On March 14, 2024, Madrigal Pharmaceuticals received the first regulatory approval for a drug targeting NonAlcoholic SteatoHepatitis (NASH). Specifically, FDA approved Rezdiffra (resmetirom) for the treatment of adults with noncirrhotic NASH with moderate to advanced liver scarring (fibrosis), to be used along with diet and exercise. NASH, recently renamed MASH, which stands for Metabolic dysfunction-Associated Steatotic Liver Disease, is estimated to affect 5% of the population in the Western world, one third of which is thought to have moderate to advanced fibrosis (F2/F3).
Resmetirom is an activator of the thyroid hormone β receptor. The positive risk benefit balance of resmetirom was based on an analysis at month 12 in a 54-month, randomized, double-blind placebo-controlled trial. The completion of the trial to month 54 is required as a postapproval study, at which point a reduction in end stage liver disease and hepatocellular carcinoma can hopefully be shown. In the pivotal trial, 888 subjects were randomly assigned to receive one of the following: placebo (294 subjects); 80 milligrams of resmetirom (298 subjects); or 100 milligrams of resmetirom (296 subjects); once daily, in addition to diet and exercise (standard care). At 12 months, liver biopsies showed that a greater proportion of subjects who were treated with resmetirom achieved NASH resolution or an improvement in fibrosis as compared with those who received placebo.
The most common side effects of resmetirom were diarrhea and nausea. Other side effects included pruritus, vomiting, constipation and dizziness. The resmetirom label includes warnings and precautions on drug-induced liver toxicity, gallbladder-related side effects and interactions with certain statins, which should be dosed in submaximal doses.
Although serial liver biopsies were required during the pivotal trial, the US label does not require this, which is of course a big plus when it comes to patient access to the drug. No clear guidance is given to clinicians on how to establish ‘noncirrhotic NASH with moderate to advanced fibrosis’ and updates of existing guidelines will hopefully give guidance on this.
EMA has set the hurdle for approval of a NASH drug slightly higher than FDA. Whereas FDA required either resolution of NASH or improvement of fibrosis, EMA requires both. However, resmetirom met both of these endpoints in the pivotal trial. Thus, EMA will likely follow suit with a positive assessment. Nevertheless, the reimbursement hurdle in the EU may be high with an announced annual price in the US of $ 47.700.
A final notable point is the relation between lowering of liver fat and histology outcomes. After one year, the lowest 80 mg dose of resmetirom resulted in a 35% reduction from baseline in liver fat as assessed by MRI-PDFF, for a difference of 26.7% with placebo. At 16 weeks, this difference had already established itself almost completely. This will raise the bar in a competitive field where many drug candidates have failed. But for today, congratulations to Madrigal Pharmaceuticals and FDA for a landmark approval!