Slides
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Corporate presentation DEC E M B E R, 2 0 2 4
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Disclaimer 2 IMPORTANT NOTICE – YOU MUST READ THE FOLLOWING BEFORE CONTINUING. THIS PRESENTATION HAS BEEN PREPARED BY GENFIT AND IS FOR INFORMATION PURPOSES ONLY. CERTAIN OF THE INFORMATION CONTAINED HEREIN CONCERNING ECONOMIC TRENDS AND PERFORMANCE IS BASED UPON OR DERIVED FROM INFORMATION PROVIDED BY THIRD-PARTY CONSULTANTS AND OTHER INDUSTRY SOURCES. WHILE GENFIT BELIEVES THAT SUCH INFORMATION IS ACCURATE AND THAT THE SOURCES FROM WHICH IT HAS BEEN OBTAINED ARE RELIABLE, GENFIT HAS NOT INDEPENDENTLY VERIFIED THE ASSUMPTIONS ON WHICH PROJECTIONS OF FUTURE TRENDS AND PERFORMANCE ARE BASED. IT MAKES NO GUARANTEE, EXPRESS OR IMPLIED, AS TO THE ACCURACY AND COMPLETENESS OF SUCH INFORMATION. This presentation contains certain forward-looking statements, including those within the meaning of the Private Securities Litigation Reform Act of 1995 with respect to GENFIT, including, but not limited to statements about GENFIT’s corporate strategy and objectives, the potential of elafibranor to receive marketing authorization in the United States, Europe and United Kingdom for PBC, expected milestone and royalty payments for elafibranor in PBC, Ipsen’s expectations regarding global peak sales for elafibranor in PBC, Ipsen’s ability to effectively maximize commercialization of elafibranor, the potential scope and size of the market for ACLF, commercial certainty within that market, development plans for our pipeline programs and expected timing for potential regulatory approvals and clinical milestones for our drug candidates, as well as projections regarding our cash runway and sources of funding of our research and development. The use of certain words, including “believe, “potential,” “expect” and “will” and similar expressions, is intended to identify forward- looking statements. Although the Company believes its expectations are based on the current expectations and reasonable assumptions of the Company’s management, these forward-looking statements are subject to numerous known and unknown risks and uncertainties, which could cause actual results to differ materially from those expressed in, or implied or projected by, the forward-looking statements. These risks and uncertainties include, among other things, the uncertainties inherent in research and development, including in relation to safety of drug candidates, cost of, progression of, and results from, our ongoing and planned clinical trials, review and approvals by regulatory authorities in the United States, Europe and worldwide, of our drug and diagnostic candidates, potential commercial success of elafibranor if approved, exchange rate fluctuations, our continued ability to raise capital to fund our development, as well as those risks and uncertainties discussed or identified in the Company’s public filings with the AMF, including those listed in Chapter 2 “Main Risks and Uncertainties” of the Company’s 2022 Universal Registration Document filed with the AMF on April 18, 2023, which is available on the Company’s website (www.genfit.com) and on the website of the AMF (www.amf-france.org) and public filings and reports filed with the U.S. Securities and Exchange Commission (“SEC”) including the Company’s 2022 Annual Report on Form 20-F filed with the SEC on April 18, 2023 and subsequent filings and reports filed with the AMF or SEC, including the Half-Year Business and Financial Report at June 30, 2023 or otherwise made public, by the Company. In addition, even if the Company’s results, performance, financial condition and liquidity, and the development of the industry in which it operates are consistent with such forward-looking statements, they may not be predictive of results or developments in future periods. These forward-looking statements speak only as of the date of publication of this document. Other than as required by applicable law, the Company does not undertake any obligation to update or revise any forward-looking information or statements, whether as a result of new information, future events or otherwise.
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Towards a new GENFIT ACLF disease state GENFIT’s approach to ACLF ACLF market opportunity Highlights on newsflow
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GENFIT Highlights 4 Lille & Paris Zurich Cambridge, MA Cash position: €96M as of Sept 30, 2024 Cash runway: ~4Q25** From IPSEN: €48.7M in milestone payment (June 2024) and €0.9M in royalty revenue from U.S. sales of Iqirvo®/elafibranor from IPSEN 5 assets in ACLF & its complications *with GENFIT formulation **We expect that our existing cash and cash equivalents will enable us to fund our operating expenses and capital expenditurerequirements until approximately the fourth quarter of 2025. This is based on current assumptions and programs and does not include exceptional events. This estimation includes our expectations to receive future milestone revenue in 2024, subject to approval by applicable regulatory authorities and US and European commercial launches of elafibranor in PBC by Ipsen, representing a total of approximately €75.2 million. Who we are Our Pipeline Financial elements Worldwide Offices French biopharmaceutical company Dual-listed on EURONEXT & NASDAQ (GNFT) Improving the life of patients with liver diseases Specific focus on rare and severe liver diseases with high unmet medical need Expertise bringing early-stage assets to commercial readiness VS-01 (UNVEIL-IT® - Phase 2) VS-01 (Proof of Concept) NTZ (Proof of Concept) SRT-015 (First-in-Human Study*) CLM-022 (preclinical) VS-02-HE (preclinical) Iqirvo® (elafibranor) in PBC Approval U.S. FDA , EMA, UCHMRA UK GNS561 CCA (Phase 2) VS-01-HAC UCD/OA (preclinical) Diagnostic programs NIS2+® (‘at risk’ MASH) TS-01 (ammonia) Other conditions 4th promotion of
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Towards a new GENFIT 5 Development of Research & Development know-how via collaborations with Big Pharma In-house discovery of elafibranor (GFT505) Inception & early years Clinical development in chronic liver diseases Focus on rare and life-threatening liver diseases with high unmet needs A diversified pipeline in ACLF (6 programs) and other life-threatening diseases (2 programs) ▪ Acute-on-Chronic Liver Failure (ACLF) Know-how and experience in liver diseases • Research (collaborations with academia, liver disease models, spheroids, etc.) • Clinical (large international trials, KOL networks, patient engagement, etc.) • Regulatory (FDA/EMA interactions, etc.) Positive 52-week ELATIVE Phase 3 trial evaluating elafibranor in PBC ▪ VS-01 (Phase 2 initiated) ▪ VS-01 (Proof of Concept) ▪ NTZ (Proof of Concept) ▪ SRT-015 (First-in-Human Study1) ▪ CLM-O22 (preclinical) ▪ VS-02-HE (preclinical) ▪ Other life-threatening liver diseases ▪ GNS561 (Phase 2 initiated) ▪ VS-01-HAC (preclinical) Potential future milestone payments and royalties from PBC2 to partially fund pipeline development Development of elafibranor in MASH up to Phase 3 included 1999 2024 2: https://ir.genfit.com/news-releases/news-release-details/genfit-ipsen-and-genfit-enter-exclusive-licensing-agreement Strategic Shift 1: with GENFIT formulation
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The elafibranor story in PBC 6 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 Filing 1st PCT international patent application claiming elafibranor Start of Phase 1 clinical trials for GFT505 elafibranor accepted as the generic name for GFT505 by the WHO IND cleared to proceed with Phase 2 trial Positive Phase 2 results in PBC Exclusive licensing agreement with Ipsen Positive Phase 3 results in PBC U.S. FDA Accelerated Approval of Ipsen’s IQIRVO® EMA Approval of Ipsen’s IQIRVO® (elafibranor) CHMRA UK Approval of Ipsen’s IQIRVO®
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Pipeline 7 VS-01‡ GNS5617 ‡ ‡ NTZ4 VS-01-HAC (UCD ‡ ‡ ‡ /OA) VS-02 in HE Preclinical Phase 2 Phase 3Phase 1 Next expected/targeted steps3 Clinical data readout 2H25 Preliminary data 2H24 – final data 2H25 IND* enabling studies completion in 2024 IND* enabling studies completion in 2025 Proof of Concept Proof of Concept SRT-0155 First-in-Human Study (with GENFIT formulation) TS-01 (ammonia) NIS2+® in MASH In EASL/EASD/EASO Guidelines – Qualified NIMBLE – 4 scientific publications – 13 scientific posters IVD Prototype CLM-0226 Preclinical Proof of Concept in 2024 Therapeutics2Diagnostics Research and Clinical Development stage – Data Readout from 5 Clinical Trials 2H25 1. Out-licensed to Terns Pharmaceuticals and Ipsen | US-FDA-accelerated-approval | UE-EMA-approval 2. All drugs under development are investigational compounds that have not been reviewed nor been approved by a regulatory authority in targeted indications 3. Reflects management's anticipated timelines, which are subject to change | based on industry benchmark/average 4. Repurposed molecule (Nitazoxanide) 5. In-licensed from Seal Rock Therapeutics 6. In-licensed from Celloram 7. In-licensed from Genoscience Pharma 8. Potentially eligible for priority review voucher upon approval by the FDA * IND = Investigational New Drug UNVEIL-IT® - Phase 2 VS-01‡ ‡ Orphan Drug Designation for ACLF (US) & ALF (EU) ‡ ‡ Orphan Drug Designation (ODD) FDA ‡ ‡ ‡ Rare Pediatric Disease Designation FDA ; ODD FDA Study initiation 1H25 Study initiation 1H25 Study initiation 1H25 Clinical data readout 2H25 Clinical data readout 2H25 Clinical data readout 2H25 ACLF franchise ▪ Approval U.S. FDA June 10, 2024 ▪ Approval EMA September 19, 2024 ▪ Approval CHMRA UK October 8, 2024 Commercial stage CCAHAC Iqirvo® (elafibranor1,8) in PBC
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ACLF Disease state – PART I P r . R . M o r e a u , M D, S e n i o r S c i e n t i s t ( O u t s t a n d i n g G r a d e ) , I N S E R M Towards a new GENFIT GENFIT’s approach to ACLF ACLF market opportunity Highlights on newsflow
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Professeur Richard Moreau, Founding Member of EF-CLIF and Worldwide Leader in ACLF 9
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Richard Moreau, MD, FAASLD,1,2,3 1European Foundation for the Study of Chronic Liver Failure (EF CLIF), Barcelona, Spain; 2Centre de Recherche sur l’Inflammation (CRI), INSERM, Université Paris Cité, CNRS, Paris, France; 3Service d’hépatologie, Hôpital Beaujon, APHP, Cichy, France. Acute-on-Chronic Liver Failure (ACLF) ACLF Day December 12, 2023
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Outline • Cirrhosis & ACLF • Defining ACLF • Pathophysiology • Medical management • Liver transplantation • Unmet needs
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Cirrhosis • 11th most common cause of death o 2 million deaths worldwide/year (~4% of deaths worldwide) • 2 billion consume alcohol o At risk for alcohol-associated cirrhosis • 2 billion overweight/obese o At risk for metabolic-associated cirrhosis Asrani et al. J Hepatol 2019;70:151-71. Devarbhavi et al. J Hepatol 2023;79:516-37. •.
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• Chronic liver disease • Compensated for years • Decompensated: ascites, gastrointestinal hemorrhage, hepatic encephalopathy o Recent onset defines acute decompensation • Acute decompensation: often leads to nonelective hospital admission • ACLF: cause of death in acute decompensation. Characteristics of Cirrhosis
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• Men ~55 yr • Seen among patients nonelectively admitted for acutely decompensated cirrhosis • Defined by impaired function of major organ systems & intense systemic inflammation • Associated with high short-term mortality (by 28 & 90 days) • Engages health-care system resources (ICU, liver transplantation) Characteristics of ACLF
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ACLF Burden in Europe • Under evaluation (commissioned by Journal of Hepatology) • Currently estimated to ~150,000 cases/yr (projection from German data).
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Evidence-Based Knowledge Produced by EF CLIF • Studies in patients nonelectively admitted for acute decompensation: o CANONIC: 1343 European patients o PREDICT: 1273 European patients o ACLARA: 1274 LATAM patients Moreau et al. Gastroenterology 2013;144:1426-37. Trebicka et al. J Hepatol 2020;73:842-54. Farias, Curto Vilalta, et al. Gastroenterology 2023;165:696-16.
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Outline • Cirrhosis & ACLF • Defining ACLF • Pathophysiology • Medical management • Liver transplantation • Unmet needs
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Organ system Diagnostic criteria* Prevalence (%) Liver Bilirubin ≥12 mg/dL 15.4 Kidney Creatinine ≥2 mg/dL or RRT 12.6 Coagulation INR ≥2.5 7.8 Brain Grade 3 or 4 HE 7.4 Circulation Use of vasopressor 4.8 Respiration SpO2/FiO2 ≤214 2.4 Diagnostic Criteria & Prevalence of Organ System Failures (CANONIC Study) *According to CLIF-C OF score. Moreau et al. Gastroenterology 2013;144:1426-37.
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1343 patients nonelectively admitted for acutely decompensated cirrhosis (new ascites, encephalopathy, infection, GI hemorrhage) Absence of ACLF • Low-grade systemic inflammation • No organ failure • Low 28-day mortality Presence of ACLF • High-grade systemic inflammation • Organ failures (ACLF-1, ACLF-2, ACLF-3) • High 28-day mortality (ACLF-3>ACLF-2>ACLF-1) 70% 30% The CANONIC Study Defined ACLF Moreau et al. Gastroenterology 2013;144:1426-37.
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Trigger Prevalence Type: Bacterial infection 44% Alcohol-related hepatitis 44% GI hemorrhage with shock 6% Toxic encephalopathy 6% Number: 1 46% ≥ 2 25% 0 29% Triggers of Inflammation & ACLF (PREDICT Study) Trebicka, Fernandez, et al. J Hepatol 2021:74;1097-108.
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Clinical Course of ACLF Within the 1st Week ACLF Grade at Day 7 Initial Grade 0 1 2 3 % patients ACLF-1 55 24 8 12 ACLF-2 35 15 25 25 ACLF-3 16 4 12 68 Gustot, Fernàndez, et al. Hepatology 2015;62:243-52.
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90-Day Transplantation-Free Survival According to Status at Day 7 Among 329 Patients Had ACLF on Admission Arroyo, Moreau, Jalan. N Engl J Med 2020;382:2137-45.
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ACLF is a Global Disorder Europe USA Asia Latin America Arroyo, Moreau, Jalan. N Engl J Med 2020;382:2137-45.
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Outline • Cirrhosis & ACLF • Defining ACLF • Pathophysiology • Medical management • Liver transplantation • Unmet needs
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Inducers of Inflammation • Pathogen-associated molecular patterns (PAMPs) = bacterial byproducts immediately recognized by immune system; induce inflammation • Damage-associated molecular patterns (DAMPs) = intracellular molecules released by dying cells; immediately recognized by immune system; induce inflammation
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Infection Liver injury (cell death) No apparent trigger PAMPs DAMPs PAMPs Systemic inflammation Organ failures Inducers of Inflammation According to Triggers Arroyo, Moreau, Jalan. N Engl J Med 2020;382:2137-45.
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• Changes in gut microbiome (↑ pathobionts = “bad” bacteria) • ↑ Intestinal permeability to bacteria and/or bacterial PAMPs • Translocation of bacteria and/or bacterial PAMPs to blood flowing to the liver • ↓ Function of the “hepatic filter”; bacteria and/or bacterial PAMPs reach systemic circulation • Bacteria can cause infection & inflammation; isolated bacterial PAMPs can cause inflammation. Impaired Gut Barrier in Decompensated Cirrhosis Bajaj, Kamath, Reddy. N Engl J Med 2021;384:2317-30.
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Outline • Cirrhosis & ACLF • Defining ACLF • Pathophysiology • Medical management • Liver transplantation • Unmet needs
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Key Points • Main principle: Diagnose acute precipitants & treat them urgently • Provide supportive therapy in ICU • Objective: Bridge to early liver transplantation • No “pathophysiology-based” therapy available. Arroyo, Moreau, Jalan. N Engl J Med 2020;382:2137-45. EASL CPG. J Hepatol 2023;79:461-91.
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Supportive Therapy • Cardiovascular: vasoconstrictors. • Respiratory: mechanical ventilation. • Brain: protective intubation if necessary; lactulose; albumin dialysis (MARS) if lactulose failure. • Liver: 2 negative RCTs of extracorporeal MARS. Arroyo, Moreau, Jalan. N Engl J Med 2020;382:2137-45. EASL CPG. J Hepatol 2023;79:461-91.
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Other Interventions • Granulocyte colony-stimulating factor o No efficacy • Plasma exchange o Trial recruiting • Cell therapy o Under evaluation EASL CPG. J Hepatol 2023;79:461-91.
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Outline • Cirrhosis & ACLF • Defining ACLF • Pathophysiology • Medical management • Liver transplantation • Unmet needs
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Survival Among Patients with ACLF-2, -3 who Did or Did not Receive Early (<28 days) Liver Transplant Gustot, Fernandez, et al. Hepatology 2015;62:243-52.
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Survival Among Patients with ACLF-2, -3 who Did or Did not Receive Early (<28 days) Liver Transplant Gustot, Fernandez, et al. Hepatology 2015;62:243-52. Narrow window for liver transplantation
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Liver Transplantation in Patients with ACLF Artru et al. J Hepatol 2017; 67:708-15. ACLF-3 only
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Outline • Cirrhosis & ACLF • Defining ACLF • Pathophysiology • Medical management • Liver transplantation • Unmet needs
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Targeting Bacterial/PAMP Translocation • Current approaches are based on antibiotics • Restricted to few patients • Major issues with antibiotic use (emergence of multidrug-resistant bacteria) • Alternative approaches: unmet need.
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Conclusions • ACLF is the most severe form of acutely decompensated cirrhosis • Bacterial/PAMP translocation & systemic inflammation are key pathogenic mechanisms • There is no “pathophysiology-based” therapy currently available • Liver transplantation is effective but limited due to narrow time, organ shortage, poor access in high-level care.
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ACLF Disease state – PART II D r . J e n n i f e r L a i ( U C S F ) , M D, M B A Towards a new GENFIT GENFIT’s approach to ACLF ACLF market opportunity Highlights on newsflow
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Acute-on-Chronic Liver Failure (ACLF) Jennifer C. Lai, MD, MBA Transplant Hepatologist Endowed Professor of Liver Health & Transplantation University of California, San Francisco (UCSF)
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Acute-on-Chronic Liver Failure : Defined …a potentially reversible condition in patients with chronic liver disease with or without cirrhosis that is associated with potential for multiple organ failure and high mortality within 3 months in the absence of treatment… Bajaj J, et al. Am J Gastro 2022.
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“ There is no direct therapeutic for ACLF.
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SCOPE OF THE UNDERLYING PROBLEM : Chronic liver disease & cirrhosis
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2 million deaths worldwide (~4% of deaths worldwide) 2 billion consume alcohol At risk for non-alcoholic fatty liver disease / cirrhosis 11th most common cause of death At risk for alcohol-associated liver disease / cirrhosis Asrani S, et al. J Hep 2019. 2 billion overweight/obese Chronic Liver Disease & Cirrhosis
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Cheemerla S, et al. Clin Liv Dis 2021. https://vizhub.healthdata.org/gbd-results/ Deaths by liver disease etiology : RISING Alcohol HBV HCV NASH Other
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Economic burden of chronic conditions in the U.S. : Cirrhosis and ACLF much higher! Chronic disease Length of hospital stay Inpatient mortality Mean cost per hospitalization Pneumonia 5 days 3.3% $7,581 Congestive heart failure 5 days 3.0% $8,315 Cerebrovascular disease 6 days 4.7% $8,117 Cirrhosis 9 days 16.3% $15,732 ACLF 16 days 53.3% $54,727 Allen A, et al. Hepatol 2016.
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THE PATIENT : Clinical Course & Features
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Trajectories of liver function in 3 common liver states Mahmud N, et al. Curr Hep Reports 2020.
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Trajectories of liver function in 3 common liver states Mahmud N, et al. Curr Hep Reports 2020.
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Trajectories of liver function in 3 common liver states Mahmud N, et al. Curr Hep Reports 2020.
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Trajectories of liver function in 3 common liver states Mahmud N, et al. Curr Hep Reports 2020.
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Clinical characteristics (U.S. cohort) n=1,031 Age (years) 57 (11) Men 66% Liver disease etiology Alcohol only 31% HCV only 21% Alcohol + HCV 15% NASH 17% Other 15% Wong F, et al. Liver Transpl 2022. Reason for admission n=1,031 Bacterial infection 25% GI bleed 16% Hepatic enceph. 17% Renal dysfxn 12% Alcohol related 4% Electrolytes abnl 3% Other 23%
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Role of prior hepatic decompensation Moreau R, et al. Gastroenterol 2013. n=417 No prior event 26% <3 months prior 16% 3-12 prior 17% >12 months prior 41%
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Percent with extra-hepatic organ failure on admission Arroyo V, et al. J Hepatol 2015. RENAL CIRCULATORY NEUROLOGIC RESPIRATORY 50% 22% 23% 13%
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Organ CLIF-C ACLF Liver Total bilirubin PT-INR Kidney Creatinine Brain Hepatic encephalopathy Circulatory Blood pressure Respiratory Oxygenation Chronic Liver Failure Consortium (CLIF-C) ACLF ACLF Scoring System *CLIF-C ACLF = 10 x [0.33 x CLIF-Organ Failures + 0.04 x Age + 0.63 x ln(WBC)-2] No ACLF ACLF-1 ACLF-2 ACLF-3
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Gustot T, et al. Hepatol 2015. Arroyo V, et al. NEJM 2020. Probability of survival by ACLF severity Increasing # / severity The greater the number/severity of organ failures, the greater the risk of death.
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PATHOGENESIS : Leading hypotheses and supporting data
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Arroyo V, et al. J Hepatol 2014. Portal hypertension 101 Simonetto DA, et al. Mayo Clinic Proc 2019. ➢ Circulatory system at maximum capacity ➢ Impaired gut circulation → altered gut microbiome → impaired gut mucosal defense system The underlying condition
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Greater severity of liver disease is associated with less diverse microbiome Sole C, et al. Gastroenterol 2021. Is there a role for gut microbiota manipulation to improve ACLF outcomes?
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Arroyo V, et al. J Hepatol 2014. Portal hypertension 101 Simonetto DA, et al. Mayo Clinic Proc 2019. ➢ Circulatory system at maximum capacity The underlying condition ➢ Increased intestinal permeability → chronic bacterial translocation ➢ Impaired gut circulation → altered gut microbiome → impaired gut mucosal defense system ➢ Chronic systemic inflammation
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Arroyo V, et al. J Hepatol 2014. Systemic inflammation hypothesis of ACLF Arroyo V, et al. J Hep 2021. Fig adapted from Arroyo V, et al. J Hepatol 2014. The acute insult Acute precipitant Exacerbation of portal hypertension Acute on chronic systemic inflammation
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Arroyo V, et al. J Hep 2021. Systemic inflammatory markers and risk of ACLF Kimman M, Trebicka J. J Pers Med 2023. Escalating risk as systemic inflammatory markers increase
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Trebicka J, et al. Front Immunol 2019. Systemic inflammatory markers are elevated Is there a role for targeting systemic inflammation to improve ACLF outcomes?
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AT THE BEDSIDE : Management
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“ There is no direct therapeutic for ACLF.
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Portal hypertension - Circulatory system is maximally accommodating (little room for more insult) - Splanchnic vasodilitation Systemic inflammation - INTENSIVE CARE Bernal et al. J Hepatol 2021 Bernal W, et al. J Hepatol 2021.
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GOAL OF TREATMENT : BUY TIME To prepare for liver transplant Allow the precipitant to resolve To allow families to say goodbye
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Artru F, et al. J Hep 2017. Survival is better with transplant than without Gustot, et al. Hepatol 2015. Artru F, et al. J Hep 2017.
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Gustot, et al. Hepatol 2015. Artru F, et al. J Hep 2017. Transplant survival is acceptable in all ACLF grades
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Post-transplant healthcare utilization increases by stage of ACLF Sundaram V, et al. Clin Gastro Hep 2022.
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Post-LT quality of life is significantly impaired Sundaram V, et al. Clin Gastro Hep 2022.
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Adapted from Mahmud N, et al. Curr Hep Reports 2020 and Gustot T, et al. J Hepatol 2018. Atiemo et al. AJT 2017. Narrow window for liver transplantation ~40% will recover ACLF patient Too early Too late Transplant window ➢ ~4% of patients with cirrhosis are listed for liver transplant ➢ 1 in 4 patients listed for transplant die while waiting
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Interventions other than liver transplantation : Statements from the ACG ACLF guidelines ◦ Artificial liver support systems “whether they provide any clinical benefit is unclear” ◦ Plasma exchange “its effect in ACLF is unknown” ◦ Granulocyte colony stimulating factor “we suggest against the use of G-CSF” ◦ Stem cell therapy “evidence to support its use is currently insufficient” Bajaj J, et al. Am J Gastro 2022.
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Adapted from Mahmud N, et al. Curr Hep Reports 2020 and Gustot T, et al. J Hepatol 2018. The Opportunity ACLF patient - Systemic inflammation? - Microbiome? - Reinforce the gut brain barrier?
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ACLF is a highly lethal, resource-intensive condition that occurs in patients with chronic liver disease. Key Points : ACLF (Disease state) Portal hypertension, altered microbiome, and systemic inflammation drive ACLF. There is no direct therapeutic for ACLF. - Liver transplantation, while effective, is limited due to narrow timing, low availability of organs, and poor access to high-level care.
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GENFIT’s approach to ACLF ACLF market opportunity Highlights on newsflow ACLF disease state Towards a new GENFIT
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Building a targeted portfolio to address the unmet need that exists with current (not approved) Standard of Care in ACLF 77 Systemic inflammation1 Nf-KB Inflammasome Gut-liver axis dysfunction Necroptosis Pyroptosis Hepatic impairment & cell death Specific selection of strategic assets: based on pathophysiology1 of ACLF, as defined by liver experts and consortiums such as EF-CLIF (European Foundation for the study of Chronic Liver Failure), to address most relevant pathways Benefits of a diversified pipeline targeting complementary/relevant pathways ▪ Explore more options for patients ▪ Provides multiple opportunities for success ▪ Allows exploration of potential synergies in combinations ▪ Offers possibility to apply key learnings across all programs, to accelerate execution 1 2 3 ACLF patient management1 (no drug approved) 1. Treating acute precipitants -Antimicrobial therapy -Corticosteroids for alcoholic hepatitis -Acute variceal haemorrhage Inhibition of the innate immune system to limit the cytokine storm Inhibition of hepatocyte cell death in the liver and other functional cells in other injured organs Restoration of the normal gut-liver action to limit bacterial translocation 1: JHEP, Moreau, 2021 (https://www.jhep-reports.eu/article/S2589-5559(20)30110-5/pdf) / Critical Care, Moreau& Li, 2023 ( https://ccforum.biomedcentral.com/articles/10.1186/s13054-023-04540-4) 2. Organ support -Intravenous fluids -Renal replacement therapy -Extracorporeal liver support -Liver transplantation
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5 assets with complementary mechanisms of action targeting key pathways 78 We are developing a diversified pipeline to better address the complexities of ACLF and improve treatment outcomes VS-01-ACLF NTZ SRT-015 CLM-022 VS-02-HE Liposomal-based technology Anti-inflammatory and anti-bacterial Urease inhibitor ASK1 inhibitor NLRP3 inflammasome inhibitor To drain out ammonia and ACLF toxins from the blood To reduce systemic inflammation and impede PAMPs release and bacterial translocation [New formulation under development for dosing flexibility] To reduce hyperammonemia, stabilize blood ammonia and prevent HE To inhibit cell death apoptosis, inflammation (liver-centricity), and fibrosis To inhibit inflammation (systemic), and cell death (pyroptosis) Peritoneal Oral OralInjectable
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Patient Journey & Window of Opportunity for Treatment 79 Recovery TREATMENT GOALS Golden Treatment Window Death Transplantation (Tx) Multiorgan support in the early course of ACLF - DYSBIOSIS - PAMPS - BACTERIAL TRANSLOCATION VS-01 NTZ SRT-015 VS-02 CLM-022 ▪ Resolve ACLF ▪ Improve survival ▪ Chance of liver transplant increased ▪ Healthcare costs reduced
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VS-01 Clinical Stage Program in ACLF
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Extraction of Metabolites to Reduce Mortality 81 Harnesses the intraperitoneal route of administration following paracentesis Ascites drainage Standard of care VS-01 VS-01 scavenging liposomes ACLF metabolites VS-01 drained along with ammonia and ACLF metabolites High unmet medical need in ACLF with no approved treatment and 112’000 cases1 VS-01 in brief Early ACLF treatment may reduce • Length of hospital/ ICU stay Targets first-line treatment for ACLF to reverse the disease Delivered via in-place peritoneal access catheter Targets multiorgan support: brain, liver, and kidney • Acute need of transplantation • Re-hospitalization • Healthcare and hospital costs 1. Prevalence US+EU5 of patients with ascites and candidates for VS-01 Source: third-party US Market Research, December 2021 VS-01
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First in Human Study 82 OUTCOME ✓ Generally safe and well tolerated ✓ Promising preliminary efficacy results ✓ Confirmed ease of i.p. administration ✓ Data selected for Clinical Hepatology Debrief at AASLD 2021 DETAILS • Study population (n=12): - Decompensated liver cirrhosis with ◦ Ascites ◦ Covert hepatic encephalopathy (minimal HE & HE 1) • Principal investigator: Prof Dr Jonel Trebicka • Clinical site: Part A: Single Ascending Dose (n = 9) Part B: Multiple Doses (n = 3) Cohort 1 Cohort 2 Cohort 3 Cohort 4IDSMB 15 mL/kg 30 mL/kg 45 mL/kg 34-42 mL/kg daily for 4 days SOC, standard of care | IDSMB, Independent Data and Safety Monitoring Board | HE, hepatic encephalopathy VS-01
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Phase 1b Preliminary Efficacy Results on Liver & Brain Function 83 Uschner FE et al., Oral presentation at AASLD 2021, Abstract # 208 IMPROVEMENT IN PSYCHOMETRIC TESTS FOR HE e.g., number connection test was performed faster Part A 15mL/kg Part A 30mL/kg Part A 45mL/kg Part B Reference DOSE-DEPENDENT AMMONIA REMOVAL FROM THE BODY Ammonia clearance increased with VS-01 dosage in peritoneal fluid Patient #1 Patient #2 Patient #3 Mean Linear (Mean) 180 160 140 120 100 80 60 40 20 0 Peritoneal fluid ammonia clearance (mL/min) Cohort 1 Cohort 2 Cohort 3 31.5 74.4 96.8 y = 32.688x + 2.1998 R2 = 0.968 15 mL/kg 30 mL/kg 45 mL/kg IMPACT ON OVERALL LIVER DISEASE SEVERITY e.g., assessed by Child-Pugh Score (CPS) 66,7 16,7 8,3 8,3 improved stable worsened missing Percentage (%) PART A & B N O P A T I E N T S P R O G R E S S E D T O A C L F Improved or stable disease: 83.4% VS-01
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UNVEIL-IT® Phase 2 Proof-of-Concept Trial 84 * www.efclif.com Screening Follow-up Period Treatment Period Patient Population Adult patients with Acute-on- Chronic Liver Failure (ACLF) grade 1 and 2 and ascites Phase 2a Proof Of Concept Study of VS-01 in Patients with Acute-on-Chronic Liver Failure Number of Patients N=30 | VS-01 + Standard of Care N=30 | Standard of Care Primary Objective Efficacy measured by CLIF-C ACLF score* at Day 7 90 day - mortality 28 day - mortality Time to death ACLF grade change Transplant-free survival Safety and tolerability 1 : 1 R A N D O M I Z E D M U L T I - C E N T E R G L O B A L S T U D YC O N T R O L L E DO P E N - L A B E L ~60 Secondary Objectives Screening period Day 1 Day 4 Day 90 C L I N I C A L D A T A R E A D O U T T A R G E T E D 2 H 2 0 2 5 Number of Sites 50 (EU/US) VS-01
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NTZ Clinical Stage Program in ACLF NTZ (Nitazoxanide) is a repositioned molecule
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NTZ Impacts Multiple Pathways 86 NTZ anti-inflammatory activity at least through NF-kB/MAPK pathway NTZ antibacterial activity through inhibition of PFOR NTZ
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Activity in Disease Models Support ACLF Clinical Development 87 * Poster presentation at the ILC 2022 (London) – EASL Selected for The Best of ILC Reduces LPS-induced inflammation in healthy rats* Beneficial effects on liver function markers (bil, alb) in models of cirrhosis* Reduces brain edema, inflammation markers and reverses the ACLF-induced gene signature in a model of ACLF (BDL+LPS) Alleviates liver and renal damages in a model of ACLF (CCL4+LPS) Improves survival in treatment models of Sepsis (CLP) Poster presentation at EASL in June 2023 Brain edema Kidney function marker Circulating cytokines ACLF-induced gene signature in liver and kidney NTZ
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Completed Ph1 studies in subjects with hepatic impairment (HI) and renal impairment (RI) 88 Design • Mild, Moderate and Severe RI subjects vs healthy subjects • 8-10 Subjects in each group • Treatment period 7 days • PK and safety Healthy control subjects (n=7-8) Mild renal impairment (n=7-8) Moderate renal impairment (n=7-8) Severe renal impairment (n=7-8) An Open-label, Phase 1, Multiple-dose Study to Evaluate the Pharmacokinetics and Safety of NTZ 500 mg twice daily for 7 days in Adult Subjects with Mild, Moderate & Severe Renal Impairment and Adult Healthy Control Subjects An Open-label, Phase 1, Multiple-dose Study to Evaluate the Pharmacokinetics and Safety of NTZ 500 mg twice daily for 7 days in Adult Subjects with Moderate & Severe Hepatic Impairment and Adult Healthy Control Subjects Design • Moderate to Severe HI subjects vs healthy subjects • 6-8 Subjects in each group • Treatment period 7 days • PK, safety, pharmacodynamics Healthy control subjects (n=8) Moderate hepatic impairment (n=8) Severe hepatic impairment (n=8) NTZ
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Development of a New Formulation, Proof-of-concept, Study initiation targeted for 1H25 and Clinical data readout for 2H25 89 Objectives of the POC Phase 1b ▪ To evaluate safety and tolerability of NTZ across a range of doses in patients with ACLF ▪ To evaluate NTZ dose response relationship in patients with ACLF ▪ To select the optimal NTZ dose for evaluation in Phase 2a Phase 2a ▪ To evaluate clinical outcomes in patients with ACLF following administration of NTZ ▪ To evaluate safety and tolerability of NTZ in patients with ACLF ▪ To evaluate NTZ PK/PD relationships in patients with ACLF Patient Population: Patients with ACLF1 or ACLF2 New formulation under development To permit greater dosing flexibility and ultimately better serve the ACLF patients: ▪ This population is known to have impaired/organs failure, and this new formulation will also permit to optimize safety and drug exposure in this patient population. ▪ Optimization of the future potential of NTZ, taking into account specific needs of the targeted patients. NTZ
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SRT-015 Preclinical stage program in ACLF SRT-015 has been in-licensed from Seal Rock Therapeutics
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An Injectable Formulation of ASK1 Inhibitor 91 1. ASK1 inhibition: a therapeutic strategy with multi-system benefits: Journal of Molecular Medicine (2020) ASK1 inhibitor in-licensed from Seal Rock Therapeutics in acute liver diseases SRT-015 in brief Injectable formulation Targets inhibition of cellular apoptosis, inflammation and fibrosis ASK1 inhibition has shown several potentially beneficial effects that may be relevant in ACLF Scientific rationale › Blocking LPS (lipopolysaccharide) associated hyperinflammatory response › Reducing the ROS (Reactive Oxygen Species)-related immune response › Reducing apoptosis › Reducing release of the proinflammatory cytokines › Reducing fibrosis › Protecting macrophage mitochondrial function SRT-015
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Target Engagement, MoA, Activity and Data Supporting Development in ACLF 92 Inhibits: -ASK-1 -phosphorylation of p38 -phosphorylation of JNK Activity: -Anti-inflammatory -Anti-apoptotic -Anti-fibrotic SRT-015 alleviates hepatic injury in a model of drug-induced liver injury, in association with reduction of phosphorylation of both JNK and ASK1 SRT-015 alleviates hepatic injury in a model of alcoholic hepatitis SRT-015
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Clinical Data Support Development in Liver Diseases 93 1. ASK1 inhibition: a therapeutic strategy with multi-system benefits: Journal of Molecular Medicine (2020) 2. https://www.sealrocktx.com/science.html 3. NCT04887038 › SRT-015 has demonstrated efficacy in multiple preclinical models2 of acute and chronic liver injury › SRT-015 phase 1 FiH trial3 completed in healthy volunteers, achieving therapeutically relevant exposure with safety and tolerability profile supportive of ongoing clinical investigation Upcoming milestone First-in-Human study targeted for 1H25 and Clinical data readout for 2H25 Multi-organ benefits of ASK1 modulation have been observed in several animal models and clinical trials1 In kidney diseases => limits renal inflammation, apoptosis and fibrosis In liver diseases => prevents hepatocyte death, inflammation and fibrosis In brain disorders => ASK-1 modulation limits neurodegeneration In inflammatory diseases => limits damaging immune responses In cardiopulmonary disease => slows the onset of heart failure SRT-015
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CLM-022 Preclinical stage program in ACLF CLM-022 has been in-licensed from Celloram Inc.
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Supporting Evidence and Next Steps 95 CLM-022 NLRP3 inflammasome inhibitor Preclinical • Blocks NLRP3 inflammasome activated by ATP and Nigericin • Blocks the endotoxin-induced production of inflammatory cytokines in an LPS sepsis model • Blocks ASC speck formation at nanomolar concentrations • Decreases IL-1 secretion by macrophages stimulated with LPS and nigericin • Protects against nigericin-induced pyroptosis in LPS-primed macrophages • Active in-vivo in rodent preclinical models of sepsis and IBD. • Well tolerated Preclinical Proof of Concept in 2024 LPS T1h CLM-022/Veh 1mg/kg, po T0 Sacrifice T+5h Serum TNF levels CLM-022
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VS-02-HE Preclinical program in ACLF and its complications
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Supporting Evidence and Next Steps 97 VS-02 in ACLF-HE Urease inhibitor Preclinical data • Superior urease inhibitory activity in vitro • Cytotoxicity and mutagenicity assessment (Ames test) • Reduces plasmatic ammonia in a model of acute liver failure in rats • Reduces plasmatic ammonia and brain glutamine in the bile duct-ligated model in rats 1. Forster V. et al. Sci Transl Med 2014 2. Agostoni V. et al., Adv Funct Mater 2016 3. Giacalone G. et al., J Cont Release 2018 4. Matoori S. et al., J Cont Release 2020 5. VS-01 Phase 1b data compared to independent published studies About HE - Major complications of advanced liver disease and portal hypertension6 - 30-40% of patients with cirrhosis will experience at least 1 episode5 - Independent risk factor of mortality in ACLF6 Urease inhibitory activity in the caecal content of Wistar rats IND enabling studies completion in 2025 VS-02-HE
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Highlights on newsflow ACLF disease state Towards a new GENFIT GENFIT’s approach to ACLF ACLF market opportunity IQVIA
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99 • IQVIA is not an “authorized person” for the purposes of the Financial Services and Markets Act 2000 (“FSMA”) and does not provide investment advice or carry on any other regulated activity under Part II of the FSMA 2000 (Regulated Activities) Order 2001. • Projections and related information contained herein are made and provided subject to the assumptions, methodologies, caveats, and variables described in this report. Proprietary and third party Source on which analyses are conducted are reasonably believed to be reliable. No warranty is made as to the completeness or accuracy of such third party Source or Data. • This report, in part or in whole, is not intended to constitute investment advice, and is not a recommendation to purchase or not purchase, an endorsement of, or an opinion as to the value of, any security or any investment instrument of our client or any other entity. • As with any attempt to estimate future events, projections, conclusions, and other information included herein are subject to certain risks and uncertainties, and are not to be considered guarantees of any particular outcome. • This report shall not be published, nor shall any public references to IQVIA be made regarding these services or this report,without IQVIA’s prior written approval, provided that, this report may be given to third party organizations as contemplated in the contract terms. When so provided, this report and the information herein must always be provided and used in its entirety, including this complete Disclaimer page. • This report is subject to the IQVIA Standard Terms and Conditions. Disclaimer Genfit –AASLD presentation - November 2023
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100 We conducted secondary market research / literature review to assess the commercial opportunity in ACLF Genfit –AASLD presentation - November 2023 SCOPE ACLF disease landscape • Performed a literature review and secondary market research to understand: • Demographics and epidemiology / burden of disease with healthcare costs associated • Treatment algorithm • Competitive landscape • Expected future market events ACLF addressable market estimation • Overall ACLF market size estimated based on epidemiology and potential price point from secondary market research No detailed pricing primary market research was conducted. Estimation is not a forecast – calculations represent potential overall market size based on secondary research / literature review.
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101 ACLF is a life-threatening disease involving multiple organs failure and characterized by short term mortality Genfit –AASLD presentation - November 2023 1) Shah NJ, et al. StatPearls (2022) 2) Moreau R et. al.,Gastro, (2013); 3) Hernaez R, et al., Gut (2017); 4) IQVIA Analysis; 5) Kamath 2017; 6) Hernandez et al 2019; 7) Wong F, et al., Liver Transpl 2022; 8) Arroyo v., et al, J. Hepatol (2015) Acute on chronic liver failure 30% Hospital readmission rate after 30 days since discharge1 40-50% mortality rate at 90 days for ACLF1 & ACLF2; and up to 79% for ACLF3 2,3 52-57 average age at diagnosis mostly driven by onset of alcohol related cirrhosis and/or hepatitis B or D5,6,7 65% of diagnosed patients are male5,6,7 Life-threating disease characterized by acute decompensation of chronic liver disease associated with multiple organ failures and high short-term mortality1
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102 Management of ACLF results in significant economic burden on healthcare systems, leading to a high need for innovative therapies Genfit –AASLD presentation - November 2023 1) Kamath 2017; 2) Hernandez et al 2019 3); The burden of ACLF in numbers 16 days52 000 $ 6.4 Bn $ Average cost per hospitalization per patient in US1 Average length of hospital stay1 (vs 7 days for cirrhotic patients) Estimated annual cost burden in US in 2021* (a nearly 4-fold increase since 2011*) *Note: Estimates based on triangulation of data from below mentioned publications and PMR interview (Desai et al, Clin Transl Gastroenterol. (2019); Hirode et al JAMA Netw Open. (2020); Hernaez et al, J Hepatol. (2019); Mezzano et al, Gut (2022); Moreau et al, Gastroenterology. (2013))
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103 ACLF has low epidemiology and could be eligible to orphan designation; aging population and launch of targeted Tx can increase diagnosis rate 0 10 20 30 40 50 60 70 80 90 100 ACLF 1-2 EU4+UK US Estimated current prevalence (1:100,000) FDA ODD threshold (indicative) EMA ODD threshold • In 2021, the prevalence of ACLF is estimated to be ~294K across the US, EU4 and UK1 • Approx. 45-52% of ACLF patients are grade 1 and 35% are grade 22,3 • Total addressable market (for grade 1/2 ACLF patients) is estimated to be ~150K in EU4 & UK and 90K in US • Therefore, therapies targeting ACLF are eligible for orphan drug designation given low prevalence and lack of therapies Notes:* Estimates based on triangulation of data from listed sources Sources: 1. Moreau, R., et al., (2013) Supplemental Table 10; 2. Moreau, R., et al., (2013) CANONIC study Supplemental Table 10; 3.Allen MA et al., Hepatology (2016); 4. Internal Reference (PMR 2021); 5. Desai et al, Clin Transl Gastroenterol. (2019); 6. Hirode et al JAMA Netw Open. (2020); 7.Hernaez et al, J Hepatol. (2019); 8. Mezzano et al, Gut (2022); 9. Moreau et al, Gastroenterology. (2013); Abbreviations: ACLF: Acute-on-chronic liver failure Genfit –AASLD presentation - November 2023 Overview and future outlook Note: while EMA and FDA ODD thresholds capture number of patients, the estimated ACLF prevalence refers to number of episodes rather than patients, thereby leading to potential overestimation of the disease prevalence
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104 Several analogues were selected to estimate price range of upside potential, including one-off therapies for chronic disease and drugs for acute episodes Genfit –AASLD presentation - November 2023 Analogues considered • To identify relevant price range for the ACLF drugs, different analogues were considered - Type of rare disease (i.e. life threating vs chronic) - Onset of acute episodes - Setting of treatment (hospitals vs out-patient care) - Benefit provided (significant mortality benefit vs slower progression over hard endpoint) • IQVIA identified a 100-200k$ in US as potential upside range for an upcoming ACLF therapy with mortality benefit targeting more severe patients Analogue MoA Features List Price (US) Andexxa Recombinant modified human factor Xa (FXa) protein • Adults with life threating bleeds due to use of blood thinner therapies (apixaban and rivaroxaban) • IV infusion by HCP • Immediate, significant reverse blood thinning • 25-50k$ per treatment, depending on patient features Cablivi Monoclonal antibody • Treatment of acute episode in life threating disease (i.e. acquired thrombotic thrombocytopenic purpura) • Orphan drug • Hospital setting • Significantly reduced potentially fatal and serious disease related events • 270k$ per year CAR – T cell Chimeric Antigen Receptor • One off cycle for the treatment of acute/ severe conditions patients with blood cancer with limited life expectancy • Mortality benefit over a sustained period of time • 371$k average cost Bylvay Reversible inhibitor of ileal bile acid transporter • The first non-surgical treatment for severe itching (pruritus) in PFIC • Orphan drug • Highly significant sustained improvements in pruritus • Small patient population (adult & pediatric) with high unmet need • 385k$ per year
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105 Overall, grade 1-2 ACLF may represent a potential ~4 bn USD addressable market opportunity in the US and EU4+UK by 2030 Genfit –AASLD presentation - November 2023 Base case 4.0 1.8 2.2 Assumptions / considerationsBallpark overall market size by 2030, bn USD1 • Prevalence: 150K (EU4 + UK) / 90k (US) for grade 1-2 ACLF patients2 • Drug price could amount to $30-40k per patient in US and $10-20k in EU given the economic burden of hospitalizations and duration of treatment; the range was estimated based on: - Available robust data on hospitalization costs (i.e. 16 days average stay, 52k$ average associated costs in US) - Likely price range for orphan drugs for life treating disease with uncertain mortality benefit over the target population • An upside scenario can be achieved assuming the therapy provides significant mortality benefit for a restricted subpopulation (assuming 100-200k in US, 50-80k in EU price based on analogues assessment) • Potential upside of market opportunity (irrespective of price point): ACLF incidence likely to slightly increase due to higher prevalence of lifestyle diseases, drug-induced liver injuries and raising disease awareness, market opportunity could be higher US EU4+UK Note: 1) Figures based on secondary research / literature review conducted in January 2023 – not a forecast and represents an estimated overall market size. No primary market research was conducted (e.g., pricing research); 2) There is limited availability of recent US epi studies; lower prevalence vs EU is believed to be driven by differences in underlying population, Estimation includes compliance rate and gross-to-net price estimate
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106 Detailed overview of assumptions used to estimate addressable market in 2030 in US & EU4+UK Genfit –AASLD presentation - November 2023 Input Base Upside Rationale / Sources Prevalence ~100K ~190 • US: Hernaez, et al., J of Hepatol (2019) • EU4+UK: Moreau, R., et al., (2013) Table 10; ACLF 1 prevalence ACLF 2 prevalence % 45% 35% 45% 3% • IQVIA Internal reference (PMR 2022); • Moreau, R., et al., (2013) CANONIC study Supplemental Table 10 Total addressable market # ~90K ~150K Compliance % ~75% ~75% • IQVIA expertise Potential price ~40K ~20K 150K (subpop) 65K (subpop) • Base case: Hospitalization costs assessment and price of rare disease drugs without mortality benefit • Upside case: Price of rare disease analogues with mortality benefit for a subpopulation with severe ACLF Gross to net % 90% 90% • IQVIA expertise 2030 Addressable market (USD) $ 2.2 Bn 1.9 Bn >4 Bn >2.5 Bn Assumptions / considerations Note: European countries in scope included only EU4+UK
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107 ACLF is an attractive market opportunity with upside potential given significant unmet need for urgent treatment and easier clinical development Genfit –AASLD presentation - November 2023 Possibility to lead ACLF market growth with therapies being launched at a price fully representing their value ACLF is an attractive opportunity for Biotechs to address an untapped patient population with high unmet need for urgent treatment Possibility to consider commercialization on the condition that industry collaborates with the scientific community to increase disease awareness Potential orphan designation leading to easier clinical development
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ACLF disease state Towards a new GENFIT GENFIT’s approach to ACLF Highlights on newsflow ACLF market opportunity
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Highlights on newsflow 109 PBC (Primary Biliary Cholangitis) ACLF (Acute-on-Chronic Liver Failure) Other life-threatening liver diseases Expected commercialization by partner Ipsen Phase 2 UNVEIL-IT ® Proof of Concept First-in-Human study initiation Preclinical Proof of Concept IND enabling studies completion VS-02-HE IND enabling studies completion VS-01-HAC 1: Elafibranor program has been out-licensed to partner in 2021 (press release) 2: https://ir.genfit.com/news-releases/news-release-details/ipsen-confirms-us-fda-grants-priority-review-new-drug 2024 2025 Preliminary data Final dataGNS561 These targeted timelines are indicative only (based on best estimates by management and current level of knowledge) Approval U.S. FDA June 10, 2024 Approval EMA September 19, 2024 Approval CHMRA UK October 8, 2024 Iqirvo® (Elafibranor1) VS-01 NTZ SRT-015 Proof of ConceptVS-01 CLM-022
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