Genfit Sa · EURONEXT:GNFT
Genfit Sa — Investor Day (October 2022)
146 slides from Genfit Sa's investor day presentation, Oct 19, 2022
Slide 1: GENFIT Pipeline Day Corporate Presentation
October is National Liver Awareness Month: are you at risk? GENFIT Pipeline Day Corporate Presentation October 19, 2022 | Westin New-York, USA
Slide 2: Disclaimer
Disclaimer 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 sizes
Slide 3: Introduction
Introduction Objective of this PIPELINE Day Pascal Prigent, CEO of GENFIT
Slide 4: Agenda
Agenda ▪ Primary Biliary Cholangitis (PBC) ▪ Acute on-chronic liver failure (ACLF) ▪ Hepatic encephalopathy (HE) ▪ Cholangiocarcinoma (CCA) ▪ Urea cycle disorder (UCD) & and organic acidemia disorder (OAD) Closing remarks 4
Slide 5: Acute on-chronic liver failure (ACLF)
Acute on-chronic liver failure (ACLF) Disease state ▪ Jennifer C. Lai, MD, MBA, Transplant hepatologist, University of California, San Francisco (UCSF), USA – Endowed Professorship of Liver Health & Transplantation
Slide 6: Acute-on-Chronic Liver Failure (ACLF)
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)
Slide 7: Financial Disclosures
Financial Disclosures Investigator-initiated research funded by: ◦ National Institutes of Health ◦ Axcella Health, Inc ◦ Gore Medical ◦ Grifols Other paid commitments: ◦ Novo Nordisk (Advisory Board) ◦ U.S. FDA Gastrointestinal Drug Advisory Committee (Member) ◦ Associate Editor (Hepatology journal)
Slide 8: Acute-on-Chronic Liver Failure: Defined
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.
Slide 9: There is no direct therapeutic for ACLF
“ There is no direct therapeutic for ACLF.
Slide 10: Scope of the underlying problem
SCOPE OF THE UNDERLYING PROBLEM : Chronic liver disease & cirrhosis
Slide 11: Chronic Liver Disease & Cirrhosis
Chronic Liver Disease & Cirrhosis 11th most common cause of death 2 million deaths worldwide (~4% of deaths worldwide) 2 billion consume alcohol At risk for alcohol-associated liver disease / cirrhosis 2 billion overweight/obese At risk for non-alcoholic fatty liver disease / cirrhosis Asrani S, et
Slide 12: Deaths by liver disease etiology: rising
Deaths by liver disease etiology : RISING Other NASH HCV HBV Alcohol Cheemerla S, et al. Clin Liv Dis 2021. https://vizhub.healthdata.org/gbd-results/
Slide 13: Economic burden of chronic conditions in the U.S.
Economic burden of chronic conditions in the U.S. : Cirrhosis and ACLF much higher! Chronic Length of Inpatient Mean cost per disease hospital stay mortality hospitalization Pneumonia 5 days 3.3% $7,581 Congestive heart 5 days 3.0% $8,315 failure Cerebrovascular 6 days 4.7% $8,117 disease Cirrhosis
Slide 14: The Patient: Clinical Course & Features
THE PATIENT : Clinical Course & Features
Slide 15: Trajectories of liver function in common liver states
Trajectories of liver function in 3 common liver states Mahmud N, et al. Curr Hep Reports 2020.
Slide 16: Trajectories of liver function in common liver states
Trajectories of liver function in 3 common liver states Mahmud N, et al. Curr Hep Reports 2020.
Slide 17: Trajectories of liver function in common liver states
Trajectories of liver function in 3 common liver states Mahmud N, et al. Curr Hep Reports 2020.
Slide 18: Trajectories of liver function in common liver states
Trajectories of liver function in 3 common liver states Mahmud N, et al. Curr Hep Reports 2020.
Slide 19: Clinical characteristics (U.S. cohort)
Clinical characteristics (U.S. cohort) Reason for n=1,031 admission n=1,031 Age (years) 57 (11) Bacterial infection 25% Men 66% GI bleed 16% Liver disease etiology Hepatic enceph. 17% Alcohol only 31% Renal dysfxn 12% HCV only 21% Alcohol related 4% Alcohol + HCV 15% Electrolytes abnl 3% NASH 17% Ot
Slide 20: Role of prior hepatic decompensation
Role of prior hepatic decompensation n=417 No prior event 26% <3 months prior 16% 3-12 prior 17% >12 months prior 41% Moreau R, et al. Gastroenterol 2013.
Slide 21: Percent with extra-hepatic organ failure on admission
Percent with extra-hepatic organ failure on admission RENAL NEUROLOGIC CIRCULATORY RESPIRATORY 50% 22% 23% 13% Arroyo V, et al. J Hepatol 2015.
Slide 22: Probability of survival by ACLF severity
Probability of survival by ACLF severity Increasing # / severity The greater the number/severity of organ failures, the greater the risk of death. Gustot T, et al. Hepatol 2015. Arroyo V, et al. NEJM 2020.
Slide 23: Pathogenesis: Leading hypotheses and supporting data
PATHOGENESIS : Leading hypotheses and supporting data
Slide 24: Portal hypertension
The underlying condition ➢ Circulatory system at maximum capacity Portal ➢ Impaired gut circulation → altered gut microbiome → impaired gut mucosal hypertension defense system 101 Simonetto DA, et al. Mayo Arroyo V, et al. JClinic Proc Hepatol 2019. 2014.
Slide 25: Liver disease severity and less diverse microbiome
Greater severity of liver disease is associated with less diverse microbiome Sole C, et al. Gastroenterol 2021.
Slide 26: Portal hypertension
The underlying condition ➢ Circulatory system at maximum capacity ➢ Impaired gut circulation → altered gut Portal microbiome → impaired gut mucosal defense system hypertension 101 ➢ Increased intestinal permeability → chronic bacterial translocation ➢ Chronic systemic inflammation Simonetto DA, et a
Slide 27: Systemic inflammation hypothesis of ACLF
The acute insult Acute precipitant Exacerbation Acute on chronic of portal systemic hypertension inflammation Systemic inflammation hypothesis of ACLF Arroyo V, et al. J Hep 2021. Fig adapted Arroyo V, et al.from Arroyo J Hepatol V, et al. J Hepatol 2014. 2014.
Slide 28: Systemic inflammatory markers are elevated
Systemic inflammatory markers are elevated Arroyo V, et al. J Hep 2021.
Slide 29: Systemic inflammatory markers are elevated
Systemic inflammatory markers are elevated Trebicka J, et al. Front Immunol 2019.
Slide 30: At the Bedside: Management
AT THE BEDSIDE : Management
Slide 31: There is no direct therapeutic for ACLF
“ There is no direct therapeutic for ACLF.
Slide 32: Portal hypertension and systemic inflammation
Portal hypertension Systemic inflammation - Circulatory system is maximally - accommodating (little room for more insult) - Splanchnic vasodilitation Bernal W, et al. J Hepatol 2021.
Slide 33: Goal of treatment: buy time
GOAL OF TREATMENT : BUY TIME Allow the To allow To prepare precipitant families to for liver to resolve say goodbye transplant
Slide 34: Survival is better with transplant than without
Survival is better with transplant than without Gustot, et al. Hepatol 2015. Artru F, et al. J Hep 2017.
Slide 35: Transplant survival is acceptable in all ACLF grades
Transplant survival is acceptable in all ACLF grades Gustot, et al. Hepatol 2015. Artru F, et al. J Hep 2017.
Slide 36: Post-transplant healthcare utilization by ACLF stage
Post-transplant healthcare utilization increases by stage of ACLF Sundaram V, et al. Clin Gastro Hep 2022.
Slide 37: Post-LT quality of life significantly impaired
Post-LT quality of life is significantly impaired Sundaram V, et al. Clin Gastro Hep 2022.
Slide 38: Narrow window for liver transplantation
Narrow window for liver transplantation ACLF patient ~40% will recover ➢ ~4% of patients with cirrhosis are Too early listed for liver transplant ➢ 1 in 4 patients Transplant window listed for transplant die while waiting Too late Adapted from Mahmud N, et al. Curr Hep Reports 2020 and Gustot T, et
Slide 39: Interventions other than liver transplantation
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
Slide 40: The Opportunity
The Opportunity ACLF patient Adapted from Mahmud N, et al. Curr Hep Reports 2020 and Gustot T, et al. J Hepatol 2018.
Slide 41: Key Points: ACLF (Disease state)
Key Points : ACLF (Disease state) ACLF is a highly lethal, resource-intensive condition that occurs in patients with chronic liver disease. Portal hypertension, altered microbiome, and systemic inflammation drive ACLF. There is no direct therapeutic for ACLF. - Liver transplantation, while effective
Slide 42: Questions?
Short Q&A (10 minutes) Questions? 42
Slide 43: Acute on-chronic liver failure: GENFIT's programs
Acute on-chronic liver failure (ACLF) GENFIT’s programs VS-01-ACLF* ▪ Vincent Forster, PhD, GENFIT, co-founder of VERSANTIS ▪ Prof Katharina Staufer, MD, GENFIT, Chief Medical Officer of VERSANTIS NTZ* ▪ Dean Hum, PhD, Chief Scientific Officer of GENFIT ▪ Carol Addy, MD, Chief Medical Officer of GEN
Slide 44: Acute on-chronic liver failure: GENFIT's programs
Acute on-chronic liver failure (ACLF) GENFIT’s programs VS-01-ACLF* ▪ Vincent Forster, PhD, GENFIT, co-founder of VERSANTIS ▪ Prof Katharina Staufer, MD, GENFIT, Chief Medical Officer of VERSANTIS NTZ* ▪ Dean Hum, PhD, Chief Scientific Officer of GENFIT ▪ Carol Addy, MD, Chief Medical Officer of GEN
Slide 45: VS-01 targets timely reversal of ACLF and reduced mortality
VS-01 targets timely reversal of ACLF and reduced mortality CHRONIC DRUG THERAPIES MEDICAL GAP: NO APPROVED TREATMENT FOR ACLF Obesity, lifestyle Alcohol Viruses (Hep C, Hep B, …) Immunology Compensated Decompensated ACLF Healthy Acute-on-Chronic Liver Cirrhosis cirrhosis Liver Failure Genetics 9.2M
Slide 46: VS-01 targets first-line treatment of ACLF
VS-01 targets first-line treatment of ACLF VS-01 Multiorgan support in the early course of ACLF TREATMENT GOALS Recovery R esolve ACLF I mprove survival C hance of liver transplant Transplantation (Tx) increased H ealthcare reduced costs Golden Treatment Window Death 46
Slide 47: VS-01 extracts ACLF metabolites failing organs cannot clear
VS-01 extracts ACLF metabolites failing organs cannot clear Standard of care • Targets first-line treatment for Ascites drainage ACLF to reverse the disease • Delivered via in-place peritoneal access catheter • Treating ACLF early may reduce: VS-01 scavenging liposomes o Length of hospital / ICU sta
Slide 48: VS-01 supports liver, kidneys and brain
VS-01 supports liver, kidneys and brain by clearing toxins from blood to peritoneal space BRAIN Specific capture of systemic ammonia into VS-01’s liposomes LIVER Enhanced hepatic toxins clearance KIDNEY Enhanced uremic toxins clearance INFLAMMATION Capture of bacterial endotoxins and inflammation me
Slide 49: VS-01 mechanism of action
VS-01 mechanism of action 1. UNSPECIFIC BINDING/ADSORPTION 2. SPECIFIC CAPTURE Protein-bound toxins Ammonia: (renal & liver failure): Matoori S et al., J Cont Release 2020 Shen Y et al. J. Liposome Res. 2020 Giacalone G et al., J Cont Release 2018 Shi Y et al. Perit. Dial Int 2019 Agostoni V et al.,
Slide 50: VS-01 safe and efficacious in animal models
VS-01 is safe and efficacious in small and large animal models EFFICACY Extraction of kidney/liver toxins 3 Decrease brain toxicity • 185 extracted metabolites, • Removes 20x more ammonia including ACLF-related than commercial dialysis in rats 1 metabolites & uremic toxins • Reduces ammonemia in rat
Slide 51: Phase 1b First-in-Human study
Phase 1b First-in-Human study: VS-01 on top of SOC Part A: Single Ascending Dose (n = 9) Part B: Multiple Doses (n = 3) Cohort 1 Cohort 2 Cohort 3 IDSMB Cohort 4 15 mL/kg 30 mL/kg 45 mL/kg 34-42 mL/kg daily for 4 days DETAILS OUTCOME • Study population (n=12): ✓ Generally safe and well tolerated - D
Slide 52: Phase 1b safety results
Phase 1b safety results • VS-01 was generally safe and well tolerated following single and multiple doses in patients with decompensated cirrhosis • No SAEs, no deaths, no AEs leading to discontinuation FAVORABLE SAFETY PROFILE • Citric acid • Administration route of VS-01 - no coagulation dysfuncti
Slide 53: Phase 1b efficacy: liver & brain function
Phase 1b preliminary efficacy results: liver & brain function IMPACT ON OVERALL LIVER DOSE-DEPENDENT AMMONIA IMPROVEMENT IN DISEASE SEVERITY REMOVAL FROM THE BODY PSYCHOMETRIC TESTS FOR HE e.g., assessed by Child-Pugh Score Ammonia clearance increased with VS-01 e.g., number connection test was (CPS
Slide 54: Phase 1b efficacy: ACLF metabolites & inflammation
Phase 1b preliminary efficacy results: ACLF metabolites & inflammation REDUCTION OF ACLF METABOLITES1 REDUCTION OF INFECTION-RELATED METABOLITES 1 VS-01 reduced plasma metabolites associated with organ failures2 VS-01 reduced plasma metabolites associated with bacterial infection3 • Two abstracts ac
Slide 55: VS-01 UNVEIL Phase 2 Proof-of-Concept trial
VS-01 UNVEIL Phase 2 Proof-of-Concept trial UNVEIL Target population ACLF grade 1 & 2 UN VE IL UNIQUE VERSANTIS INTRAPERITONEAL liver LIPOSOMES Study title: A phase 2, open-label, randomized, controlled, multi-center, proof of concept study, to assess the efficacy, kidneys brain safety and tolerabil
Slide 56: UNVEIL study design and key endpoints
UNVEIL – study design and key endpoints DAY 0 DAY 1-4 DAY 5-90 SCREENING RANDOMIZATION (DAY 1) FOLLOW-UP Paracentesis Active treatment group 30 PTS VS-01 on top of SOC Day 5-7 in-hospital N TOTAL = • i.p. administration of VS-01 Day 14, 28, 90: hospital visits 60 PTS * • 3 hours dwell time Day 90:
Slide 57: Acute on-chronic liver failure: GENFIT's programs
Acute on-chronic liver failure (ACLF) GENFIT’s programs VS-01-ACLF* ▪ Vincent Forster, PhD, GENFIT, co-founder of VERSANTIS ▪ Prof Katharina Staufer, MD, GENFIT, Chief Medical Officer of VERSANTIS NTZ* ▪ Dean Hum, PhD, Chief Scientific Officer of GENFIT ▪ Carol Addy, MD, Chief Medical Officer of GEN
Slide 58: ACLF pathogenesis: NTZ impacts multiple pathways
ACLF pathogenesis – NTZ impacts multiple pathways NH3 Pathway 1 Pathway 2 Precipitating Cirrhosis/ hepatocyte events Gut Microbiota injury Inflammation inducers Pathway 3 Severe systemic Systemic inflame- mation inflammation/ Additional pathways cytokine storm (e.g. metabolic dysfunction) Organ fail
Slide 59: NTZ preclinical data support ACLF development
NTZ preclinical data support ACLF clinical development 1 NTZ reduces LPS-induced inflammation in healthy rats* 2 NTZ has beneficial effects on liver function markers (bil, alb) in models of cirrhosis* 3 NTZ reduces brain edema in models of ACLF (BDL) 4 NTZ reduces inflammation markers in models of A
Slide 60: NTZ ongoing Phase 1 studies in hepatic and renal impairment
NTZ – Ongoing phase 1 studies in subjects with hepatic impairment (HI) and renal impairment (RI) 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
Slide 61: NTZ Phase 2a proof-of-concept expected 2023
NTZ – Phase 2a proof-of-concept currently expected to start in 2023 A Multicenter, Randomized, Open-label, Controlled, Phase 2a Clinical Study to Evaluate the Safety, Pharmacokinetics, and Efficacy of Nitazoxanide in Patients with Acute-on-Chronic Liver Failure Randomization 2:1 ARM A: NTZ 500 mg/BI
Slide 62: Questions?
Short Q&A (10 minutes) Questions? 62
Slide 63: ACLF market opportunity
Acute on-chronic liver failure (ACLF) Market opportunity ▪ Stephan Gauldie, PhD, Managing Director, Strategy Consulting at Back Bay Life Science Advisors ▪ Mavra Nasir, PhD, Senior Consultant, Strategy Consulting at Back Bay Life Science Advisors
Slide 64: Project approach: situation overview
64 PROJECT APPROACH Situation Overview Back Bay led a US-focused market assessment of acute-on-chronic liver failure (ACLF) for VS-01 between November 2021 – December 2021 Project Objectives Key components of the analysis included (but not limited to): • The degree of unmet need in ACLF, as defined
Slide 65: Project approach: methodology
65 PROJECT APPROACH Methodology Our evaluation included an extensive review of published literature, ten in-depth discussions with key opinion leaders (KOLs) managing patients with ACLF, two hospital pharmacists, two hospital administrators, and one MCO payer in the US Research Methodology Primary L
Slide 66: ACLF Disease Burden
66 ACLF Disease Burden Given the lack of approved treatments, high in-patient mortality, and the significant cost associated with hospitalization, there is a huge unmet need for efficacious therapies for ACLF Economic Burden of Chronic Diseases, 2010 (Table 4: Allen et al Hepatology, 2016) Mortality
Slide 67: ACLF Unmet Needs – KOL Feedback
67 ACLF Unmet Needs – KOL Feedback The greatest unmet need in the treatment of ACLF is lack of available therapies that can prevent disease progression and reduce mortality 1 2 3 Targeted treatments to prevent Generalizing definitions & developing Prevention of insult & organ failures progression an
Slide 68: ACLF Pipeline
68 ACLF Pipeline There are currently three therapies in active clinical development for ACLF in the US, with one agent (plasma exchange with human serum albumin/Grifols) in pivotal trials Mechanism Product, Company Status RoA Patient population Trial Design • NCT03702920 (APACHE): Open label, albumi
Slide 69: ACLF Total Addressable Patients
69 ACLF Total Addressable ACLF Patients Based on our conservative estimates, the current total addressable market for ACLF is ~215K across the US and EU4+UK and is expected to grow to ~300K by 2036 2022 Estimates Total Addressable ACLF Market, US & EU4+UK Prevalent Population US EU4+UK 110/100k2,3 ,
Slide 70: ACLF Economic Burden & Hospital Impact
70 ACLF Economic Burden & Hospital Impact ACLF represents a clear and growing economic burden; hospitals bear a large proportion of patient costs and are looking for ways to expand reimbursement and reduce costs, particularly the number of patients requiring high-intensity care ACLF Economic Burden1
Slide 71: ACLF KOL Feedback – VS-01 TPP
71 ACLF KOL Feedback – VS-01 TPP Overall, experts were optimistic with the VS-01 profile, and particularly liked the ease of administration and the potential to eliminate pro-inflammatory metabolites VS-01 Feedback “If you can address and remove the inflammatory markers of ACLF, you are “The motivat
Slide 72: ACLF VS-01 Positioning
72 ACLF VS-01 Positioning Physicians would use VS-01 in patients with ACLF Grade 1 and 2 who have ascites in conjunction with standard of care Hospitalized ACLF patients ACLF Grade 1 with ascites ACLF Grade 2 with ascites ACLF Grade 3 • Broad spectrum antibiotics • Continued supportive care • Liver
Slide 73: ACLF VS-01 Addressable Patients
73 ACLF VS-01 Addressable Patients The current addressable market for VS-01 if targeting ACLF grade 1 and 2 patients presenting with ascites is ~130K across the US and EU4+UK ACLF Model Flow Variable Assumptions Rationale & Source(s) • US: 330M; YoY growth: 0.4% 1 1 • US census data Prevalent Popula
Slide 74: ACLF Pharmacist & Administrator TPP Feedback
74 ACLF Pharmacist & Administrator TPP Feedback Hospital pharmacists and administrators appreciated that VS-01 addresses a patient population with high unmet need and could provide additional cost-savings Topic Key Considerations Quotes Payers understand that ACLF patients have high unmet treatment
Slide 75: ACLF Price-Value Analysis
75 ACLF Price-Value Analysis Payers view a treatment cost in the range of ~$30-$50k per patient to be reasonable given the high level of unmet need and extended hospital stays Price-Value Perception in ACLF Key Takeaways 5,0 Payers acknowledged that the target patient population has little treatment
Slide 76: Questions?
Short Q&A (10 minutes) Questions? 76
Slide 77: Hepatic encephalopathy (HE): Disease state
Hepatic encephalopathy (HE) Disease state ▪ Jennifer C. Lai, MD, MBA, Transplant hepatologist, University of California, San Francisco (UCSF), USA – Endowed Professorship of Liver Health & Transplantation
Slide 78: Hepatic encephalopathy (HE)
Hepatic encephalopathy (HE) Jennifer C. Lai, MD, MBA Transplant Hepatologist Endowed Professor of Liver Health & Transplantation University of California, San Francisco (UCSF)
Slide 79: Hepatic encephalopathy
Hepatic encephalopathy o One of the major complications of advanced liver disease and portal hypertension o 30-40% of patients with cirrhosis will experience at least 1 episode o Represents a diverse spectrum of neurologic, psychiatric, and musculoskeletal symptoms o Sleep-wake cycle disturbance o F
Slide 80: HE → death
HE → death Yu H, et al. Ann Hep 2019.
Slide 81: Increased risk of death in ACLF
Increased risk of death in ACLF Maggi DC, et al. Ann Hep 2019.
Slide 82: Ammonia clearance (normal liver function)
Ammonia clearance (normal liver function) Widjicks E. NEJM 2016.
Slide 83: Hyperammonemia (abnormal liver function)
Hyper- ammo- nemia (abnormal liver function) Widjicks E. NEJM 2016.
Slide 84: Multi-factorial etiology
Multi-factorial etiology Bajaj J. J Hep 2018.
Slide 85: Classification
Classifi- cation Vilstrup H, et al. Hepatol 2014.
Slide 86: Rose CF, et al. J Hepatol 2020.
Rose CF, et al. J Hepatol 2020.
Slide 87: Key Points: HE (Disease state)
Key Points : HE (Disease state) HE is a major, life-limiting complication of advanced liver disease. Hyperammonemia due to impaired ammonia clearance is a major driver of HE. Standard-of-care therapeutics include lactulose and rifaximin.
Slide 88: Hepatic encephalopathy: GENFIT's program VS-02-HE
Hepatic encephalopathy (HE) GENFIT’s program: VS-02-HE* ▪ Vincent Forster, PhD, co-founder of VERSANTIS * investigational product that is not approved by any health authority
Slide 89: VS-02: novel oral investigational treatment for chronic HE
VS-02: novel oral investigational treatment for chronic hepatic encephalopathy High unmet needs in hepatic Oral route, acting locally in encephalopathy (HE) the colon Growing prevalence driven by Novel urease inhibitor with obesity, alcohol abuse, modern IP protection up to 2042 lifestyle (excluding
Slide 90: HE is associated with elevated ammonia levels
Hepatic encephalopathy (HE) is associated with elevated ammonia levels Gut-Liver-Brain axis HE in brief • Major & serious complication of liver cirrhosis Hepatic encephalopathy affecting 30-45% of patients 1,2 • Glutamine accumulation • Osmotic stress • In U.S. • Alteration of cell metabolism ◦ 2M p
Slide 91: Urease inhibitors as treatment for HE
Urease inhibitors as treatment for HE Urea hydrolysis by urease-producing bacteria • Urea is secreted and actively transported NH3 NH3 into the intestine • Gut bacteria produce urease to hydrolyze urea into ammonia • 30% of all urea produced is hydrolyzed by gut microbiota, making it one of the main
Slide 92: VS-02 potential upsides vs standard of care
VS-02* has the potential to offer positive upsides vs standard of care Drug Technology Indication Limitations VS-02 Lactulose Laxative Chronic HE - Poor compliance due to treatment goals Various brands Route: oral Supportive for significant side effects (diarrhea (global) MoA: reduce ammonia acute H
Slide 93: Conclusions and forthcoming milestones
Conclusions and forthcoming milestones PROOF OF CONCEPT TO DATE • VS-02 demonstrated superior urease inhibitory activity in vitro over +15 screened hydroxamic acid derivatives • Synthesis of lead candidate optimized and straightforward • In vitro and in vivo data planned to be presented at EASL and
Slide 94: HE market opportunity
Hepatic encephalopathy (HE) Market opportunity ▪ Pascal Caisey, Chief Operating Officer and Chief Commercial Officer of GENFIT
Slide 95: Estimated market opportunity in Hepatic Encephalopathy
Estimated1 market opportunity in Hepatic Encephalopathy ▪ Hepatic encephalopathy is a serious and potentially fatal complication of both acute and chronic liver failure ▪ It affects 30 to 40% of cirrhotic patients ▪ HE is probably one of the most frequent complication of cirrhosis that leads to hosp
Slide 96: Questions?
Short Q&A (5 minutes) Questions? 96
Slide 97: Cholangiocarcinoma (CCA): Disease state
Cholangiocarcinoma (CCA) Disease state ▪ Dr Angela Lamarca, Medical Oncologist, Fundacion Jimenez Diaz University Hospital, Madrid, Spain
Slide 98: Cholangiocarcinoma State of the Art and Unmet needs
Cholangiocarinoma State of the Art and Unmet needs 19th October 2022 Dr Angela Lamarca MD, PhD, MSc FEA / Honorary Consultant Medical Oncologist Honorary Senior Lecturer Department of Medical Oncology, Oncohealth Institute, Fundación Jimenez Diaz University Hospital, Madrid, Spain Department of Medi
Slide 99: Disclosures
Disclosures • Receipt of honoraria or consultation fees: EISAI, Nutricia Ipsen, QED, Roche, Servier, Boston Scientific, Albireo Pharma, AstraZeneca, Boehringer Ingelheim, GenFit and TransThera Biosciences. • Participation in company sponsored speaker bureau: Merck, Pfizer, Ipsen, Incyte, AAA, QED, S
Slide 100: Cholangiocarcinoma: Epidemiology
Cholangiocarcinoma: Epidemiology • Rare cancers – Incidence: <6/100,000 • Incidence increasing – iCCA • Poor prognosis – 5-year OS (<20%) – Late diagnosis • 70% advanced stages – High relapse rate CCA, cholangiocarcinoma; EH, extrahepatic; iCCA, intrahepatic cholangiocarcinoma; IH, intrahepatic; OS,
Slide 101: Cholangiocarcinoma: Incidence/mortality increasing
Cholangiocarcinoma: Incidence/mortality increasing Estimated incidence projections Estimated cancer death projections (2016 → 2040) (2016 → 2040) HPB cancers will be the second and third most common causes of cancer death by 2040 AAPC, average annual percent change; CCA, cholangiocarcinoma; HPB, hep
Slide 102: Unmet needs in Cholangiocarcinoma
Unmet needs in Cholangiocarinoma More efective Better adjuvant chemotherap Early diagnosis treatments y Biomarkers for Biomarkers for chemotherap IO y Mechanism of Access to Molecular resistance drugs profiling
Slide 103: CCA - Heterogeneous
CCA - Heterogeneous Bañales Nat Rev G&H 2020
Slide 104: Cholangiocarcinoma – Management Overview
Cholangiocarcinoma – Management Overview Lamarca ESMO Open 2022
Slide 105: Unmet needs in CCA
Unmet needs in CCA More efective Better adjuvant chemotherap Early diagnosis treatments y Biomarkers for Biomarkers for chemotherap IO y Mechanism of Access to Molecular resistance drugs profiling
Slide 106: 1L and 2L overview
1L and 2L overview 1st Line Cis-Gem 2nd Line FOLFOX / NlaIRI-5FU Median OS 11.7 months (CisGem) Median OS 6.2 months (FOLFOX) Median OS 8.6 months (NalIRI-5FU) Valle NEJM 2010; Lamarca Lancet Oncol 2021; Yoo ESMO 2022
Slide 107: First-line – Durvalumab + CisGem (TOPAZ-1)
First-line – Durvalumab + CisGem (TOPAZ-1) • TOPAZ-1: improved ORR/PFS/OS in favour of Durvalumab + CisGem Median OS 12.8 months (CisGem+Durva – TOPAZ-1) Median PFS 7.2 months (CisGem+Durva – TOPAZ-1) ORR 26.7% (CisGem+Durva – TOPAZ-1) Oh NEJM Evidence 2022
Slide 108: Targeted therapies
Targeted therapies umestre Fundacion JP imenez Diaz OD the christie MEE owe Pepironsahed NHS Foundation Teust e Oncohealth Institute Tev
Slide 109: CCA: Precision medicine
CCA: Precision medicine Lamarca et al Journal of Hepatol 2020
Slide 110: CCA: Precision medicine
CCA: Precision medicine • BTC-specific – IDH-1 mutations – FGFR2 fusions – Other: BRAF, Her-2, KRAS • Disease-agnostic – NTRK fusions – MMR-deficiency Lamarca et al Journal of Hepatol 2020
Slide 111: Challenges in delivering Precision Medicine in BTC
Challenges in delivering Precision Medicine in BTC • Targetable findings in ~40% of patients • Main challenge: quality tissue sample not – But to identify this: always available • Patient testing is crucial – Cytology-based diagnosis • Adequate tissue is needed – Failed tissue samples • Early testin
Slide 112: Unmet needs in CCA
Unmet needs in CCA More efective Better adjuvant chemotherap Early diagnosis treatments y Biomarkers for Biomarkers for chemotherap IO y Mechanism of Access to Molecular resistance drugs profiling
Slide 113: Summary Slide
Summary Slide • Unmet needs • Opportunities – Novel mechanisms of action (e.g., autophagy inhibition) – Potential for combination/complementary MOAs – New targeted therapies (e.g., targeting KRAS)
Slide 114: Cholangiocarcinoma: GENFIT's program GNS561
Cholangiocarcinoma (CCA) GENFIT’s program: GNS561* ▪ Dean Hum, PhD, Chief Scientific Officer of GENFIT ▪ Carol Addy, MD, Chief Medical Officer of GENFIT * investigational product that is not approved by any health authority
Slide 115: Autophagy and GNS561
Autophagy and GNS561 Autophagy is a process that maintains cellular homeostasis and confers adaptation to environmental stresses, preventing cellular damage, and promoting cell survival. * * In established tumors, autophagy facilitates development by promoting cancer cell proliferation * and tumor g
Slide 116: GNS561 Mechanism of Action
GNS561 Mechanism of Action GNS561 localizes in lysosomes where it binds and inhibits PPT1 resulting in: • lysosomal unbound Zn2+ accumulation, • impairment of cathepsin activity, • autophagic flux inhibition, • altered location of MTOR, • lysosomal membrane permeabilization1 All these events induce
Slide 117: GNS561 antitumor activity in cancer cell lines and HCC cells
GNS561 has antitumor activity in human cancer cell lines and HCC* patient derived cells * *HCC Hepatocellular Carcinoma • GNS561 displays activity against human cancer cell lines and HCC patient-derived cells • GNS561 was at least 10-fold more effective than HCQ in tested cancer cell lines • GNS561
Slide 118: GNS561 antitumor activity in iCCA cells
GNS561 has antitumor activity in iCCA cell lines and iCCA patient-derived cells GNS561 significantly reduced cell viability in two iCCA GNS561 was more potent than cisplatin or gemcitabine in 2 cell lines (IC50 of 1.5 ± 0.2 μM in HuCCT1 and IC50 of models (CC6638 and CC6279, and CC6638 and CC6625, 1
Slide 119: GNS561 accumulated in liver, stomach and lung
GNS561 mainly accumulated in the liver, stomach and lung Whole body tissue distribution of GNS561. Mass spectrometry imaging of a control rat (top) and a rat treated with GNS561 (bottom) at a dose of 40 mg/kg/day for 28 days. From Brun S et al. GNS561, a new lysosomotropic small molecule, for the tr
Slide 120: GNS561 decreases tumor number and size in HCC mouse model
GNS561 decreases tumor number and size in transgenic HCC mouse model * Philippe Halfon1, Madani Rachid1, Cindy Serdjebi1, Annemilaï Tijeras-Raballand2 , Sonia Brun1, Christelle Ansaldi1, Eric Raymond1,2, 1Genoscience Pharma, Marseille, France, 2AFR Oncology, Boulogne-Billancourt, France GNS561, A NE
Slide 121: Therapeutical approach in CCA
Therapeutical approach in CCA Signalling pathways involved in CCA development and progression1 • CCA identified as RAS driven cancer with important role of MAPK pathway activation1 • Evidence for targeting autophagy, through the concomitant blocking of MAP kinase pathway (activated in KRAS CCA) to c
Slide 122: Combination of existing therapy with GNS561
Combination of existing therapy with GNS561 (inhibition of autophagy) to synergistically decrease cancer cell survival and tumor growth autophagy Promotes cancer cell survival, tumor Cancer cells growth and resistance to treatment Anti-cancer Therapies Survival mechanisms Five stages of autophagy. A
Slide 123: Rate of KRAS mutation in CCA
Rate of KRAS mutation in CCA is frequent: estimated between 20% (iCCA) and 40% (eCCA) 20% of iCCA are estimated to have KRAS mutations2,3 40% of eCCA are estimated to have KRAS mutations2,3 From Banales JM et al, Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroe
Slide 124: First-In-Human PPT1 Inhibition with GNS561 – Study design
First-In-Human Effects of PPT1 Inhibition Using the Oral Treatment GNS561 in Patients with Primary and Secondary Liver Cancers – Study design/Results Flow diagram of the Phase I, open-label, dose-escalation trial (3 + 3 design) Objectives I: to determine GNS561 recommended phase II dose (RP2D) and s
Slide 125: First-In-Human PPT1 Inhibition with GNS561 – Results
First-In-Human Effects of PPT1 Inhibition Using the Oral Treatment GNS561 in Patients with Primary and Secondary Liver Cancers – Results 26 evaluable patients for safety • Five patients experienced tumor stable diseases, including one minor response. Adverse events (AEs) included gastrointestinal gr
Slide 126: GNS561 Phase 1b/2a study design
GNS561 Phase 1b/2a study design Patients with KRAS mutated cholangiocarcinoma who have failed treatment with 1st line treatment and who do not have an actionable mutation (e.g., IDH1, FGFR2) PHASE Ib PHASE II POC RP2C SINGLE ARM Cohort 3 PHASE II PHASE II GNS XX mg qd + MEKi Futility analysis Cohort
Slide 127: CCA market opportunity
Cholangiocarcinoma (CCA) Market opportunity ▪ Pascal Caisey, Chief Operating Officer and Chief Commercial Officer of GENFIT
Slide 128: Estimated market opportunity in Cholangiocarcinoma
Estimated market opportunity in Cholangiocarcinoma ▪ Epidemiology (source: IQVIA) ▪ 9,000 new diagnosed patients / y in US ▪ 10,000 new diagnosed patients / y in EU5 ▪ > 66,000 cases/year in the 9MM in 2030 ▪ Market (source: Olympus Research Global) Market ▪ Global market of $1.2bn in 2021 opportuni
Slide 129: Questions?
Short Q&A (5 minutes) Questions? 129
Slide 130: Urea cycle disorder (UCD) and organic acidemia disorder (OAD)
Urea cycle disorder (UCD) and organic acidemia disorder (OAD) Disease state ▪ Vincent Forster, PhD, GENFIT, co-founder of VERSANTIS
Slide 131: Hyperammonemic crises in inborn errors of metabolism
Overview of hyperammonenic crises in inborn errors of metabolism Hyperammonemic Crisis Presence Urea Cycle Disorders Organic Acidemia Ornithine Transcarbamylase Deficiency (OTCD) Maple Syrup Urine HMG CoA lyase Disease (MSUD) deficiency Propionic Acidaemia Argininosuccinate Lyase Deficiency (ASLD) (
Slide 132: Unmet needs in acute hyperammonemic crises
Urgent unmet needs in the treatment of acute hyperammonemic crises (HAC) Urea Cycle • Ultra-rare disease: 1,900 HAC in children in US + EU5 per year 1,2,3 • High mortality (75% at 5 years); survivors often have severe brain injuries • No acute treatment available for early onset crises • Neonatal he
Slide 133: UCD and OAD: GENFIT's programs VS-01-UCD
Urea cycle disorder (UCD) and organic acidemia disorder (OAD) GENFIT’s programs: VS-01-UCD* ▪ Vincent Forster, PhD, GENFIT, co-founder of VERSANTIS * investigational product that is not approved by any health authority
Slide 134: VS-01 potential first-line treatment for HAC
VS-01 is a potential first-line lifesaving treatment for acute hyperammonemic crises (HAC) • Optimal treatment setup • Regulatory - Peritoneal route is well adapted to pediatric patients - Orphan drug & rare pediatric disease designated (FDA) - Rapid treatment onset in all hospitals - Projected time
Slide 135: VS-01 ammonia clearance vs. dialysis modalities
VS-01 ammonia clearance vs. current dialysis modalities BLOOD FLOW DIALYSATE FLOW TYPE OF DIALYSIS AMMONIA CL (ML/MIN) DIALYSIS DURATION (H) REFERENCES (ML/MIN) (ML/MIN) CPD NA NA 1.4 ± 1.1 59 ± 87.2 Arbeiter et al., 2010 CAVHD 16 8.3 2.86 33 Picca et al., 2001 HD 10 500 9.5 9 Picca et al., 2001 HD
Slide 136: KOLs feedback on VS-01 commercial advantages
KOLs feedback on VS-01 anticipated commercial advantages “If efficacy of VS01 to reduce hyperammonemia is at least equal to superior to current hemofiltration options, we will switch to VS01 in our neonatology department because of easier implementation and • Potential first-line treatment for acute
Slide 137: Competitive landscape
Competitive landscape Approved drugs Company Technology Population Limitations Buphenyl® (US), (US) Ammonaps® (EU), Ammonia scavenger UCDs - Not approved/effective for acute hyperammonemia Pheburane® (EU) (EU) (Sodium phenylbutyrate) Ammonul® (US) (US) - Associated HE (Sodium phenylacetate Ammonia s
Slide 138: Conclusions and forthcoming milestones
Conclusions and forthcoming milestones VS-01 in HAC • Demonstrated superior ammonia clearance than commercial peritoneal dialysis in vivo 1,2,3,4. Ammonia clearance in adult patients with decompensated cirrhosis at least comparable with hemodialysis 5 • Received Rare Pediatric Diseases Designation a
Slide 139: UCD and OAD market opportunity
Urea cycle disorder (UCD) and organic acidemia disorder (OAD) Market opportunity ▪ Pascal Caisey, Chief Operating Officer and Chief Commercial Officer of GENFIT
Slide 140: Market opportunity for Hyperammonemic Crisis in IEM
Estimated* market opportunity for Hyperammonemic Crisis (HAC) in Inborn Errors of Metabolism (IEM) (HAC) ▪ Epidemiology ▪ HAC occurs in babies suffering from 2 diseases - Urea Cycle Disorder (UCD) ▪ 157 babies with UCD / year ▪ 2,826 patients with HAC potential up to 18 years old ▪ Untreated patient
Slide 141: Questions?
Short Q&A (5 minutes) Questions? 141
Slide 142: Closing remarks
Closing remarks Take home messages ▪ Pascal Prigent, CEO of GENFIT
Slide 143: 5 main indications and 6 programs across development stages
5 main indications and 6 programs across a variety of development stages (PC/Ph1/2/3) CHOLESTATIC DISEASES ACLF UCD HE DIAGNOSIS CCA PBC NTZ VS-01 VS-01 VS-02 NASH AMMO- Ph1 data Ph2 start Preclinical Preclinical Commercia NIEMIA GNS561 ELA -lization TS-01 Ph2 start Q4 2022 Ph1b/2 start Ph3 data as
Slide 144: Regular newsflow expected for the next 4 years
A regular newsflow expected for the next 4 years, with several inflexion points (clinical data) 2022 2023 2024 2025 ELA Ph3 NTZ PBC NTZ Ph1 NTZ Ph2 ACLF (HI) ACLF Ph1 ACLF (RI) GNS561 GNS561 GNS561 Ph1 Ph2 (int.) Ph2 CCA CCA CCA VS-01 VS-01 Ph2 (int.) Ph2 ACLF ACLF Estimated timelines 144
Slide 145: Significant opportunities in all therapeutic indications
Significant opportunities in all therapeutic indications CHOLESTATIC DISEASES ACLF UCD (& OAD) HE CCA PBC $1.2bn $330M $4bn $2bn $1.5bn $4.1bn (2021) (2022) (2030) (2030) (2021) (2026) $3.2bn $1bn (2030) (2025) (Total market size estimates (Total 2L market size estimates (Total market size estimates
Slide 146: Thank you
TOWARDS BETTER MEDICINE Thank you