Pharmaceutical Technology

FDA approves Madrigal’s Rezdiffra as the first NASH therapy

Madrigal’s Rezdiffra received an accelerated approval as a treatment for noncirrhotic NASH, also known as MASH.

Madrigal Pharmaceuticals’ Rezdiffra (resmetirom) has become the first drug to be approved by the US Food and Drug Administration (FDA) as a treatment for noncirrhotic nonalcoholic steatohepatitis (NASH), which is also known as metabolic dysfunction-associated steatohepatitis (MASH).

The NASH treatment landscape has seen multiple disappointments, with multiple companies like AstraZeneca ultimately terminating the development of their NASH therapies. The latest in this line of disappointments was the US FDA rejection of Intercept Pharmaceuticals’ new drug application (NDA) for its NASH therapy, obeticholic acid. The agency cited concerns over the therapy’s safety profile, especially the potential risks of causing liver injury and diabetes.

Redziffra’s approved use is intended for NASH patients with moderate to advanced liver fibrosis, and is to be administered in conjunction with diet and exercise. “The approval will allow Madrigal market exclusivity in NASH for two years, allowing the company to generate considerable profit”, said Jay Patel, a GlobalData analyst specialising in NASH. According to GlobalData’s patient-based forecast, Rezdiffra is expected to generate $1bn in global sales in 2027.

GlobalData is the parent company of Pharmaceutical Technology.

Rezdiffra is a thyroid hormone receptor beta (THR-β) agonist, which helps maintain liver homeostasis and improve lipid metabolism. The therapy will be available in the US in April, and in the last few months, the company has been raising funds to finance the launch and commercialisation of Rezdiffra.

Rezdiffra’s accelerated approval was based on the results from the Phase III MAESTRO-NASH trial (NCT03900429). The study met its two primary endpoints by showing a significant improvement in disease resolution and liver fibrosis. NASH resolved in 25.9% of patients who received an 80mg dose of Rezdiffra and 29.9% of those taking the 100mg dose without the worsening of fibrosis, compared to the 9.7% of patients in the placebo group. Madrigal expects the 54 month-follow-up data from the trial to support full approval for Rezdiffra.

Patel added that although Rezdiffra’s approval marks a major step forward for the NASH therapeutic space, Madrigal is likely to face competition as more NASH assets get approved, especially from the more efficacious FGF21 analogue drug class in more severe fibrotic NASH patient populations. He also mentioned the next-generation THR-β agonists, such as Viking’s VK2809 that aim to build on Rezdiffra’s success, as significant competitors. The approvals for other NASH therapies are expected from 2027–2030.

Patel also cautioned that Madrigal’s success may not last beyond the two-year exclusivity period. “Patients with less severe NASH will also likely be treated initially with incretin-modulating therapies, like Novo Nordisk’s semaglutide (which is marketed as Ozempic or Wegovy or Rybelsus) or Lilly’s tirzepatide (which is marketed as Zepbound or Mounjaro), even prior to the approval of this drug class for NASH, given the extent of comorbid type 2 diabetes and obesity within the NASH population,” he said.

In addition to Novo Nordisk trialling its blockbuster drug as a monotherapy, it is also exploring combinations. For treating NASH, semaglutide is being studied in combination with Akero Therapeutics’ efruxifermin. In June 2023, Akero and Novo reported positive data from the Phase IIb trial showing that patients who received the efruxifermin and Ozempic combination treatment had a 65% relative reduction in liver fat in patients with type 2 diabetes and liver fibrosis due to NASH, compared to a 10% reduction seen in patients receiving only Ozempic. Altimmune’s incretin mimetic, pemvidutide, when trialled as a monotherapy showed a 68.5% relative reduction in liver fat content at 12 weeks in a Phase IIb trial.