FDA Accelerates Approval of Rezdiffra, the First Drug for Non-Alcoholic Fatty Liver Disease

In the early hours of March 15, Madrigal Pharmaceuticals announced on their official website that the FDA has granted accelerated approval for Rezdiffra (resmetirom) in combination with diet and exercise to treat non-cirrhotic non-alcoholic steatohepatitis (NASH) patients with moderate to advanced liver fibrosis (consistent with fibrosis stage F2 to F3). This approval fills a significant gap in the treatment of metabolic dysfunction-related fatty liver disease (MASH, formerly known as NASH), making Rezdiffra the first and only drug approved by the FDA for the treatment of non-alcoholic fatty liver disease.

NASH, a severe form of non-alcoholic fatty liver disease (NAFLD), is characterized by excessive fat accumulation in the liver, leading to cellular stress, inflammation, fibrosis, and potential progression to liver cirrhosis, liver failure, cancer, or even death. For the past 40 years since the term NASH was coined by researchers at Mayo Clinic, finding effective treatments for NASH has been a challenge, with unmet needs and no cure or specific therapies available.

Resmetirom, as a potential first-in-class oral selective agonist of the thyroid hormone receptor (THR)-β, aims to target non-alcoholic fatty liver disease. Now, with its FDA approval, it becomes the first drug for NASH to receive regulatory clearance in the past 40 years.

The accelerated approval of Rezdiffra is based on recent results from the MAESTRO-3 phase NASH trial, which were published in the New England Journal of Medicine.

The ongoing MAESTRO-3 trial is a phase 3 clinical trial that recruited 1,759 biopsy-confirmed NASH patients. The patients were randomly assigned in a 1:1:1 ratio to receive either a once-daily dose of 80 mg or 100 mg of Rezdiffra or a placebo. The two primary endpoints at week 52 were improvement in NASH fibrosis without worsening, and improvement in fibrosis by at least one stage with no worsening of NAFLD activity score. A key secondary endpoint was the percentage change in LDL cholesterol from baseline at week 24.

Rezdiffra met the primary and key secondary endpoints of the MAESTRO trial for NASH. Additionally, compared to the placebo, Rezdiffra demonstrated improvements in liver enzymes, fibrosis biomarkers, and imaging tests. The primary results of the trial were published in the New England Journal of Medicine in February 2024.

Patients participating in the MAESTRO-3 trial for NASH will continue treatment for an additional 54 months after the initial 52-week treatment period to accumulate and measure clinical liver outcome events, including progression to cirrhosis and decompensated liver function, as well as all-cause mortality. The 54-month results of this trial are intended to generate confirmatory data that, if positive, could support the full approval and clinical benefits of Rezdiffra.

A Multi-billion Dollar Market Opportunity

Non-alcoholic fatty liver disease, as a more advanced form of non-alcoholic fatty liver (NAFLD), has become a leading cause of liver-related deaths, putting a significant burden on the global healthcare system. Particularly for patients with metabolic risk factors such as hypertension and type 2 diabetes, NASH significantly increases the risk of cardiovascular events, overall morbidity, and mortality.

Once patients progress to the stage of moderate to advanced liver fibrosis in non-alcoholic fatty liver disease (equivalent to fibrosis stages F2 to F3), the risks of adverse liver outcomes escalate rapidly. NASH is becoming a major indication for liver transplantation.

According to Madrigal's estimates, there are approximately 1.5 million NASH patients in China, with around 525,000 already in the moderate to advanced liver fibrosis stage. During the launch period of Rezdiffra, Madrigal plans to focus on approximately 315,000 NASH patients diagnosed with moderate to advanced liver fibrosis under the supervision of liver specialists.

NASH is also known as metabolic dysfunction-associated fatty liver disease (MASH). In order to establish a more positive and unbiased disease nomenclature and diagnosis, the Global Liver Institute, along with patient advocacy groups, decided in 2023 to rename non-alcoholic fatty liver disease (NAFLD) as metabolic dysfunction-associated fatty liver disease (MASLD) and non-alcoholic steatohepatitis as MASH. They introduced an overarching term, fatty liver disease (SLD), to encompass various liver diseases related to hepatic fat accumulation. It's worth noting that MASH patients often present with at least one related comorbidity such as obesity, hypertension, dyslipidemia, or type 2 diabetes.