Genfit Sa · EURONEXT:GNFT
Genfit Sa — Investor Day (October 2022)
129 slides from Genfit Sa's investor day presentation, Oct 5, 2022
Slide 1: GENFIT Pipeline Day Corporate Presentation
October is National Liver Awareness Month: are you at risk? GENFIT Pipeline Day Corporate Presentation October 5, 2022 | Paris, France
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 ▪ Univ.-Prof. Dr. J. Trebicka, Director Medical Clinic (Gastroenterology, Hepatology, Endocrinology, Clinical infectiology), Münster, GERMANY
Slide 6: Acute-on-chronic liver failure
ACUTE-ON-CHRONIC LIVER FAILURE JONEL TREBICKA DEPARTMENT OF INTERNAL MEDICINE B, UNIVERSITY MÜNSTER, GERMANY - GASTROENTEROLOGY, HEPATOLOGY, ENDOCRINOLOGY, INFECTIOUS DISEASES – EUROPEAN FOUNDATION FOR CHRONIC LIVER FAILURE, EFCLIF, BARCELONA, SPAIN
Slide 7: Disclosures
Disclosures Advisory boards Presentations/Talks Gore Gore Versantis Grifols Genfit Norgine Grifols Falk Pharma CSL Behring CSL Behring
Slide 8: Cirrhosis is relevant
Cirrhosis is relevant Gu. et al. The Lancet RHE 2022
Slide 9: Natural history of liver cirrhosis
Natural history of liver cirrhosis Trebicka. et al. Nat Rev Gastroenterol Hepatol 2020
Slide 10: Agenda
Agenda - Diagnosis and grading of ACLF - Development and precipitants - Clinical course - Pathogenesis - Management Trebicka, Reberger, Laleman. Visc Med 2018
Slide 11: Diagnosis and grading
fo) DIAGNOSIS AND GRADING
Slide 12: Diagnosis and grades of ACLF (EASL-CLIF)
Diagnosis and grades of ACLF (EASL-CLIF) The diagnosis and the grading of ACLF is based on the assessment of organ function as defined by the CLIF-C OF score. Arroyo et al. NEJM 2020
Slide 13: Diagnosis and grades of ACLF (EASL-CLIF)
Diagnosis and grades of ACLF (EASL-CLIF) ACLF development and death within 90 days Pre-ACLF Unstable decompensated cirrhosis (UDC) Stable decompensated cirrhosis (SDC) Trebicka et al. J Hepatol 2020 Arroyo et al. J Hepatol 2021
Slide 14: Development, precipitants
fo) DEVELOPMENT, PRECIPITANTS
Slide 15: Portal hypertension and systemic inflammation
Portal hypertension and systemic inflammation Circulatory Cerebral Cardiac output Effective dysfunction dysfunction blood volume Pulmonary Hepatic dysfunction Systemic resistance Hepatic Coagulatory inflammation dysfunction dysfunction Portal Renal pressure dysfunction Splanchnic Renal vasodilatatio
Slide 16: Portal Hypertension and systemic inflammation
Portal Hypertension and systemic inflammation severe portal systemic hypertension inflammation Trebicka, et al. J Hepatol 2020 Gu. et al. The Lancet Regional Health 2022
Slide 17: Precipitating events
Precipitating events CANONIC-study 40% bacterial infection 23% active alcoholism 30% more than one 43% no precipitating event Jalan et al. J Hepatol 2015
Slide 18: Precipitants and drivers of systemic inflammation in ACLF
PRECIPITANTS AND DRIVERS OF SYSTEMIC INFLAMMATION IN ACLF = BACTERIAL TRANSLOCATION In 30-60% of cases no precipitant identified. Trebicka et al. J Hepatol 2021
Slide 19: Microbiome interaction with host in cirrhosis
Microbiome interaction with host in cirrhosis Trebicka. et al. Nat Rev Gastroenterol Hepatol 2020
Slide 20: Clinical course
fo) CLINICAL COURSE
Slide 21: Clinical features
Clinical features Younger More ascites More alcoholic cirrhosis More organ failure Jalan et al. J Hepatol 2015
Slide 22: Role of previous decompensation
Role of previous decompensation Time from 1st AD to LT/Mortality/ 60 End follow-up(months) 50 40 30 20 10 0 C C LF D SD C U A e- Pr Trebicka, et al. J Hepatol 2020 Moreau et al. Gastroenterology 2013
Slide 23: Dynamic clinical course of ACLF
Dynamic clinical course of ACLF Gustot et al. Hepatology 2015;62(1):243-52. Arroyo et al. J Hepatol 2021
Slide 24: Pathogenesis
fo) PATHOGENESIS
Slide 25: Systemic inflammation
Systemic inflammation Arroyo, et al. J Hepatol 2021
Slide 26: Extent of systemic inflammation in cirrhosis
EXTENT OF SYSTEMIC INFLAMMATION IN CIRRHOSIS Compensated Acute Healthy controls cirrhosis decompensation ACLF Trebicka, et al. Front Immunol 2019
Slide 27: Extensive systemic inflammation leads to ACLF
EXTENSIVE SYSTEMIC INFLAMMATION LEADS TO ACLF Trebicka, et al. Front Immunol 2019
Slide 28: Metabolomics data suggest an energetic crisis
METABOLOMICS DATA SUGGEST AN ENERGETIC CRISIS Ruiz-Margain et al. Liver Transplantation 2018 Claria, et al. Hepatology 2018; Moreau et al. J Hepatol 2019
Slide 29: Management
fo) MANAGEMENT
Slide 30: Treating portal hypertension and liver dysfunction
Treating portal hypertension and liver dysfunction Decreasing portal pressure (TIPS) Artificial liver support (MARS) Banares et al. Therapeutic Advances in Gastroenterology 2019 Trebicka et al. J Hepatol 2020
Slide 31: Managing bacterial infections
Managing bacterial infections Fernandez et al. J Hepatol 2021
Slide 32: Intensive care
INTENSIVE CARE Bernal et al. J Hepatol 2021
Slide 33: Liver transplantation
LIVER TRANSPLANTATION Gustot et al. Hepatology 2015;62(1):243-52. Artru et al. J Hepatol 2017 Trebicka et al. Liv Transplant 2020
Slide 34: Liver transplantation
LIVER TRANSPLANTATION Gustot et al. Hepatology 2015;62(1):243-52. Artru et al. J Hepatol 2017 Trebicka et al. Liv Transplant 2020
Slide 35: Summary
SUMMARY ▪ ACLF is a deadly disease and the common end-stage of all chronic liver diseases ▪ ACLF may be prevented or treated mostly, but more knowledge is necessary ▪ Organ failures such as liver, kidney and brain (HE) failures are the most common and deciding on prognosis. ▪ NOVEL STRATEGIES (PREVE
Slide 36: Questions?
Short Q&A (10 minutes) Questions? 36
Slide 37: Acute on-chronic liver failure (ACLF): GENFIT's programs
Acute on-chronic liver failure (ACLF) GENFIT’s programs VS-01-ACLF* ▪ Vincent Forster, PhD, GENFIT, co-founder of VERSANTIS ▪ Meriam Kabbaj, PhD, GENFIT, co-founder of VERSANTIS NTZ* ▪ Dean Hum, PhD, Chief Scientific Officer of GENFIT ▪ Carol Addy, MD, Chief Medical Officer of GENFIT * VS-01 and NTZ
Slide 38: Acute on-chronic liver failure (ACLF): GENFIT's programs
Acute on-chronic liver failure (ACLF) GENFIT’s programs VS-01-ACLF* ▪ Vincent Forster, PhD, GENFIT, co-founder of VERSANTIS ▪ Meriam Kabbaj, PhD, GENFIT, co-founder of VERSANTIS NTZ* ▪ Dean Hum, PhD, Chief Scientific Officer of GENFIT ▪ Carol Addy, MD, Chief Medical Officer of GENFIT * investigation
Slide 39: 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 40: 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 40
Slide 41: 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 42: VS-01 supports liver, kidneys and brain by clearing toxins
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 43: 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 44: VS-01 is safe and efficacious in small and large 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 45: Phase 1b First-in-Human study: VS-01 on top of SOC
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 46: 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 47: Phase 1b preliminary efficacy results: 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 48: Phase 1b preliminary efficacy results: 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 49: 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 50: 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 51: Acute on-chronic liver failure (ACLF): GENFIT's programs
Acute on-chronic liver failure (ACLF) GENFIT’s programs VS-01-ACLF* ▪ Vincent Forster, PhD, GENFIT, co-founder of VERSANTIS ▪ Meriam Kabbaj, PhD, GENFIT, co-founder of VERSANTIS NTZ* ▪ Dean Hum, PhD, Chief Scientific Officer of GENFIT ▪ Carol Addy, MD, Chief Medical Officer of GENFIT * investigation
Slide 52: 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/ cytokine storm Additional pathways (e.g. metabolic dysfunction) Organ fail
Slide 53: NTZ preclinical data support ACLF clinical 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 54: 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 55: NTZ – Phase 2a proof-of-concept expected to start in 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 56: Questions?
Short Q&A (10 minutes) Questions? 56
Slide 57: 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 58: Project approach: situation overview
58 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 59: Project approach: methodology
59 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 60: ACLF Disease Burden
60 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 61: ACLF Unmet Needs – KOL Feedback
61 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 62: ACLF Pipeline
62 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 63: ACLF Total Addressable Patients
63 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 64: ACLF Economic Burden & Hospital Impact
64 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 65: ACLF KOL Feedback – VS-01 TPP
65 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 66: ACLF VS-01 Positioning
66 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 67: ACLF VS-01 Addressable Patients
67 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 68: ACLF Pharmacist & Administrator TPP Feedback
68 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 69: ACLF Price-Value Analysis
69 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 70: Questions?
Short Q&A (10 minutes) Questions? 70
Slide 71: Hepatic encephalopathy (HE): Disease state
Hepatic encephalopathy (HE) Disease state ▪ Univ.-Prof. Dr. J. Trebicka, Director Medical Clinic (Gastroenterology, Hepatology, Endocrinology, Clinical infectiology), Münster, GERMANY
Slide 72: Pathogenesis of HE
PATHOGENESIS OF HE Romero-Gomez et al. J Hepatol 2014 Vilstrup et al. Hepatology 2014
Slide 73: Diagnosis of HE
DIAGNOSIS OF HE Vilstrup et al. Hepatology 2014
Slide 74: Precipitants correction and treatment
Breathing Circulation Correct HE confirmed CORRECTIONAdmit OF to ICUPRECIPITANTS Electrolytes Glycemia if associated with ACLF or airway at risk AND TREATMENT Precipitating factor? Yes No General Specific Direct treatment at precipitating factor Infection: Systemic Antibiotics Diuretics: Volume expa
Slide 75: Rifaximin
Rifaximin Caraceni et al. J Hepatol 2021 Caraceni et al. Hepatology 2021
Slide 76: Fecal microbial transplant in cirrhosis and hepatic encephalopathy
FECAL MICROBIAL TRANSPLANT (FMT) IN CIRRHOSIS AND HEPATIC ENCEPHALOPATHY Study Study design Number of patients Route and duration of FMT Outcomes Kao et al. Hepatology Case report 1 patient with HE 1 FMT delivered via • Subjective and objective improvement in symptoms, and 20161 colonoscopy followed
Slide 77: FMT in cirrhosis and hepatic encephalopathy
FMT IN CIRRHOSIS AND HEPATIC ENCEPHALOPATHY Courtesy of Kibble & Schawcross
Slide 78: Hepatic encephalopathy (HE): GENFIT's program VS-02-HE
Hepatic encephalopathy (HE) GENFIT’s program: VS-02-HE* ▪ Vincent Forster, PhD, co-founder of VERSANTIS ▪ Meriam Kabbaj, PhD, co-founder of VERSANTIS * investigational product that is not approved by any health authority
Slide 79: 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 80: 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 81: 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 82: 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 83: 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 84: Hepatic encephalopathy (HE): Market opportunity
Hepatic encephalopathy (HE) Market opportunity ▪ Pascal Caisey, Chief Operating Officer and Chief Commercial Officer of GENFIT
Slide 85: 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 86: Questions?
Short Q&A (5 minutes) Questions? 86
Slide 87: Cholangiocarcinoma (CCA): Disease state
Cholangiocarcinoma (CCA) Disease state ▪ Dr Mark Yarchoan, Associate Professor of Oncology at John Hopkins Medicine (Baltimore, MD)
Slide 88: Mark Yarchoan Disclosure
Mark Yarchoan Associate Professor of Oncology Disclosure ▪ - Consulting fees from AstraZeneca, Eisai, Exelixis, and Genentech ▪ - Research funding (to Johns Hopkins) from Bristol- Myers Squibb, Exelixis, Incyte, and Genentech
Slide 89: What is Cholangiocarcinoma?
What is Cholangiocarcinoma? Hepatocellular Intrahepatic cholangiocarcinoma carcinoma • Arises in the intrahepatic bile ducts • Arises from hepatocytes “Klatskin tumor” also called “hilar cholangiocarcinoma” • Cholangiocarcinoma that arises at the bifurcation of the biliary system Extrahepatic cholan
Slide 90: Etiology of Cholangiocarcinoma
Etiology of Cholangiocarcinoma ► Intrahepatic cholangiocarcinoma shares risk factors with HCC ► Cirrhosis/hepatitis from any cause ► Anything that chronically inflames the biliary tract ► Primary sclerosis cholangitis (PSC)/Ulcerative colitis ► Cholelithiasis (particularly gallbladder cancer) ► Cyst
Slide 91: Clinical Presentation
Clinicalpresentation Clinical Presentation • The clinical presentation of cholangiocarcinoma depends on the anatomic location of the tumor(s). • Patients with hilar cholangiocarcinoma, (tumor located in the area of confluence of right and left hepatic ducts) most commonly present with jaundice, prur
Slide 92: Diagnosis of Cholangiocarcinoma
Diagnosisofofcholangiocarcinoma Diagnosis Cholangiocarcinoma • Laboratory tests • Biochemical tests of liver function may reveal a cholestatic picture with elevated total bilirubin and alkaline phosphatase. • Carcinoembriogenic antigen (CEA) and CA 19-9 are blood tests for non- specific markers of u
Slide 93: Treatment
y JOHNS HOPKINS UNIVERSITY Treatment
Slide 94: Treatment Options – Surgery
Treatmentoptions Treatment Options– -Surgery Surgery • Surgical excision of biliary tract tumors is the treatment of choice in cholangiocarcinoma as it is the only therapeutic option that offers the potential for cure. • Curative treatment is dependent upon aggressive excision, which involves a majo
Slide 95: Non-Surgical Treatment Options
Non-Surgicaltreatment Non-surgical Treatmentoptions Options • In the advanced setting, the SoC for first line therapy is a combination of gemcitabine and platinum-based chemotherapy; other gemcitabine- or fluoropyrimidines-based regimens are also commonly used • US Food and Drug Administration (FDA)
Slide 96: Overall summary of Treatment
Overall summary of Treatment Resectable Unresectable Adjuvant Capecitabine Gemcitabine/cisplatin/ Gem/cis/Nab-paclitaxel durvalumab Looks promising but no Better than placebo Better than gem/cis randomized data yet to support Chemoradiotherapy is also sometimes used for R1 resection or extrahepatic
Slide 97: Targets for Personalized Intervention
Targets for Personalized Intervention INTRAHEPATIC EXTRAHEPATIC/GALLBLADDER ► Approximately half of intrahepatic BRAF MSI cholangiocarcinomas and some IDH1 HER2 extrahepatic cholangiocarcinomas have (potentially) targetable mutations FGFR2 Fusions ► IDH1 mutations, FGFR2 fusions, BRAFV600E, MSI, HER
Slide 98: Summary
Summary ► Unmet needs in CCA ► Opportunities for new targeted therapies ► Opportunities for new mechanisms of action/combinations 98
Slide 99: Cholangiocarcinoma (CCA): 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 100: 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 101: 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 102: GNS561 has antitumor activity in human 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 103: GNS561 has antitumor activity in iCCA cell lines and patient-derived 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 104: GNS561 mainly accumulated in the 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 105: 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 106: 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 107: Rate of KRAS mutation in CCA is frequent
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 108: 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 109: 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 110: Cholangiocarcinoma (CCA): Market opportunity
Cholangiocarcinoma (CCA) Market opportunity ▪ Pascal Caisey, Chief Operating Officer and Chief Commercial Officer of GENFIT
Slide 111: 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 112: Questions?
Short Q&A (5 minutes) Questions? 112
Slide 113: Urea cycle disorder (UCD) and organic acidemia disorder (OAD): Disease state
Urea cycle disorder (UCD) and organic acidemia disorder (OAD) Disease state ▪ Vincent Forster, PhD, GENFIT, co-founder of VERSANTIS
Slide 114: Overview of 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 115: Urgent unmet needs in treatment of 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 116: UCD and OAD: GENFIT's programs VS-01
Urea cycle disorder (UCD) and organic acidemia disorder (OAD) GENFIT’s programs: VS-01* ▪ Vincent Forster, PhD, GENFIT, co-founder of VERSANTIS * investigational product that is not approved by any health authority
Slide 117: VS-01 is a potential first-line treatment for acute hyperammonemic crises
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 118: VS-01 ammonia clearance vs. current 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 119: KOLs feedback on VS-01 anticipated 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 120: 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 121: 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 122: 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 123: Estimated 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 124: Questions?
Short Q&A (5 minutes) Questions? 124
Slide 125: Closing remarks
Closing remarks Take home messages ▪ Pascal Prigent, CEO of GENFIT
Slide 126: 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 127: 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 127
Slide 128: 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 129: Thank you
TOWARDS BETTER MEDICINE Thank you