• 19 Mar 2024
• Admin
• News Article

Madrigal’s Rezdiffra Receives Approval to Treat NASH

Madrigal Pharma’s Rezdiffra receives US FDA approval to treat noncirrhotic NASH with moderate to advanced liver fibrosis

Overview

Madrigal Pharmaceuticals

• Madrigal Pharmaceuticals, Inc., a biopharmaceutical company focused on delivering novel therapeutics for NASH, announced that the US Food and Drug Administration (FDA) has granted accelerated approval for Rezdiffra (resmetirom) in conjunction with diet and exercise for the treatment of adults with noncirrhotic nonalcoholic steatohepatitis (NASH) with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis).
• Continued approval for this indication may be contingent upon verification and description of clinical benefit in ongoing confirmatory trials.

Words from CEO: Madrigal Pharmaceuticals

Bill Sibold, chief executive officer of Madrigal, stated, “NASH with moderate to advanced liver fibrosis is a serious and progressive liver disease that, until now, has not had an FDA-approved therapy. The accelerated approval of Rezdiffra is a culmination of more than 15 years of research from our founder Dr. Becky Taub and a small R&D team that took on one of the biggest challenges in drug development. This is a historic moment for the NASH field and represents the best of what our industry is capable of. We’re excited to deliver Rezdiffra to patients in need.”

Words from CMO: Madrigal

Becky Taub, M.D., the founder, chief medical officer and president of research & development of Madrigal, stated, “Madrigal would like to thank the many patients who made the accelerated approval of Rezdiffra possible by participating in our clinical studies. We believe Rezdiffra will change the treatment paradigm for NASH with moderate to advanced liver fibrosis, giving physicians a liver-directed therapy to help improve fibrosis and resolve NASH before their patients progress to cirrhosis.”

Words from Fatty Liver Foundation

Wayne Eskridge, co-founder and chief executive officer of the Fatty Liver Foundation, stated, “This is a day of celebration for patients with NASH who have been waiting many years for the first approved therapy. I believe this approval milestone will bring new energy and momentum to the NASH community, accelerating our efforts to improve disease education, build care pathways, and expand investment in NASH research.”

Rezdiffra is a once-daily, oral THR-ß agonist designed to target key underlying causes of NASH. The accelerated approval of Rezdiffra was based on results from the phase 3 MAESTRO-NASH trial, which was recently published in the New England Journal of Medicine. MAESTRO-NASH is an ongoing pivotal, multicenter, randomized, double-blind, placebo-controlled trial that enrolled 1,759 patients with biopsy-confirmed NASH. Following 52 weeks of treatment, both 100 mg and 80 mg doses of Rezdiffra demonstrated statistically significant improvement compared to placebo on two primary endpoints: NASH resolution (including a reduction in the nonalcoholic fatty liver disease [NAFLD] activity score by =2 points) with no worsening of fibrosis, and an improvement in fibrosis by at least one stage with no worsening of the NAFLD activity score. Fibrosis improvement and NASH resolution were consistent regardless of age, gender, type 2 diabetes status, or fibrosis stage.

The Rezdiffra prescribing information does not include a liver biopsy requirement for diagnosis. The recommended dosage of Rezdiffra is based on actual body weight. For patients weighing <100 kg (220 lbs.), the recommended dosage is 80 mg orally once daily. For patients weighing =100 kg (220 lbs.), the recommended dosage is 100 mg orally once daily.

Words from Expert

• Stephen Harrison, M.D., chairman for both Pinnacle Clinical Research and Summit Clinical Research, San Antonio, Texas, Visiting Professor of Hepatology, Oxford University, and lead Principal Investigator of the MAESTRO studies, commented, “The approval of the first medication for NASH is a true game-changer for healthcare providers, the research community and, most importantly, patients living with this serious liver condition. Based on the robust efficacy and safety data generated in two large phase 3 MAESTRO studies, I believe Rezdiffra will become the foundational therapy for patients with NASH with moderate to advanced liver fibrosis.”
• Dr. Harrison continued, “Importantly, we continue to study Rezdiffra to determine if the positive results observed in the MAESTRO studies will lead to reduced risk of progression to cirrhosis, liver failure, need for liver transplant and premature mortality.”
• MAESTRO-NASH remains ongoing as an outcomes study designed to generate confirmatory data that, if positive, will help verify clinical benefit and may support full approval. A second ongoing outcomes trial is evaluating progression to liver decompensation events in patients with well-compensated NASH cirrhosis treated with Rezdiffra versus placebo.

Common Adverse Reactions

• Rezdiffra should not be used in patients with decompensated cirrhosis. 
• The most common adverse reactions reported in patients treated with Rezdiffra included diarrhoea, nausea, pruritis, abdominal pain, vomiting, constipation, and dizziness. Diarrhoea and nausea typically began early in treatment initiation and were mild to moderate in severity. 
• A separate, noninvasive phase 3 trial, MAESTRO-NAFLD-1, evaluated the safety and tolerability of Rezdiffra and contributed to the safety database supporting regulatory benefit-risk assessment.

Expected Timeline

• Rezdiffra is expected to be available to patients in the US in April and will be distributed through a limited specialty pharmacy network. 
• Madrigal is committed to helping appropriate patients who may benefit from Rezdiffra access the medication through the Madrigal Patient Support program. 
• This program is designed to help patients navigate insurance and affordability challenges and provide co-pay support for eligible patients. Madrigal has also established a patient assistance program (PAP) to help patients with no insurance access Rezdiffra.

MAESTRO-NASH Trial

• MAESTRO-NASH is an ongoing phase 3 trial that enrolled 1759 patients with biopsy-confirmed NASH. 
• Patients were randomly assigned in a 1:1:1 ratio to receive once-daily Rezdiffra at a dose of 80 mg or 100 mg or placebo. 
• The two primary endpoints at week 52 were NASH resolution with no worsening of fibrosis and an improvement in fibrosis by at least one stage with no worsening of the NAFLD activity score. 
• The key secondary endpoint was the percent change from baseline in LDL cholesterol at week 24.

Result Endpoints 

• Rezdiffra achieved both primary endpoints and the key secondary endpoint of the MAESTRO-NASH trial. 
• Additionally, Rezdiffra improved liver enzymes, fibrosis biomarkers and imaging tests as compared with placebo. 
• The primary results of the trial were published in the New England Journal of Medicine in February 2024.

Patients enrolled in the MAESTRO-NASH trial 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 and hepatic decompensation events, as well as all-cause mortality. The 54-month outcomes portion of the trial is designed to generate confirmatory data that, if positive, will help verify Rezdiffra’s clinical benefit and may support full approval.

About Nonalcoholic Steatohepatitis

• Nonalcoholic steatohepatitis (NASH) is a more advanced form of nonalcoholic fatty liver disease (NAFLD). 
• NASH is a leading cause of liver-related mortality and an increasing burden on healthcare systems globally. 
• Additionally, patients with NASH, especially those with more advanced metabolic risk factors (hypertension, concomitant type 2 diabetes), are at increased risk for adverse cardiovascular events and increased morbidity and mortality.
• Once patients progress to NASH with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis), the risk of adverse liver outcomes increases dramatically. NASH is rapidly becoming the leading cause of liver transplantation in the US.

NASH: Epidemiology

• Madrigal estimates that approximately 1.5 million patients have been diagnosed with NASH in the US, of which approximately 525,000 have NASH with moderate to advanced liver fibrosis. 
• Madrigal plans to focus on approximately 315,000 diagnosed patients with NASH with moderate to advanced liver fibrosis under the care of the liver specialist physicians during the launch of Rezdiffra.
• NASH is also known as metabolic dysfunction associated steatohepatitis (MASH). 
• In 2023, global liver disease medical societies and patient groups came together to rename the disease, with the goal of establishing an affirmative, non-stigmatizing name and diagnosis. 
• Nonalcoholic fatty liver disease (NAFLD) was renamed metabolic dysfunction-associated steatotic liver disease (MASLD), NASH was renamed MASH, and an overarching term, steatotic liver disease (SLD), was established to capture multiple types of liver diseases associated with fat buildup in the liver. 
• In addition to liver disease, patients with MASH have at least one related comorbid condition (e.g., obesity, hypertension, dyslipidemia, or type 2 diabetes).

About Rezdiffra

• Rezdiffra is a prescribed medicine used along with diet and exercise to treat adults with nonalcoholic steatohepatitis (NASH) with moderate to advanced liver scarring (fibrosis), but not with cirrhosis of the liver.
• It is not known if Rezdiffra is safe and effective in children (under 18 years old).
• This indication is approved based on improvement of NASH and liver scarring (fibrosis). There are ongoing studies to confirm the clinical benefit of Rezdiffra.

Madrigal Pharmaceuticals

Madrigal Pharmaceuticals, Inc. is a biopharmaceutical company pursuing novel therapeutics for nonalcoholic steatohepatitis (NASH), a liver disease with high unmet medical need.