Specifically, the FDA granted Rezdiffra (resmetirom) accelerated approval to treat adults with non-cirrhotic MASH and moderate-to-advanced liver fibrosis consistent with stages F2 to F3 fibrosis, in conjunction with diet and exercise. A biopsy is not required for diagnosis.
The THR-β selective agonist will be available to US patients starting April, after months of building excitement. In a 70-physician FirstWord poll conducted last month, 30% of respondents said they were very enthusiastic about prescribing the drug (see: Physician Views Results: Potential new NASH drug gets positive assessment from US docs).
This greenlight will most likely open the MASH floodgates. Despite the difficulty designing drugs for the heterogeneous liver disease, which has a variety of etiologies and paths of progression, a series of promising candidates across multiple mechanisms have lined up behind Rezdiffra, such as FGF21 analogues and GLP-1 agonists. For more on the development landscape, see Spotlight On: MASH pipeline holds promise of multiple mechanisms for disease management.
Rezdiffra, a once-daily, oral candidate secured FDA approval on Thursday thanks to 52-week data from the pivotal MAESTRO-NASH study, which met the co-primary endpoints of MASH resolution with no worsening of fibrosis, and at least a one-stage reduction in fibrosis with no worsening of non-alcoholic fatty liver disease (NAFLD) activity score.
According to results, 25.9% of patients who received the 80mg dose, and 29.9% in the 100mg arm, achieved MASH resolution endpoint, compared with 9.7% for placebo. For fibrosis improvement, the rates were 24.2% and 25.9% for the low- and high-dose arms, respectively, versus 14.2% for placebo.
Most of the reported side effects were mild-to-moderate, with a roughly 11-13% serious adverse event rate across each of the three cohorts. There was no incidence of drug-induced liver injury, increases in bone fractures or adverse events linked to thyroid hormone effects outside the liver such as heart rate changes.
Madrigal’s journey to FDA approval comes after the failures of several other drug developers to show both safety and efficacy of their MASH programmes, most notably that of obethicholic acid from Intercept.
The biotech received its first complete response letter for the candidate in 2020, which said that the predicted benefit of obethicholic acid "does not sufficiently outweigh the potential risks.” Three years later, FDA again rejected the treatment, saying that approval would require, at a minimum, the successful completion of a long-term outcomes Phase III trial.
Now that Madrigal has shown approval is possible, drugmakers waiting in the wings may be more bullish on the prospects for their own programmes.
FirstWord spoke with 89bio chief medical officer Hank Mansbach earlier this week on the chances of accelerated approval for FGF21 analogue pegozafermin, for which it just launched a Phase III trial. At the time, Mansbach said an approval for resmetirom would give the company a confidence boost.
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