Stephen Harrison, MD: FDA Approval of Resmetirom Ends Lengthy Road to First NASH Treatment

The historic approval of resmetirom (Rezdiffra) for noncirrhotic nonalcoholic steatohepatitis (NASH) with moderate to advanced fibrosis recently brought to an end the long wait for a US Food and Drug Administration (FDA)-approved treatment.¹

Last year saw what many hoped would be the end of the NASH treatment drought with Intercept Pharmaceuticals’ obeticholic acid (OCA), only to be squandered by a Complete Response Letter (CRL) indicating it could not be approved in its present form and would require at least the successful completion of the long-term outcomes phase of the REGENERATE study for resubmission. With OCA’s second FDA rejection, Intercept opted to discontinue its NASH-related investments. Thus, in 2024, attention shifted to Madrigal Pharmaceuticals’ resmetirom.²

“Fail stands for ‘first attempt in learning’, right? So, obeticholic acid failed not once but twice with the FDA, and we learned a lot from that,” Stephen Harrison, MD, founder and chairman of Pinnacle Clinical Research and Summit Clinical Research, explained in an interview with HCPLive.

Specifically, he noted OCA’s CRL emphasized the importance of adverse event profiles and treatment safety, suggesting both may be of more value to the FDA than efficacy.

“If you have a drug that has efficacy, but it's relatively minor, which obeticholic acid had no improvement on NASH resolution, it had a 10% treatment effect on fibrosis for 1 stage improvement, then the adverse event profile becomes the focal point,” he explained.

Resmetirom, on the other hand, showed far more efficacy with fewer, if any, safety concerns. The oral, thyroid hormone receptor (THR)-β selective agonist was backed by a lengthy clinical development program consisting of 12 phase 1 studies, a pair of phase 2 studies, and 4 phase 3 studies, enough to support its accelerated approval.¹

Even prior to resmetirom’s March 14 PDUFA date, Harrison expressed confidence that the clinical trial data would be enough to support its approval: “The FDA typically wants to see around 1500 patients of safety data, and there's a lot more than that that's gone in with Madrigal’s filing. From that data, from my vantage point, I don't see any safety concerns. I'm not the FDA and who knows what they're looking at or what is on their mind from a safety perspective, but I don't see anything,” Harrison said, pointing out the lack of thyroid axis, sex hormone, and bone mineral density issues, additionally addressing theoretical concerns brought up in the editorial.

Though resmetirom was granted accelerated approval, the March 14 release from Madrigal Pharmaceuticals noted the continued approval for this indication may be contingent upon verification and description of clinical benefit in ongoing confirmatory trials. To support its full approval, a postapproval study is required to verify and describe resmetirom’s clinical benefit, which will be done by completing the ongoing 54-month, randomized, double-blind placebo-controlled MAESTRO-NASH trial measuring the extent of liver inflammation and scarring. Additionally, a second ongoing outcomes trial is evaluating progression to liver decompensation events in patients with well-compensated NASH cirrhosis treated with resmetirom versus placebo.¹

“I think what's really cool about the launch of this drug, what this means to the field, it's transformative. This is like a magnitude 8 earthquake, like seismic shifts are about to take place,” Harrison concluded.

^{Editor's note: this conversation was recorded prior to the March 14, 2024 FDA approval of resmetirom.}

^{Harrison has relevant disclosures with Madrigal Pharmaceuticals, Intercept Pharmaceuticals, Novartis, Novo Nordisk, 89bio, Pfizer, and others.}

References:

1. Brooks, A. Resmetirom (Rezdiffra) Receives Historic FDA Approval for Noncirrhotic NASH. HCPLive. March 14, 2024. Accessed March 18, 2024. https://www.hcplive.com/view/resmetirom-rezdiffra-receives-historic-fda-approval-for-noncirrhotic-nash
2. Walter, K. Intercept Cancels Plans For NASH Treatment After CRL. HCPLive. June 23, 2023. Accessed March 18, 2024. https://www.hcplive.com/view/intercept-cancels-plans-nash-treatment-crl