Madrigal Pharmaceuticals, Inc. (NASDAQ: MDGL) announced today that it has initiated its Phase 3 trial in NASH with its once daily, oral thyroid hormone receptor beta selective agonist, MGL-3196 (resmetirom).
This double-blind, placebo-controlled study will be conducted at more than 150 sites in the United States and the rest of the world. Patients with liver biopsy confirmed NASHwith stage 2 or 3 fibrosis will be randomized 1:1:1 to receive a single oral daily dose of placebo, resmetirom 80 mg or resmetirom 100 mg. A second liver biopsy at week 52 in the first 900 patients will be the basis of filing for subpart H-accelerated approval; the primary endpoint will be the percent of patients treated with either dose of resmetirom as compared with placebo who achieve NASH resolution on the week 52 liver biopsy, defined as the absence of hepatocyte ballooning (score=0), and minimal lobular inflammation (score 0-1), associated with at least a 2 point reduction in NAS, and no worsening of fibrosis stage.
Two key secondary endpoints are reduction in LDL-cholesterol and a 1-point or more improvement in fibrosis stage on the week 52 biopsy with no worsening of NASH. Patients will continue in the study for a total of 54 months, and will be evaluated for a composite clinical outcome including cirrhosis on liver biopsy, or a liver related event such a hepatic decompensation. The total anticipated enrollment is approximately 2,000 patients, and will include up to 15% high risk F1 fibrosis stage NASH patients whose efficacy responses will be evaluated as exploratory endpoints.
‘We are pleased to announce the start of the Phase 3 NASH study,’ said Dr. Paul Friedman, Chief Executive Officer of Madrigal. ‘In the 36 Week Phase 2 study, NASHresolution was highly correlated with the magnitude of liver fat reduction on MRI-PDFF. In Phase 2, 25% of all resmetirom treated patients, and 37% of treated patients who were on adequate doses of resmetirom, achieved the Phase 3 NASH resolution endpoint (NASH resolution with at least a 2-point reduction in NAS and no fibrosis stage worsening); both results demonstrated statistically significant differences relative to placebo. The resmetirom doses used in Phase 2, in which nearly half of the patients took 60 mg, were lower than the optimal doses of 80 and 100 mg that will be used in Phase 3. Coupling these Phase 2 results with the higher doses in Phase 3 and with longer treatment duration, we believe there is great potential to achieve statistically significant NASH resolution and liver fibrosis reduction relative to placebo at both the 80 and 100 mg doses.’
Dr. Stephen Harrison, M.D., Principal Investigator of the study, and Medical Director for Pinnacle Clinical Research, San Antonio, Texas, and Visiting Professor of Hepatology, Oxford University, commented, ‘To date, the results with resmetirom are highly encouraging. In Phase 2, this once a day, oral compound was well tolerated and showed statistically significant superiority to placebo in the 12 week primary endpoint of hepatic fat reduction, as measured by MRI-PDFF, in resolution of NASH on biopsy at 36 weeks, and in lowering elevated liver enzymes, fibrosis markers and atherogenic lipids.’ Dr. Harrison continued, ‘The added requirement of at least a 2 point reduction in NAS to the NASH resolution endpoint, which was used in Phase 2 and will be used in the Phase 3 study, provides the potential to predict ultimate clinical benefit with more certainty.’
Dr. Rebecca Taub, M.D., Chief Medical Officer and Executive Vice President of Madrigal, Research & Development, added, ‘In our Phase 2 study, half of the resmetirom treated patients with NASH resolution also completely resolved their fibrosis, demonstrating the critical importance of treating the underlying NASH in order to achieve fibrosis benefit. The recent publication by Brunt et al 1, reviewing NASH liver biopsy data from two large Phase 2 studies conducted by the NASH CRN in which several therapeutics and placebo were tested, found that resolution of NASH, a 2-point or more improvement in NAS or a decrease in steatosis, were all strongly predictive of fibrosis improvement. Based on these data and our Phase 2 study results, we believe there is great potential for resmetirom to achieve a key secondary endpoint in our Phase 3 study: at least a 1-point improvement in fibrosis without worsening of NASH.’
Dr. Taub continued, ‘We are also excited to be working with Summit Clinical Research, LLC and PRA Health Sciences to rapidly enroll our Phase 3 study with a targeted timeline of 15-18 months for enrollment of the first 900 patients. ‘
‘In addition,’ added Dr. Taub, ‘we believe resmetirom has a unique potential among NASH drugs in development to decrease cardiovascular risk, through reduction of hepatic fat and reduction in the levels of multiple atherogenic lipids including LDL-cholesterol at a magnitude that is consistent with approval for a dyslipidemia indication. As NAFLD/NASH patients are at significantly increased risk of cardiovascular morbidity and mortality, and based on the cardiovascular risk reducing profile of resmetirom, we project a potential for resmetirom to demonstrate a highly favorable benefit to risk profile in patients with advanced NASH in the Phase 3 NASH study and, ultimately, in early NASH/NAFLD patients treated for LDL-cholesterol and atherogenic lipid lowering.’
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