Madrigal Pharmaceuticals : EASL 2023 MAESTRO-NASH Primary Results Presentation

Primary Results From MAESTRO-NASH:

A Pivotal Phase 3 52-week Serial Liver Biopsy Study

in 966 Patients With NASH & Fibrosis

Stephen A. Harrison,1 Pierre Bedossa,2 Cynthia D. Guy,3 Jörn M. Schattenberg,4 Rohit Loomba,5 Rebecca Taub,6 Dominic Labriola,6 Sam E. Moussa,7 Guy W. Neff,8 Arun J. Sanyal,9 Mazen Noureddin,10 Meena Bansal,11 Naim Alkhouri,12 Vlad Ratziu13

1University of Oxford, Oxford, UK & Pinnacle Clinical Research, San Antonio, TX, USA; 2Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; 3Duke University Medical Center, Durham, NC, USA; 4University Medical Center, Mainz, Germany; 5University of California San Diego, La Jolla, CA, USA; 6Madrigal Pharmaceuticals, Conshohocken, PA, USA; 7University of Arizona for Medical Sciences, Tucson, AZ, USA; 8Covenant Metabolic Specialists, Sarasota, FL, USA;

9Virginia Commonwealth University, Richmond, VA, USA; 10Houston Research Institute, Houston, TX, USA; 11Mt Sinai, New York, NY, USA; 12Arizona Liver Health, Tucson, AZ, USA; 13Pitie-Salpetriere Hospital, Institute of Cardiometabolism & Nutrition, Sorbonne Universite, Paris, France.

Presented at The International Liver Congress; 21-24 June 2023; Vienna, Austria.

Disclosures

DISCLOSURES: I disclose the following financial relationship(s) with a commercial interest:

• Scientific advisor or consultant for Akero, Aligos, Altimmune, Arrowhead, Bluejay Therapeutics, Boxer Capital, Chronwell, Echosens, Enyo, Foresite Labs, Galectin, Galecto, Gilead, GSK, Hepagene, Hepion, Hepta Bio, HistoIndex, Humana, Intercept, Ionis, Madrigal, Medpace, NeuroBo Pharmaceuticals, Northsea, Novo Nordisk, Perspectum, Pfizer, Sonic Incytes, Sagimet, Terns, Viking.
• Stock options: Akero, Chronwell, Cirius, Galectin, Genfit, Hepion, Hepta Bio, HistoIndex, Metacrine, NGM Bio, Northsea, Sonic Incytes
• Grant/Research support: Akero, Altimmune, Axcella, BMS, Corcept, Cymabay, Enyo, Galectin, Genentech, Genfit, Gilead, GSK, Hepion, Hightide, Immuron, Intercept, Inventiva, Ionis, Madrigal, NGM Bio, Novartis, Novo Nordisk, Northsea, Pfizer, Poxel, Sagimet, Terns, Viking.

Resmetirom

• Resmetirom is an oral, liver-targetedTHR-βselective agonist in development for NASH1
• In patients with NASH, selectivity for THR-β may provide metabolic benefits of thyroid hormone that are mediated by the liver (reduction of excess hepatic fat & atherogenic lipids/lipoproteins), while avoiding negative systemic effects of excess thyroid hormone in heart & bone
• In the randomized, double-blind,placebo-controlled Phase 2 serial liver biopsy trial in adults with biopsy- confirmed NASH (NCT02912260), resmetirom treatment resolved NASH in a significantly greater percentage of patients & reduced liver enzymes, inflammatory biomarkers, & fibrosis compared with placebo2
• MAESTRO-NASHis a randomized, double-blind,placebo-controlled Phase 3 serial liver biopsy trial evaluating the efficacy & safety of resmetirom in adults with biopsy-confirmed NASH (NCT03900429)

Here we report Week 52 data in 966 patients with NASH & F1B, F2, or F3 fibrosis from the MAESTRO-NASH trial

1. Kelly MJ, et al. J Med Chem. 2014;57(10):3912-3923. 2. Harrison SA, et al. Lancet. 2019;394(10213):2012-2024

.

NASH, nonalcoholic steatohepatitis; THR, thyroid hormone receptor.

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MAESTRO-NASH Trial Design

KEY ELIGIBILITY CRITERIA

Presence of ≥3 metabolic risk factors

NASH on biopsy: NAS ≥4

(with ≥1 in each component) Fibrosis stage F1B, F2, or F3 ≥8% hepatic fat by MRI-PDFF

MAESTRO-NASH

1:1:1

Randomization

Placebo

Resmetirom 100 mg

Resmetirom 80 mg

Liver Biopsy	Screening	D1
MRI-PDFF/MRE
LDL-C/Biomarkers
VCTE/CAP

W16	W24	W52	Month 54
		52 Week	54 Month Outcome
		Primary Endpoint	Primary Endpoint

DUAL PRIMARY

ENDPOINT

AT WEEK 52

NASH resolution (ballooning score=0, inflammation score=0/1, & ≥2-point reduction in NAS) with no worsening of fibrosis

≥1-stage improvement in fibrosis with no

worsening of NAS

LDL-C,low-density lipoprotein cholesterol; MRI-PDFF, magnetic resonance imaging-proton density fat fraction; NAS, nonalcoholic fatty liver disease activity score; NASH, nonalcoholic steatohepatitis.	4

Demographic & Baseline Characteristics (Primary Analysis Population n=966)

		Resmetirom 80mg	Resmetirom 100mg	Placebo
		(n=322)	(n=323)	(n=321)
	Age, years	55.9 (11.5)	57.0 (10.8)	57.1 (10.5)
	Sex, male	140	(43.5)	141	(43.7)	143	(44.5)
	Race, White	291 (90.4%)	291 (90.1%)	281 (87.5%)
	Ethnicity, Hispanic or Latino	71 (22.0%)	81 (25.1%)	52 (16.2%)
	Body mass index	35.5 (6.4)	36.2 (7.4)	35.3 (6.5)
	Type 2 diabetes	224	(69.6)	213	(65.9)	210	(65.4)
	Hypertension	243	(75.5)	254	(78.6)	257	(80.1)
	Dyslipidemia	230	(71.4)	236	(73.1)	224	(69.8)
	Hypothyroidism*	39 (12.1)	46 (14.2)	45 (14.0)
	FibroScan VCTE/LSM, kPa	13.3 (6.8)	13.6 (7.1)	12.9 (5.5)
	FibroScan CAP, dB/m	346.1 (37.2)	349.4 (38.7)	347.2 (37.0)
	MRI-PDFF, % fat fraction	18.2 (6.8)	17.2 (6.6)	17.8 (6.8)
	MRE, kPa	3.5 (0.9)	3.7 (1.1)	3.5 (1.0)
	Baseline medications
	GLP-1 RA	54 (16.8)	41 (12.7)	42 (13.1)
	Statin	149	(46.3)	166	(51.4)	157	(48.9)
	Baseline liver biopsy
	NAS ≥5	266	(82.6)	288	(89.2)	253	(78.8)
	Fibrosis 1B	16	(5.0)	15	(4.6)	18	(5.6)
	Fibrosis 2	107	(33.2)	100	(31.0)	112	(34.9)
	Fibrosis 3	194	(60.2)	203	(62.8)	186	(57.9)

Data are mean (SD) or n (%)

*Patients on thyroxine replacement therapy at screening.

CAP, controlled attenuation parameter; GLP-1 RA, glucagon-likepeptide-1 receptor agonist; LSM, liver stiffness measurement; mITT, modified intent-to-treat; MRE, magnetic resonance elastography; MRI-PDFF, magnetic resonance imaging-proton density fat fraction; NAS, nonalcoholic fatty liver disease activity score; SD, standard deviation; VCTE, vibration-controlled transient elastography.

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