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Lanifibranor KOL Breakfast Lanifibranor KOL Breakfast Boston November 2019 Lanifibranor: a pan-PPAR Agonist with Therapeutic Potential in NASH and NASH Cirrhosis November 9, 2019 2019 Confidential – Property of Inventiva S.A. │1 Lanifibranor is a next generation panPPAR with moderate and well balanced activity on PPAR and Lanifibranor dose response curves and EC50s for hPPARs (nM) PPAR PPAR PPAR Lanifibranor presents a similar profile for Compound EC50 (nM) EC50 (nM) EC50 (nM) the 3 rodent PPAR isoforms 150 Lanifibranor(1) 1630 850 230 125 hPPAR Fenofibrate 2400 - - 100 hPPAR 75 hPPAR Pioglitazone - - 263 50 %Activation Rosiglitazone - - 13 25 Elafibranor(2) 10 100 - 0 -10 -8 -6 -4 Seladelpar(3) -2 - Lanifibranor (M) Lanifibranor binds differently than rosiglitazone to PPARγ inducing a different coactivator recruitment(4) Potency scale: red 10 nM; grey: 500 nM; green 5 000 nM Source: (1) Company data (2) Hanf R et al, Diabetes & Vascular Dis Res 2014 (3) Cimabay company presentation (4) J Med Chem. 2018 Feb 15. doi: 10.1021/acs.jmedchem.7b01285 2019 Confidential – Property of Inventiva S.A. │2 PPAR efficacy is well established in NASH PPAR activation by pioglitazone significantly improves steatosis, ballooning and inflammation as well as metabolic markers in NASH patients after 6 or 18 months of treatment: Belfort NASH study Cusi NASH study Pioglitazone (PPAR) 6 month treatment 18 month treatment Placebo Pio p Placebo Pio p Steatosis (% patients improved) 38% 65% < 0.001 26% 71% < 0.001 Inflammation (% patients improved) 29% 65% < 0.001 22% 49% < 0.001 Ballooning (% patients improved) 24% 54% < 0.001 24% 51% < 0.001 NASH resolution (% patients) - NA - 19% 51% < 0.001 Fibrosis (mean change in score) - NS - 0 - 0.5 = 0.039 Pioglitazone improves advanced fibrosis (stage F3-F4) as indicated by an increase in the number of NASH patients whose fibrosis stage changed from F3-F4 to F0-F2 at the end of treatment Source: Musso G et al, Hepatology 2017 2019 Confidential – Property of Inventiva S.A. │3 PPAR activity can also be completed by PPAR and efficacy PPAR/ activation by elafibranor 120mg/day leads to significant improvement of ballooning and inflammation as well as metabolic markers in NASH patients vs. placebo after 12 months of treatment NASH resolution in ITT: 19% vs 12%, p = 0.045 (elafibranor 120mg, n=89; placebo, n=92) In patients with bNAS≥4 and randomized in centers that included in each treatment arm % patients with decrease of at least 1 point (elafibranor 120mg, n=31; placebo, n=39) Steatosis: 35% vs 18%, p = 0.10 Inflammation: 55% vs 33%, p < 0.05 Ballooning: 45% vs 23%, p = 0.02 Patients who resolved NASH showed significant reduction in liver fibrosis while non-responders did not show any change from baseline (elafibranor 120mg, responders, n=17; non-responders, n=61) Source: Ratziu V, et al. Gastroenterology 2016 2019 Confidential – Property of Inventiva S.A. │4 Lanifibranor shows consistent improvements in metabolic parameters and histology while displaying anti-fibrotic activity NASH & NAFLD Metabolic models models Fibrosis models Cirrhosis models Diet induced obesity Methionine Choline Carbon tetrachloride Thiocetamide (TAA) high fat / high sucrose Deficient diet (MCD) (CCL4) Foz / Foz Choline-deficient amino-acid and high fat diet Hepatoma and muscle Macrophages biology HSC biology cells biology Endothelial biology Lanifibranor improves Lanifibranor reduces Lanifibranor reduces Lanifibranor reduces Insulin resistance Steatosis fibrosis Portal pressure Non fasting glucose Inflammation Lanifibranor inhibits Established fibrosis stellate cell activation Homa-IR Ballooning Lanifibranor reverses Lipid profile Lanifibranor improves NASH In Vivo Lanifibranor maintains NAS score body weight In Vitro 2019 Confidential – Property of Inventiva S.A. │5 Lanifibranor significantly improves insulin sensitivity without increasing body weight gain in preclinical models of NASH DIO mice model (HF/HS) Foz/foz mice model HOMA Non fasting Glucose Insulin 1000 *** *** 3 6 ## ## ** * ** 100 2 4 ** * 10 1 2 ** Glucose (g/L) Glucose Insulin(ng/mL) ** 0 1 Vehicle Vehicle 3 10 30 0 Vehicle Vehicle 3 10 30 g s k ol lanifibranor (mg/kg) HFD r lanifibranor (mg/kg) 0 mg/ ont ND controls 3 C HF/HS Diet r 10 mg/kg r D ND controls HF/HS Diet o no N fibran fibra ni Body weight a D + l F 50 HFD + lani H ### Body weight 40 * 100 *** *** ** 30 80 20 60 Body weight (g) weight Body 10 40 0 weight (g)Body 20 Vehicle Vehicle 3 10 30 lanifibranor (mg/kg) 0 D g g ls ND controls HF/HS Diet k k o HF g/ g/ tr m m 0 1 30 or ND con n ranor a b br ifi n a lanifi l + + D D ##, ###: vs ctrl vehicle p<0,01 or p<0,001 respectively HF HF *, **, ***: vs HF:HS or HFD P<0,05, P<0,01 or P<0,001 respectively 2019 Confidential – Property of Inventiva S.A. │6 Lanifibranor significantly reduces steatosis, inflammation, ballooning and fibrosis in preclinical models of NASH Lanifibranor inhibits steatosis Lanifibranor significantly Lanifibranor reverses and inflammation in the mice reduces ballooning and the established liver fibrosis in MCD model NAS score in the foz/foz model mice CCL4 model NAS-ballooning Steatosis Ballooning 3 400 2.0 *** *** *** ** 300 1.5 2 200 1.0 *** *** 1 % of areaof % 100 0.5 *** *** *** score ballooning Average numberof Average droplets/HPF lipid 0 0.0 0 HFD HFD + HFD + ND Vehicle Lani Lani (High Lani Lani (Norm 3 weeks 3 + 3 weeks 10mg/kg 30mg/kg Fat 10 30 al Diet) Diet) mg/kg mg/kg CCl4 model Inflammation Oil + vehicle NASNAS score Score *** CCL4 + vehicle 10 *** 3 ** CCL4 + Lanifibranor 15 mg/kg 8 CCL4 + Lanifibranor 30 mg/kg 2 6 *** 4 1 2 (Histology) *** 0 t t 0 kg kg Average inflammatory inflammatory score Average HFDDie HFD /+ HFD/ + ND g g l Die (Highat Lanim Lanim (Normao Vehicle Lani Lani F 0 0 tr h 1 3 g Fat 7 10 7 30 l Diet) 10mg/kg 30mg/kg Con Hi 33 33 Diet) A mg/kg A mg/kg IV IV Lanifibranor associated with beneficial effects on all NASH-relevant liver features Source: Company data; The new-generation Pan-Peroxisome Proliferator-Activated Receptor Agonist IVA337 Protects the Liver From Metabolic Disorders and Fibrosis; Hepatology Communications, June 2017 2019 Confidential – Property of Inventiva S.A. │7 HSCs, the ultimate effectors of fibrogenesis in the liver, are regulated by PPAR Large literature describing PPAR as a key modulator of human HSC fate Activation or high expression of PPAR maintains human HSC in a quiescent state Inhibition or decreased expression of PPAR leads to human HSC activation (myofibroblasts) The transition from one state to another could be modulated by PPAR alone and is reversible Some authors described that PPAR inhibits HSC activation by reducing phosphoSMAD3 (Park et al. hepatology 2010 and Zhao et al. Biochem Biophys Res Commun 2006) PPAR is not expressed in human HSC Park et al hepatology 2010 2019 Confidential – Property of Inventiva S.A. │8 Lanifibranor significantly inhibits human HSC activation in preventive and curative settings Stiffness-induced HSC activation Stiffness-induced HSC activation (7 days) concomitant (7 days of stiffness + 3 or 7 days of stiffness and lanifibranor treatment) curative aSMA 1.5 lanifibranor aSMA 3 days HSC activation 7 days 2.0 D10 1.0 DMSO 0.1% D4 7days DMSO 0.1% D7 # D14 Lanifibranor 3 µM 1.5 D4 Arbitrary unit 0.5 * D7 DMSO 0.1% D10 1.0 ** lanifibranor 10 µM D10 0.0 DMSO 0.1% D14 Arbitrary unit lanifibranor 10 µM D14 D4 D7 % % ### .1 1 0.5 ## ### 0 0. O O S S *** *** *** DM DM Lanifibranor 3 µM Compounds (µM) 0.0 D4 D7 10 D10 D D14 D14 0.1% TGF-β1-induced HSC activation 10 µM 10 µM O r S no M (48 h) concomitant DMSO 0.1% a D fibranor ifibr n ani aSMA la l 3 [Compounds] µM DMSO 0.1% DMSO 0.1% + TGF IVA337 3 µM + TGF Lanifibranor inhibits HSC activation (stiffness- or TGF-β1- ** IVA337 10 µM + TGF 2 IVA337 30 µM + TGF induced) after concomitant or curative treatment ** Fenofibrate (PPARα) has no effect in preventing HSC Arbitrary unit 1 activation *** GW501516 (PPARδ) has a moderate effect in preventing 0 HSC activation but no effect in a curative mode % GF GF GF TGF T T T + + + M µM µM + DMSO 0.1 0 µ PPAR agonists prevents HSC activation 7 1 3 A337 3 DMSO 0.1% IV A3 A337 30 IV IV [Compounds] µM 2019 Confidential – Property of Inventiva S.A. │9 Dual PPAR and activation shows therapeutic efficacy in a preclinical model of chronic advanced liver disease Liver fibrosis Collagen deposition PPAR/ LSEC inflammation Activated HSC LSEC capillarization Endothelial dysfunction Intrahepatic angiogenesis PPARα/ HSC contractility PPARα/ Portal pressure Intestinal hyperpermeability Splanchnic inflammation and neoangiogenesis Porto-systemic shunts Intrahepatic vascular Extrahepatic complication complication 2019 Confidential – Property of Inventiva S.A. │10 Lanifibranor significantly reverses HSC activation and liver fibrosis in a model of advanced chronic liver disease Lanifibranor reverses liver fibrosis Lanifibranor reverses HSC activation Veh Lani 3 -SMA 2 1 Relative Relative protein * expression expression of 30 0 Veh Lani * 20 2.0 1.5 -SMA 10 1.0 ** Fibrosis Fibrosis percentage 0 mRNA Relative 0.5 Veh Lani expression of 0.0 Veh Lani Source: “The pan-PPAR agonist lanifibranor improves portal hypertension and hepatic fibrosis in experimental advanced chronic liver disease”, The Liver Meeting® 2019; Methods. Cirrhotic rats (due to 12-week TAA) randomly received lanifibranor (100mg/kg/day, po) or vehicle for 14 days (n=12 per group). In vivo systemic and hepatic hemodynamics (mean arterial pressure, MAP; portal pressure, PP; portal blood flow, PBF; and hepatic vascular resistance, HVR), serum AST, ascites degree (0-III), liver inflammation (IL-6 & IL-10), fibrosis (Sirius red staining, collagen I, MMPs & TIMPs), hepatic stellate cells activation (a-SMA, p-moesin and desmin) and liver sinusoidal endothelial cells de-differentiation (ICAM-1, VCAM-1, E-Sel, and sinusoidal porosity through scanning electron microscopy) were determined.
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