About Madrigal Pharmaceuticals

Madrigal Pharmaceuticals, Inc. (Madrigal), a clinical-stage biopharmaceutical company, engages in pursuing novel therapeutics for nonalcoholic steatohepatitis, or NASH. The company’s lead product candidate, resmetirom, is a proprietary, liver-directed, selective thyroid hormone receptor-ß, or THR-ß, agonist being developed as a once-daily oral pill for the treatment of NASH. Resmetirom is the first selective small molecule THR-ß agonist compound. Resmetirom, along with MGL-3745, a potential backup compound to resmetirom, was discovered at Hoffmann-La Roche, or Roche, in Nutley, New Jersey, by utilizing a novel functional assay that, unlike a simple receptor binding assay, assessed the functional activity of compounds, which interacted with thyroid hormone receptors. Strategy A key element is building a multi-therapy NASH focused company. The company plans to complete clinical development and seeks regulatory approval of resmetirom in NASH; establish commercial capabilities to market resmetirom as a leading treatment for NASH; and expand the resmetirom market opportunity to include patients with compensated NASH cirrhosis. Resmetirom in NASH The company is developing resmetirom for the treatment of non-cirrhotic NASH with fibrosis and NASH with compensated cirrhosis. Resmetirom is an excellent candidate for the chronic treatment of NASH. The company has completed multiple studies in animal models of metabolic diseases, dyslipidemia and NASH in which resmetirom demonstrated a statistically significant reduction in liver TGs, insulin resistance, liver enzymes (which may be elevated in NASH), and markers of inflammation and fibrosis. Resmetirom will treat the underlying lipotoxicity that drives the inflammation and liver cell damage observed in NASH patients, and after the underlying lipotoxicity is treated, NASH-related liver fibrosis will resolve as the liver regenerates. Madrigal has ongoing Phase 3 resmetirom studies for patients with NASH or presumed NASH. The designs of the company’s Phase 2 and Phase 3 NASH studies are consistent with principles for NASH drug development outlined by the Food and Drug Administration (FDA) in its public communications and draft guidance for industry and based on the company’s past interactions with FDA, including its end of Phase 2 meeting with the FDA in 2019. In March 2019, the company announced that it had initiated MAESTRO-NASH, a Phase 3 trial of resmetirom in patients with NASH. MAESTRO-NASH is a multicenter, randomized, double-blind, placebo-controlled Phase 3 study of resmetirom in patients with liver biopsy-confirmed NASH and was initiated in March 2019. In December 2022, the company reported topline results from the subpart H portion of the study: resmetirom achieved both primary endpoints with both daily oral doses, 80 mg and 100 mg, relative to placebo. In December 2019, the company announced it had opened for enrollment MAESTRO-NAFLD-1, a 52-week, double-blind, placebo controlled Phase 3 clinical study in 700 patients with biopsy-confirmed or presumed NASH recruited from sites in the U.S. In November of 2021, the company reported data from the open label non-cirrhotic arm of MAESTRO-NAFLD-1. In January 2022, the company announced that it achieved primary and secondary endpoints for the double-blind portion of MAESTRO-NAFLD-1. In January 2022, Madrigal announced topline results from the Phase 3 MAESTRO-NAFLD-1 safety study of resmetirom. Primary and key secondary endpoints from the double-blind placebo-controlled 969-patient portion of the study were achieved. On March 28, 2019, the company announced that it had initiated MAESTRO-NASH, a Phase 3 trial in NASH with its once daily, oral thyroid hormone receptor beta selective agonist, resmetirom. This double-blind, placebo-controlled study is being conducted at more than 220 sites in the United States and the rest of the world. MAESTRO-NASH is a multicenter, randomized, double-blind, placebo-controlled Phase 3 study of resmetirom in patients with liver biopsy-confirmed NASH and was initiated in March 2019. On July 13, 2021, the company announced first patient dosed in a planned 52-week open label active treatment extension study of MAESTRO-NAFLD-1, named MAESTRO-NAFLD-Open Label Extension (OLE). The OLE study allows patients who complete MAESTRO-NAFLD-1 to consent to 52 weeks of active treatment with resmetirom, making this treatment available to both patients who were assigned to placebo in MAESTRO-NAFLD-1 and patients who were on resmetirom in MAESTRO-NAFLD-1. In August 2022, Madrigal initiated MAESTRO-NASH-OUTCOMES, a randomized double-blind placebo-controlled study in approximately 700 patients with early NASH cirrhosis to allow for noninvasive monitoring of progression to liver decompensation events. A positive outcome is expected to support the full approval of resmetirom for noncirrhotic NASH, potentially accelerating the timeline to full approval. In addition, this study has the potential to support an additional indication for resmetirom in patients with well-compensated NASH cirrhosis. In August 2022, the company announced initiation of MAESTRO-NASH OUTCOMES, a Phase 3, double-blind, randomized, placebo-controlled study that will noninvasively measure progression to liver decompensation events in approximately 700 patients with compensated NASH cirrhosis. Collaborations VIA Pharmaceuticals, Inc., or VIA, entered into a research, development and commercialization agreement, or the Roche Agreement, with Hoffmann-La Roche (Roche), on December 18, 2008. The company subsequently assumed all of VIA’s rights in, to and under, and all of VIA’s obligations under, the Roche Agreement pursuant to an asset purchase agreement, dated September 14, 2011. Pursuant to the terms of the Roche Agreement, the company, as successor-in-interest to VIA, assumed control of all development and commercialization of resmetirom and will hold exclusive worldwide rights for all potential indications. Sales and Marketing Madrigal has established a commercial leadership team with expertise in launching pharmaceutical products. As resmetirom nears potential accelerated approval in the U.S., the company intends to expand its marketing organization, establish a sales organization, and build distribution capabilities to commercialize resmetirom. Research and Development The company’s research and development expenses were $245.4 million for the year ended December 31, 2022. Intellectual Property As of December 7, 2022, the company owned or co-owned five United States and 38 foreign issued patents; five United States and 43 foreign pending patent applications; and three international patent applications filed under the Patent Cooperation Treaty. Each of these patents and applications relates to resmetirom, including composition-of-matter, certain dosage forms, methods of making resmetirom, its use in the treatment of key disease indications, or other THR beta analogs and uses thereof. The company’s patent portfolio covers the United States and certain other jurisdictions worldwide. The three international patent applications can be used as the basis for multiple additional patent applications worldwide. In addition, pursuant to the Roche Agreement, Roche granted the company an exclusive license to certain United States and foreign patents and patent applications owned by Roche and Roche know-how relating to resmetirom. The Roche Agreement imposes various diligence, milestone payment, royalty payment, insurance, indemnification, and other obligations on the company. Issued patents directed to resmetirom, including certain dosage forms, have statutory expiration dates between 2026 and 2037, excluding any patent term extensions or equivalents thereof that might be available following the grant of marketing authorizations. The company has pending patent applications for resmetirom that, if issued, would be expected to expire in the United States and in countries outside of the United States between 2033 and 2042, excluding any patent term adjustment that might be available following the grant of the patent and any patent term extensions that might be available following the grant of marketing authorizations. The company has a pending patent application for other THR beta analogs that, if issued, would be expected to expire in the United States and in countries outside of the United States in 2043, excluding any patent term adjustment that might be available following the grant of the patent and any patent term extensions that might be available following the grant of marketing authorizations. Government Regulation Any drug products manufactured or distributed by the company pursuant to FDA approvals are subject to continuing regulation by the FDA, including, among other things, record-keeping requirements, reporting of adverse experiences with the drug, providing the FDA with updated safety and efficacy information, drug sampling and distribution requirements, complying with certain electronic records and signature requirements, and complying with FDA promotion and advertising requirements. When conducting clinical trials in the EU, the company must adhere to the provisions of the EU Clinical Trials Directive and the laws and regulations of the EU Member States implementing them.