First Flight

FDA Approves Resmetirom: First Ever for MASH with Fibrosis

Firsts are worth celebrating. In this case, the cause for celebration is especially great. MASH or metabolic steatohepatitis is a disease that is growing dramatically more common and more harmful to the health of the population. Late this week, FDA approved resmetirom to be the first ever treatment for MASH with fibrosis.

Note that the indication for patients with fibrosis is significant. Because this signals progression of the disease and other drugs have had a tough time showing a benefit in this advanced stage of MASH.

The American Liver Foundation hailed this news as groundbreaking, saying:

“Until now, there were no approved treatments for NASH and today’s decision by the FDA provides hope to millions of Americans dealing with this dangerous and progressive disease.”

A Handsome Price

Such innovation as this comes at a handsome price. Madrigal Pharmaceuticals will sell the drug under the brand name of Rezdiffra at a list price of $47,400 per year. This lines up with estimates of the drug’s economic value by ICER, which said that a price tag between $39,600 and $50,100 “would achieve common thresholds for cost-effectiveness.”

Many factors make this a reasonable price. The cost burden of MASH with fibrosis is considerable. It can lead to liver cancer, liver failure, transplantation, and death. None of that is good. All of it is costly.

And the road to this breakthrough has been littered with failures – another reason this first is something to celebrate.

A Distinct Mechanism of Action in the Liver

Resmetirom works on an enzyme receptor specifically inside the liver – thyroid hormone receptor-beta (THR-β). By activating this receptor, resmetirom works to reduce the formation of triglycerides – a type of fat that accumulates in the liver when a person has MASH. It is this accumulation of fat in the liver that defines MASH and produces the damage that can lead to liver failure and death.

This is distinct from the mechanisms that GLP-1 agonists employ to exert an effect on MASH. Semaglutide, tirzepatide, and survodutide all are under study for a benefit in MASH. But those drugs have an effect on the accumulation of fat in the whole body, not just the liver. So those drugs have the effect of reducing body weight that results from accumulation of excess fat (i.e. obesity) while resmetirom has no such effect. Body weight in clinical trials with resmetirom was unchanged.

The Promise of Much More Progress

It remains to be seen how any benefits that obesity drugs might have in MASH will compare to or complement the benefits that resmetirom has for patients with MASH and fibrosis. This is why firsts are so exciting. They bring the promise of much learning and progress to come.

Click here for the announcement from the FDA and here for the approved labeling. (Note that the agency is still stuck on the obsolete terminology of NASH instead of MASH.) Click here for clinical trial results recently published in NEJM. For further perspective on this news, click here, here, and here.

First Flight, photograph by John T. Daniels / Wikimedia Commons

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March 16, 2024