Madrigal Pharmaceuticals, Inc. · NASDAQ:MDGL
Madrigal Pharmaceuticals — AASLD 2020
41 slides from Madrigal Pharmaceuticals's conference presentation, November 2020
Slide 1: Resmetirom for the Treatment of NASH: Early Data from Phase 3 MAESTRO
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 M
Slide 2: Conflicts
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
Slide 3: NAFLD Ranges from Simple Steatosis to NASH, a Progressive Liver Disease
Non-Alcoholic Fatty Liver Disease (NAFLD) Ranges from Simple Steatosis (NAFL) to NASH, a Progressive Form of Liver Disease D I ◼ NAFLD results from accumulation of NAFLD Spectrum excess fat within the liver (steatosis) S Fat Accumulation E unrelated to alcohol use A ◼ Some patients with NAFLD have N
Slide 4: Mechanism of Action: The Importance of Liver THR-β in NASH
Mechanism of Action: The Importance of Liver THR-β in NASH Thyroid In humans, thyroid hormone receptor-β (THR-β) agonism: Nuclear THR-α, THR-β Gland Lowers LDL-cholesterol T44 Lowers triglycerides T3 Lowers liver fat, potentially reducing T4, prohormone Liver lipotoxicity, NASH T3, active horm
Slide 5: Phase 3 NASH Clinical Trials: MAESTRO-NASH and MAESTRO-NAFLD-1
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 Phase 2 • 36 week with 36 week open-label
Slide 6: Resmetirom Development Path Across the Spectrum of NAFLD/NASH
Resmetirom Development Path Across the Spectrum of NAFLD/NASH NASH/NAFLD Spectrum1 US Patient Numbers Phase 3 MAESTRO-NASH study: F2/F3 NASH with 1.3 million F4 Metabolic Syndrome 2.0 million F3 NASH Resolution (primary), LDL-C, fibrosis (key Resmetirom secondary); Phase 4 (post-approval): cirrhosis
Slide 7: Phase 2 NASH Study Design
Phase 2 NASH Study Design: Randomized, Double-Blind, PBO Controlled MRI-PDFF MRI-PDFF Liver Biopsy PK MRI-PDFF Liver Biopsy MRI-PDFF MRI-PDFF Screening D1 W2 W4 W12 W36 OLED1 W12 W36 36 Week Main Study Open-label Extension (OLE) Study ◼ Comparator/Arms — 2:1 Resmetirom to placebo — 125 patients enro
Slide 8: Resmetirom: Non-invasive and Liver Biopsy Readouts Phase 2
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
Slide 9: Resmetirom: Fibrosis, Non-invasive and Liver Biopsy Readouts Phase 2
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 NASH improvement in fibrosis Fibrosis — Half of F3 pa
Slide 10: Non-invasive Biomarkers and Imaging to Follow Patient Response to Resmetirom
Non-invasive Biomarkers and Imaging to Follow Patient Response to Resmetirom 30 PDFF PRO-C3 Fibroscan (OLE) Fibroscan (kPa) Pbo/Res Res/Res 80 mg 100 mg 36 Week Main Study 36 Week OLE Study 25 *BL 8.3 12.7 10 11.6 PDFF% or PRO-C3 (ng/ml) Dose adjusted to 60 or 80 mg Dose increased to ≥80 or 100 mg n
Slide 11: Secondary Phase 2 Analysis: MRI-PDFF Response vs NASH Biopsy Response
Secondary Phase 2 Study Analysis: Relationship of MRI-PDFF Response to NASH Biopsy Response ◼ To determine the potential predictive power of liver fat reduction on NASH resolution, data were analyzed from 107 NASH patients (n=34 placebo, n=73 resmetirom) with paired baseline/week 36 liver biopsies (
Slide 12: Resmetirom responders with ≥30% PDFF reduction had higher rates of NASH resolution
Results from Phase 2 Study Relative Fat Reduction (%) ◼ Primary endpoint achieved, relative reduction in hepatic fat on 0 MRI-PDFF at Week 12 -10 -14 -10 — Dose dependent 50% reduction of hepatic fat at 80 mg -20 -36 -40 -39 dose -50 -55 ◼ Key secondary and exploratory endpoints achieved -30 -64 — S
Slide 13: Association of NASH Resolution with Early (Week 12) PDFF Response
Association of NASH Resolution with Early (Week 12) PDFF Response PDFF vs NASH resolution (ROC) ◼ The predictive accuracy of PDFF response for 100% NASH resolution was determined by calculating the area under the receiver operating True positive (sensitivity) 80% characteristic curve (AUROC) and its
Slide 14: PDFF Responder Analysis: NASH Resolution
PDFF Responder Analysis: NASH Resolution ◼ Two blinded pathologists (Path A, Path B) Path A>=30% independently reviewed the Phase 2 slides p<0.0001 ◼ Compared to MRI-PDFF non-responders Path A>=40% (<30% fat reduction) at Week 12 (n=56), p=0.0022 MRI-PDFF responders (≥30% fat reduction) Path A>=50%
Slide 15: Relationship of PDFF Response to Biopsy Component Response
Relationship of PDFF Response to Biopsy Component Response ◼ All patients in the study with serial evaluable liver biopsies 100% (baseline and week 36) and 90% PDFFs (baseline and week 12) were included in the analysis 80% 70% ◼ Statistically significant 60% differences were observed 50% between Wee
Slide 16: Association of PDFF Response with NASH Resolution and Fibrosis Reduction
Association of PDFF Response with NASH Resolution and Fibrosis Reduction - Resmetirom ◼ Percentages of patients with NASH resolution 70 Resmetirom Treated increased with greater PDFF reduction (agreement 60 between two independent central pathology 50 % Response readers) 40 ◼ In resmetirom-treated p
Slide 17: Analysis of Patient Reported Outcome in Phase 2 NASH Study
Analysis of Patient Reported Outcome in 36 Week Phase 2 NASH Study ◼ In the resmetirom Phase 2 NASH study, Health Related Quality of Life (HRQL) was assessed using self- administered Short Form-36 (SF-36) using 8 domains throughout 36 weeks of treatment and was pre-specified as an exploratory study
Slide 18: MRI-PDFF Response at Week 12 Associates with Improved HRQL at Week 36
MRI-PDFF Response at Week 12 Associates with Improved HRQL at Week 36 HRQL Change from Baseline at Week 36 HRQL Score Change from Baseline at Week 36 Physical Physical Component Mental Component Functioning Role Physical Bodily Pain General Health Vitality Social Functioning Role Emotional Mental He
Slide 19: Comparison of Resmetirom-treated Relative to Placebo
Comparison of Resmetirom-treated Relative to Placebo HRQL Change at Week 1 HRQL Change from Baseline 36 Resmetirom at Week PDFF 36 for Resmetirom Responders MRI-PDFF Responders ◼ In line with its safety and tolerability Mental Component Summary profile, improvements at Week 36 Physical Component Sum
Slide 20: Summary of Patient Reported Outcomes from Phase 2
Summary of Patient Reported Outcomes from Phase 2 ◼ Resmetirom Phase 2 data demonstrated a statistically significant improvement in several components of physical well-being at 36 weeks in patients with ≥ 30% PDFF reduction, including improvements in resmetirom-treated relative to placebo ◼ Ongoing
Slide 21: Phase 3 MAESTRO-NASH Study Design
Phase 3 MAESTRO-NASH Study Design: Randomized, Double- Blind, PBO Controlled: Serial Liver Biopsy Study Randomization Placebo 100 mg MRI-PDFF Liver Biopsy 80 mg LDL-C Screening D1 W16 W24 W52 Month 54 52 Week Primary Endpoint Outcome Endpoint Comparator/Arms ◼ 1:1:1 MGL-3196 80, 100 mg , placebo ◼ 9
Slide 22: Algorithm for Predicting Advanced NASH Fibrosis on Screening Biopsy
AASLD, 2020 #1657 ALGORITHM FOR PREDICTING ADVANCED NASH FIBROSIS ON SCREENING BIOPSY IN RESMETIROM PHASE 3 MAESTRO-NASH CLINICAL TRIAL Stephen A. Harrison, Oxford University; Rebecca Taub, Madrigal Pharmaceuticals; Morten A. Karsdal, Nordic Bioscience; John Franc, Madrigal Pharmaceuticals; Mustafa
Slide 23: MAESTRO-NASH Screening Algorithm
MAESTRO-NASH Screening Algorithm RISK FACTORS for NASH MAESTRO-NASH 8 Week Screening Process ≥3 Liver Biopsy Metabolic NAS≥4 > Age >50 Risk All NAS > BMI >30 Factors components MRI-PDFF F2-F3, > Elevated Liver enzymes (AST >20 Labs ≥ 8% Randomize Fibroscan F1B or U/L, AST/ALT ≥1) Liver Fat kPa>=8.5
Slide 24: Biopsy Success Rate in MAESTRO-NASH
Biopsy Success Rate in MAESTRO-NASH Qualifying Liver Biopsies with NAS≥4, all components, F1-F3 % Total Fibrosis stage F2-F3 60.3% Fibrosis stage F1B or F1A/C with PRO-C3>14 ng/mL 10.3% Total Qualifying Biopsies 70.6% Non-qualifying Biopsies with NASH, F1-F4 NAS, >=3 (<4) with F2-F3 fibrosis 3.2% F1
Slide 25: PRO-C3 and Fibroscan Alignment with Baseline Biopsy Fibrosis Stage
PRO-C3 and Fibroscan Alignment with Baseline Biopsy Fibrosis Stage PRO-C3 by Biopsy Fibrosis Stage LSM (fibroscan kPa) by Biopsy Fibrosis Stage PRO-C3 by Fibrosis stage TE by Fibrosis stage 45 rho = 0.24, p < 0.001 40 rho = 0.3, p < 0.001 without stage 4: rho = 0.28, p < 0.001 41.1 without stage 4:
Slide 26: PRO-C3 Alignment with NAS Components
PRO-C3 Alignment with NAS Components PRO-C3 by Biopsy Ballooning PRO-C3 by Biopsy Lobular Inflammation 45 50 42.3 47.1 40 rho = 0.34, p < 0.001 45 rho = 0.29, p < 0.001 35 40 31.3 35 PRO-C3 (ng/mL) 30 PRO-C3 (ng/mL) 33.7 25.9 30 30.1 29.4 25 24.0 21.3 25 24.4 20 19.7 21.8 21.9 18.2 20 15.8 16.6 18.4
Slide 27: Summary: MAESTRO-NASH Enrollment Data
Summary: MAESTRO-NASH Enrollment Data ◼ In a large dataset, presence of 3 metabolic risk factors and Fibroscan TE≥8.5kPa predicted biopsy- confirmed NASH in 81% of patients ◼ PRO-C3 is a marker not only of fibrosis stage in NASH but also of the level of NASH activity (inflammation and ballooning) in
Slide 28: Phase 3 MAESTRO-NAFLD-1 Study Design
Phase 3 MAESTRO-NAFLD-1 (presumed NASH) Study Design: Randomized, Double-Blind, PBO Controlled Randomization Placebo 100 mg 52 Week Primary Endpoint MRI-PDFF Fibroscan 80 mg LDL-C (lipids) 100 mg Open Label Screening D1 W16 W24 W52 Extension Comparator/Arms ◼ 1:1:1:1 resmetirom 80, 100 mg , placebo,
Slide 29: Resmetirom in MAESTRO-NAFLD-1 Open Label Arm: Biomarkers and Imaging
#1707 TREATMENT WITH RESMETIROM IN PHASE 3 MAESTRO-NAFLD-1 NASH STUDY OPEN LABEL ARM: EFFECTS ON BIOMARKERS AND IMAGING Dr. Stephen A Harrison, Pinnacle Clinical Research, Dr. Naim Alkhouri, Arizona Liver Health, Dr. Rebecca A. Taub, Madrigal Pharmaceuticals, Dr. Guy Neff, Covenant Research, LLC, Dr
Slide 30: Baseline Characteristics
Baseline Characteristics Parameter Other lab parameters, mean (SD) Mean age, years (SD) 55.7(11.3) MELD 7.0(1.6) ◼ Demographics include Male, n (%) 36(29%) — Mean age 55.7, NAFLD fibrosis score -1.2(1.3) Female, n (%) 87(71%) — female 71%, Fib-4 0.99(0.50) Hispanic/Latino, n (%) 32(26%) — BMI 36.2,
Slide 31: Week 16 MRI-PDFF and MRE Changes from Baseline
Week 16 MRI-PDFF (%) and MRE (kPa) Changes from Baseline All SHBG (high) MRI-PDFF (%) ◼ MRI-PDFF reduction of 53% fat fraction overall, and MRE Baseline (%) 17.6 17.9 (-0.34) were observed at Week 16 Relative % Change -53% -62% p-value <0.0001 <0.0001 ◼ MRE, unlike other elastography techniques, pro
Slide 32: MRI-PDFF Subgroups
MRI-PDFF Subgroups Week 16 MRI-PDFF Relative % Change from Baseline) ◼ PDFF reduction of ≥60% was observed in subgroups: stable GLP-1 (no weight loss), ≥5% weight loss, or high SHBG response ◼ Factors that mildly decreased PDFF response included diabetes, thyroxine treatment, low baseline MRI-PDFF o
Slide 33: Inflammatory and Fibrosis Biomarker Responses
Inflammatory and Fibrosis Biomarker Responses Post- Biomarker* Baseline SD Baseline* SD CFB P value ALT (BL >34 U/L) 58.3 47.4 38.9 16.1 -17.7 <0.0001 AST (BL >26 U/L) 39.3 12.2 31.8 11.3 -6.9 0.0060 GGT (BL >30 U/L) 70.2 58.3 54.6 47.8 -16.2 0.0015 Adiponectin (ug/mL) 5.0 3.5 5.9 1.6 0.9 <0.0001 Re
Slide 34: Reduction in Lipids and Lipoproteins
Reduction in Lipids and Lipoproteins ◼ LDL-C, apolipoprotein-B (-24%), ApoB LDL-C Lipoprotein (a) Lp(a) (Q2) Non-HDL-C Triglycerides triglycerides (23%), and 0 lipoprotein(a) (-27%)) were statistically significantly reduced -10 (p<0.0001) compared to baseline -20 -30 ◼ The magnitude of atherogenic l
Slide 35: Safety
Safety AEs N=123 Patients with treatment-emergent adverse Events, n (%) 75 (61) ◼ Resmetirom was well-tolerated with loose Severe 0 (0) stools lasting <2 weeks in 6.5% Moderate 36 (29) Mild 61 (50) ◼ No other AEs above historic placebo rates Patients with SAEs 1 (0.7) Patients with drug-related SAEs
Slide 36: Summary
Summary ◼ In this 52 week Phase 3 open label study, NASH patients identified using non-invasive imaging and biomarkers were treated with resmetirom 100 mg and demonstrated rapid reduction in hepatic fat, liver stiffness on MRE, fibrosis and inflammation biomarkers and atherogenic lipids after 16 wee
Slide 37: Backup
BACKUP 37
Slide 38: Monitoring Individual Patient Response to Treatment
Monitoring Individual Patient Response to Treatment ◼ The magnitude of SHBG increase (16 weeks, mean % increase (132% (84%)) was significantly correlated with reductions in liver enzymes, MRI-PDFF, LDL-C and other lipids ◼ Taken together, serial non-invasive biomarkers and imaging tests may have the
Slide 39: PDFF Response, Biopsy and Non-invasive Tests
PDFF Response, Biopsy and Non-invasive Tests Week 12 PDFF Change VS Change in Steatosis on Biopsy 80 60 ◼ All NAS component changes showed a relationship to % relative change in PDFF 40 20 PDFF response 0 -20 ◼ High correlation R2~0.4 between steatosis change on -40 -60 biopsy and PDFF response at b
Slide 40: Phase 2: Robust Lipid Lowering
Phase 2: Another Important Non-invasive Measure of Efficacy- Robust Lipid Lowering Lipids (% Change from Baseline) 0 ◼ Resmetirom is the only NASH therapeutic in advanced development -10 -22.3 able to lower lipids, consistent with -27.6 regulatory approval for dyslipidemia; -36 -36.8 -36.5 -20 and a
Slide 41: Week 36: Change in Fibrosis Score on Liver Biopsy
Week 36: Change in Fibrosis Score on Liver Biopsy 4.0 ≥1 pt reduction in fibrosis 3.5 SHG Score on liver biopsy (SHG) 50 SHG (qfibrosis) 3.0 40 2.5 3 % biopsies 30 2.0 47 2 20 1.5 32 1 10 1.0 12 0 0 0 0.5 All F3 0.0 p=0.03 p=0.05 0 1A 1B 2 3 Pathologist Score Placebo MGL-3196 ◼ Second Harmonic Gener