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Emerging Therapies in NASH

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Emerging Therapies in NASH Emerging Therapies in NASH Stephen A Harrison, MD, FACP, FAASLD COL (ret.), USA, MC Visiting Professor of Hepatology Radcliffe Department of Medicine, University of Oxford Medical Director, Pinnacle Clinical Research President, Summit Clinical Research San Antonio, TX Disclosures • Scientific advisor or consultant for Akero, Alentis, Altimmune, Arrowhead, Axcella, Canfite, Cirius, CiVi Biopharma, Cymabay, Echosens, Fibronostics, Forest Labs, Galectin, Genfit, Gilead, Hepion, HistoIndex, Intercept, Madrigal, Medpace, Metacrine, NGM Bio, Northsea, Novartis, Novo Nordisk, PathAI, Poxel, Liminal, Ridgeline, Sagimet, Terns, Viking, 89 Bio. • Stock options: Akero, Cirius, Galectin, Genfit, Hepion, HistoIndex, PathAI, Metacrine, NGM Bio, Northsea. • Grant/Research support: Akero, Axcella, BMS, Cirius, CiVi Biopharma, Conatus, Cymabay, Enyo, Galectin, Genentech, Genfit, Gilead, Hepion, Hightide, Intercept, Madrigal, Metacrine, NGM Bio, Novartis, Novo Nordisk, Northsea, Pfizer,Sagimet, Viking. Goals of NASH Treatment • Improve metabolic abnormalities • Decrease inflammation • Prevent/arrest/reverse liver fibrosis – AASLD recommends pharmacological treatments aimed primarily at improving liver disease should generally be limited to those with biopsy-proven NASH and fibrosis • Prevent advanced liver disease, liver failure, liver cancer and related outcomes • Systemic outcomes (eventually) Chalasani N et al. Hepatology. 2018;67:328-35. Lifestyle Recommendations for Treating NASH Caloric intake Weight loss Exercise No heavy alcohol reduction of 3% to 5% can improve alone may reduce steatosis, consumption steatosis, but 6% to 10% is ≥30% or but effect on other histologic Insufficient data to guide needed to improve NASH/fibrosis ~750-1,000 kcal/day features unknown recommendations regarding improved insulin resistance nonheavy alcohol consumption and hepatic steatosis **Drink ≥ 2 cups of caffeinated *Limit consumption of coffee daily fructose-enriched beverages *Fructose increases the odds of the development of nonalcoholic fatty liver in high-risk patients and of nonalcoholic steatohepatitis and more advanced liver fibrosis in patients who already have nonalcoholic fatty liver disease. **Caffeinated coffee reduces the risk of liver fibrosis in several liver diseases, including nonalcoholic fatty liver disease. Chalasani N et al. Hepatology. 2018;67(1):328-357; Diehl AM, Day C. New Engl J Med. 2017; 377:2063-72. Sources of Excess Clinical Outcomes in NAFLD and Where Interventions Will Have Greatest Impact Closest to cirrhosis and most likely to benefit Most closely tied to from prevention liver-related mortality of progression NAFL NASH NASH with fibrosis NASH Cirrhosis Cardiovascular, CKD and all-cause cancer outcomes Liver decompensation Pathogenesis of NASH and Related Fibrosis ANTI-INFLAMMATORY Insulin resistance METABOLIC SGLT Regulatory T cells Insulin/glucose FGF21 Adiponectin ACC TNF-α TR Immune cell FFA trafficking VLDL Mitochondrial Lipogenesis dysfunction Apoptosis NLRP3 SHP SREPB-1 DNL inflammasom FFA ROS e ER Stress FGF19 FXR/TGR5 Collagen JNK deposition UPR Bile acids Hepatic stellate Kupffer cell activation cell ANTI-FIBROTIC LPS ACC, acetyl-CoA carboxylase; AOC, amine oxidase, copper containing; ASK, apoptosis signal-regulating kinase; CCR, CC chemokine receptor; DNL, de novo lipogenesis; ER, endoplasmic reticulum; FFA, free fatty acids; FGF, fibroblast growth factor; FXR, farnesoid X receptor; IL, interleukin; JNK, Jun N-terminal kinases; LPS, lipopolysaccharide; NLRP3, nucleotide-binding oligomerization domain and leucine rich repeat and pyrin domain containing protein 3; PPAR, peroxisome proliferator-activated receptor; ROS, reactive oxygen species; SCD, stearoyl CoA desaturase; SGLT, sodium-glucose linked transporter; SHP, small heterodimer partner; SREBP, sterol regulatory element binding proteins; TGF, transforming growth factor; TGR5, G protein-coupled bile acid receptor 1; TLR, toll like receptor; TNF, tumor necrosis factor; TR, thyroid receptor; UPR, unfolded protein response VLDL, very low density lipoprotein. Adapted from Konerman MA et al. J Hepatol. 2018;68:362–375. NASH: Potential Therapeutic Targets SGLT2 inhibitor ANTI-INFLAMMATORY METABOLIC GLP1 ag Insulin sensitizer MPC inh Insulin resistance Regulatory FGF21 analog/agonist SGLT ACC inhibitor T cells Insulin/glucose FGF21 PPAR agonists FASN inh Adiponectin ACC TNF-α THRᵦ ag Immune cell FFA trafficking VLDL Mitochondrial Apoptosis SCD1 inh Lipogenesis dysfunction NLRP3 SHP SREPB-1 DNL inflammasome FFA ROS ER Stress FGF19 FXR/TGR5 Collagen JNK FGF19 analog deposition UPR Bile acids Hepatic stellate Kupffer FXR ag cell activation cell LPS ANTI-FIBROTIC ACC, acetyl-CoA carboxylase; AOC, amine oxidase, copper containing; ASK, apoptosis signal-regulating kinase; CCR, CC chemokine receptor; DNL, de novo lipogenesis; ER, endoplasmic reticulum; FFA, free fatty acids; FGF, fibroblast growth factor; FXR, farnesoid X receptor; IL, interleukin; JNK, Jun N-terminal kinases; LPS, lipopolysaccharide; NLRP3, nucleotide-binding oligomerization domain and leucine rich repeat and pyrin domain containing protein 3; PPAR, peroxisome proliferator-activated receptor; ROS, reactive oxygen species; SCD, stearoyl CoA desaturase; SGLT, sodium-glucose linked transporter; SHP, small heterodimer partner; SREBP, sterol regulatory element binding proteins; TGF, transforming growth factor; TGR5, G protein-coupled bile acid receptor 1; TLR, toll like receptor; TNF, tumor necrosis factor; TR, thyroid receptor; UPR, unfolded protein response VLDL, very low density lipoprotein. Adapted from Konerman MA et al. J Hepatol. 2018;68:362–375. Targeting Pathophysiological Processes NORMAL LIVER STEATOSIS STEATOHEPATITIS CIRRHOSIS Targets related to Targets related to Targets related to Targets related to Targets related to insulin resistance cell death lipotoxicity & inflammation and fibrogenesis & and/or lipid (apoptosis and oxidative stress immune activation collagen turnover metabolism necrosis) PPARγ: Pioglitazone PPARα/∂: Elafibranor CCR2/5: Cenicriviroc ASK1 Selonsertib LOXL2: Simtuzumab Liraglutide, PPARα/∂/γ: Lanifibranor GLP-1: AOC3: BI 1467335 Galectin GR-MD-02 Semaglutide PPARα/γ: Saroglitazar Caspase Emricasan GLP-1/GR: MEDI0382 MPC MSDC-0602K, PXL065 TLR4: JKB-121 CRV431 GS-0976, PF- CRV431 ACC: OCA, GS-9674, Anti-LPS: IMM-124E 05221304 FXR: tropifexor, LMB-763, CRV431 SCD1: Aramchol EYP001, MET409 SGLT1/2: LIK066 TGR5: INT-767, INT-777 BMS-986036, AKR- FGF21: 001,BIO89-100 ASBT: Volixibat THR-β: MGL-3196, VK2809 FGF19: NGM282 FGFR1/KLB BFKB8488A Vitamin E Some drugs have pleiotropic effects MPC MSDC-0602K, PXL065 Mixed ag- antagonist GR and Miricorilant antagonist MR Making Sense of NASH Clinical Development Clinical trial endpoints • Phase 2 • Phase 3 registration trials Clinical Trial Landscape – Ongoing NASH Trials • Phase 2 • Phase 3 • Combination trials Clinical Trials- Comparison of endpoints Making Sense of NASH Clinical Development Clinical trial endpoints • Phase 2 • Phase 3 registration trials Clinical Trial Landscape – Ongoing NASH Trials • Phase 2 • Phase 3 • Combination trials Clinical Trials – Comparison of endpoints Endpoints for Outcome Measures in NASH Surrogate Endpoints Outcomes Hard Endpoints in Early-Phase Studies • Progression to cirrhosis VCTE and MRE, wet biomarkers* Clinical • All-cause mortality • Liver-related mortality, hepatic CTP and MELD scores, HVPG decompensation • Reduction in liver fat content MRI-PDFF, multiparametric MRI, CAP • Improvement in IR A1C, fasting glucose, HOMA-IR Metabolic • Impact on lipids • Change in weight/BMI • Change in necroinflammation Multiparametric MRI, liver enzymes Inflammatory • Change in ballooning Fibrosis • Change in fibrosis stage VCTE and MRE, wet biomarkers* *eg, pro-C3, FIB-4, NFS, ELF. Konerman. J Hepatol. 2018;68:362. Clinical Trial Endpoints in Early Phase 2 Development ALT Liver fat fraction (MRI-PDFF) • 10 Units/L reduction associated with • ≥ 5% absolute reduction associated histologic improvement or resolution of with improvement NASH in steatosis • ≥ 17 Units/L reduction predicted • ≥ 30% relative reduction associated histologic with improvement in NAFLD activity response score without fibrosis worsening In large clinical trials that include paired biopsies, surrogate endpoints can be validated against histologic endpoints MRI-PDFF has shown to be correlated to histological response ALT, alanine aminotransferase; MRI, magnetic resonance imaging; PDFF, proton density fat fraction, U/L, units per liter. Vuppalanchi R et al. Clin Gastroenterol Hepatol. 2014;12:2121; Loomba R et al. Gastroenterology. 2019;156:88–95; Middleton MS et al. Gastroenterology. 2017;153:753–761; Patel J et al. Therap Adv Gastro. 2016;9:692–701. Regulatory Endpoints for Registration Trials – Phase 2B/3 FDA: Sub-part H conditional approval Endpoints NASH Resolution Fibrosis Improvement Resolution of steatohepatitis Improvement ≥ 1 fibrosis stage (Ballooning = 0, Inflammation = 0/1) AND AND No worsening of steatohepatitis No worsening of liver fibrosis Full approval • Progression to cirrhosis: – Number of individuals who progressed to cirrhosis in the treatment-arm versus placebo • Clinical endpoints – Hepatic decompensation (clinical ascites, SBP, HE, Variceal bleeding or HRS [HCC] • MELD ≥15 US FDA. Draft Guidance. Noncirrhotic Nonalcoholic Steatohepatitis With Liver Fibrosis: Developing Drugs for Treatment Guidance for Industry. December 2018. ALT (Marker of Liver Injury) Reduction Among Top in NASH Leading
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