Stephen Harrison, MD: The Role of Weight Loss, Resmetirom in NASH Management

In the absence of a pharmacologic treatment prior to the landmark US Food and Drug Administration (FDA) approval of resmetirom (Rezdiffra), weight loss served as the cornerstone of nonalcoholic steatohepatitis (NASH) management.^1,2

Now that resmetirom has been granted accelerated approval for noncirrhotic NASH with moderate to advanced fibrosis, the role of glucagon-like peptide 1 (GLP-1)s has come into question, especially given their apparent lack of significant impact on fibrosis.^1,2

“GLP-1 based therapy targets weight and gets at the core tenet of the root cause of many different diseases, including MASLD or steatotic liver disease,” Stephen Harrison, MD, founder and chairman of Pinnacle Clinical Research and Summit Clinical Research, explained in an interview with HCPLive. “For all the good things that GLP-based therapies do, there is no evidence that you're doing anything positive on fibrosis.”

Although Harrison was careful to note GLP-1 agonists improve insulin sensitivity and address key drivers of fibrosis, he also pointed out most patients cannot stay on therapy long enough to see the potential fibrosis benefit. Citing the uptick in complications from liver disease seen at F2, he emphasized the need for liver-directed therapies with a faster, more direct impact on fibrosis. This, he explained, is where resmetirom comes into play.

An oral, thyroid hormone receptor (THR)-β selective agonist, resmetirom was granted accelerated approval on March 14, following 18 clinical studies in its development program. Resmetirom’s safety and efficacy for adults with NASH has been demonstrated in phase 2 and 3 trials, the latest of which includes MAESTRO-NASH, an ongoing phase 3, double-blind, randomized, placebo-controlled trial, 1 of 4 phase 3 studies in resmetirom’s clinical development program supporting the approval for its use in adult patients with NASH and moderate to advanced (F2 - F3) fibrosis.¹

“The issue really becomes as you advance beyond F2 and you get to F3 or even early stage F4,” Harrison explained. “Then, I worry a little bit about GLP-1-based therapy because we really need to pull those people back from the brink of falling over the cliff into decompensation. Our effort really should be on halting and reversing fibrosis, first and foremost. Weight loss at that point is secondary.”

For patients with F0 or F1, Harrison said he would continue to use GLP-based therapies. For patients with F2, he noted this is where the “crossroad” begins: “If they're on [a GLP-1], I'm going to keep them on it and add resmetirom. If they're not on it, then I think I have a little bit of play. But at F3, I think we really need to start with liver-directed therapy.”

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. Kaltenbach, M. Why are GLP-1 agonists being used to treat patients with nonalcoholic fatty liver disease? AASLD. May 8, 2023. Accessed March 18, 2024. https://www.aasld.org/liver-fellow-network/core-series/why-series/why-are-glp-1-agonists-being-used-treat-patient