CONSHOHOCKEN, Pa., Aug. 31, 2022 (GLOBE NEWSWIRE) -- Madrigal Pharmaceuticals, Inc. (NASDAQ:MDGL), a clinical-stage biopharmaceutical company pursuing novel therapeutics for nonalcoholic steatohepatitis (NASH), today announced initiation of the “MAESTRO-NASH Outcomes” study of resmetirom (recruiting, first patient screened). MAESTRO-NASH Outcomes is 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. It is the fourth Phase 3 MAESTRO study of resmetirom, joining the MAESTRO-NAFLD-1 safety study, which reported positive data in January 2022, the ongoing MAESTRO-NAFLD Open-Label Extension study, and the pivotal MAESTRO-NASH biopsy study, which is on track for a topline data readout in Q4 2022.
The primary endpoint of MAESTRO-NASH Outcomes is the incidence of composite liver-related outcome events, including all-cause mortality, liver transplant, hepatic decompensation (ascites, hepatic encephalopathy, gastroesophageal variceal hemorrhage), and confirmed increase of Model for End-Stage Liver Disease (MELD) score from <12 to ≥15 due to progression of NASH cirrhosis. Key inclusion criteria are well-compensated NASH cirrhosis (Child-Pugh A) and presence of three metabolic risk factors (metabolic syndrome). Patients will be randomized 3:1 in a blinded manner to receive 80 mg resmetirom or matching placebo, given orally once daily. The study duration is expected to be two to three years for accrual of the required number of composite clinical outcome events.
Paul Friedman, M.D., Chief Executive Officer of Madrigal, stated, “The MAESTRO-NASH Outcomes study is designed to address an urgent unmet need for patients and expand the long-term commercial opportunity for resmetirom. Positive results from this study could support full approval in the noncirrhotic population and potential for approval in an additional indication in patients with well-compensated NASH cirrhosis. Importantly, MAESTRO-NASH Outcomes does not impact the timeline for our MAESTRO-NASH biopsy study readout or initial new drug application filing in the noncirrhotic NASH population.”
Becky Taub, M.D., Chief Medical Officer and President of Research & Development of Madrigal, stated, “Our decision to conduct MAESTRO-NASH Outcomes is supported by promising 52-week data from 180 patients with well-compensated NASH cirrhosis studied in a resmetirom active treatment arm of our Phase 3 study, MAESTRO-NAFLD-1; initial findings from this cohort were featured in an oral presentation at EASL’s International Liver Congress in June and we plan to share additional analyses at the AASLD Liver Meeting in November.”
Stephen Harrison, M.D., Medical Director for Pinnacle Clinical Research, San Antonio, Texas, Visiting Professor of Hepatology, Oxford University, and Principal Investigator of the MAESTRO studies, commented, “As the first noninvasive Phase 3 study in well-compensated NASH cirrhosis, the initiation of MAESTRO-NASH Outcomes is an important milestone for the field. This study avoids the variability and invasiveness of liver biopsy and instead focuses on the treatment goals that are most important to liver specialists and patients: halting progression of NASH cirrhosis and improving long-term outcomes.”
More than 100 sites in the United States and Europe are expected to participate in the MAESTRO-NASH Outcomes study. Further information is available at ClinicalTrials.gov (NCT05500222).
About the Resmetirom Phase 3 Registration Program for the Treatment of NASH
Madrigal is currently conducting four Phase 3 clinical trials to demonstrate the safety and efficacy of resmetirom for the treatment of NASH: MAESTRO-NASH, MAESTRO-NAFLD-1, MAESTRO-NAFLD-OLE, and MAESTRO-NASH Outcomes.
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. The study enrolled more than 1,000 patients with biopsy-proven NASH (at least half with F3 (advanced) fibrosis, the remainder F2 or F1B (moderate fibrosis, with a few earlier F1 patients), randomized 1:1:1 to receive once-daily resmetirom 80 mg, resmetirom 100 mg, or placebo. After 52 weeks of treatment, a second biopsy is performed. The dual primary surrogate endpoints on biopsy are NASH resolution with ≥2-point reduction in NAS (NAFLD Activity Score), and with no worsening of fibrosis OR a 1-point decrease in fibrosis with no worsening of NASH. Achievement of either primary endpoint is considered a successful trial outcome. A key secondary endpoint is lowering of LDL-C. The planned target enrollment was announced as completed on June 30, 2021.
All patients enrolled in the MAESTRO-NASH study (up to 2,000 in total) continue on therapy after the initial 52-week treatment period for up to 54 months to accrue and measure hepatic clinical outcome events including progression to cirrhosis on biopsy (52 weeks and 54 months) and hepatic decompensation events.
MAESTRO-NAFLD-1 was initiated in December 2019 and the 52-week multicenter, randomized, placebo-controlled Phase 3 study of resmetirom in over 1,200 patients with NAFLD, presumed NASH, has completed the double-blind arms and an open-label 100 mg arm. An additional open-label active treatment arm in patients with early (well-compensated) NASH cirrhosis is ongoing. The primary endpoint was to evaluate the safety and tolerability of resmetirom. A separate 52 week Phase 3 clinical trial, an open-label extension study of MAESTRO-NAFLD-1 (MAESTRO-NAFLD-OLE) is ongoing.
Patients in the 52-week Phase 3 MAESTRO-NAFLD-1 study were randomized 1:1:1:1 to receive once-daily resmetirom 80 mg, resmetirom 100 mg, placebo in double-blind arms or resmetirom 100 mg in an open-label arm. MAESTRO-NAFLD-1 (unlike MAESTRO-NASH), did not include a liver biopsy and represents a “real-life” NASH study. Patients with 3 metabolic risk factors were documented with NASH or NAFLD by historical liver biopsy or noninvasive techniques. Using noninvasive measures, MAESTRO-NAFLD-1 was designed to provide incremental safety information to support the NASH indication as well as provide additional data regarding clinically relevant key secondary efficacy endpoints to better characterize the potential clinical benefits of resmetirom on cardiovascular- and liver-related endpoints. The primary safety endpoint and several key secondary endpoints were met, including LDL-C, apolipoprotein B, and triglyceride lowering and reduction of liver fat as determined by MRI-PDFF. Additional secondary and exploratory endpoints were assessed including reduction in liver enzymes, FibroScan, and MRE scores, and other NASH biomarkers.
Data from the 52-week first 1,000 patient portion of MAESTRO-NASH, together with data from MAESTRO-NAFLD-1 and other data, including safety parameters, will form the basis for a potential subpart H submission to FDA for accelerated approval of resmetirom for treatment of NASH.
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.
About Madrigal Pharmaceuticals
Madrigal Pharmaceuticals, Inc. (Nasdaq: MDGL) is a clinical-stage biopharmaceutical company pursuing novel therapeutics for nonalcoholic steatohepatitis (NASH), a liver disease with high unmet medical need. Madrigal’s lead candidate, resmetirom, is a once daily, oral, thyroid hormone receptor (THR)-β selective agonist designed to target key underlying causes of NASH in the liver. Resmetirom is currently being evaluated in two Phase 3 clinical studies (MAESTRO-NASH and MAESTRO-NAFLD-1) designed to demonstrate multiple benefits in patients with NASH. For more information, visit www.madrigalpharma.com.
