Inventiva SA · EURONEXT:IVA
Inventiva SA — KOL Webcast Event from EASL 2021
66 slides from Inventiva SA's conference presentation, Jun 29, 2021
Slide 1: KOL Webcast Event From EASL 2021
KOL Webcast Event From EASL 2021 June 29, 2021
Slide 2: Today's speakers
Today’s speakers Frédéric Cren, MA/MBA, Chairman, CEO and cofounder Pierre Broqua, Ph.D., CSO and cofounder Michael Cooreman, MD, CMO Prof. Naim Alkhouri, MD VP of Academic Affairs Chief of Transplant Hepatology, Director of the Fatty Liver Program Arizona Liver Health Prof. Sven Francque, MD Head o
Slide 3: Update on the NASH field
Update on the NASH field Prof. Naim Alkhouri, MD Director of the Fatty Liver Program VP of Academic Affairs Chief of Transplant Hepatology Arizona Liver Health (ALH)
Slide 4: NITs to Predict Response to Treatment
NITs to Predict Response to Treatment FDA Efficacy Endpoints for Phase 3 Trials: Liver Histologic Improvement NASH Resolution Fibrosis Improvement • Resolution of steatohepatitis on Improvement ≥ 1 fibrosis stage overall histopathologic reading and and No worsening of steatohepatitis • No worsen
Slide 5: Biomarkers to Assess Treatment Response
Biomarkers to Assess Treatment Response Liver Fat Fraction ALT/ AST ?MRE/ cT1/ LSM? (MRI‐PDFF) • ≥ 17 U/L reduction MRE: ≥ 15% relative reduction from BL? predicts histologic ≥ 5% absolute/ ≥ 30% response cT1: > 88 ms reduction from relative reduction BL or change in category? associated with
Slide 6: Future Treatments for NASH
Future Treatments for NASH
Slide 7: NASH Clinical Trial Overview: The $40B Race to Treatment
NASH Clinical Trial Overview The $40B Race to Treatment NAFLD NASH Fibrotic NASH Cirrhotic NASH Insulin resistance Inflammation and Cell death Lipotoxicity and Fibrogenesis and and/or lipid immune (apoptosis and oxidative stress collagen turnover metabolism activation necrosis) PPARγ: Pioglitazone P
Slide 8: Metabolic Targets
Metabolic Targets 8
Slide 9: Resmetirom: selective thyroid hormone receptor-beta agonist
Resmetirom (MGL‐3196): selective thyroid hormone receptor‐beta agonist TSH T4, prohorm one T3, ac/ ve horm one In humans THR‐β agonism: TSH, thyroid s/ m ula/ ng horm one Thyroid Gland Nuc Thyroid Hormone Lowers LDL‐cholesterol Receptor α or β Lowers triglycerides TT44 T3 Lowers liver fat, pot
Slide 10: Resmetirom significantly decreases hepatic fat in NASH patients at week 12
Resmetirom significantly decreases hepatic fat in NASH patients at week 12 MRI‐PDFF, and was associated with NASH resolution at week 36 biopsy Fat Reduction at week 12 MRI‐PDFF NASH Resolution at week 36 biopsy Relative Change in MRI-PDFF (%) ≥30% Fat Reduction (%) High MGL- Low MGL- High MGL- Low M
Slide 11: Lanifibranor: A pan-PPAR agonist
Lanifibranor: A pan‐PPAR agonist Francque et al. Nature Rev Gastroenterol Hepatol 2020 11
Slide 12: Lanifibranor: improvements in NASH resolution and fibrosis regression
Lanifibranor: Significant improvements in both resolution of NASH and regression of fibrosis 12
Slide 13: Semaglutide: Efficacy and safety of once-daily SQ
Semaglutide: Efficacy and safety of once‐daily SQ Trial objective: To compare the effect of three different doses of semaglutide subcutaneous (s.c.) once daily versus placebo on histological resolution of NASH 0.05 mg 0.1 mg 0.2 mg 0.3 mg Semaglutide 0.4 mg once daily Eligible patients Matched place
Slide 14: Resolution of steatohepatitis and no worsening in liver fibrosis
Resolution of steatohepatitis and no worsening in liver fibrosis Patients with fibrosis stage 2 or 3 at baseline p=0.0100 100 p=0.0359 Proportion of patients (%) 80 p<0.0001 58.9 60 40.4 40 35.6 20 17.2 0 Semaglutide 0.1 mg Semaglutide 0.2 mg Semaglutide 0.4 mg Placebo (n=57) (n=59) (n=56) (n=58) Da
Slide 15: Gut-Liver Axis/ Bile Acids/ FGFs
Gut‐Liver Axis/ Bile Acids/ FGFs
Slide 16: REGENERATE Study Design: OCA in Non-Cirrhotic NASH
REGENERATE Study Design: OCA in Non‐Cirrhotic NASH Phase 3 (target ~2400 patients) Total Study Duration Driven by the Time Required to Accrue 264 Outcome Events (~6 years) -Biopsy confirmed NASH -Fibrosis stage 2 or 3 (NASH CRN) Obeticholic Acid 10 mg qd -NAFLD activity score ≥4 -Interim analysis: M
Slide 17: REGENERATE Study: Interim Efficacy Analysis
REGENERATE Study: Interim Efficacy Analysis at 18 Months Primary Efficacy Endpoints (ITT) • Fibrosis improvement (≥1 stage) and no 30 Obeticholic acid 10 mg (n=312) worsening of NASH in patients (obeticholic Obeticholic acid 25 mg (n=308) acid versus placebo) 25 23%† Placebo (n=311) 10 mg: 18% versu
Slide 18: Hepatic efficacy endpoints
Drug (route of Lanifibranor Resmetirom Semaglutide Efruxifermin Aldafermin Pioglitazone administration) (Oral) (Oral) (Injectable) (Injectable) (Injectable) (Oral) Hepatic efficacy endpoints NASH Resolution Fibrosis __ __ Improvement MRI‐PDFF No Data No Data No Data ALT Effects on MetS Weight Weight
Slide 19: Safety and Efficacy of Combination Therapies Including Semaglutide, Cilofexor, and Firsocostat
Safety and Efficacy of Combination Therapies Including Semaglutide, Cilofexor, and Firsocostat in Patients with NASH Naim Alkhouri,1 Robert Herring,2 Heidi Kabler,3 Zeid Kayali,4 Tarek Hassanein,5 Anita Kohli,1 Ryan Huss,6 Yanni Zhu,6 Jun Xu, 6 Lars Holm Damgaard,7 Kristine Buchholtz,7 Mette Skalshø
Slide 20: Study Design
Study Design Week 0 4 8 12 16 24 n=21 SEMA n=22 SEMA + FIR 20 mg N=108 n=22 SEMA + CILO 30 mg n=22 SEMA + CILO 100 mg n=21 SEMA + FIR 20 mg + CILO 30 mg SEMA QW dose escalation 0.24 mg 0.5 mg 1 mg 1.7 mg 2.4 mg MRI‐PDFF, MRE, CAP, and LS by VCTE Serum biomarkers Key inclusion criteria ‒ Histologic
Slide 21: MRI-PDFF: Greater Improvements with Combinations
MRI‐PDFF: Greater Improvements with Combinations Absolute Change at Week 24 Relative Change from Baseline SEMA SEMA + SEMA + SEMA + SEMA + FIR FIR CILO 30 mg CILO 100 mg + CILO 30 mg Median (IQR), % n=15 n=15 n=18 n=15 n=13 0 LSMean Change (95% CI), % -8,6 -11,6 -10,6 -9,8 -12,6 SEMA -5 SEMA + FIR -
Slide 22: NASH Drugs Got Houses
NASH DRUGS GOT HOUSE of FXRs HOUSE of PPARs HOUSE of FGFs/ GLP1 HOUSE of THRs HOUSE of Anti-Fibrotics 22
Slide 23: Take Home Message
Take Home Message • NITs are rapidly replacing liver biopsy to determine disease severity and response to treatment. • Promising results from several clinical trials including combination therapy. • @AlkhouriNaim • @azliver 23
Slide 24: Review of lanifibranor EASL 2021 abstracts
Review of lanifibranor EASL 2021 abstracts Prof. Sven Francque, MD Head of the Department of Gastroenterology and Hepatology of the Antwerp University Hospital, Co-Principal Investigator of NATIVE trial
Slide 25: Lanifibranor: activating the PPAR isotypes for optimal NASH treatment
Lanifibranor: activating the 3 PPAR isotypes could lead to an optimal treatment of NASH INFLAMMATION AND METABOLISM STEATOSIS BALLOONING PPARα PPARδ PPARγ PPARγ PPARα PPARδ PPARγ PPARα Insulin sensitivity FA uptake NFkB-dependent gene activation HDLc FA catabolism Inflammasome Triglycerides Lipogene
Slide 26: Lanifibranor: a pan-PPAR agonist entering phase 3 in NASH
Lanifibranor: a pan-PPAR agonist entering phase 3 in NASH Moderate and balanced pan-PPAR agonist activity PPARα Small molecule that activates all three PPAR isotypes in humans Differentiated chemical structure: not a fibrate or a TZD Once daily oral administration Beneficial effect on NASH r
Slide 27: Liver fibrosis is the most important predictor of mortality in NAFLD
Liver fibrosis is the most important predictor of mortality in NAFLD Dulai et al. Hepatology 2017
Slide 28: Lanifibranor improves lipid, insulin resistance, liver injury and fibrosis markers
Lanifibranor therapy improves markers of lipid metabolism, insulin resistance, liver injury and fibrosis in patients with NASH and F2 and F3 fibrosis stages: a subgroup analysis of the phase 2b NATIVE study Sven Francque, Michael P. Cooreman, Martine Baudin, Philippe Huot-Marchand, Lucile Dzen, Jean
Slide 29: Phase 2b trial design
Phase 2b trial design Clinicaltrials.gov identifier: NCT03008070 24-week treatment + 4-week follow-up Screening Double blind, randomized, placebo-controlled End of treatment Liver biopsy Liver biopsy Placebo Lanifibranor, 800 mg once daily • Randomisation 1/1/1 • Stratification on T2DM Lanifibra
Slide 30: Patient disposition in F2-F3
Patient disposition in F2-F3 247 patients with F1-F2-F3 fibrosis at screening 188 patients with F2-F3 at screening Placebo Lanifibranor 800 mg/day Lanifibranor 1200 mg/day N = 57 N = 68 N = 63 51 (89%) patients completed 64 (94%) patients completed 58 (92%) patients completed the 24-week treatment t
Slide 31: Effect of lanifibranor on histological endpoints in F2-F3
Effect of lanifibranor therapy on histological endpoints, in F2-F3 Reduction of 2 points of SAF Activity Score and Fibrosis improvement w/o worsening of NASH no worsening of fibrosis 51% 48% 43% 30% 32% 21% p=0.048 P<0.001 p=0.01 p=0.736 Placebo Lanifibranor 800mg Lanifibranor 1200mg Placebo Lanifib
Slide 32: Histological endpoints: overall population and F2-F3 subgroup
Effect of lanifibranor therapy on histological endpoints, in the overall population and the subgroup of F2-F3 Reduction of 2 points of SAF Activity Score and Fibrosis improvement w/o worsening of NASH no worsening of fibrosis 48% 49% 51% 42% 41% 43% 30% 32% 28% 27% 24% 21% p=0.061 p=0.004 p=0.53 p=0
Slide 33: Effect of lanifibranor on liver enzymes in F2-F3
Effect of lanifibranor therapy on liver enzymes in F2- F3 Absolute change from baseline in ALT Absolute change from baseline in AST Absolute change +/- 95%CI Absolute change +/- 95%CI AST (U/L) ALT (U/L) * * * ** * ** * * ** ** ** ** * p<0.01 **p<0.001 Absolute change from baseline in GGT Absolute c
Slide 34: Effect of lanifibranor on liver enzymes in F2-F3
Effect of lanifibranor therapy on liver enzymes in F2- F3 Percentage of patients with normal ALT values Percentage of patients with normal AST values 75% 78% 72% 64% End of 47% 44% 41% 40% Baseline treatment 32% 29% (Week 24) 25% 25% Placebo Lanifibranor 800mg Lanifibranor Placebo Lanifibranor 800mg
Slide 35: Effect on markers of lipid metabolism, inflammation and fibrosis
Effect of lanifibranor therapy on markers of lipid metabolism, inflammation and fibrosis in F2-F3 Absolute Change from baseline at End of Treatment (Week 24): Mean (SE) P value* vs placebo Lanifibranor 800 mg Lanifibranor 1200 mg Lanifibranor pooled Placebo -0.09 (0.02) -0.07 (0.02) -0.08 (0.01) APO
Slide 36: Safety and tolerability in F2-F3
Safety and tolerability in F2-F3 Placebo 800 mg 1200 mg N (%) patients reporting Adverse Event (AE) (N = 57) (N = 68) (N = 63) Any Treatment-Emergent AE (TEAE) 36 (63.2%) 50 (73.5%) 46 (73.0%) - Drug-related TEAE 13 (22.8%) 22 (32.4%) 18 (28.6%) Any Serious TEAE 2 (3.5%) 2 (2.9%) 5 (7.9%) - Drug-rel
Slide 37: Lanifibranor has beneficial effects on cardiovascular risk biomarkers in NASH
Lanifibranor, a pan-PPAR agonist, has beneficial effects on cardiovascular risk biomarkers in patients with NASH Sven Francque, Michael P. Cooreman, Martine Baudin, Philippe Huot-Marchand, Lucile Dzen, Jean-Louis Junien, Pierre Broqua, Manal F. Abdelmalek 37
Slide 38: Liver fibrosis is the most important predictor of mortality in NAFLD
Liver fibrosis is the most important predictor of mortality in NAFLD Dulai et al. Hepatology 2017
Slide 39: Lanifibranor: activating the PPAR isotypes for optimal NASH treatment
Lanifibranor: activating the 3 PPAR isotypes could lead to an optimal treatment of NASH INFLAMMATION AND METABOLISM STEATOSIS BALLOONING PPARα PPARδ PPARγ PPARγ PPARα PPARδ PPARγ PPARα Insulin sensitivity FA uptake NFkB-dependent gene activation HDLc FA catabolism Inflammasome Triglycerides Lipogene
Slide 40: Cardiovascular disease is a major cause of morbidity and mortality in NASH
Cardiovascular disease (CVD) is a major cause of morbidity and mortality in patients with NASH Cardiovascular risk biomarkers considered in NASH Lipids Inflammatory marker: • Triglycerides (mmol/L) • Hs-CRP (mg/l) • HDL-c (mmol/L) Glucose metabolism • LDL-c (mmol/L) • Fasting glucose (mmol/l)
Slide 41: Patient Baseline Demographics and Characteristics
Patient Baseline Demographics and Characteristics Placebo Lanifibranor Lanifibranor Overall Parameters (unit) - 800 mg/day 1200 mg/day - n (%) or mean ± SD N = 81 N = 83 N = 83 N = 247 Demographics Female 31 (54%) 48 (71%) 35 (56%) 114 (61%) Age (years) 54.7 ± 12.9 55.4 ± 10.4 54.1 ± 13.2 54.7 ± 12.
Slide 42: Patient Baseline Demographics and Characteristics
Patient Baseline Demographics and Characteristics Placebo Lanifibranor Lanifibranor Overall Parameters (unit) - 800 mg/day 1200 mg/day - n (%) or mean ± SD N = 81 N = 83 N = 83 N = 247 Demographics Female 31 (54%) 48 (71%) 35 (56%) 114 (61%) Age (years) 54.7 ± 12.9 55.4 ± 10.4 54.1 ± 13.2 54.7 ± 12.
Slide 43: Effect of lanifibranor therapy on lipids
Effect of lanifibranor therapy on lipids Absolute change from baseline in HDL-C Absolute change from baseline in triglycerides ** ** ** * ** ** ** ** ** ** * p<0.01 **p<0.001 Statistically significant increase in HDL‐C after 4 weeks Statistically significant decrease in triglycerides after 14 we
Slide 44: Effect on other lipids and inflammatory markers
Effect of lanifibranor therapy on other lipids and inflammatory markers Absolute Change from baseline at End of treatment (Week 24): Mean (SE) P value* vs placebo Lanifibranor 800 mg Lanifibranor 1200 mg Lanifibranor pooled Placebo Lipids -0.29 (2.19) -4.39 (2.16) -2.37 (1.55) APO-A1 (mg/dl) 0.03 (2
Slide 45: Effect of lanifibranor therapy on glucose metabolism
Effect of lanifibranor therapy on glucose metabolism Absolute change from baseline in Absolute change from baseline in Fasting Glucose (mmol/L) Fasting Insulin (pmol/L) ** ** ** ** ** ** ** ** Insulin collected only at baseline and Week 24 * p<0.01 **p<0.001 Statistically significant increase in f
Slide 46: Glycaemic control in T2DM patients
Glycaemic control in T2DM patients Lanifibranor Lanifibranor ACFB: Absolute change from Placebo 800 mg p-value 1200 mg p-value baseline N=35 N=33 N=35 Fasting glucose (mmol/L) 0.28 -1.39 <0.001 -0.93 <0.001 Fasting insulin (pmol/L) -40.2 -145.9 <0.001 -108.6 0.018 HbA1c (%) 0.08 -0.61 <0.001 -0.65 <
Slide 47: Blood pressure (BP)
Blood pressure (BP) Absolute change from baseline Absolute change from baseline in systolic BP (mmHg) in diastolic BP (mmHg) 4 2 2 0 0 * -2 * ** -2 -4 * * * -4 -6 Baseline Week 4 Week 14 Week 24 Baseline Week 4 Week 14 Week 24 Treatm ent group 800mg 1200mg Plac ebo Treatm ent group 800mg 1200mg Plac
Slide 48: Conclusion
Conclusion ► In patients with NASH and F2/F3 fibrosis, lanifibranor showed significant efficacy on all primary and secondary histological end-points ► Efficacy was similar in patients with and without diabetes. ► Serum markers of liver injury, inflammation and fibrosis also improved with lanifibrano
Slide 49: Lanifibranor and firsocostat combination in a murine NASH model
The Home of Hepatology Combination therapy of lanifibranor and firsocostat further improves steatohepatitis and fibrosis compared to monotherapy in a diet- induced murine model of NASH , G. WETTSTEIN 1, F. BRIAND 2, T. SULPICE 2, J-L. JUNIEN 1, P,. BROQUA* Daix, France 2 Physiogenex, Escalquens, Fra
Slide 50: Further developments?
Further developments? Haas, Francque & Staels. Ann Rev Physiol 2016 Francque & Vonghia. Advances in Therapy 2019 50
Slide 51: Study design
Study design 2° FASL’ C57B16/J, male, 8 weeks old HFCC+CDxX diet for 3 weeks 2 weeks diet + treatments randomization Blood and liver collection Group 1: vehicle 1 p.o. QD + vehicle 2 p.o. QD; n=10 Group 2: lanifibranor p.o. QD + vehicle 2 p.o. QD; n=10 Group 3: vehicle 1 p.o. QD + firsocostat p.o. Q
Slide 52: Effect of lanifibranor and firsocostat on hepatic lipids content
Effect of lanifibranor and firsocostat alone, or in combination, on hepatic lipids content 52
Slide 53: Effect on steatosis and inflammation
Effect of lanifibranor and firsocostat alone, or in combination, on steatosis and inflammation Steatosis Inflammation 4 4 vehicle §§§§ §§§§ inflammation grade lanifibranor steatosis grade 3 3 firsocostat **** **** **** *** *** **** lani/firso 2 2 1 1 0 0 o t o at e or e or ta cl cl irs irs st an an
Slide 54: Effect on fibrosis
Effect of lanifibranor and firsocostat alone, or in combination, on fibrosis fibrosis fibrosis PSR sirius red % over total liver area 1.5 0.20 vehicle §§ §§ lanifibranor fibrosis grade 0.15 1.0 firsocostat lani/firso ** 0.10 * 0.5 0.05 0.0 0.00 o at r e no o at r e cl rs no st cl rs st hi /fi ra co
Slide 55: Effect on markers of inflammation and fibrosis
Effect of lanifibranor and firsocostat alone, or in combination, on markers of inflammation and fibrosis 55
Slide 56: Conclusion
Conclusion Lanifibranor and firsocostat combination reached greater efficacy than monotherapy on • hepatic lipid content • steatosis • fibrosis • total scoring. These data emphasize the complementary effect of these two compounds on lipid metabolism leading to further improvement of NASH and fib
Slide 57: Lanifibranor: overview of phase III NASH trial
Lanifibranor: overview of phase III NASH trial Michael Cooreman, MD, CMO
Slide 58: NATiV3 Trial - Overview
NATiV3 Trial - Overview Design – Part 1: accelerated (FDA) and conditional (EMA) approval – Part 2: full approval – Central reading of liver histology Clinical Operations – Status – Time frame │ 58
Slide 59: NATiV3 Study Design
NATiV3 Study Design A randomised, double-blind, placebo-controlled, multicentre, Phase 3 study evaluating long-term efficacy and safety of lanifibranor in adult patients with non-cirrhotic non- alcoholic steatohepatitis (NASH) and fibrosis 2 (F2)/fibrosis 3 (F3) stage of liver fibrosis │ 59
Slide 60: NATiV3 study design
NATiV3 study design Randomization and stratification Randomisation 1:1:1 Stratification on T2DM Stratification on F2/F3 patients Statistical powering: 90% considered for sample size Main inclusion criteria Adults 18 years of age DIAGNOSED with NASH using SAF scoring (steatosis ≥1, activity ≥
Slide 61: NATiV3 – Part 1
NATiV3 – Part 1 Primary efficacy endpoint – Evaluated at Week 72 in ca 900 patients – Composite endpoint of patients having both NASH resolution and improvement of fibrosis of at least one stage Key secondary endpoints – NASH resolution and no worsening of fibrosis – Improvement of fibrosis and
Slide 62: NATiV3 – Part 2
NATiV3 – Part 2 Primary efficacy endpoint based on ‘time to first clinical event’ Clinical events – Progression to cirrhosis (histological diagnosis) – All cause mortality – Hepatic decompensation Hepatic encephalopathy Upper gastrointestinal variceal bleeding Ascites (requiring treatment)
Slide 63: Central Reading of liver biopsies - process
Central Reading of liver biopsies - process Pathologist A Pathologist B Pathologist C Glass slides sent at random to one of the 3 pathologists, review on glass and digital slides done in parallel by a second one Patient randomized if both agree on eligibility - Glass slides, sent by batches of 80 sl
Slide 64: NATiV3 – Timelines to submission for accelerated approval
NATiV3 – Timelines to submission for accelerated approval PHASE III MILESTONES 2021 2022 2023 2024 F2-F3 Phase III Q3 2021 H2 2022 H1 2024 First Patient Part 1: Last Patient Part 1: Last First Visit First Visit Patient Last Visit (c.900 patients) (c.900 patients) Q2 2021 First Site Active H2 2024 Pa
Slide 65: NATiV3 – Status today
NATiV3 – Status today The study is conducted with our CRO partner PRA Health Sciences Protocol finalized Target number of sites: approx. 300 Site feasibility started Qualified sites (as of June 14): >150 ‒ Enrollment potential for Part 1: >1000 patients ‒ Approx. 60% expected from the U.S.
Slide 66: Q&A
Q&A