Merck released topline data from a Phase IIa study (NCT04944992) in mid-June 2023, revealing that patients treated with MK-6024 (efinopegdutide) saw a 72.7% mean reduction in liver fat content (LFC) at week 24 compared to semaglutide’s 42.3%. Although it is early data, the findings from the Phase IIa study further validate the use of glucagon like peptide-1 receptor agonists (GLP-1RAs), particularly Novo Nordisk’s semaglutide and Eli Lilly’s tirzepatide (dual agonist; GIP-GLP), in nonalcoholic steatohepatitis (NASH), says GlobalData, a leading data and analytics company.

Sravani Meka, Senior Immunology Analyst at GlobalData, comments: “While the early study data is encouraging for Merck and the wider GLP-1RA drug class, a closer analysis reveals a prominent caveat related to MK-6024’s dosing. It should be noted that the trial compared 20mg of MK-6024 to 1.34mg of semaglutide, which is normally dosed up to 2.0mg for Type 2 Diabetes (T2D) and 2.4mg for obesity. Additionally, in Novo Nordisk’s Phase II trial (NCT03987451), patients were given up to 2.4mg of semaglutide once weekly. As such, it will be interesting to see how MK-6024 will compare to semaglutide at equal doses, given that Merck plans to initiate a Phase IIb study, comparing efinopegdutide to semaglutide at a higher dose by the end of June 2023.”

For context, therapies employing GLP-1RAs-based mechanism of action form an integral part of the current pipeline landscape for NASH.  Novo Nordisk’s semaglutide in NASH program is currently in Phase III development, with ongoing studies for semaglutide as monotherapy for patients with stage F2/F3 NASH (NCT04822181) and semaglutide as a combination therapy (with Gilead Sciences’ investigational FXR agonist cilofexor and investigational ACC inhibitor firsocostat) for patients with stage F4 NASH with cirrhosis (NCT04971785).

Meanwhile, Lilly’s tirzepatide in NASH program remains in early Phase II development (NCT04166773); the dual agonist has shown impressive results in both its tirzepatide in diabetes (SURPASS) and obesity programs (SURMOUNT). Data from these programs were the foundation from which Lilly planned the expansion of tirzepatide in other indications, including for heart failure with preserved ejection fraction (HFpEF), obstructive sleep apnea (OSA), NASH, chronic kidney disease (CKD), and in morbidity/mortality in obesity.

Although it is speculated that semaglutide and tirzepatide may be the lead GLP-1RAs in development for NASH, it remains to be seen whether the class’s therapeutic efficacy is strong enough for FDA approval across all NASH patient groups. Specifically, despite strong performance as a weight loss drug, data from a Phase II trial (NCT03987451) showed that semaglutide failed to meet its primary endpoint of improving NASH-related cirrhosis compared to placebo.

Meka continues: “With Novo Nordisk’s decision to develop semaglutide both as a monotherapy and combination therapy for different patient segmentations across NASH, this strategy could not only support the use of GLP-1RAs for NASH, but also provide a rationale for combination therapies in the treatment of NASH.”

While it is certain that GLP-1RAs have a definite potential in NASH, results from ongoing clinical studies are anticipated to provide more insights into this drug class’s potential.

Meka concludes: “Given Lilly’s tirzepatide in NASH program remains in its early days, it will be interesting to see how the Phase II data will compare to that of Novo Nordisk’s semaglutide in NASH program. As tirzepatide is a dual agonist (GIP-GLP) and has shown superior results in diabetes and obesity against semaglutide, it is possible that the pattern will hold true for NASH as well. Equally, it is possible that data from Phase II study could be similar to that of Novo’s semaglutide in NASH, with mixed results across the different patient segmentations across NASH.

“Therefore, it is possible that Lilly will choose to develop tirzepatide as both a standalone and combination therapy. While further studies are needed to determine whether MK-6024 is truly superior to semaglutide, the data from its early Phase IIa data further reinforces the utility of GLP-1RAs in NASH, especially Novo Nordisk’s semaglutide and Lilly’s tirzepatide.”