Blind spots remain in semaglutide and other GLP-1s’ bid for label expansion in NASH, experts say

Back in 2020, before semaglutide became a household name — before it was even approved to treat obesity — Novo Nordisk quietly notched a breakthrough therapy designation in a hot indication: nonalcoholic steatohepatitis, or NASH.

Three years later, the GLP-1 receptor agonist has emerged as one of the “most recognized and anticipated” new treatment for a disease that’s been dubbed a silent killer and defeated multiple experimental drugs. Novo is still recruiting NASH patients with fibrosis in a 1200-patient Phase IIIa study, with data not expected until 2028.

Although clinical trial investigators see the potential of semaglutide and other GLP-1 agonists in treating NASH, questions swirl as to the limits of the drugs’ efficacy in the later stages of the liver disease.

Arun Sanyal

“The results of the semaglutide Phase III trial are going to be extremely important in the field,” noted Arun Sanyal, professor at the Virginia Commonwealth University School of Medicine.

NASH is the umbrella term for different stages of liver disease that starts with a fatty liver, which triggers inflammation and ballooning and ultimately causes fibrosis and then cirrhosis.

But GLP-1 agonists are currently “long on promise and short in results” in NASH, said Stephen Harrison, founder and chairman for clinical research groups Pinnacle and Summit. While it makes sense that glycemic control and weight loss would also ease fat concentration in the liver, there are still limited data to see if the mechanism can directly improve liver health, he explained.

Companies like Eli Lilly, Boehringer Ingelheim, Merck and Hanmi Pharmaceutical are banking that their own assets that have targets in addition to GLP-1 may potentially edge out semaglutide. But those drugs are still undergoing Phase II tests and their profiles in NASH remain premature.

Nevertheless, even if GLP-1 agonists deliver lower-than-expected results in fibrosis or cirrhosis, there will still be a huge market for these drugs, experts say. “You have to remember that half the patients with NASH also have type 2 diabetes, and about two thirds of them are obese,” NASH investigator Sanyal said. This argues the case of even broader use for these blockbuster drugs — if approved.

Limits of semaglutide data in NASH

While there are positive GLP-1 agonist data in NASH, they come with caveats. A Novo Nordisk spokesperson pointed Endpoints News to a presentation noting that, in a 320-patient Phase II semaglutide study, there is a positive dose relationship between the drug and NASH resolution. But in the same trial, it was lackluster in improving fibrosis, NASH investigator Harrison noted. There was no statistical difference between patients who received semaglutide (43%) and placebo (33%) in the secondary outcome of fibrosis stage improvement (p=0.48).

Stephen Harrison

NASH resolution may have been due to improvements to the patient’s overall metabolic health, so there are questions about how GLP-1 agonists impact the liver directly. In fact, GLP-1 receptors are not present in the liver, Harrison noted.

However, GLP-1 agonists may still have a valuable indirect liver impact. GLP-1 agonists improve insulin sensitivity, and thus, there should be a reduction in free fatty acid (FFA) flux in the liver, he explained. FFA is an energy source, but when there’s too much of it, it can lead to fatty liver disease. Reduced FFA can ease liver inflammation, which can then downregulate processes that can cause fibrosis.

“You’re not an organ, you’re an organ system — they all function together,” Harrison added. As such, he noted, the ideal NASH drug treats not only the liver disease but also dysregulated energy metabolism linked to diabetes, for which semaglutide is already approved for.

Indeed, there have been efforts to rename NASH into metabolic dysfunction-associated steatohepatitis (MASH). Patients need to be treated holistically, Sanyal added.

Still, there is little evidence that GLP-1 agonists can help patients with cirrhosis. In a separate 71-patient Phase II trial recruiting NASH cirrhotic patients, the difference between semaglutide and placebo arms was not statistically different in the primary endpoint of fibrosis impact of one stage or more without worsening of NASH at 48 weeks (P=0.087).

With the liver, “if you treat it long enough eventually the liver will begin to heal itself,” Harrison noted. Yet, trials have not been run long enough to see if GLP-1 agonists can trigger a positive cascade. “If you treat cirrhosis for five years, is there going to be a difference? Maybe. But no study lasts that long,” he added.

Does more targets mean better efficacy?

It is possible that second- or third-generation assets — dubbed as “double G” or “triple G” drugs — may best GLP-1 agonists.

Double G drugs target GLP-1 and gastric inhibitory polypeptide (GIP), such as Mounjaro (with Phase II NASH data reporting next year), or ones that also target glucagon, such as survodutide (which has Phase II NASH and fibrosis data expected late this year).

Survodutide may be the first anti-obesity drug that can offer both reduced energy intake and increased energy expenditure in the liver, a Boehringer Ingelheim spokesperson said.  A Merck spokesperson noted its Phase II double-G candidate efinopegdutide has the advantage of glucagon-mediated direct effects on fatty acid metabolism (study data are expected late next year).

Triple-G drugs like Hanmi’s HM15211 target all three. HM15211 has Phase II NASH data expected in 2025. Lilly and Hanmi did not respond to a request for comment.

Although GLP-1 is absent in the liver, GIP and glucagon are present. Early-phase efficacy data from such second- and third-generation assets show a glimmer of an edge over ones that only target GLP-1, Sanyal said. But he also cautions it’s still too early to tell, with these assets still in the Phase II stage and some not having histological data yet.

It may also be too early to tell if the efficacy of these three drug generations has a class effect. “There may be differences based on whether it is heavy on the GLP or whether it is heavy on the other target,” Harrison explained.

Efinopegdutide, for example, has a relative potency of about 2:1 for the GLP-1 and glucagon receptors, respectively, the Merck spokesperson noted. How effectively the drug can penetrate the liver can also play a part, Sanyal added.

One concern among certain drugs that target GLP-1s is the loss of muscle mass among NASH patients. Liver cirrhosis and age-related loss of muscle mass called sarcopenia go hand in hand, meaning that such drugs might not be ideal for cirrhotic patients, Harrison noted.

For now, investigators are still on the hunt for where these drugs’ limits are — how far into the NASH disease spectrum will these drugs be most efficacious? “They will definitely have a role… the question that still remains is how broad ranging is that role going to be,” Harrison said.

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