Developing breakthrough therapies in NASH and mucopolysaccharidosis - Corporate Presentation - Inventiva Pharma

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Developing breakthrough therapies in NASH and mucopolysaccharidosis - Corporate Presentation - Inventiva Pharma
Developing breakthrough therapies in
NASH and mucopolysaccharidosis

Corporate Presentation
April 2019
Developing breakthrough therapies in NASH and mucopolysaccharidosis - Corporate Presentation - Inventiva Pharma
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Corporate Presentation | 2019 Non-confidential – Property of Inventiva │ 2
Developing breakthrough therapies in NASH and mucopolysaccharidosis - Corporate Presentation - Inventiva Pharma
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 RORγ program in phase I with AbbVie, Phase I data due in 2019
 – YAP-TEAD program in late pre-clinical stage, clinical candidate selection expected in
 2019

 Strong balance sheet and experienced senior management team with a track record of
 operational and scientific excellence

Corporate Presentation | 2019 Non-confidential – Property of Inventiva │ 3
Developing breakthrough therapies in NASH and mucopolysaccharidosis - Corporate Presentation - Inventiva Pharma
Management team with extensive experience across all stages of
drug development and commercialization
 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
 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

 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

 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

Corporate Presentation | 2019 Non-confidential – Property of Inventiva │ 4
Developing breakthrough therapies in NASH and mucopolysaccharidosis - Corporate Presentation - Inventiva Pharma
Validated oral small molecule-focused discovery engine targeting
nuclear receptors, transcription factors and epigenetic modulation

  Expertise: nuclear
 receptors,
 transcription
 factors, epigenetic
  Library of ~240,000  Wholly-owned targets
 compounds of which 129,000 square
 60% proprietary foot pharma-like
 R&D facilities

  Strong
 scientific team
 of ~90 people

 Power of discovery engine underpins deep pipeline of clinical and discovery stage assets

Corporate Presentation | 2019 Non-confidential – Property of Inventiva │ 5
Developing breakthrough therapies in NASH and mucopolysaccharidosis - Corporate Presentation - Inventiva Pharma
Deep pipeline approaching major near term value inflection points

Candidate / IND Commercial
 Indication Discovery Phase I Phase II Phase III
Program Enabling Rights

 Phase IIb
Lanifibranor NASH pan-PPAR results: H1
 2020

 Phase IIa
Odiparcil MPS VI GAG clearance results: H2
 2019

 Phase I
ABBV-157  Moderate to ROR 
 severe psoriasis
 results: 2019

  Non-small cell Candidate
Hippo YAP/TEAD
 lung cancer and Selection:
 mesothelioma 2019

  Idiopathic
TGF-β Lead Op(1)
 pulmonary
 fibrosis (IPF)

(1) Lead optimization means refining molecules in advance of selecting candidates

 Corporate Presentation | 2019 Non-confidential – Property of Inventiva │ 6
Developing breakthrough therapies in NASH and mucopolysaccharidosis - Corporate Presentation - Inventiva Pharma
Key financials and shareholder base

Key financials Shareholder base

 Free float*
 22.1%
 *Including
ISIN code FR0013233012 Perceptive
 Founders Advisors

Market Euronext Paris 43,9%
 BVF
 15,0%
Shares outstanding 22.294.677
Market cap €66m
(April 3 2020) Novo 8,8%
 Employees & Others
 €56,7m compared to €59.1m 3,1% Sofinnova 7,1%
 as of December 2017.
Cash position Successful €48.5m Euronext Analyst coverage
(December 31 2018) IPO (February 2017) and
 Jefferies Peter Welford
 €35.5m private placement
 (April 2018) HC Wainwright Ed Arce
 KBC Lenny Van Steenhuyse
Revenues €3.2m compared to €4.8m in
(December 31 2018) 2017 Société Générale Delphine Le Louët
 Gilbert Dupont Jamila El Bougrini
R&D expenditures €31,6m compared to €26,7m Kepler Chevreux Arsene Guekam
(December 31 2018) in 2017 LifeSci Capital Patrick Dolezal

Corporate Presentation | 2019 Non-confidential – Property of Inventiva │ 7
Developing breakthrough therapies in NASH and mucopolysaccharidosis - Corporate Presentation - Inventiva Pharma
Lanifibranor in Nonalcoholic
Steatohepatitis (NASH)
Developing breakthrough therapies in NASH and mucopolysaccharidosis - Corporate Presentation - Inventiva Pharma
Lanifibranor: only pan-PPAR agonist in clinical development for the
treatment of NASH

  Differentiated chemical structure with moderate and balanced pan-PPAR agonist activity
 (PPARα, PPARγ and PPARδ)
  Oral administration
 Activity  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
  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
 Safety • 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

  Composition of matter patent granted in 53 countries: LOE(2) August 2031 including 5-
 year extension
 IP
  Use patent granted in US covering several fibrotic diseases including NASH and SSc:
 LOE(1) 2035

(1) Conducted by Abbott prior to our funding (2) LOE: Loss of exclusivity

Corporate Presentation | 2019 Non-confidential – Property of Inventiva │ 9
Developing breakthrough therapies in NASH and mucopolysaccharidosis - Corporate Presentation - Inventiva Pharma
Lanifibranor is a differentiated pan-PPAR agonist with moderate and
 well balanced activity on the 3 PPAR isoforms
 Lanifibranor human dose response curves and EC50s for various PPAR agonists
 PPARα PPARδ PPARγ
 Compound
 EC50 (nM) EC50 (nM) EC50 (nM)
 150
 hPPARα
  Lanifibranor(1) 1630 850 230
 125 hPPARδ
%Activation

 100
 hPPARγ  Fenofibrate 2400 - -
 75  Pioglitazone - - 263
 50
  Rosiglitazone - - 13
 25

 0  Elafibranor(2) 10 100 -
 -10 -8 -6 -4
 Lanifibranor (M)  Seladelpar(3) - 2 -

 Lanifibranor binds differently than rosiglitazone to PPARγ inducing different coactivator
 recruitment(4)

 Potency scale: red 10 nM; grey: 500 nM; green 5 000 nM
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

 Corporate Presentation | 2019 Non-confidential – Property of Inventiva │ 10
Favorable safety profile differing from previously developed PPARs

 PPAR isoforms Reported Lanifibranor
 Organ
 activated PPAR liabilities effects
  Fluid retention
 Heart  PPARγ  Cardiac hypertrophy Not observed

 Skeletal muscle  PPARα  Myofiber degeneration Not observed
  > 50% increases in
 Kidney  PPARα creatinine, degenerative Not observed
 changes in renal tubules
  Proliferative changes in
 Urinary bladder  PPARγ bladder epithelium Not observed
 Plasma volume and heart weight after administration of PPAR agonists
 60
 Plasma Volume 0.6 Heart Weight

 * * Heart weight (% BW)
 Plasma volume (mL)

 Control
 * * Rosi (3 mg/kg/d)
 40 * 0.4 * * * Rosi (10 mg/kg/d)
 Mura (10 mg/kg/d)
 Mura (100 mg/kg/d)
 20 0.2 Lani
 IVA337 (100 mg/kg/d)
 Lani
 IVA337 (1000 mg/kg/d)
 Tesa (1 mg/kg/d)
 Tesa (10 mg/kg/d)
 0 0.0
 Rosi Mura Lani
 IVA337 Tesa Rosi Mura Lani
 IVA337 Tesa mg/kg/day; 9 W rat study
 Single Dual Pan Dual Single Dual Pan Dual
 PPAR PPAR PPAR PPAR PPAR PPAR PPAR PPAR
 γ α,γ α,δ,γ α,γ γ α,γ α,δ,γ α,γ

 Lanifibranor not associated with plasma volume expansion or heart weight increase
Source: Company data

Corporate Presentation | 2019 Non-confidential – Property of Inventiva │ 11
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 PPARγ 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 │ 12
No cardiac or renal safety concern observed in the phase IIb study in
 systemic sclerosis study after one year of treatment

 Description of fold in creatinine over time Description of fold in NT-ProBNP over
 – observed cases under treatment - mITT time– observed cases under treatment -
 population mITT population
Value (Mean ± 95% CI)

 Value (Mean ± 95% CI)
 Week 12 Week 24 Week 48 Week 12 Week 24 Week 48

 Baseline Value (median) Baseline Value (median)
 Placebo: 60.1 Placebo: 71.0
 Lanifibranor 800 mg: 54.8 Lanifibranor 800 mg: 87.0
 Lanifibranor 1200 mg: 57.5 Lanifibranor 1200 mg: 89.0

 Corporate Presentation | 2019 Non-confidential – Property of Inventiva │ 13
Phase I and Phase IIa clinical studies(1) demonstrated beneficial
effects on key metabolic markers
Lanifibranor metabolic markers in type II diabetic patients
 Insulin resistance (HOMA-IR, adiponectin)
 Dyslipidemia (increase in HDL-C, reduction of TG)

 Adiponectin (PPARγ) HDL Cholesterol (PPARα/δ) Triglycerides (PPARα/δ)
 baseline

 baseline

 baseline
 300 p=0.05 40 0
 baseline

 baseline

 baseline
 p=0.05 p
NASH overview

A severe disease with no currently approved treatment

 Healthy
 15-20%
 Liver Cirrhosis

 NASH Hepato-
 Death
 NAFLD NASH with carcinoma
 2-3% per year 30-40%
 fibrosis
 Severe liver
 Reversible
 damage
 40-50% Liver transplant

 The overall NASH prevalence in the adult population of the United States is
 believed to be approximately 12%

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 Non-confidential – Property of Inventiva │ 15
Lanifibranor’s mechanism of action addresses all the key features of
NASH

 Metabolism Steatosis

 Insulin sensitivity FA uptake
 PPARα,δ,γ HDLc PPARα,γ FA catabolism
 TG Lipogenesis

 Inflammation and Ballooning Fibrosis
 Stellate cell
 NFkB-dependent gene
 proliferation and
 PPARα,δ,γ activation PPARγ activation
 Inflammasome
 Collagen and
 Ballooning fibronectin production

Corporate Presentation | 2019 Non-confidential – Property of Inventiva │ 16
Lanifibranor: differentiated potential to address all features of NASH
in safe and efficacious manner

 Lanifibranor Ocaliva Elafibranor Cenicriviroc Selonsertib

Metabolism

Steato-hepatitis

Necro-inflammation

Fibrosis Unclear

Corporate Presentation | 2019 Non-confidential – Property of Inventiva │ 17
PPARγ efficacy is well established in NASH
 PPARγ 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:
 Belfort NASH study Cusi NASH study
 Pioglitazone (PPARγ)
 6 month treatment 18 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 increase
 in the number of NASH patients whose
 fibrosis 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
Corporate Presentation | 2019 Non-confidential – Property of Inventiva │ 18
Pioglitazone PPARγ NASH resolution efficacy
 results are still unmatched
 Resolution of NASH without worsening of fibrosis
 60%

 50%
Patients with improvement, %

 40%

 30%

 51%

 20%

 27%
 10% pbo
 19% 19% 19%
 pbo
 pbo 12% 12% pbo 8% pbo pbo
 8% 6% 6% 7%
 0%
 Pioglitazone Ocaliva Elafibranor CVC MGL-3196 Aramchol

 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

 Corporate Presentation | 2019 Non-confidential – Property of Inventiva │ 19
PPARγ activity can also be completed by PPARα
and δ efficacy
 PPARα/δ 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

Source: Ratziu V, et al. Gastroenterology 2016. Note: (1) GOLDEN 505 study conducted by Genfit

Corporate Presentation | 2019 Non-confidential – Property of Inventiva │ 20
Lanifibranor significantly reduces steatosis, inflammation,
ballooning and fibrosis in preclinical models
 Lanifibranor inhibits steatosis Lanifibranor significantly Lanifibranor reverses
 and inflammation in the MCD reduces ballooning and the established liver fibrosis in
 model NAS score in the foz/foz model CCL4 models
 NAS-ballooning
 400
 Steatosis 2.0
 Ballooning 3
 ***
 *** *** **

 ballooning score
 Average number of

 300 1.5

 % of area
 lipid droplets/HPF

 2

 200 1.0
 *** *** 1
 ***
 100
 *** *** 0.5

 0 0.0 0
 HFD HFD + HFD + ND
 Vehicle Lanifibranor Lanifibranor 3 weeks
 (High Lanifibr Lanifibr (Normal 3 + 3 weeks
 10mg/kg 30mg/kg
 Fat anor 10 anor 30 Diet) CCl4 model
 Diet) mg/kg mg/kg
 Oil + vehicle
 CCL4 + vehicle
 Inflammation NAS
 NAS Score
 score CCL4 + Lanifibranor 15 mg/kg
 10
 *** CCL4 + Lanifibranor 30 mg/kg
 3 ***
 **
 Average inflammatory score

 8

 2 6
 (Histology)

 *** 4

 1
 *** 2

 0
 0 HFD HFD + HFD + ND
 t

 kg

 kg

 t
 ie
 ie

 g/

 g/

 D
 tD

 (High Lanifibr Lanifibr (Normal
 m

 m

 ol
 Vehicle Lanifibranor Lanifibranor
 Fa

 tr
 10

 30

 Fat anor 10 anor 30 Diet)
 on
 h

 10mg/kg 30mg/kg
 ig

 7

 7

 C
 33

 33
 H

 Diet) mg/kg mg/kg
 A

 A
 IV

 IV

 Lanifibranor associated with beneficial effects on all NASH-relevant liver features
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

Corporate Presentation | 2019 Non-confidential – Property of Inventiva │ 21
Overview of NATIVE trial design (I/II)
Trial design
Principal investigator Inclusion criteria
 Prof. Francque (Universitair Ziekenhuis, Antwerpen,  Liver biopsy
 Belgium)  Severe patients with an inflammation and
 Prof. Manal Abdelmalek (Duke University, USA) ballooning score of 3 or 4
Randomisation  Steatosis score ≥ 1 and fibrosis score < 4 (no
 1/1/1, stratification on T2DM patients cirrhosis)
 Study powered with 75 patients per group Primary endpoint
Status  Decrease from baseline ≥ 2 points of the
 Trial enrolling inflammation and ballooning score without
 worsening of fibrosis
 Results expected first-half 2020
  Central reading
Clinicaltrials.gov identifier: NCT03008070
 225 patients
 24 week treatment
 Double blind randomized placebo controlled
 Screening End of treatment
  Liver biopsy Placebo, 75 patients  Liver biopsy

 Lanifibranor, 800 mg once daily, 75 patients
 Lanifibranor, 1200 mg once daily, 75 patients

 More information on: http://www.native-trial.com/
Corporate Presentation | 2019 Non-confidential – Property of Inventiva │ 22
Overview of NATIVE trial design (II/II)

 17 countries worldwide
 ► 13 in EU
 ► United States
 ► Canada
 ► Australia
 ► Mauritius

14 sites selected in
the United-States

 92 sites involved
 78 sites activated
 68 sites screening

  Status March 28, 2019: 601 patients screened, 167 patients randomized
  3 positive DSMB reviews
  Results expected first-half 2020
 Corporate Presentation | 2019 Non-confidential – Property of Inventiva │ 23
NATIVE study results will also be backed by the Phase II trial in T2DM
patients with NAFLD
Trial design
Principal investigator Primary endpoint
 Prof. Kenneth Cusi (University of Florida)  Change from baseline to week 24 in IHTG
Randomisation Key secondary endpoints
 Randomized (1:1), double-blind, placebo-controlled  Proportion of responders (IHTG, NAFLD
 Non-obese subject control group for the metabolic resolution)
 and imaging procedures  Change in hepatic fibrosis (MRE(2), biomarkers)
 N=64 calculated assuming a 35% relative reduction  Change in metabolic outcomes (insulin
 of IHGT (1)
 sensitivity, DNL(3), glycemic control, lipids)
Status  Safety
 IND approved Clinicaltrials.gov identifier: NCT03459079
 First Patient First Visit: August 2018
 64 patients
 Results expected first-half of 2020
 24 week treatment
 Double blind randomized placebo controlled

 Healthy non-obese control group, 10 subjects
 Placebo, 32 patients
 Lanifibranor, 800 mg once daily, 32 patients

 A positive study result would further reinforce lanifibranor’s profile in NAFLD
 and NASH patients with type 2 diabetes
(1) Intrahepatic triglycerides (2) Magnetic resonance elastography (3) De-novo lipogenesis

Corporate Presentation | 2019 Non-confidential – Property of Inventiva │ 24
PanNASH Initiative: a group of well recognized international experts
working to promote NASH and the role of PPARs
  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 physiopathological
 mechanisms involved in NASH.

 Specialty Country Member Affiliation
 Hepatology Belgium Pr. Sven Francque Antwerp University Hospital
 Hepatology Germany Pr. Frank Tacke University Hospital Aachen
 Pr. Jean-François
 Hepatology Switzerland University Clinic Bern
 Dufour
 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
 Harvard T.H. Chan School of Public
 Cardiology United States Pr. Frank Sacks
 Health

Corporate Presentation | 2019 Non-confidential – Property of Inventiva │ 25
Lanifibranor: overall development plan

 2015 2016 2017 2018 2019 2020
 H2 H1 H2 H1 H2 H1 H2 H1 H2 H1 H2
NASH

 Phase IIb

 Results
NAFLD

 Prof. Cusi study in
 TD2M patients with Phase II
 NAFLD
 Results
Toxicology

 52-week study

 Carcinogenicity studies
 Results

 Start of FASST, NATIVE and Prof. Cusi trials corresponds to first patient screened

 Non-confidential – Property of Inventiva │ 26
 Corporate Presentation | 2019
Odiparcil – MPS
Mucopolysaccharidoses (MPS) are devastating diseases with high
unmet medical need
MPS is a group of inherited lysosomal storage disorders
 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)
 Kathleen (MPS I)
 – 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)
MPS has devastating clinical consequences: example MPS I, II and VI
 Consequences MPS I MPS II MPS VI
 Scotty (MPS II)
 Mental retardation  
 Coarse facies, short stature   
 Dysostosis multiplex   
 Joint stiffness   
 Spinal cord compression   
 Organomegaly   
 Poor vision (corneal clouding)  (1) 
 Hearing loss   
 Cardiac/respiratory disease    Karima (MPS VI)
 (1) Retinal degeneration with no corneal clouding  Pebbled skin  Odontoid hypoplasia
  Diarrhoea  Kyphoscoliosis, genu valgum

Source: (1) Source: Rheumatology 2011 Therapy for mucopolysaccharodises; Vassili Valayannopoulos and Frits A. Wijburg

Corporate Presentation | 2019 Non-confidential – Property of Inventiva │ 28
Enzyme replacement therapy (ERT) is commercially successful, but
with limited therapeutic efficacy
Enzyme replacement therapies are standard of care in MPS
 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
 Source: Sales - Company annual reports 2017; WAC without discounts for a 25-kg patient - BioCentury “Making of MEPSEVII” Dec 11, 2017; (1) 2017 sales

 ERT is expensive and usually requires outpatient administration. Significant unmet
 need remains in addressing symptoms in organs where ERT fails to penetrate
Source: H. Noh, J. I. Lee; Current and potential therapeutic strategies for mucopolysaccharidoses; Journal of Clinical Pharmacy

Corporate Presentation | 2019 Non-confidential – Property of Inventiva │ 29
Odiparcil: an orally available small molecule substrate reduction
therapy to treat several forms of MPS

  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
 Activity
  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

  Low toxicity in vivo

 Safety  Favorable safety and tolerability profile in multiple Phase I and Phase II clinical
 studies in unrelated indication(1) (administered to >1,800 subjects) allowing the
 commencement of a POC study in MPS VI patients

  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
 IP  MPS VI Orphan Drug Designation granted in the US and in the EU
  Rare Pediatric Disease Designation in MPS VI granted in the US

(1) Trial conducted by GSK prior to Inventiva’s founding (2) LOE: Loss of exclusivity

Corporate Presentation | 2019 Non-confidential – Property of Inventiva │ 30
Unique mechanism of action potentially synergistic with ERT

Odiparcil diverts endogenous protein-bound GAG synthesis to soluble odiparcil-bound
chondroitin sulfate (CS) and dermatan sulfate (DS) synthesis
 Galactosyl transferase I (GTI) Galactosyl transferase I (GTI)
 Synthesis
 Synthesis of Odiparcil of soluble
 proteoglycans
 DS and CS
 (HS, CS, DS)
 Odiparcil

 Odiparcil decreases intracellular GAG accumulation in vitro in MPS VI patient cells

 Intracellular CS storage MPS VI fibroblasts Extracellular GAG

 Total sulfated GAGS (µg/mL)
 300000 GAG overloaded 25
 MPS VI (IC50=3 µM)
 cells
 Fluorescence intensity

 20
 200000
 Odiparcil 15

 10
 100000

 Control (IC50=2.8 µM) 5
 MPS VI (IC50=2.7 µM)
 0
 Veh. 10 - 8 10 - 7 10 - 6 10 - 5 0
 Veh. 10 - 8 10 - 7 10 - 6 10 - 5
 Odiparcil concentration (M)
 Odiparcil concentration (M)

 Odiparcil observed to reduce GAG accumulation in MPS VI patient cells
Source: H. Noh, J. I. Lee; Current and potential therapeutic strategies for mucopolysaccharidoses; Journal of Clinical Pharmacy, company data

Corporate Presentation | 2019 Non-confidential – Property of Inventiva │ 31
By producing soluble dermatan and chondroitin sulfates, odiparcil
can address several types of MPS

 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  

 Maroteaux-Lamy
 MPS VI
 syndrome  
 MPS VII Sly syndrome   

Source: Rheumatology 2011 Therapy for mucopolysaccharodises; Vassili Valayannopoulos and Frits A. Wijburg

Corporate Presentation | 2019 Non-confidential – Property of Inventiva │ 32
Odiparcil decreases GAG content in vivo and improves mobility in a
MPS VI model

 6 months ► Sulfated GAGs in organs/tissues and urine
 Wild-type and MPS VI mice
 ► Mobility test
 Treatment starts when
 ± Odiparcil* ► Corneal structure/clouding
 animals are one month old
 Given in food
 * The doses administered provide exposure levels similar to that to be used in clinic

 Odiparcil decreases GAG Odiparcil decreases intra-cellular Odiparcil improves
 accumulation in tissues GAG animal mobility
 40 Liver 40
 p
Odiparcil penetrates tissues that ERT cannot reach

Odiparcil is well distributed in tissues and organs poorly penetrated by recombinant
enzymes

 Heart Bone Cornea Cartilage

 Odiparcil(1)
 rhASB(2) Not tested Not detected Not detected

 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 Non-confidential – Property of Inventiva │ 34
Visual impairment and cartilage-linked manifestations in MPS VI are a
major medical unmet need
Cornea – impaired vision Cartilage – impaired mobility
 Visual impairment affects many MPS VI patients  GAGs accumulate in cartilages of MPS VI patients leading to
 Preservation of vision is important as lifespan and other cartilage thickening
 morbidities improve – Tracheal stenosis and/or tracheomalacia could lead to
 airway obstruction
Corneal opacification is a major driver of visual acuity decrease
 – Articular joint thickening leads to reduction of range of
 Diffuse, ‘ground-glass’ corneal opacification motion, pain, and poor quality of life
 Slowly progressive but may be present from infancy – GAG accumulation in cardiac valves leads to dysmorphic
Pathophysiology of corneal clouding and poorly mobile leaflets and subsequent valvular disease
 (regurgitation) requiring valve replacement (90% of MPS VI
 Corneal clarity depends on regular arrangement of collagen fibrils patients are affected)
 in corneal stroma
 Intracellular and extracellular deposition of GAGs in corneal
 Galsulfase does not efficiently penetrate the cartilage and does
 stroma leads to the disruption of collagen spacing, size and
 not address cartilage-linked manifestations
 arrangement and results in corneal clouding

Galsulfase does not penetrate the eye, does not address corneal
opacification and subsequent ocular manifestations

 Mild Moderate Severe

 Slowing or halting progression or decreasing GAG accumulation in these
 organs would represent a major contribution to patient care
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 Non-confidential – Property of Inventiva │ 35
Odiparcil impact on corneal GAG accumulation and corneal structure
in MPS VI mice
 epithelium stroma

 WT MPSVI MPS VI + Odi
 control

 Odiparcil effect on corneal Odiparcil effect on corneal Odiparcil effect on GAG storage in corneal
 epithelium thickness epithelium cell layers stroma
 p
Odiparcil decreases GAG accumulation in cartilages in MPS VI mice

 Trachea Odiparcil decreases trachea
 cartilage thickness
 p
Odiparcil has the potential to positively differentiate versus current
MPS treatment options
 Aldurazyme, Elaprase,
 Odiparcil Naglazyme, Vimizim, Mepsevii HSCT
 (Hematopoietic stem
 cell transplantation)

 Effect on mobility

 Effect on eye,
 cartilage, bones,
 heart valves, spinal
 cord compression

 Distribution type Oral Intravenous Infusion Transplantation

Source: Company evaluation

Corporate Presentation | 2019 Non-confidential – Property of Inventiva │ 38
LeukoGAG biomarker for MPS VI demonstrates the incomplete
 impact of ERT and opportunity for odiparcil
  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)
 ARSB(1) activity in leukocytes is MPS VI patients treated with
 MPS VI patients treated with ERT have increased by 8 fold after ERT ERT have increased CS (and DS
 increased CS and DS levels in urine infusion levels) in leukocytes

 CS DS 200 60
 7-15y >16y 10
 10.0 10

 creatinine)
 creatinine)
 150
 8

 (nmol/hr/mg)

 (nmol/hr/mg)
 40
 (mg/mol creatinine)

 8
(mg/mol creatinine)

 7.5
 6 6 100

 (mg/mol
 5.0
 4 4 (mg/mol 20
 50
 2.5 2
 2

 0.0 0 0 0 0
 control MPS VI control MPS VI control MPS VI control Pre-
 control Pre- 1 h post- 1 h post-
 subjects patients subjects patients subjects patients
 receiving ERT receiving ERT receiving ERT subjects infusion infusion subjects infusion infusion
 MPS VI patients MPS VI patients
 receiving ERT receiving ERT

 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

 (1) Arylsulfatase B, which is involved in the breakdown of GAGs

 Corporate Presentation | 2019 Non-confidential – Property of Inventiva │ 39
iMProveS Phase IIa trial of odiparcil in MPS VI
Phase IIa Population
► Phase III enabling study with evidence for dose selection ► Receiving ERT (N=18)
 and PK / PD response characterization ► Not receiving ERT (N=6)
► Clinicaltrials.gov identifier: NCT03370653
 ≥ 16yo
 18 patients double blind + 6 patients open label
 6 weeks 4 weeks 26 week treatment 4 weeks

 Screening Placebo + ERT, 6 patients
 (4w) and
 Screening, Odiparcil, 250 mg bid + ERT, 6 patients
 preliminary
 baseline and Follow up
 safety
 assessment
 randomization Odiparcil, 500 mg bid + ERT, 6 patients
 (2w)
 Odiparcil, 500 mg bid, 6 patients ERT naive
 End of treatment
Endpoints
Safety Efficacy
 Clinical and biological  Leukocyte, skin and urinary GAG content
 assessments (standard tests)  Activity and mobility tests (6 minute walk test, upper limb function, shoulder mobility
Pharmacokinetics range)
 Odiparcil plasma levels  Cardiac, vascular and respiratory functions
  Eye impairment, hearing capacity, pain assessment, quality of life questionnaires
Status
 1st DSMB (Oct 2018): no safety concerns;  EU, multicenter: UK, Germany, France, Portugal
 recommendation to initiate the core study  Results expected second-half of 2019

 More information on: http://www.improves-mpsvi-trial.com/
Corporate Presentation | 2019 Non-confidential – Property of Inventiva │ 40
Safe-KIDDS phase Ib/II study of odiparcil in MPS VI children

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

Design Population 5 - 15yo

► Adaptive design (randomized, placebo controlled, double-blind) ► 9 MPS VI children receiving ERT (N=9)
► Sequential inclusion

Endpoints
Safety Efficacy
 Clinical and biological assessments (standard tests)  Endurance and motor proficiency (walking test,
 Palatabilitty respiratory), mobility, ophthalmology, hearing,
 cardiovascular test, Quality of life questionnaires
Pharmacokinetics (including pain)
 PK & PD (GAG levels in urine, leukocytes and skin)

Status
 EU multicenter  First patient first visit: second-half 2019

 More information on: http://www.improves-mpsvi-trial.com/
Corporate Presentation | 2019 Non-confidential – Property of Inventiva │ 41
Odiparcil overall anticipated development plan in MPS VI

 2017 2018 2019 2020 2021 2022
 H1 H2 H1 H2 H1 H2 H1 H2 H1 H2 H1

 Biomarker
 study
 Rare paediatric designation
 Clinic

 Phase IIa
 (MPS VI adults) Start of pivotal
 Results
 study
 Phase Ib/II
 (MPS VI children)
 Results
 Toxicology

 Juvenile
 Carcinogenicity
 Tox

Note: Start of iMProves trial corresponds to corresponds to first patient screened

Corporate Presentation | 2019 Non-confidential – Property of Inventiva │ 42
R&D collaborations and
Hippo pathway program update
Key validating collaborations with AbbVie and Boehringer Ingelheim

RORγ collaboration in inflammatory
disease Fibrosis collaboration

 RORγ program addresses large markets  Multi-year R&D collaboration and licensing
 currently dominated by biologics and could partnership. Joint team until pre-CC stage.
 prove to be superior to biologics BI to take full responsibility of clinical
 AbbVie has started Phase I study with development and commercialization
 ABBV-157  Inventiva eligible to up to ~€170m in
 Inventiva remains eligible to future milestone milestones plus royalties
 payments and sales royalties on all ROR
 molecules identified during the collaboration

 Program progressing as planned with
 ABBV-157: Phase I studies initiated
 first screening performed

Corporate Presentation | 2019 Non-confidential – Property of Inventiva │ 44
YAP-TEAD program: significant progress achieved and clinical
candidate selection planned in 2019

 Novel cancer pathway involved in Proprietary chemistry
 drug resistance, immune evasion,
 tumor progression and metastases Lead and back-up compounds
 available
 Relevant in multiple, commercially
 attractive cancer indications IP protected

 First in class
 YAP-TEAD program

 Preclinical candidate screening In vitro evidence for synergies with
 ongoing standard of care and suppression of
 tumor resistance
 Clinical candidate selection in 2019
 In vivo efficacy shown (alone and in
 Phase I/II start planned in 2020 combination with standard of care)

 The program is expected to enter into Phase I/II enabling preclinical
 development in 2019

Corporate Presentation | 2019 Non-confidential – Property of Inventiva │ 45
Conclusions
Recent achievements and upcoming expected milestones

 2018 2019
 
 Lanifibranor

 2 year carcinogenicity study results  Last patient Phase IIb NASH
  US fibrosis indication patent  Last patient Prof. Cusi study in NAFLD
  US IND patients with TD2M
  First patient in NAFLD Phase II
  MPS VI biomarker study results  Phase IIa MPS VI results - H2 2019
 Odiparcil

  Juvenile tox results  Rare pediatric disease designation MPS VI

  Start Phase I with ABBV-157
   Phase I ABBV-157 results - 2019
 Collab.

  YAP/TEAD: In vivo POC  Clinical candidate selection
 Discovery

  Capital increase
 Finance

Corporate Presentation | 2019 Non-confidential – Property of Inventiva │ 47
Contacts
Inventiva Brunswick LifeSci Advisors

Frédéric Cren Julien Trosdorf / Yannick Tetzlaff Monique Kosse

CEO Media relations Investor relations

info@inventivapharma.com inventiva@brunswickgroup.com monique@lifesciadvisors.com

+33 (0)3 80 44 75 00 + 33 1 53 96 83 83
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