After a long list of failures, a much-awaited treatment for noncirrhotic non-alcoholic steatohepatitis (NASH), recently renamed metabolic dysfunction-associated steatohepatitis (MASH), has finally arrived with the US Food and Drug Administration’s (FDA’s) accelerated approval of Madrigal Pharmaceuticals’ Rezdiffra (resmetirom).
Rezdiffra is approved for use in adults with NASH/MASH who have moderate to advanced liver scarring (fibrosis) that has progressed to stage 2 or 3 (F2, F3, respectively) in severity, in conjunction with diet and exercise.
NASH was formally given a name around four decades ago. It is a type of non-alcoholic fatty liver disease characterized by liver inflammation, which can lead to liver scarring and liver dysfunction over time.
The condition is often associated with metabolic problems such as type 2 diabetes and high blood pressure.
It is thought that around 6 to 8 million people in the US, or five percent of American adults, have NASH with moderate to advanced liver scarring, and the FDA says this number is expected to rise in the coming years.
Rezdiffra is a thyroid hormone receptor-beta (THR-β) agonist that partially activates the receptor. In the liver, the receptor’s activation leads to reduced fat accumulation.
The oral, once-daily drug is the first approved treatment for NASH, making it a landmark approval.
Bill Sibold, CEO of Madrigal, said in a statement: “NASH with moderate to advanced liver fibrosis is a serious and progressive liver disease that, until now, has not had an FDA-approved therapy. The accelerated approval of Rezdiffra is a culmination of more than 15 years of research from our founder, Dr. Becky Taub, and a small R&D team that took on one of the biggest challenges in drug development. This is a historic moment for the NASH field and represents the best of what our industry is capable of. We’re excited to deliver Rezdiffra to patients in need.”
Becky Taub, MD, Madrigal founder, chief medical officer and president of R&D, stated, “Madrigal would like to thank the many patients who made the accelerated approval of Rezdiffra possible by participating in our clinical studies. We believe Rezdiffra will change the treatment paradigm for NASH with moderate to advanced liver fibrosis, giving physicians a liver-directed therapy to help improve fibrosis and resolve NASH before their patients progress to cirrhosis.”
Of significance, the FDA isn’t requiring a liver biopsy to determine eligibility for Rezdiffra. Investors had been discussing how a cumbersome and invasive biopsy requirement would limit access to Rezdiffra.
Clinical Win
Rezdiffra’s safety and efficacy were evaluated based on analysis of data from the ongoing Phase III MAESTRO-NASH clinical trial that is planned to run for 54 months.
At the 12-month mark, among 966 patients with MASH confirmed by biopsy, 25.9 percent of patients who received 80 mg of resmetirom achieved NASH resolution, including a reduction in nonalcoholic fatty liver disease (NAFLD) activity and with no worsening of fibrosis, compared to 9.7 percent who received placebo. This increased to 29.9 percent of patients achieving NASH resolution with a 100 mg dose of the drug.
In addition to NASH resolution, the trial’s other primary endpoint was improvement in fibrosis by at least one stage with no worsening of the NAFLD activity score. In the 80-mg resmetirom group, 24.2 percent of patients achieved improvement in fibrosis and 25.9 percent in the 100-mg resmetirom group, compared with 14.2 percent in the placebo group.
Low-density lipoprotein (LDL) cholesterol levels from baseline to week 24 dropped by 13.6 percent in the 80-mg resmetirom group and 16.3 percent in the 100-mg resmetirom group, compared with 0.1 percent in the placebo group.
Results from the trial were published in The New England Journal of Medicine.
The most common side effects of Rezdiffra included diarrhea and nausea. Rezdiffra comes with warnings and precautions on its label for drug-induced liver toxicity and gallbladder-related side effects.
Rezdiffra received FDA Breakthrough Therapy, Fast Track and Priority Review designations for the indication.
As part of the accelerated approval, Madrigal has agreed to provide additional confirmatory data backing Rezdiffra’s benefits that could lead to a full approval. The company plans to go ahead with the ongoing 54-month extension of MAESTRO-NASH that will assess disease progression and other outcomes such as liver transplants and development of cirrhosis.
A separate study called MAESTRO-NASH Outcomes is evaluating Rezdiffra in patients with well-compensated NASH cirrhosis, a more advanced stage of the disease.
“Previously, patients with NASH who also have notable liver scarring did not have a medication that could directly address their liver damage,” said Nikolay Nikolov, MD, acting director of the Office of Immunology and Inflammation in the FDA’s Center for Drug Evaluation and Research (CDER), in the FDA’s news release. “Today’s approval of Rezdiffra will, for the first time, provide a treatment option for these patients, in addition to diet and exercise.”
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Rezdiffra Market Launch
Madrigal has set Rezdiffra’s price at the wholesale acquisition cost of $47,400 per year before any discounts. Last year, the Institute for Clinical and Economic Review (ICER), a drug pricing watchdog, estimated that the drug would meet the cost-to-effectiveness benchmark if it was priced between $39,600 and $50,100 per year.
Madrigal’s shares spiked 24 percent to $301.99 in extended trading after Rezdiffra’s approval was announced.
As the first treatment in the space, Rezdiffra will be shaping an entirely new market. Madrigal says it could take about a year to establish the drug’s commercial foundation to foster rapid uptake.
Other NASH/MASH Contenders
Several other companies, ranging from small to large pharma and biotech companies, are developing NASH/MASH treatments. This included Intercept Pharmaceuticals’ Ocaliva (obeticholic acid), formerly a close contender of Rezdiffra, but the FDA served it a second rejection letter last June after having rebuffed it three years prior.
The FDA said Ocaliva, which is currently approved for primary biliary cholangitis (PBC), another chronic liver disease, must have long-term patient outcomes data if Intercept wants to submit another application with the agency.
Intercept isn’t planning for a third try as the company said it could take up to three years to accrue the requested clinical benefit data. In its analysis, ICER noted that an independent appraisal committee found that the current evidence for obeticholic acid was “deemed inadequate to demonstrate a net health benefit.”
Akero Therapeutics and 89bio are developing fibroblast growth factor 21 (FGF21) analogs, efruxifermin and pegozafermin, respectively. Administered subcutaneously, they analogs have demonstrated promising results in patients with F2 and F3 MASH in early-stage trials. The companies are moving rapidly forward with Phase III studies for the candidates.
Other companies including Pfizer have attempted to develop FGF21 analogs but faced the challenge of rapid clearance of the agents from the circulation. The latest generation of FGF21 candidates have extended half-lives owing to PEGylation and other modifications at key residues, which allow for subcutaneous administration once weekly or even once every two weeks.
Viking Therapeutics’ VK2809 is an oral THR-β agonist like Rezdiffra. In a midstage study, the drug resulted in an average relative change in liver fat of just over 51 percent after 12 weeks of treatment.
GLP-1 agonists are also on the NASH/MASH horizon. Eli Lilly shared positive Phase II data for its GIP/GLP-1 dual agonist tirzepatide (approved for diabetes as Mounjaro and obesity as Zepbound) in overweight or obese people with MASH. Effects on liver fibrosis were not measured due to statistical limitations.
Boehringer Ingelheim is also co-developing its glucagon/GLP-1 agonist survodutide with partner Zealand Pharma. The company boasted about promising Phase II data but hasn’t disclosed any specifics on measures of fibrosis.
Boehringer is also testing genetic strategies to target the fatty liver disease. Earlier this month, the company announced a new, potentially $2 billion partnership with siRNA biotech RiboCure to develop new NASH/MASH treatments.
For Rezdiffra, Madrigal expects the drug to be a chronic treatment that patients continue to take until there are no more signs of the disease and contributing factors such as obesity are eliminated.
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