WAYFIND: Exploring Combination Therapy for MASH Cirrhosis, With Naim Alkhouri, MD

While cirrhosis has traditionally been viewed as an irreversible stage of chronic liver disease, emerging data from pharmacologic trials have begun to challenge that notion. Among these, the phase 2 WAYFIND trial has drawn considerable attention for testing a novel combination approach in patients with biopsy-proven metabolic dysfunction-associated steatohepatitis (MASH) cirrhosis, with results recently presented at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025.1

In the past 2 years, the MASH treatment landscape has seen the addition of the first 2 US Food and Drug Administration approved therapies in the form of resmetirom and semaglutide. However, neither agent indicated for patients with cirrhotic MASH, representing a substantial unmet need for this population.2,3

Seeking to address this therapeutic gap, the Naim Alkhouri, MD, chief academic officer of Summit Clinical Research and director of the Steatotic Liver Program at North Shore Gastroenterology, and investigators on the WAYFIND trial assessed the efficacy and safety of semaglutide alone and in fixed-dose combination with cilofexor and firsocostat in patients with compensated cirrhosis due to MASH. The multicenter, double-blind, phase 2b study randomly assigned adults with biopsy-proven F4C due to MASH in a 3:3:3:2 ratio to receive semaglutide 2.4 mg/week + cilofexor 30 mg/firsocostat 20 mg/day, semaglutide 2.4 mg/week, cilofexor 30 mg/firsocostat 20 mg/day, or placebo for 72 weeks.

The primary endpoint was the proportion of patients with fibrosis improvement without MASH worsening at week 72 with semaglutdie+cilofexor/firsocostat versus placebo. Secondary (with prespecified testing hierarchy) and exploratory efficacy endpoints and safety were also assessed.

Of 457 patients who were randomized in the trial, 453 had ≥1 study drug dose. Their mean age was 62 years, 68.2% had type 2 diabetes, and mean platelets were 191×109/L.

Investigators noted there was no significant difference in the proportions of patients with fibrosis improvement without MASH worsening at week 72 with semaglutide+cilofexor/firsocostat versus placebo (13.7% vs 8.3%; P = .2289). However, fibrosis improvement was observed with cilofexor/firsocostat versus placebo (20.3% vs 8.3%; P = .0174).

Further analysis with PathAI analysis revealed a difference with semaglutide+cilofexor/firsocostat versus placebo (21.0% vs 6.0%; P = .0011). Investigators noted MASH resolution was greater with semaglutide+cilofexor/firsocostat versus cilofexor/firsocostat or placebo and with semaglutide versus placebo in both pathologist and PathAI analyses.

The most frequent adverse events (AEs) occurring more often with semaglutide+cilofexor/firsocostat versus placebo were nausea (47.6% vs 22.6%), diarrhea (27.4% vs 17.9%), constipation (24.2% vs 8.3%), vomiting (21.8% vs 7.1%), and decreased appetite (15.3% vs 6.0%). Serious AEs and AEs leading to study discontinuation were similar across all groups. A single death occurred in each of the semaglutide and cilofexor/firsocostat groups.

“In my opinion, these data speak to the potential of reversing cirrhosis, [which has a] very high unmet need, and although we did not hit the primary endpoint, I think we see several secondary endpoints that improved with these treatments,” Alkhouri said.

Editors’ note: Alkhouri reports relevant disclosures with Altimmune, Madrigal Pharmaceuticals, Merck, Novo Nordisk, Rivus, Takeda, and others.

References

1. Alkhouri N, Kowdley K, Lawitz E, et al. A randomized, placebo-controlled, phase 2 study of the safety and efficacy of combination treatment with semaglutide, cilofexor and firsocostat in patients with compensated cirrhosis due to metabolic dysfunction-associated steatohepatitis (WAYFIND). Presented at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025. Washington, DC. November 7-11, 2025.

2. Brooks A. Resmetirom (Rezdiffra) Receives Historic FDA Approval for Noncirrhotic NASH. HCPLive. March 14, 2024. Accessed November 18, 2025. https://www.hcplive.com/view/resmetirom-rezdiffra-receives-historic-fda-approval-for-noncirrhotic-nash

3. Brooks A. FDA Approves Semaglutide (Wegovy) Injection 2.4 mg for Noncirrhotic MASH. HCPLive. August 15, 2025. Accessed November 18, 2025. https://www.hcplive.com/view/fda-approves-semaglutide-wegovy-injection-2-4-mg-for-noncirrhotic-mash