Headway in Hepatology: Resmetirom’s Historic FDA Approval, What’s Next in MASH

For many years, metabolic dysfunction-associated steatohepatitis (MASH) was a clinical enigma – prevalent, progressive, and without a targeted treatment. That narrative changed in 2024, a year that will undoubtedly be remembered as a turning point in hepatology when the US Food and Drug Administration (FDA) granted accelerated approval to resmetirom (Rezdiffra).1

While MASH management has historically relied exclusively on weight loss, resmetirom now provides the first and only pharmacologic option for treatment of the progressive liver disease and is indicated specifically for patients with noncirrhotic MASH and moderate to advanced fibrosis. Conditionally approved for use alongside diet and exercise, the thyroid hormone receptor (THR)-β selective agonist has redefined the approach to care for a disease long deemed untreatable.1

This landmark approval sets the stage for a new era in hepatology, proving that targeted therapies can effectively address the complexities of MASH. Building on this momentum, a robust pipeline of agents in clinical development hints at a future where additional innovative treatments could expand and complement the therapeutic landscape for a disease state that has historically faced limited treatment options and significant unmet needs.

Resmetirom Approval Revolutionizes MASH Care

Supported by 12 phase 1 studies, a pair of phase 2 studies, and 4 phase 3 studies in its vast clinical development program, resmetirom is the first and only drug to receive FDA approval for the treatment of MASH. Although its continued approval for this indication is contingent upon verification and description of clinical benefit in ongoing confirmatory trials, resmetirom’s ability to resolve MASH with no worsening of fibrosis and improve fibrosis by ≥ 1 stage with no worsening of the NAFLD activity score was enough to support its accelerated approval and bring the drug to the market in 2024, much to the joy of patients and clinicians alike.1,2

“We have been waiting for a MASH drug approval for at least 2 decades, and we finally have an FDA-approved drug this year,” Mazen Noureddin, MD, MHSc, director of the Houston Liver Institute and a professor of medicine and transplant hepatologist at Houston Methodist Hospital, told HCPLive. “Patients are so happy that they have options. The market responded positively to it, especially not needing a liver biopsy and using NITs to diagnose the disease, start treatment, and monitor response. It has been a huge step this year.”

Adelina Hung, MD, a clinical assistant professor at Rosalind Franklin University Chicago Medical School and director of the IBD program at Sinai Health System Chicago, explained to HCPLive how weight loss for MASH management has historically been both a struggle for patients and a source of frustration for healthcare providers.

“Resmetirom allows patients to utilize pharmacologic therapy in conjunction with lifestyle changes to treat steatohepatitis and reverse fibrosis. This is a game changer for the disease state and gives hope to patients who previously struggled to achieve their treatment goals,” she said, going on to describe how this approval energized the MASH community and paved the way for innovative clinical trials exploring other unique pathways for treating the disease.

Important Lessons from Obeticholic Acid’s FDA Failure

Resmetirom may have been the first MASH drug to meet the FDA’s expectations for an approvable therapeutic for the progressive liver disease, but it certainly was not the first to try.

In 2023, many in the hepatology community believed Intercept Pharmaceuticals’ obeticholic acid was on its way to becoming the first-ever FDA-approved MASH therapeutic. With a PDUFA date on the horizon and positive phase 3 safety and efficacy data demonstrating the agent’s response rate without worsening fat, inflammation, or fibrosis, obeticholic acid seemed like a prime candidate to make history by crossing the FDA finish line.

However, just a month before the June 22, 2023, PDUFA date, an FDA Gastrointestinal Drugs Advisory Committee meeting voted against the risk-benefit profile of obeticholic acid and supported deferring approval until further clinical outcomes data was submitted and reviewed. Indeed, rather than the long-awaited approval many patients and providers were hoping for, the New Drug Application for obeticholic acid was instead met with a Complete Response Letter requiring successful completion of the long-term outcomes phase of the 3 REGENERATE study for resubmission, to which Intercept responded by discontinuing all MASH-related investments.3,4

Despite its failure to earn FDA approval, Jörn Schattenberg, MD, director of the department of Internal Medicine II at Saarland University Medical Center, explained the significance of what the MASH community learned from obeticholic acid’s shortcomings.

“[Obeticholic acid] showed us that the endpoints we've selected are doable. I think that was the very important field message for the field, so we knew it could be achieved,” he said, later describing the approval of resmetirom as a “turning point” in the history of MASH drug development.

First MASH FDA Approval Marks Progress, But Not Perfection

Noureddin was careful to note that even with the advent of the first FDA-approved therapeutic, there’s still more to be done in the MASH treatment landscape. Specifically, he cited the need for additional drugs targeting other disease pathways and pointed to the potential of combining different drugs for added efficacy.

Additionally, Noureddin pointed to the need for more noninvasive tests (NITs) to eliminate the need for liver biopsy in patients with MASH, describing how converting clinical trials from biopsy-based to NIT-based could expedite drug development and subsequent approval.

“We've seen effective drugs, but not everybody responds. There's room for improvement, I think that’s the important message,” Schattenberg added, describing the MASH pipeline as “interesting” and noting the different mechanisms of action that could potentially be combined.

What’s Next in MASH?

“This is an exciting time for MASH given the increasing number of promising phase 3 trials underway,” Hung told HCPLive, citing data expected in the near future for new targets in MASH like GLP-1, peroxisome proliferator-activated receptor (PPAR), fibroblast growth factor 21 (FGF21), and fatty acid synthase (FASN).

Second only to the conditional approval of resmetirom, Schattenberg described data from the ESSENCE trial of once-weekly subcutaneous semaglutide 2.4 mg in adults with MASH and moderate to advanced fibrosis as the next “big news” for MASH in 2024. Headline results from the first part of the ongoing phase 3 trial showed the study met its primary endpoint for statistically significant and superior improvement in liver fibrosis with no worsening of steatohepatitis as well as resolution of steatohepatitis with no worsening of liver fibrosis.5

According to a press release from Novo Nordisk, the company expects to file for regulatory approvals in the US and EU in the first half of 2025, and a readout from part 2 of the ESSENCE trial is expected in 2029.5

Looking further ahead in the MASH pipeline at agents the hepatology community may see more of in 2025, Schattenberg cited data presented at The Liver Meeting 2024 from the American Association for the Study of Liver Diseases (AASLD) in San Diego, California, pointing to the potential of GLP-1s, THR-β agonists, FGF21s, and diacylglycerol acyltransferase (DGAT) inhibitors.

Like Schattenberg, Noureddin also referenced promising data from The Liver Meeting when looking ahead in the MASH pipeline, additionally calling attention to data presented at the European Association for the Study of the Liver Congress. From these 2 meetings, he outlined 4 drugs he is most looking forward to seeing more of in 2025: efruxifermin, a long-acting, bivalent Fc–FGF21 analog; survodutide, a dual glucagon/GLP-1 receptor agonist that received FDA Breakthrough Therapy Designation this year; pemvidutide, a peptide-based dual GLP-1/glucagon receptor agonist; and efimosfermin alfa, a once-monthly investigational and long-acting FGF21 analog.6

“I think MASH is super exciting and the future is bright. I'm really optimistic about what we're going to do with MASH,” Noureddin said. “I think it's just going to keep getting better and better every year, so stay tuned.”

References

1. Brooks, A. Resmetirom (Rediff) Receives Historic FDA Approval for Noncirrhotic NASH. HCPLive. March 14, 2024. Accessed December 20, 2024. https://www.hcplive.com/view/resmetirom-rezdiffra-receives-historic-fda-approval-for-noncirrhotic-nash
2. Brooks, A. Resmetirom (Rezdiffra) Now Available in US Pharmacies, Marks Turning Point in NASH Management. HCPLive. April 9, 2024. Accessed December 20, 2024. https://www.hcplive.com/view/resmetirom-rezdiffra-now-available-in-the-us-pharmacies-marks-turning-point-in-nash-management
3. Campbell P. FDA Committee Votes Against Risk-Benefit Profile of OCA 25 mg for NASH. HCPLive. May 19, 2023. Accessed December 20, 2024. https://www.hcplive.com/view/fda-committee-votes-against-risk-benefit-profile-of-oca-25-mg-for-nash
4. Walter K. Intercept Cancels Plans For NASH Treatment After CRL. HCPLive. June 23, 2023. Accessed December 20, 2024. https://www.hcplive.com/view/intercept-cancels-plans-nash-treatment-crl
5. Brooks A. ESSENCE: Semaglutide Improves Fibrosis, Resolves Steatohepatitis in MASH. HCPLive. November 1, 2024. Accessed December 23, 2024. https://www.hcplive.com/view/essence-semaglutide-improves-fibrosis-resolves-steatohepatitis-in-mash
6. Brooks A. FDA Grants Breakthrough Therapy Designation to Survodutide for Noncirrhotic MASH. HCPLive. October 8, 2024. Accessed December 23, 2024. https://www.hcplive.com/view/fda-grants-breakthrough-therapy-designation-survodutide-noncirrhotic-mash