on: http://www.native-trial.com/
Trial design
225 patients24 week treatment
Double blind randomized placebo controlledEnd of treatment Liver biopsyPlacebo, 75 patients
Lanifibranor, 800 mg once daily, 75 patientsLanifibranor, 1200 mg once daily, 75 patients
Principal investigator Prof. Francque (Universitair Ziekenhuis, Antwerpen,
Belgium) Prof. Manal Abdelmalek (Duke University, USA)Randomisation 1/1/1, stratification on T2DM patients Study powered with 75 patients per groupStatus Trial enrolling Results expected first-half 2020
Clinicaltrials.gov identifier: NCT03008070
Inclusion criteria Liver biopsy Severe patients with an inflammation and
ballooning score of 3 or 4 Steatosis score ≥ 1 and fibrosis score < 4 (no
cirrhosis)Primary endpoint Decrease from baseline ≥ 2 points of the
inflammation and ballooning score without worsening of fibrosis
Central reading
Screening Liver biopsy
Non-confidential – Property of Inventiva │ 24
Overview of NATIVE trial design (II/II)
Corporate Presentation | 2019
17 countries worldwide► 13 in EU► United States► Canada► Australia► Mauritius
92 sites involved86 sites activated74 sites screening
Status April 26, 2019: 674 patients screened, 178 patients randomized 3 positive DSMB reviews
Results expected first-half 2020
14 sites selected in the United-States
Non-confidential – Property of Inventiva │ 25
NATIVE study results will also be backed by the Phase II trial in T2DM patients with NAFLD
(1) Intrahepatic triglycerides (2) Magnetic resonance elastography (3) De-novo lipogenesis
A positive study result would further reinforce lanifibranor’s profile in NAFLD and NASH patients with type 2 diabetes
Corporate Presentation | 2019
64 patients24 week treatment
Double blind randomized placebo controlled
Healthy non-obese control group, 10 subjectsPlacebo, 32 patientsLanifibranor, 800 mg once daily, 32 patients
Principal investigator Prof. Kenneth Cusi (University of Florida)Randomisation Randomized (1:1), double-blind, placebo-controlled Non-obese subject control group for the metabolic
and imaging procedures N=64 calculated assuming a 35% relative reduction
of IHGT(1)
StatusIND approved First Patient First Visit: August 2018
Results expected first-half of 2020
Primary endpoint Change from baseline to week 24 in IHTGKey secondary endpoints Proportion of responders (IHTG, NAFLD
resolution) Change in hepatic fibrosis (MRE(2), biomarkers) Change in metabolic outcomes (insulin
sensitivity, DNL(3), glycemic control, lipids) SafetyClinicaltrials.gov identifier: NCT03459079
Trial design
Non-confidential – Property of Inventiva │ 26
PanNASH Initiative: a group of well recognized international experts working to promote NASH and the role of PPARs
Corporate Presentation | 2019
Specialty Country Member AffiliationHepatology Belgium Pr. Sven Francque Antwerp University Hospital
Hepatology Germany Pr. Frank Tacke University Hospital Aachen
Hepatology Switzerland Pr. Jean-François Dufour University Clinic Bern
Hepatology United States Pr. Manal Abdelmalek Duke University
Hepatology United States Pr. Gyongyi Szabo University of Massachusetts
Diabetology Germany Pr. Michael Roden Heinrich Heine University
Diabetology United States Pr. Kenneth Cusi University of Florida
Cardiology UK Pr. Christopher Byrne University of Southampton
Cardiology United States Pr. Frank Sacks Harvard T.H. Chan School of Public Health
Inventiva created panNASH™, a committee of international independent experts aiming to play an active role in developing and disseminating their NASH expertise among the scientific community, patients and other key stakeholders within the healthcare system. The committee includes European and American medical experts in areas related to NASH such as hepatology, diabetes and cardiology, along with renowned scientific experts focused on promoting a better understanding of the physiopathologicalmechanisms involved in NASH.
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Lanifibranor: overall development plan
Corporate Presentation | 2019
Phase IIb
ResultsNA
SHTo
xico
logy 52-week study
Carcinogenicity studiesResults
Start of FASST, NATIVE and Prof. Cusi trials corresponds to first patient screened
Phase II
Results
Prof. Cusi study in TD2M patients with NAFLDN
AFL
D
2015H2
2017H1 H2
2018H1 H2
2019H1 H2
2020H1 H2
2016H1 H2
Odiparcil – MPS
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Mucopolysaccharidoses (MPS) are devastating diseases with high unmet medical need
Corporate Presentation | 2019
Source: (1) Source: Rheumatology 2011 Therapy for mucopolysaccharodises; Vassili Valayannopoulos and Frits A. Wijburg
Autosomal recessive disorders characterized by accumulation of glycosaminoglycan(s) (GAGs) due to deficient lysosomal enzymes
Seven distinct clinical types based on the enzyme affected: odiparcil could be the first substrate reduction therapy for five forms of MPS with the following incidences:– MPS I: 1/100,000(1)
– MPS II: 1/100,000(1)
– MPS IV type A: 1/40,000 to 1/200,000(1)
– MPS VI: 1/240,000 to 1/400,000 (1)
– MPS VII: very rare (1)
Kathleen (MPS I)
Scotty (MPS II)
Karima (MPS VI)
MPS is a group of inherited lysosomal storage disorders
MPS has devastating clinical consequences: example MPS I, II and VI
MPS I
Mental retardation Coarse facies, short stature Dysostosis multiplex Joint stiffness Spinal cord compression Organomegaly Poor vision (corneal clouding) Hearing loss Cardiac/respiratory disease
MPS II MPS VIConsequences
(1) Retinal degeneration with no corneal clouding Odontoid hypoplasia Kyphoscoliosis, genu valgum
Pebbled skin Diarrhoea
(1)
Non-confidential – Property of Inventiva │ 30
Enzyme replacement therapy (ERT) is commercially successful, but with limited therapeutic efficacy
Source: H. Noh, J. I. Lee; Current and potential therapeutic strategies for mucopolysaccharidoses; Journal of Clinical Pharmacy
Corporate Presentation | 2019
Recombinant human enzymes, administered once a week as an intravenous infusion over 4 hours Approximately 50% of patients experience infusion reactions initially, some can be life threatening Limited penetration into protected or poorly vascularized tissues such as cornea or cartilage, where MPS
symptoms often manifest
Product Company MPS Est. yearly cost 2018 sales
MPS I $ 217K $ 206M
MPS II $ 522K $ 616M(1)
MPS IVA $ 578K $ 482M
MPS VI $ 476K $ 345M
MPS VII $ 550K $ 8M
ERT is expensive and usually requires outpatient administration. Significant unmet need remains in addressing symptoms in organs where ERT fails to penetrate
Enzyme replacement therapies are standard of care in MPS
Source: Sales - Company annual reports 2017; WAC without discounts for a 25-kg patient - BioCentury “Making of MEPSEVII” Dec 11, 2017; (1) 2017 sales
Non-confidential – Property of Inventiva │ 31
Odiparcil: an orally available small molecule substrate reduction therapy to treat several forms of MPS
Corporate Presentation | 2019
(1) Trial conducted by GSK prior to Inventiva’s founding (2) LOE: Loss of exclusivity
Activity
Decreases lysosomal accumulation of GAGs by modifying how DS and CS are synthesised – promotes formation of soluble DS / CS which can be excreted in the urine, rather than accumulating in cells
Oral administration Widely distributed in tissues that are poorly penetrated by enzyme replacement therapy Odiparcil-mediated reduction of intracellular GAG accumulation demonstrated in in vitro
and in vivo models US biomarker study finalized and Phase IIa study in MPS VI initiated - data expected H2
2019 Potential to be prescribed in combination with ERT and also as potential monotherapy
Safety
Low toxicity in vivo Favorable safety and tolerability profile in multiple Phase I and Phase II clinical
studies in unrelated indication(1) (administered to >1,800 subjects) allowing thecommencement of a POC study in MPS VI patients
IP
Method of use patent filed in 2013 and granted in EU (Nov. 2015) and the US (Feb. 2017): LOE(2) 2039 including 5-year extension
MPS VI Orphan Drug Designation granted in the US and in the EU Rare Pediatric Disease Designation in MPS VI granted in the US
Non-confidential – Property of Inventiva │ 32
Unique mechanism of action potentially synergistic with ERT
Corporate Presentation | 2019
Source: H. Noh, J. I. Lee; Current and potential therapeutic strategies for mucopolysaccharidoses; Journal of Clinical Pharmacy, company data
Odiparcil diverts endogenous protein-bound GAG synthesis to soluble odiparcil-bound chondroitin sulfate (CS) and dermatan sulfate (DS) synthesis
Odiparcil decreases intracellular GAG accumulation in vitro in MPS VI patient cells
Galactosyl transferase I (GTI)
Synthesis of proteoglycans (HS, CS, DS)
Synthesis of soluble DS and CS
Odiparcil
Odiparcil
Galactosyl transferase I (GTI)
MPS VI fibroblastsGAG overloaded
cells
Intracellular CS storage Extracellular GAG
0
5
10
15
20
25
10- 8 10- 7 10- 6 10- 5
MPS VI (IC50=3 µM)
Veh.Odiparcil concentration (M)
Tota
l sul
fate
d G
AGS
(µg/
mL)
0
100000
200000
300000
10- 8 10- 7 10- 6 10- 5
Control (IC50=2.8 µM)MPS VI (IC50=2.7 µM)
Veh.Odiparcil concentration (M)
Fluo
resc
ence
inte
nsity
Odiparcil observed to reduce GAG accumulation in MPS VI patient cells
Odiparcil
Non-confidential – Property of Inventiva │ 33
By producing soluble dermatan and chondroitin sulfates, odiparcilcan address several types of MPS
Source: Rheumatology 2011 Therapy for mucopolysaccharodises; Vassili Valayannopoulos and Frits A. Wijburg
Type Name DS CS HS KS
MPS I-H Hurler syndrome
MPS I-S Scheie syndrome
MPS I-H/S Hurler-Scheie syndrome
MPS II Types A & B Hunter syndrome
MPS IV Type A Morquio syndrome
MPS VI Maroteaux-Lamysyndrome
MPS VII Sly syndrome
Corporate Presentation | 2019
Non-confidential – Property of Inventiva │ 34
Odiparcil decreases GAG content in vivo and improves mobility in a MPS VI model
Corporate Presentation | 2019
Source: Company data
0
10
20
30
40 p<0.001
WT MPS VI MPS VI + Odi
p<0.05
time
on p
ole
[sec
]
In vivo in MPS VI affected mice Odiparcil decreases GAG accumulation in various tissues and intracellular GAG accumulation in
lymphocytes Odiparcil decreases GAG accumulation in cornea, restores corneal structure and decreases GAG
accumulation in cartilage Odiparcil restores mobility
0
10
20
30
40p<0.001
WT MPS VI MPS VI + Odi
p<0.001
GAG
in li
ver
[Are
a *
Inde
x]
± Odiparcil*Given in food
6 monthsWild-type and MPS VI miceTreatment starts when animals are one month old
► Sulfated GAGs in organs/tissues and urine► Mobility test► Corneal structure/clouding
* The doses administered provide exposure levels similar to that to be used in clinic
Liver
Odiparcil decreases GAG accumulation in tissues
-100%
Odiparcil decreases intra-cellular GAG
Odiparcil improves animal mobility
Leukocytes
0
20
40
60
80
%ce
lls w
ith >
10
GAG
gra
nule
s
p<0.001p<0.001
MPS VI MPS VI+OdiWT
Leukocytes Pole Test
GA
G in
live
r[A
rea
* Ind
ex]
% o
f cel
ls w
ith >
10
GA
G g
ranu
les
Tim
e on
pol
e [s
econ
ds]
Non-confidential – Property of Inventiva │ 35
Odiparcil penetrates tissues that ERT cannot reach
Meaningful concentrations of odiparcil observed also in tissues that are poorly vascularized or protected by a barrier: bone, corneal tissue and cartilage
Corporate Presentation | 2019
Odiparcil is well distributed in tissues and organs poorly penetrated by recombinant enzymes
Heart CorneaBone Cartilage
Odiparcil(1)
rhASB(2) Not detectedNot tested Not detected
Non-confidential – Property of Inventiva │ 36
Visual impairment and cartilage-linked manifestations in MPS VI are a major medical unmet need
Source: Design, baseline characteristics, and early findings of the MPS VI (mucopolysaccharidosis VI) Clinical Surveillance Program (CSP); Journal of Inherited Metabolism Disorders (2013)
Corporate Presentation | 2019
Visual impairment affects many MPS VI patients Preservation of vision is important as lifespan and other
morbidities improve
Corneal opacification is a major driver of visual acuity decrease Diffuse, ‘ground-glass’ corneal opacification Slowly progressive but may be present from infancy
Pathophysiology of corneal clouding Corneal clarity depends on regular arrangement of collagen fibrils
in corneal stroma Intracellular and extracellular deposition of GAGs in corneal
stroma leads to the disruption of collagen spacing, size and arrangement and results in corneal clouding
Galsulfase does not penetrate the eye, does not address corneal opacification and subsequent ocular manifestations
Slowing or halting progression or decreasing GAG accumulation in these organs would represent a major contribution to patient care
Moderate SevereMild
GAGs accumulate in cartilages of MPS VI patients leading to cartilage thickening
– Tracheal stenosis and/or tracheomalacia could lead to airway obstruction
– Articular joint thickening leads to reduction of range of motion, pain, and poor quality of life
– GAG accumulation in cardiac valves leads to dysmorphic and poorly mobile leaflets and subsequent valvular disease (regurgitation) requiring valve replacement (90% of MPS VI patients are affected)
Galsulfase does not efficiently penetrate the cartilage and does not address cartilage-linked manifestations
Cornea – impaired vision Cartilage – impaired mobility
Non-confidential – Property of Inventiva │ 37
Odiparcil impact on corneal GAG accumulation and corneal structure in MPS VI mice
Corporate Presentation | 2019
Source: Company data
Decreases in GAG accumulation and improvements in corneal structure expected to improve corneal function and ocular impairment
WT control
MPSVI
epithelium stroma
MPS VI + Odi
0
10
20
30
40p<0.001
WT MPS VI
p<0.0001
MPS VI + Odi
thic
knes
s (µ
m)
0
1
2
3
4
5 p<0.001
WT MPS VI
p<0.0001
MPS VI + Odi
num
ber o
f cel
l laye
rs
Blinded corneal stroma vacuolation scoring
WT 0.0
MPS VI 2.9
MPS VI + Odi 0.5
scale (0‐3)0. no detectable vacuolation, no GAG accumulation1. some large vacuolation with some distended cells2. extensive area of large vacuolation with GAG accumulation3. extensive area of large vacuolation with GAG accumulation and separate collagen fibers
Odiparcil effect on corneal epithelium thickness
Odiparcil effect on corneal epithelium cell layers
Odiparcil effect on GAG storage in corneal stroma
Chow dietOdiparcil : 4.5 g/kg in food
Chow dietOdiparcil : 4.5 g/kg in food
Non-confidential – Property of Inventiva │ 38
Odiparcil decreases GAG accumulation in cartilages in MPS VI mice
Corporate Presentation | 2019
Source: Company data
By decreasing GAG storage in cartilage, odiparcil improves cartilage-linked disease manifestations
WT MPS VI
WT MPS VI
Knee
Trachea
0
20
40
60
80
100p<0.0001
-31%
Trac
hea
carti
llage
thic
knes
s in
µm
MPS VI MPS VI + OdiWT
0
100
200
300p<0.0001
-26%
WT MPS VI
p<0.0001
MPS VI + Odi
Dis
tal f
emor
al g
row
th p
late
thic
knes
s[µ
m]
Odiparcil decreases trachea cartilage thickness
Odiparcil decreases knee cartilage thickness
Chow dietOdiparcil : 4.5 g/kg in food
Chow dietOdiparcil : 4.5 g/kg in food
Non-confidential – Property of Inventiva │ 39
Odiparcil has the potential to positively differentiate versus current MPS treatment options
Corporate Presentation | 2019
Source: Company evaluation
Effect on mobility
Effect on eye, cartilage, bones, heart valves, spinal cord compression
Distribution type Oral Intravenous Infusion Transplantation
OdiparcilAldurazyme, Elaprase,
Naglazyme, Vimizim, Mepsevii HSCT(Hematopoietic stem cell transplantation)
Non-confidential – Property of Inventiva │ 40
LeukoGAG biomarker for MPS VI demonstrates the incomplete impact of ERT and opportunity for odiparcil
Corporate Presentation | 2019
(1) Arylsulfatase B, which is involved in the breakdown of GAGs
MPS VI patients treated with Naglazyme maintained a high level of intracellular DS and CS levels in leukocytes compared to age matched healthy volunteers suggesting the possibility to further reduce this level with odiparcil
>16y
0
2
4
6
8
10
controlsubjects
MPS VIpatients
receiving ERT
7-15y
0.0
2.5
5.0
7.5
10.0
controlsubjects
MPS VIpatients
receiving ERT
(mg/
mol
cre
atin
ine)
0
2
4
6
8
10
controlsubjects
MPS VIpatients
receiving ERT
(mg/
mol
cre
atin
ine)
CS DS
0
50
100
150
200
(mg/
mol
cre
atin
ine)
0
50
100
150
200
controlsubjects
MPS VI patientsreceiving ERT
Pre-infusion
1 h post-infusion
(nm
ol/h
r/mg)
0
20
40
60
(mg/
mol
cre
atin
ine)
0
20
40
60
controlsubjects
MPS VI patientsreceiving ERT
Pre-infusion
1 h post-infusion
(nm
ol/h
r/mg)
MPS VI patients treated with ERT have increased CS and DS levels in urine
ARSB(1) activity in leukocytes is increased by 8 fold after ERT infusion
MPS VI patients treated with ERT have increased CS (and DS levels) in leukocytes
Leukocytes are promising cells: easy to collect; intracellular GAG levels are seen to be increased in animal model of MPS where odiparcil decreases intra-cellular GAG content
Objectives of Inventiva’s non-interventional study: develop a robust quantification method to measure intracellular HS, CS and DS in leukocytes and an activity biomarker to be used in clinical trials
Population: 6 MPS VI patients on ERT and 6 age matched control subjects not affected with MPS Investigational site: Dr. Paul Harmatz (PI), UCSF Benioff Children’s Hospital in Oakland (CA, USA)
Non-confidential – Property of Inventiva │ 41
iMProveS Phase IIa trial of odiparcil in MPS VI
Corporate Presentation | 2019
More information on: http://www.improves-mpsvi-trial.com/
End of treatment
4 weeks
Placebo + ERT, 6 patients
Odiparcil, 250 mg bid + ERT, 6 patients
Odiparcil, 500 mg bid + ERT, 6 patients
Odiparcil, 500 mg bid, 6 patients ERT naive
Follow up
18 patients double blind + 6 patients open label26 week treatment 4 weeks
Screening, baseline and
randomization
6 weeks
Screening (4w) and
preliminary safety
assessment (2w)
Safety Clinical and biological
assessments (standard tests)Pharmacokinetics Odiparcil plasma levels
Efficacy Leukocyte, skin and urinary GAG content Activity and mobility tests (6 minute walk test, upper limb function, shoulder mobility
range) Cardiac, vascular and respiratory functions Eye impairment, hearing capacity, pain assessment, quality of life questionnaires
Endpoints
≥ 16yo
Phase IIa► Phase III enabling study with evidence for dose selection
and PK / PD response characterization► Clinicaltrials.gov identifier: NCT03370653
Population► Receiving ERT (N=18)► Not receiving ERT (N=6)
Status 1st DSMB (Oct 2018): no safety concerns;
recommendation to initiate the core study 2d positive DSMB review in March
EU, multicenter: UK, Germany, France, Portugal Results expected second-half of 2019
Non-confidential – Property of Inventiva │ 42
Safe-KIDDS phase Ib/II study of odiparcil in MPS VI children
Corporate Presentation | 2019
More information on: http://www.improves-mpsvi-trial.com/
Safety Clinical and biological assessments (standard tests) Palatabilitty
Pharmacokinetics PK & PD (GAG levels in urine, leukocytes and skin)
Efficacy Endurance and motor proficiency (walking test,
respiratory), mobility, ophthalmology, hearing, cardiovascular test, Quality of life questionnaires (including pain)
Endpoints
Phase Ib/II► A Phase Ib/II safety, pharmacokinetics, pharmacodynamics and efficacy, dose-ranged, three-period, randomized, double-
blind, placebo-controlled study of odiparcil as add-on to ERT in a pediatric population with MPS type VI from 5 to 15 years of age
► Phase III enabling study► PK / PD of escalating doses► Assessment of palatability
Population► 9 MPS VI children receiving ERT (N=9)
Status EU multicenter
5 - 15yoDesign► Adaptive design (randomized, placebo controlled, double-blind)► Sequential inclusion
Non-confidential – Property of Inventiva │ 43
Odiparcil overall anticipated development plan in MPS VI
Corporate Presentation | 2019
Clin
ic
Biomarker study
Phase IIa(MPS VI adults)
Phase Ib/II(MPS VI children)
2017H1 H2
2018H1 H2
2019H1 H2
2020H1 H2
Juvenile Tox Carcinogenicity
Toxi
colo
gy
2021H1 H2
2022H1
Rare paediatric designation
Start of pivotal study
Results
Results
Note: Start of iMProves trial corresponds to corresponds to first patient screened
R&D collaborations and Hippo pathway program update
Non-confidential – Property of Inventiva │ 45
Key validating collaborations with AbbVie and Boehringer Ingelheim
Corporate Presentation | 2019
Inventiva eligible to future milestone payments and sales royaltieson all ROR molecules identified during the collaboration
RORγ collaboration in inflammatory disease
RORγ program addresses large markets currently dominated by biologics and could prove to be superior to biologics
Single ascending dose phase I completed with ABBV-157, the clinical candidate coming from the partnership
Next step: A randomized, double-blind, placebo-controlled, multiple-dose study to evaluate the pharmacokinetics, safety and tolerability of ABBV-157 in 60 healthy volunteers and patients with chronic plaque psoriasis (clinicaltrials.gov identifier: NCT03922607)– Study start date: May 2019– Study completion: September 2020
Inventiva eligible to up to ~€170m in milestones and sales royalties
Fibrosis collaboration
Multi-year R&D collaboration and licensing partnership. Joint team until pre-CC stage. BI to take full responsibility of clinical development and commercialization
Program progressing as planned with first screening performed
Non-confidential – Property of Inventiva │ 46
YAP-TEAD program: significant progress achieved and clinical candidate selection planned in 2019
The program is expected to enter into Phase I/II enablingpreclinical development in 2019
Corporate Presentation | 2019
Novel cancer pathway involved in drug resistance, immune evasion, tumor progression and metastases
Relevant in multiple, commercially attractive cancer indications
Proprietary chemistry
Lead and back-up compounds available
IP protected
Preclinical candidate screening ongoing
Clinical candidate selection in 2019
Phase I/II start planned in 2020
In vitro evidence for synergies with standard of care and suppression of tumor resistance
In vivo efficacy shown (alone and in combination with standard of care)
First in class YAP-TEAD program
Conclusions
Non-confidential – Property of Inventiva │ 48
Recent achievements and upcoming expected milestones
Corporate Presentation | 2019
2018
Lani
fibra
nor
Odi
parc
ilC
olla
b.
Phase IIa MPS VI results - H2 2019Rare pediatric disease designation MPS VI
Dis
cove
ryFi
nanc
e
Last patient Phase IIb NASH Last patient Prof. Cusi study in NAFLD
patients with TD2M
2019
Start Phase I with ABBV-157
Clinical candidate selection
MPS VI biomarker study resultsJuvenile tox results
Capital increase
YAP/TEAD: In vivo POC
2 year carcinogenicity study resultsUS fibrosis indication patentUS INDFirst patient in NAFLD Phase II
ABBV-157 multiple-ascending dose phase I initiation: May 2019
SAD(1) Phase I with ABBV-157 completed
(1) SAD: Single Ascending Dose
Contacts
Inventiva
Frédéric Cren
CEO
+33 (0)3 80 44 75 00
Brunswick
Julien Trosdorf / Yannick Tetzlaff
Media relations
+ 33 1 53 96 83 83
LifeSci Advisors
Monique Kosse
Investor relations