Product Theater : “ Resmetirom for the Treatment of NASH: Early Data from the Phase 3 MAESTRO Clinical Trials.” Dr. Stephen Harrison, M.D., Medical Director for Pinnacle Clinical Research, San Antonio, Texas, and Visiting Professor of Hepatology, Oxford University, and Principal Investigator of the MAESTRO studies AASLD 2020
Conflicts Advisory Board/Panel: Akero, Altimmune, Arrowhead, Axcella, Blade Therapeutics, Cirius, Civi Biotherma, CLDF, Cymabay, Echosens, Foresite Labs, Galectin, Galmed, Gelesis, Genfit, Gilead, Hepion, Hightide Bio, Histoindex, Indalo, Innovate, Intercept, Madrigal, Medpace, Merck, Metacrine, NGM Bio, Northsea, Novartis, Novo Nordisk, Perspectum, Poxel, Prometic, Ridgeline Therapeutics, Sagiment, Terns, Viking Consultant: Akero, Altimmune, Axcella, Blade Therapeutics, Cirius, Civi Biopharma, CLDF, Cymabay, Echosens, Enyo, Foresite Labs, Fortress, Galectin, Galmed, Gelesis, Genfit, Gilead, Hepion, Hightide Bio, Histoindex, Indalo, Innovate, Intercept, Kowa, Madrigal, Medpace, Medpace, Merck, Metacrine, NGM Bio, Northsea, Novartis, Novo Nordisk, Perspectum, Poxel, Prometic, Ridgeline Therapeutics, Sagiment, Silverback, Terns, Viking Principal Investigator of Grant Research: Axcella, BMS, Cirius, Civi Biopharma, Conatus, Cymabay, Enyo, Galectin, Galmed, Genetech, Genfit, Gilead, Hepion, Hightide Bio, Immuron, Intercept, Madrigal, NGM Bio, Northsea, Novartis, Novo Nordisk, Pfizer, Sagiment, Second Genome, Tobira/Allergan, Viking Stock/Shares (self-managed): Akero, Cirius, Galectin, Genfit, Histoindex, Madrigal, Metacrine, NGM Bio, Northsea 2
Non-Alcoholic Fatty Liver Disease (NAFLD) Ranges from Simple Steatosis (NAFL) to NASH, a Progressive Form of Liver Disease D ◼ NAFLD results from accumulation of I NAFLD Spectrum excess fat within the liver (steatosis) S unrelated to alcohol use E Fat Accumulation ◼ A Some patients with NAFLD have NASH S (nonalcoholic steatohepatitis) Nonalcoholic Normal Liver E Fatty Liver (NAFL) Isolated I Steatosis ◼ 25 – 30% of all adults in Western N countries have NAFLD C ◼ I NASH afflicts 3 – 12% of the U.S. D population. In certain populations such as Harmful E diabetics fat in the liver is virtually always Steatosis N NASH C NASH. E Lobular ◼ NAFLD leads to an increased risk of inflammation O morbidity and mortality from: U — Cardiovascular disease (leading cause NASH Fibrosis T of death for NAFLD patients) C Ballooning — Liver-related events O degeneration ◼ 11% of advanced NASH patients progress M NASH Cirrhosis E to cirrhosis over a 15-year period 3
Mechanism of Action: The Importance of Liver THR- β in NASH In humans, thyroid hormone receptor- β (THR - β) agonism: Thyroid Nuclear THR- α , THR- β Gland Lowers LDL-cholesterol Lowers triglycerides T 4 T 4 T 3 Lowers liver fat, potentially reducing Liver lipotoxicity, NASH T4, prohormone T 4 ➔ T 3 T3, active hormone No thyrotoxicosis (THR- α effect) Thyroid Hormone Pathway Resmetirom (MGL-3196) ◼ THR- β selective liver targeted molecule, once a day oral, with proven safety and efficacy in more than 500 subjects and patients treated — No exposure outside the liver or activity at the systemic THR- α receptor ◼ Pleiotropic effects in the liver with potential for addressing the underlying metabolic syndrome and hallmark features of NASH: steatosis/lipotoxicity, inflammation, ballooning, fibrosis (both directly and indirectly) — Reduction of liver fat through breakdown of fatty acids, normalization of mitochondrial and liver function Sinha and Yen Cell Biosci (2016) 6:46 DOI 10.1186/s13578-016-0113-7; Autophagy, 11:8, 4 1341-1357, DOI: 10.1080/15548627.2015.1061849
Phase 3 NASH Clinical Trials, Ongoing : MAESTRO-NASH and MAESTRO- NAFLD-1 Madrigal is focused on developing resmetirom for the treatment of NASH Compound/ Pre- Clinical Trial Phase 1 Phase 2 Phase 3 Description Indication Clinical ◼ MRI-PDFF, biopsy: positive • 36 week with 36 week Phase 2 open-label extension MGL-3196-05 Harrison Lancet. 2019 Nov Completed NCT02912260 Resmetirom 30;394(10213):2012-2024. doi: 10.1016/S0140- (MGL-3196) 6736(19)32517-6 Thyroid Hormone ◼ Treatment of NASH Receptor- β (THR- Phase 3 with Fibrosis Stage 2-3 β ) Agonist MAESTRO-NASH • Serial liver biopsy Recruiting • 52 week Phase 3; 54 NCT03900429 Treatment of month Phase 4 Nonalcoholic ◼ Treatment of NASH Steatohepatitis • 52 week (NASH) • Safety, Lipids and NASH Phase 3 biomarker and imaging MAESTRO-NAFLD-1 Recruiting study (presumed NASH) • Enrollment of double- NCT04197479 blind arms completed • Open label 100 mg arm; includes NASH cirrhotics 5
Resmetirom Development Path Across the Spectrum of NAFLD/NASH NASH/NAFLD Spectrum 1 US Patient Numbers Phase 3 MAESTRO-NASH study: F2/F3 NASH with F4 1.3 million Metabolic Syndrome NASH Resolution (primary), LDL-C, fibrosis (key F3 2.0 million Resmetirom secondary); Phase 4 (post-approval): cirrhosis and MACE CV Benefits F2 3.4 million Fatty liver LDL-C Phase 3 MAESTRO-NAFLD-1 study: ApoB F1-F3 NASH with Metabolic Syndrome diagnosed F1B Triglycerides non-invasively (no liver biopsy requirement) Lp(a) 100 mg Open label arm Endpoints; Safety, LDL-C, lipids, MRI-PDFF, PRO-C3 F1 6.3 million Total US NAFLD: F0 3.5 million (NASH plus NAFL) 83 million (2015) Data show that NASH with fibrosis is associated with highest CV risk 2 1 Estes et al; Hepatology , Vol. 67, No. 1, 2018 2 Henson Aliment Pharmacol Ther. 2020;51(7):728-736; 6 Clinical Gastroenterology and Hepatology 2020;18:2324 – 2331 .
Phase 2 NASH Study Design: Randomized, Double-Blind, PBO Controlled MRI-PDFF MRI-PDFF PK Liver Biopsy Liver Biopsy MRI-PDFF MRI-PDFF MRI-PDFF Screening OLED1 D1 W2 W4 W12 W36 W12 W36 Open-label Extension (OLE) Study 36 Week Main Study ◼ Comparator/Arms — 2:1 Resmetirom to placebo — 125 patients enrolled in USA, 18 sites — Resmetirom or placebo, oral, once daily; dose 60-80 mg ◼ Inclusion/Exclusion — NASH on liver biopsy: NAS≥4 with fibrosis stage 1 -3 — ≥10% liver fat on MRI -PDFF — Includes diabetics, statin therapy, representative NASH population ◼ 36 week extension study (OLE) in 31 patients who completed the Main 36 week study- all received 80 or 100 mg of resmetirom Harrison Lancet. 2019 Nov 30;394(10213):2012-2024. doi: 10.1016/S0140-6736(19)32517-6 7
Resmetirom: Non-invasive and Liver Biopsy Readouts Phase 2 ( Lancet ) ◼ Reduces steatosis on biopsy ◼ At Phase 3 doses (80 or 100 mg/qd) clears fat on MRI-PDFF, average 55% reduction ◼ About 90% of patients should clear ≥30% liver fat at 80, 100 mg — ≥30% hepatic fat reduction predicts higher rates of NASH resolution & decreased fibrosis on biopsy Steatosis ◼ Decreases ballooned hepatocytes on biopsy ◼ Hypothesized mechanism: stimulates mitochondrial biogenesis reducing hepatocyte dysfunction and death ◼ Reduces GGT and CK-18 markers of oxidative damage/ballooning Ballooning ◼ Decreases inflammation on biopsy ◼ Continued, sustained decreases in elevated liver enzymes, many reaching normal levels (60% with ALT <30 by 36 weeks) ◼ Reduces reverse T3, a marker of liver inflammation Lobular Inflammation 8
Resmetirom: Fibrosis, Non-invasive and Liver Biopsy Readouts Phase 2 ◼ Liver biopsy trend favoring resmetirom for 1-point improvement in fibrosis — 56% of patients who resolved NASH also resolved fibrosis, 61% of NASH resolvers achieved ≥ 1 point improvement in fibrosis NASH Fibrosis — Half of F3 patients showed ≥ 1 -point improvement in fibrosis, compared to no placebo F3 patients, using Second Harmonic Generation ◼ Statistically significant reductions by resmetirom in multiple fibrosis biomarkers including PRO-C3, ELF, most pronounced in patients with advanced fibrosis pro-collagen collagen pro-peptide at baseline (F2 / F3) cleavage ◼ Biomarker of net collagen formation (PRO-C3/C3M) myofibroblasts – reduced by resmetirom blood Fibrogenesis: PRO-C3, P3NP, ◼ Reduction in fibroscan (kPa), a measure of liver hyaluronic acid, TIMP-1 stiffness (fibrosis), in 36 week open-label extension Fibrinolysis: C3M study Phase 3 NASH study is >90% powered to show a 1-point improvement in fibrosis on biopsy *Schuppan 2018 https://doi.org/10.1016/j.matbio.2018.04.006 9
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