Product Theater : Resmetirom for the Treatment of NASH: Early Data - - PowerPoint PPT Presentation

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

• f 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

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Non-Alcoholic Fatty Liver Disease (NAFLD) Ranges from Simple Steatosis (NAFL) to NASH, a Progressive Form of Liver Disease

3 O U T C O M E

◼ NAFLD results from accumulation of excess fat within the liver (steatosis) unrelated to alcohol use ◼ Some patients with NAFLD have NASH (nonalcoholic steatohepatitis) ◼ 25 – 30% of all adults in Western countries have NAFLD ◼ NASH afflicts 3 – 12% of the U.S.

• population. In certain populations such as

diabetics fat in the liver is virtually always NASH. ◼ NAFLD leads to an increased risk of morbidity and mortality from: — Cardiovascular disease (leading cause

• f death for NAFLD patients)

— Liver-related events ◼ 11% of advanced NASH patients progress to cirrhosis over a 15-year period Harmful Steatosis

Normal Liver

Lobular inflammation Ballooning degeneration Fat Accumulation

NAFLD Spectrum

Isolated Steatosis

Nonalcoholic Fatty Liver (NAFL) NASH Fibrosis NASH Cirrhosis NASH

D I S E A S E I N C I D E N C E

Mechanism of Action: The Importance of Liver THR-β in NASH

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 Lowers LDL-cholesterol  Lowers triglycerides  Lowers liver fat, potentially reducing lipotoxicity, NASH No thyrotoxicosis (THR-α effect) In humans, thyroid hormone receptor-β (THR-β) agonism:

Sinha and Yen Cell Biosci (2016) 6:46 DOI 10.1186/s13578-016-0113-7; Autophagy, 11:8, 1341-1357, DOI: 10.1080/15548627.2015.1061849

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 Thyroid Gland Liver T4➔ T3 T3

Nuclear THR-α, THR-β

Thyroid Hormone Pathway T4 T4

T4, prohormone T3, active hormone

Compound/ Indication Clinical Trial Pre- Clinical Phase 1 Phase 2 Phase 3 Description

Resmetirom

(MGL-3196) Thyroid Hormone Receptor-β (THR- β) Agonist Treatment of Nonalcoholic Steatohepatitis (NASH) Phase 2 MGL-3196-05

NCT02912260

◼ MRI-PDFF, biopsy: positive

• 36 week with 36 week
• pen-label extension

Harrison Lancet. 2019 Nov 30;394(10213):2012-2024. doi: 10.1016/S0140- 6736(19)32517-6

Phase 3 MAESTRO-NASH

NCT03900429

◼ Treatment of NASH with Fibrosis Stage 2-3

• Serial liver biopsy
• 52 week Phase 3; 54

month Phase 4

Phase 3 MAESTRO-NAFLD-1

(presumed NASH) NCT04197479

◼ Treatment of NASH

• 52 week
• Safety, Lipids and NASH

biomarker and imaging study

• Enrollment of double-

blind arms completed

• Open label 100 mg arm;

includes NASH cirrhotics 5

Recruiting Recruiting

Phase 3 NASH Clinical Trials, Ongoing: MAESTRO-NASH and MAESTRO- NAFLD-1

Completed

Madrigal is focused on developing resmetirom for the treatment of NASH

Resmetirom Development Path Across the Spectrum of NAFLD/NASH

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F3 F4

Phase 3 MAESTRO-NASH study: F2/F3 NASH with Metabolic Syndrome NASH Resolution (primary), LDL-C, fibrosis (key secondary); Phase 4 (post-approval): cirrhosis and MACE

F2 F1B F1 F0 Resmetirom CV Benefits

Fatty liver LDL-C ApoB Triglycerides Lp(a) Phase 3 MAESTRO-NAFLD-1 study: F1-F3 NASH with Metabolic Syndrome diagnosed non-invasively (no liver biopsy requirement) 100 mg Open label arm Endpoints; Safety, LDL-C, lipids, MRI-PDFF, PRO-C3

2.0 million 3.5 million 6.3 million 3.4 million 1.3 million

NASH/NAFLD Spectrum1

US Patient Numbers

1 Estes et al; Hepatology, Vol. 67, No. 1, 2018 2 Henson Aliment Pharmacol Ther. 2020;51(7):728-736;

Clinical Gastroenterology and Hepatology 2020;18:2324–2331 .

Total US NAFLD: (NASH plus NAFL) 83 million (2015)

Data show that NASH with fibrosis is associated with highest CV risk2

Phase 2 NASH Study Design: Randomized, Double-Blind, PBO Controlled

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◼ 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

Open-label Extension (OLE) Study Screening MRI-PDFF Liver Biopsy MRI-PDFF Liver Biopsy MRI-PDFF MRI-PDFF PK D1 W2 W4 W12 W36 W12 W36 OLED1 36 Week Main Study MRI-PDFF

Harrison Lancet. 2019 Nov 30;394(10213):2012-2024. doi: 10.1016/S0140-6736(19)32517-6

◼ 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 ◼ 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

◼ 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

Resmetirom: Non-invasive and Liver Biopsy Readouts Phase 2 (Lancet)

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Steatosis Ballooning Lobular Inflammation

Resmetirom: Fibrosis, Non-invasive and Liver Biopsy Readouts Phase 2

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◼ 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 — 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 at baseline (F2 / F3) ◼ Biomarker of net collagen formation (PRO-C3/C3M) –reduced by resmetirom ◼ Reduction in fibroscan (kPa), a measure of liver stiffness (fibrosis), in 36 week open-label extension study

NASH Fibrosis

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

collagen pro-collagen myofibroblasts blood

Fibrogenesis: PRO-C3, P3NP, hyaluronic acid, TIMP-1 Fibrinolysis: C3M pro-peptide cleavage

Non-invasive Biomarkers and Imaging to Follow Patient Response to Resmetirom

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36 Week OLE Study

W12

36 Week Main Study

W36 BL OLE W12 OLE W36 BL-E

Res-Res Pbo-Res PDFF PDFF PDFF PDFF PDFF Biopsy Biopsy Biomark Biomark Biomark Biomark Biomark

Dose adjusted to 60 or 80 mg Dose increased to ≥80 or 100 mg

Resmetirom (Res) Placebo (Pbo)

5 10 15 20 25 30 12 36 OLE W12 OLE W36 PDFF% or PRO-C3 (ng/ml) Pbo/Res PRO-C3 Res/Res PRO-C3 Pbo/Res PDFF Res/Res PDFF

• 2
• 2.2
• 1.8
• 3.4
• 5
• 4
• 3
• 2
• 1

p=.006 p=.001 p<.001 p<0.001 n=11 n=14 n=19 n=5 *BL 8.3 12.7 10 11.6 Pbo/Res Res/Res 80 mg 100 mg Change from OLE Baseline (kPa)

Fibroscan (kPa)

0.0 0.5 1.0 1.5 2.0 2.5 Baseline Week 12 Week 38 OLE W12 OLE W36 PRO-C3/C3M

Open-Label Extension (OLE) study

Pbo/Res Res/Res

0.0 0.5 1.0 1.5 2.0 2.5 Baseline Week12 Week 36 PRO-C3/C3M

Main Study

Pbo Res

In addition to routine assessments like liver enzymes,

• ther non-invasive tests such as MRI-PDFF (liver fat) ,

fibroscan (liver stiffness/fibrosis stage) and fibrosis biomarkers (e.g PRO-C3 and PRO-C3/C3M) may be used to monitor resmetirom response over time in individual NASH patients Fibroscan (OLE) PDFF PRO-C3 PRO-C3/C3M Marker of Net Fibrosis Formation

OLE: active treatment open-label extension study

Phase 2

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 (read by two independent blinded central pathologists) and paired baseline/week 12 MRI-PDFFs

— There were 5 placebo (4/5 with >5% weight loss) and 45 resmetirom patients who had at least 30% fat fraction reduction at Week 12 and a paired liver biopsy at Week 36 (PDFF Responders)

◼ Including the MRI-PDFF/biopsy data from both MRI-PDFF responders and non-responders the relationship to a NASH resolution response, NAS component and fibrosis responses were assessed

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Results from Phase 2 Study

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◼ Primary endpoint achieved, relative reduction in hepatic fat on MRI-PDFF at Week 12 — Dose dependent 50% reduction of hepatic fat at 80 mg dose ◼ Key secondary and exploratory endpoints achieved — Statistically significant reduction and resolution of NASH as compared with placebo — Statistically significant reduction in fibrosis biomarkers — Statistically significant reduction in liver enzymes — Statistically significant reduction in LDL-cholesterol, apolipoprotein B, triglycerides and lipoprotein(a) ◼ Safety — No change in Grade 2 or higher AEs — No safety signals related to mechanism of action

Resmetirom responders with  30% PDFF reduction had higher rates of NASH resolution (37%) on Week 36 liver biopsy compared to non-responders (4%)1— hypothesis generating

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• 36
• 40
• 39
• 50
• 55
• 64
• 70
• 60
• 50
• 40
• 30
• 20
• 10

All All 60mg 80mg 80-100 mg 100 mg Wk 12 Wk 36 Wk 12 Wk 36 Week 36 Week 36 Week 36 Week 36 Placebo Resmetirom (NASH Phase 2) Resmetirom (Phase 2 Ext) % Relative Reduciton in Hepatic Fat

Relative Fat Reduction (%)

1Harrison Lancet. 2019 Nov 30;394(10213):2012-2024.

doi: 10.1016/S0140-6736(19)32517-6

Association of NASH Resolution with Early (Week 12) PDFF Response

◼ The predictive accuracy of PDFF response for NASH resolution was determined by calculating the area under the receiver operating characteristic curve (AUROC) and its 95% confidence intervals (CI)s. ◼ The AUROC was 0.87, the optimal MRI-PDFF reduction with best balance of true positive and false negative rates was 41.5% (p<0.001) with a sensitivity of 82% (95% confidence interval (CI) 61%, 93%) and specificity of 83% (95%CI 0.74%, 90%) ◼ In patients with NASH resolution, the mean week 12 fat reduction (MRI-PDFF) was 56%

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0% 20% 40% 60% 80% 100% 0% 20% 40% 60% 80% 100% True positive (sensitivity) False positive (100%-specificity)

PDFF vs NASH resolution (ROC)

ROC 95% CI Lower 95% CI Upper 41.5% PDFF reduction

PDFF Responder Analysis: NASH Resolution

◼ Two blinded pathologists (Path A, Path B) independently reviewed the Phase 2 slides ◼ Compared to MRI-PDFF non-responders (<30% fat reduction) at Week 12 (n=56), MRI-PDFF responders (≥30% fat reduction) (n=51) p<0.0001 had significantly higher

• dds of NASH resolution, as independently

determined by both Pathologists A and B ◼ The positive predictive values of PDFF reduction for NASH resolution at cutoffs of ≥30%, ≥40%, ≥50% were ~40%, 50% and 65%, respectively, and the negative predictive values were high for all three cutoffs.

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1 10 100

Path B>=50% p<0.0001 Path B>=40% p<0.0001 Path B>=30% p<0.0001 Path A>=50% p=0.0005 Path A>=40% p=0.0022 Path A>=30% p<0.0001

Odds Ratio (log)

Relationship of PDFF Response to Biopsy Component Response

◼ All patients in the study with serial evaluable liver biopsies (baseline and week 36) and PDFFs (baseline and week 12) were included in the analysis ◼ Statistically significant differences were observed between Week 12 PDFF responders(≥30% fat reduction) and non- responders ◼ Improvement and less worsening of all component responses (ballooning, inflammation, steatosis and fibrosis) were observed in PDFF responders

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0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% >=30 PDFF Response <30% >=30 PDFF Response <30% >=30 PDFF Response <30% >=30 PDFF Response <30% >=30 PDFF Response <30% p=0.0003 p=0.0007 p=0.0026 p=0.0058 p=0.025 NAS (>=1 point) Steatosis Ballooning Lob Inf Fibrosis

Improved Unchanged Worse

Association of PDFF Response with NASH Resolution and Fibrosis Reduction - Resmetirom

◼ Percentages of patients with NASH resolution increased with greater PDFF reduction (agreement between two independent central pathology readers) ◼ In resmetirom-treated patients with ≥ 50% fat reduction at Week 12, 64% had NASH resolution with a component response driven primarily by ballooning and inflammation ◼ PDFF reduction  30 and  50% at Week 12 was also associated with

— Fibrosis reduction on subsequent liver biopsy — Achievement of both endpoints: NASH resolution and  1 point fibrosis reduction

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10 20 30 40 50 60 70 NASH Resolution (NR) Fibrosis Reduction Both NR and fibrosis reduction % Response >50% PDFF >=30% PDFF MRI-PDFF Non-Responder

Non Responder: <30% fat reduction on Week 12 MRI-PDFF

1%fibrosis reduction in biopsies with NR

Resmetirom Treated

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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 endpoint ◼ Wilcoxon paired rank sign tests were conducted for SF-36 domains changes from Baseline at Week 36 (completers only) for within-group differences of placebo vs resmetirom, PDFF responder vs Non-responder, sex hormone binding globulin (SHBG) increase 88% vs <88%, and low vs high resmetirom exposure, body weight decrease ≥5% vs <5% subgroups. PDFF Responders were defined as having a decrease of ≥30% in MRI-PDFF at Week 12 from baseline

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#1675 IMPROVEMENT OF HEALTH-RELATED QUALITY OF LIFE IS ASSOCIATED WITH IMPROVEMENT OF FAT FRACTION BY MRI-PDFF IN PATIENTS WITH NONALCOHOLIC STEATOHEPATITIS TREATED WITH RESMETIROM Zobair M. Younossi, Center for Liver Disease, Department of Medicine, Inova Health System; Maria Stepanova, Center for Outcomes Research in Liver Diseases; Rebecca Taub, Madrigal Pharmaceuticals; Jordan Mark Barbone, Madrigal Pharmaceuticals; Sam Moussa, Adobe Gastroenterology; Stephen A. Harrison, Pinnacle Clinical Research AASLD 2020

MRI-PDFF Response at Week 12 Associates with Improved HRQL at Week 36

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2 4 6 8 10 12 14 Physical Functioning Role Physical Bodily Pain General Health Vitality Social Functioning Role Emotional Mental Health Physical Component Summary Mental Component Summary

HRQL Score Change from Baseline at Week 36

All PDFF Responder All PDFF Non Responder MGL-3196 PDFF Responder

PDFF responder : >=30% liver fat reduction on PDFF at Week 12

◼ HRQL score change from baseline at Week 36 for each individual component and summary components, ALL PDFF responders (treatment arms pooled), and resmetirom-treated PDFF responders experienced improvement in health-related scores at Week 36 (PDFF responder >=30% fat reduction at Week 12)

HRQL Change from Baseline at Week 36

Comparison of Resmetirom-treated Relative to Placebo

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Role Physical Bodily Pain General Health Vitality Social Functioning Physical Component Summary Mental Component Summary

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• 5

5 10 15

HRQL Change from Baseline at Week 36 for Resmetirom MRI-PDFF Responders

Role Physical Bodily Pain General Health Vitality Social Functioning Physical Component Summary Mental Component Summary

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• 5

5 10 15

HRQL Change from Baseline at Week 36 for Placebo

◼ In line with its safety and tolerability profile, improvements at Week 36 were observed in resmetirom-treated Week 12 PDFF Responders compared to placebo

— Bodily Pain (mean(SE): 9.6(3.4), p=0.045) — Resmetirom high exposure patients compared to placebo for Bodily Pain (mean(SE): 8.88(3.12), p=0.036) and resmetirom-treated PDFF Responders for Physical Component Summary (mean(SE): 3.35(0.82), p=0.051).

HRQL Change at Week 36 Placebo HRQL Change at Week 36 Resmetirom PDFF Responders1

1 ≥30% liver fat reduction on Week 12 MRI-PDFF

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 Phase 3 MAESTRO-NASH (NCT03900429) and MAESTRO-NAFLD-1 (NCT04197479) studies will assess Improvement in Quality of Life parameters associated with resmetirom treatment

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Phase 3 MAESTRO-NASH Study Design: Randomized, Double- Blind, PBO Controlled: Serial Liver Biopsy Study

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Comparator/Arms ◼ 1:1:1 MGL-3196 80, 100 mg , placebo ◼900 F2/F3 patients enrolled in USA, Europe for primary Week 52 analysis, ~200 F1 patients ◼ Up to 2000 patients total enrollment for Phase 4 including first 900 ◼ >150 centers, world-wide Key Inclusion/Exclusion ◼ Requires 3 metabolic risk factors (Metabolic Syndrome); Fibroscan kPa consistent with F2-F3, CAP≥280 ◼ NASH on liver biopsy: NAS≥4 with fibrosis stage 1A (up to 3%) 1B, total F1 up to 15%; F3, at least 50%, the rest F2 ◼ ≥8% liver fat on MRI-PDFF Primary Endpoints ◼ Resolution of NASH at Week 52 with at least 2 point reduction in NAS —Key secondary endpoints LDL-C lowering at Week 24, reduction in fibrosis stage Week 52 biopsy ◼ Composite liver-related outcome at 54 months [histologic evidence of cirrhosis on biopsy, MELD>=15, hepatic decompensation, liver transplant, all cause mortality]

Outcome Endpoint Screening

MRI-PDFF Liver Biopsy LDL-C

D1 W16 W24 W52 52 Week Primary Endpoint Month 54

80 mg 100 mg Placebo

Randomization

AASLD, 2020

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#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 R. Bashir, Department

• f Radiology, Duke University Medical Center; Jordan Barbone, Madrigal Pharmaceuticals; Guy

Neff, Covenant Research, LLC; Nadege T. Gunn, Pinnacle Clinical Research; Sam Moussa, Adobe Gastroenterology

MAESTRO-NASH Screening Algorithm

Enrolling NASH fibrosis studies is particularly challenging because most patients at the time of screening do not have a definitive diagnosis of NAFLD (or NASH) and their fibrosis stage is unknown

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RISK FACTORS for NASH

> Age >50 > BMI >30 > Elevated Liver enzymes (AST >20 U/L, AST/ALT ≥1) > Type 2 Diabetes > Hypertension > Dyslipidemia > Metabolic Syndrome > Historical Fibroscan >8.5 kpa, CAP >280 dB/M (Ideally 300)

MAESTRO-NASH 8 Week Screening Process

≥3 Metabolic Risk Factors Fibroscan kPa>=8.5 CAP>=280 Medical history Labs MRI-PDFF ≥ 8% Liver Fat Liver Biopsy NAS≥4 All NAS components F2-F3, F1B or F1A/1C with PRO-C3 ≥14 (OR historic liver biopsy) Randomize

Biopsy Success Rate in MAESTRO-NASH

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◼ ~70% of biopsies met eligibility requirements ◼ ~80% had NASH, some with NASH cirrhosis, or advanced NASH (F2-F3) with NAS<4 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 NAS=3, all components 1.8% F4 NASH cirrhosis 2.2% NAS4 F1A/C with PRO-C3<14 ng/mL 3.2% Total non-qualifying biopsies with NASH 10.5% Total biopsies with NASH

81.1%

Total biopsies without definite NASH or with F0 NASH 18.8% NAS: NAFLD Activity Score

PRO-C3 and Fibroscan Alignment with Baseline Biopsy Fibrosis Stage

◼ When measured in patients with baseline fibroscan kPa≥8.5, PRO-C3 aligned with biopsy F1-F3 NASH fibrosis stages ◼ Fibroscan appeared to be more predictive of NASH cirrhosis than PRO-C3 NOTE: the study only assessed biopsies in patients with biopsy-eligible fibroscan scores (≥8.5)

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6.1 21.6 10.3 12.0 15.6 12.8 7.2 29.9 10.7 14.4 18.4 15.3 7.7 24.4 12.7 14.3 18.6 15.9 7.8 32.8 12.3 15.7 20.8 17.4 6.1 41.1 12.6 17.4 25.0 20.1 9.4 26.0 11.2 13.9 19.8 15.6

(n = 47) 1A/1C n = 69 1B (n = 37) 2 (n = 125) 3 (n = 186) 4 (n = 11) PRO-C3 (ng/mL) 5 10 15 20 25 30 35 40 45

PRO-C3 by Fibrosis stage

rho = 0.24, p < 0.001 without stage 4: rho = 0.28, p < 0.001

5.3 14.4 8.8 9.8 11.8 10.8 5.1 15.6 8.5 9.9 11.5 10.0 4.0 15.8 8.9 10.3 12.2 11.1 5.3 17.8 9.2 11.1 12.9 11.7 5.4 23.8 9.8 12.0 15.5 13.8 9.2 35.4 12.2 21.0 34.6 26.7

(n = 40) 1A/1C n = 56 1B (n = 32) 2 (n = 113) 3 (n = 171) 4 (n = 9) TE (kPa) 5 10 15 20 25 30 35 40

TE by Fibrosis stage

rho = 0.3, p < 0.001 without stage 4: rho = 0.28, p < 0.001

10 20 30 40 50 60 20 40 60 80 TE (kPa) PRO-C3 (ng/mL)

PRO-C3 and TE

PRO-C3 by Biopsy Fibrosis Stage LSM (fibroscan kPa) by Biopsy Fibrosis Stage PRO-C3 vs Fibroscan Score

LSM, liver stiffness measure

PRO-C3 Alignment with NAS Components

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6.1 24.0 10.3 12.3 15.8 13.4 6.1 31.3 11.8 15.4 19.7 16.6 7.8 42.3 13.9 18.2 25.9 21.3

(n = 88) 1 (n = 232) 2 (n = 152) PRO-C3 (ng/mL) 5 10 15 20 25 30 35 40 45 rho = 0.34, p < 0.001

6.1 12.1 9.7 11.7 12.1 12.1 6.1 30.1 10.5 13.9 18.4 15.6 6.1 33.7 13.2 16.6 21.8 18.2 9.9 47.1 13.5 21.9 29.4 24.4

(n = 13) 1 (n = 200) 2 (n = 217) 3 (n = 41) PRO-C3 (ng/mL) 5 10 15 20 25 30 35 40 45 50 rho = 0.29, p < 0.001

PRO-C3 by Biopsy Ballooning PRO-C3 by Biopsy Lobular Inflammation

9.20 12.00 9.20 11.80 12.00 11.00 9.30 12.10 9.85 11.75 12.08 11.23 6.10 24.00 8.95 10.70 16.98 13.54 6.10 21.80 10.15 11.85 15.50 13.31 6.10 26.00 11.10 13.90 17.80 15.91 6.10 31.40 12.83 16.45 20.78 17.28 8.10 38.10 13.63 18.05 24.40 20.02 8.80 41.10 14.10 17.90 26.10 21.57 9.90 27.40 12.53 18.75 26.65 24.33

(n = 3) 1 (n = 4) 2 (n = 24) 3 (n = 54) 4 (n = 105) 5 (n = 124) 6 (n = 92) 7 (n = 51) 8 (n = 14) PRO-C3 (ng/mL) 5 10 15 20 25 30 35 40 45 rho = 0.37, p < 0.001

Score: NAFLD Activity Score (NAS)

PRO-C3 by Biopsy NAS

◼ PRO-C3 levels were significantly correlated with ballooning, lobular inflammation and NAS ◼ Biopsy steatosis score was weakly aligned with PRO-C3

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 the NASH liver — Findings are consistent with recent literature1 ◼ In the absence of a liver biopsy, elevated PRO-C3 in the setting of metabolic syndrome (or FIBC3 (PRO- C3 (age, BMI, platelets, T2D)), fibroscan and MRI-PDFF may predict advanced NASH

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1https://doi.org/10.1016/j.jhepr.2019.06.004

Phase 3 MAESTRO-NAFLD-1 (presumed NASH) Study Design: Randomized, Double-Blind, PBO Controlled

Comparator/Arms ◼ 1:1:1:1 resmetirom 80, 100 mg , placebo, open label 100 mg ◼ 700 NASH patients enrolled in the USA (~65 sites); 700 patient target exceeded by Sept 2020 Inclusion/Exclusion ◼ Requires 3 metabolic risk factors (Metabolic Syndrome) ◼ Fibroscan kPa≥ F1, CAP≥280, except where eligible for MAESTRO-NASH; includes MAESTRO-NASH patients who screen fail at the biopsy stage ◼ ≥8% liver fat on MRI-PDFF ◼ Open label arm, >100 patients — NASH patients on 100 mg resmetirom to assess non-invasive measure of safety and efficacy — Open-label treatment of special safety population, e.g. compensated cirrhosis Endpoints ◼ Primary safety objective: to evaluate the safety and tolerability of once-daily, oral administration of 80 or 100 mg resmetirom versus matching placebo as measured by: Incidence of Adverse Events [ Time Frame: 52 weeks ] ◼Key efficacy objectives: percent change from baseline in LDL-C; percent change from baseline in ApoB; percent change from baseline in hepatic fat fraction by MRI-PDFF; percent change from baseline in triglycerides; change in PRO-C3 52 Week Primary Endpoint

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A “Real-life” NASH Study with Non-invasive Monitoring of Patient Response

Screening

MRI-PDFF Fibroscan LDL-C (lipids)

D1 W16 W24 W52

80 mg 100 mg Placebo

Randomization Extension

100 mg Open Label

#1707 TREATMENT WITH RESMETIROM IN PHASE 3 MAESTRO-NAFLD-1 NASH STUDY OPEN LABEL ARM: EFFECTS ON BIOMARKERS AND IMAGING

◼ An exploratory evaluation of safety, imaging and biomarkers was conducted in patients enrolled in the open label 100 mg active treatment arm of MAESTRO-NAFLD-1 ◼ Typically ~20% of the overall NASH population are on thyroxine for the treatment of hypothyroidism. Thyroxine has equal activity at the thyroid receptor alpha and beta receptors

— In order to assess the effects of resmetirom in NASH patients on thyroxine, a subgroup of the open label arm included patients on stable thyroxine (patients on thyroxine are also enrolled in the double-blind arms) — More females were on thyroxine as a percentage of enrolled open label patients (49.4% versus 19.4% male)

◼ Data analysis

— Group included open label patients that had completed at least 16 weeks of dosing — MRI-PDFFs and MREs were assessed in patients who had both baseline and Week 16 MRI-PDFFs and MREs

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• 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. Seth J Baum, Excel Medical Clinical Trials and

• Dr. Mustafa R Bashir, Department of Radiology, Duke University Medical Center AASLD 2020

Baseline Characteristics

◼ Demographics include

— Mean age 55.7, — female 71%, — BMI 36.2, — diabetes 41%, — hypertension 64%, — dyslipidemia >70%, — hypothyroid 41% — mean ASCVD score 11.1%

◼ Fibroscan (kPa 7.4) and mean MRI-PDFF 18% are consistent with, on average, F2-stage NASH

— Comparatively, MAESTRO-NASH fibroscan mean is consistent with F3

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Parameter Mean age, years (SD) 55.7(11.3) Male, n (%) 36(29%) Female, n (%) 87(71%) Hispanic/Latino, n (%) 32(26%) Mean Body weight (SD) (kg) 99.3(19.8) BMI mean (SD) (kg/m2) 36.2(6.2) Hypertension, n (%) 79(64%) Hypothyroid#, n (%) 50(41%) T2D, n (%) 50(41%) T2D Yrs since diagnosis mean (SD) 10.1(7.5) ASCVD score mean (SD) 11.1%(11.7%) Fibroscan TE mean (SD) (kPa) 7.4(2.9) Fibroscan CAP mean (SD) 341(35.0) MRI-PDFF mean (SD) (%FF) 18.0%(6.9%) MRE mean (SD) (kPa) 2.67(0.73) PRO-C3 mean (SD) (ng/ml) 12.8(5.6) HbA1c mean (SD) (%) 6.3(1.0) HOMA-IR mean (SD) 8.9(8.9) Statin use (n, %) 56(46%) GLP-1s (n, %) 15(12.2%) SGLT2s (n, %) 16(13.0%) Other lab parameters, mean (SD) MELD 7.0(1.6) NAFLD fibrosis score

• 1.2(1.3)

Fib-4 0.99(0.50) Total Cholesterol mean (SD) (mg/dL) 190.2(49.2) TG mean (SD) (mg/dL) 186.9(85.5) Lp(a) mean (SD) (nmol/L) 46.1(64.3) ApoB mean (SD) (mg/dL) 102.9(29.6) LDL-C mean (SD) (mg/dL) 117.7(42.5) HDL-C mean (SD) (mg/dL) 44.2(11.9) ALT (IU/L) 36.6(23.7) AST (IU/L) 25.5(12.4) GGT (IU/L) 44.1(46.5) CK (IU/L) 121.2(111.6) ALP (IU/L) 83.6(26.5) Total bilirubin (mg/dL) 0.55(0.21) Direct bilirubin (mg/dL) 0.10(0.04) Platelet count 263(67) Albumin (g/dL) 4.3(0.3) INR 1.1(0.3) CDT (%) 1.62(0.23)

Week 16 MRI-PDFF (%) and MRE (kPa) Changes from Baseline

◼ MRI-PDFF reduction of 53% fat fraction overall, and MRE (-0.34) were observed at Week 16 ◼ MRE, unlike other elastography techniques, provides a stiffness map (elastogram)

— The volume of liver parenchyma assessed with a single slice of MRE is about 250 cm31 — Shear wave elastography (20 cm3), point shear wave elastography (0.5–1.0 cm3), transient elastography (4 cm3), and nearly 500 times that of a liver biopsy (10–50 mm3 or < 0.05 cm3)

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All SHBG (high) MRI-PDFF (%) Baseline (%) 17.6 17.9 Relative % Change

• 53%
• 62%

p-value <0.0001 <0.0001 MRE (kPa) Baseline (≥2.9) 3.5 3.5 Absolute Change

• 0.34
• 0.46

p-value 0.003 0.003

1Top Magn Reson Imaging. 2018 October ; 27(5): 319–333. doi:10.1097 2Abdom Radiol (NY). 2018 July ; 43(7): 1590–1611. doi:10.1007/s00261-017-1383-1 !

Average MRE by fibrosis stage2

MRI-PDFF Subgroups

◼ 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 or low SHBG response

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Week 16 MRI-PDFF Relative % Change from Baseline)

◼ At weeks 12-24, decreases from baseline in ALT, AST, GGT occurred to the normal range in most patients; statistically significant reductions in inflammatory and fibrosis biomarkers PRO-C3, hsCRP and reverse T3 were observed ◼ Liver enzyme and biomarker responses were consistent with Phase 2 data

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Inflammatory and Fibrosis Biomarker Responses

Biomarker* Baseline SD Post- 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 Reverse T3 (ng/dL) 17.7 5.4 12.4 4.8

• 5.3

<0.0001 PRO-C3 (BL ≥14) (ng/L) 19.2 4.9 16.0 3.5

• 3.4

0.019 hsCRP (mg/L) 4.9 (1.9-8.4) 3.3 (1.5-6.2)

• 1.1

0.027

*Biomarkers were assessed at Weeks 12 or 24; LE at Week 20; median is shown for hsCRP

Reduction in Lipids and Lipoproteins

◼ LDL-C, apolipoprotein-B (-24%), triglycerides (23%), and lipoprotein(a) (-27%)) were statistically significantly reduced (p<0.0001) compared to baseline ◼ The magnitude of atherogenic lipid and lipoprotein reductions was similar to reductions observed in Phase 2 ◼ Lipid baselines and reductions with resmetirom were comparable in patients on thyroxine or not on thyroxine (not shown)

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• 70
• 60
• 50
• 40
• 30
• 20
• 10

ApoB LDL-C Lipoprotein (a) Lp(a) (Q2) Non-HDL-C Triglycerides CFB (mg/dL) %CFB

all p<0.0001

CFB, change from baseline (Lp(a) nmol/L)

Safety

◼ Resmetirom was well-tolerated with loose stools lasting <2 weeks in 6.5% ◼ No other AEs above historic placebo rates ◼ No changes in thyroid axis, thyroid pathway effects, irrespective of thyroxine treatment,

• r safety flags were observed

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AEs N=123 Patients with treatment-emergent adverse Events, n (%) 75 (61) Severe 0 (0) Moderate 36 (29) Mild 61 (50) Patients with SAEs 1 (0.7) Patients with drug-related SAEs 0 (0) Vital signs BL SD CFB p-value Blood pressure, systolic (mm Hg) 127.7 16.4

• 3.8

0.0003 Blood pressure, diastolic (mm Hg) 80.4 10.3

• 2.9

0.0022 Heart rate (bpm) 72.5 11.9

• 2.8

0.015

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 weeks of treatment ◼ Safety was supportive of an 100 mg dose of resmetirom, including in patients on thyroxine ◼ Assessments of serial non-invasive biomarkers potentially supports the use of non-invasive tests to monitor individual NASH patient response to resmetirom treatment

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BACKUP

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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 potential to monitor individual patient resmetirom response to treatment

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PDFF Response, Biopsy and Non-invasive Tests

◼ All NAS component changes showed a relationship to PDFF response ◼ High correlation R2~0.4 between steatosis change on biopsy and PDFF response at both Weeks 12 and 36, p<0.0001 (all patients) ◼ Statistically significant correlations between NASH component responses (ballooning, inflammation, fibrosis) and PDFF response were found in resmetirom-treated patients ◼ Inflammation and fibrosis response were not significantly correlated with PDFF response in placebo patients ◼ Statistically significant correlations were also observed between PDFF response and changes in ALT and PRO- C3 (all patients)

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Change in Steatosis Score at Week 36 Biopsy

• 3
• 2
• 1

1 2

% relative change in PDFF

• 120
• 100
• 80
• 60
• 40
• 20

20 40 60 80 Week 12 PDFF Change VS Change in Steatosis on Biopsy

Change in Inflammation Score at Week 36 Biopsy

• 3
• 2
• 1

1 2

% relative change in PDFF

• 120
• 100
• 80
• 60
• 40
• 20

20 40 60 80 Week 12 PDFF Change VS Change in Inflammation on Biopsy

Graphs, Pathologist B

Phase 2: Another Important Non-invasive Measure of Efficacy- Robust Lipid Lowering

Significant sustained lowering effect in multiple atherogenic lipids

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Lipids (% Change from Baseline)

Resmetirom compared with placebo; all analyses and cutoffs were prespecified; based on prespecified mITT; placebo n=39; Resmetirom n=79 (LOCF)

• 22.3
• 27.6
• 36
• 36.8
• 36.5
• 50
• 40
• 30
• 20
• 10

LDL-C (BL>100) ApoB (LDL BL>100) TGs Lp(a) (BL>=10) ApoCIII p<0.0001 p<0.0001 p<0.0001 p<0.001 p<0.0001

◼ Resmetirom is the only NASH therapeutic in advanced development able to lower lipids, consistent with regulatory approval for dyslipidemia; and also reduces fatty liver, an independent CV risk factor ◼ ApoB, not LDL-C is the major risk factor in CV disease ◼ NASH patients die of CV disease more frequently than liver disease

12 32 47 10 20 30 40 50 All F3 p=0.03 p=0.05 % biopsies

Placebo MGL-3196

Week 36: Change in Fibrosis Score on Liver Biopsy

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◼ Second Harmonic Generation (SHG) microscopy provides automated fully quantitative assessment of fibrosis on liver biopsy slides based on unique architectural features of collagen ◼ SHG score was generated and aligned with the pathologist baseline score (baseline, r=0.76), (left panel), blinded to treatment code ◼ Using SHG, resmetirom treated compared with placebo showed a statistically significant ≥1-pt reduction in fibrosis score at Week 36. Based on pathology score, fibrosis was reduced by ≥ 1 point in 29% of resmetirom treated patients vs. 23% in placebo

≥1 pt reduction in fibrosis

• n liver biopsy (SHG)

Pathologist Score SHG (qfibrosis)

https://doi.org/10.1371/journal.pone.0199166 Week 36 pathology scores and treatment code were not provided to SHG readers.

3 2 1 SHG Score

1A 1B 2 3 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0