Madrigal's Rezdiffra clinches first FDA approval for MASH

2024-03-14

上市批准临床3期加速审批临床结果

After years of clinical failures and FDA rejections in the liver disease space, Madrigal Pharmaceuticals has finally taken gold in the race for the first approval in metabolic dysfunction-associated steatohepatitis (MASH), also known as non-alcoholic steatohepatitis (NASH).

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’s approval comes, in part, because it was able to demonstrate efficacy without the safety concerns that sunk Intercept Pharmaceuticals’ obeticholic acid.

Treatment defining data

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.

Rezdiffra’s label reflects the clinical safety results. The drug does not carry a boxed warning, and its label notes that the most common side effects are diarrhoea, nausea, pruritus, vomiting, constipation, abdominal pain, and dizziness.

First success of many failures

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.

Large pharmas have also seen their fair share of setbacks in the disease. Last year, Novartis ended a partnership with Pliant Therapeutics to develop the latter's integrin αVβ1 inhibitor integrin αVβ1 inhibitor PLN-1474 for MASH.

Pfizer and AstraZeneca have both recently trimmed their MASH pipelines. The UK drugmaker terminated development of late-stage injectable GLP-1/glucagon co-agonist cotadutide last year, while the US pharma has ended at least two MASH programmes in the last three years: ketohexokinase inhibitor ketohexokinase inhibitor PF-06835919, and oral GLP-1 receptor agonist danuglipron GLP-1 receptor agonist danuglipron.

MASH future looks bright

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.

Other companies who have shared promising mid-stage data include fellow FGF21 developer Akero Therapeutics, Ionis Pharmaceuticals’ antisense inhibitor, Sagimet Biosciences and its fatty acid synthase (FASN) inhibitor, partners Boehringer Ingelheim and Zealand Pharma for their dual GLP-1 and glucagon agonist, as well as Viking Therapeutics, whose candidate has the same mechanism of action as Madrigal’s.