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The weight loss and diabetes drug tirzepatide resolved metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis, according to the results of the SYNERGY-NASH phase II study.

Among 190 participants with biopsy-confirmed MASH and fibrosis, the treatment regimen estimand showed resolution of MASH without worsening of fibrosis in 44% of patients in the once-weekly 5-mg tirzepatide group, 50% in the 10-mg group, and 62% in the 15-mg group compared with 10% in the placebo group (P<0.001 for all), reported Rohit Loomba, MD, of the University of California San Diego, at the European Association for the Study of the Liver annual meeting.

Results of the trial were simultaneously published in the .

"MASH is the second most common contributor to liver transplantation in the U.S., highlighting the need for novel therapies," Loomba commented in a from tirzepatide manufacturer Eli Lilly. "The study is significant, given the urgent need for treatment options that are capable of slowing the progression of the disease and potentially reducing serious health complications."

The combination glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist received FDA approval for type 2 diabetes (Mounjaro) in 2022, followed by FDA approval for the management of obesity or overweight (Zepbound) in 2023.

Loomba also presented an efficacy analysis that included all randomized participants except for data obtained after permanent discontinuation of tirzepatide or placebo. In that analysis, the efficacy estimand showed that 51.8% of patients in the 5-mg tirzepatide group, 62.8% in the 10-mg group, and 73.3% in the 15-mg group had resolution of MASH with no worsening of fibrosis, compared with 13.2% in the placebo group.

In a key secondary endpoint, the percentage of participants who had a decrease of at least one fibrosis stage without worsening of MASH was 55%, 51%, and 51% of participants taking 5 mg-, 10 mg- and 15 mg tirzepatide, respectively, versus 30% in the placebo group (P<0.05).

When asked during a Q&A session about the 30% response rate in the placebo group, Loomba speculated that "it's really a tyranny of small numbers." The placebo group had a total of 48 patients whereas the total number of participants in the treatment groups was approximately three times that. "That's why I think the precision estimates are not clear," he explained.

Laurent Castera, MD, PhD, of the University of Paris Cité in Clichy, France, was curious to know why there appeared to be "no dose effect on fibrosis" with tirzepatide in the trial. Loomba replied that, again, this is likely an effect of the small phase II trial design. "Typically, if we had 300 patients per arm, I think we would start seeing some dose response," he noted. "It's also possible that the peak effect is somewhere in the middle."

Looking at the percentage of participants in the overall study population who had a two-point or greater decrease in the NAFLD activity score at week 52, with at least a one point decrease in two or more components of that score, researchers also found significant improvements ranging from approximately 72% to 78% of participants in the treatment groups, versus about 37% in the placebo group (P<0.001 for all).

Significant reductions were also noted in MRI-assessed liver fat content and liver fibro-inflammation, as well as liver stiffness assessed by vibration-controlled transient elastography.

"The histology findings are supported by changes in biomarkers of fibrosis," Loomba told attendees. Evaluation of the serum biomarkers revealed significant reductions in NIS4, a biomarker for MASH with NAS≥4 (P<0.001), and fibrosis stage ≥2. Also, ELF, a marker of fibrosis and Pro-C3, a fibrogenesis biomarker were also significantly reduced in the active treatment groups (P<0.001 for both). Significant reductions were also seen in ALT and AST by 26 weeks and maintaining through week 52.

In the safety analysis, adverse events were reported in 92% of tirzepatide-treated participants and in 83% in the placebo group. The most common adverse events with tirzepatide were gastrointestinal events; 96% were mild to moderate in severity. Treatment discontinuation was similar between the treatment and placebo groups, at about 4% in each group.

Percentages of serious adverse events were similar in both groups, at around 6.2%. Progression to cirrhosis was 2.8% in those receiving tirzepatide versus 4.2% in the placebo group. No participants developed hepatic decompensation, Loomba noted, and there was no evidence of drug-induced liver injury. One adjudicated major adverse cardiovascular event, a transient ischemic attack, occurred in the 5-mg tirzepatide group. Gallbladder-related adverse events occurred in 2.8% of the tirzepatide group versus 2.1% in the placebo group. No cases of acute pancreatitis were reported.

The SYNERGY-NASH trial was a dose-finding, multicenter, randomized trial that enrolled 190 participants between January 2020 and January 2023. Of participants, 57% were women, the median age was about 54 years, and 86% were white. The mean body mass index (BMI) at baseline was 36 and 58% had type 2 diabetes. F2 liver fibrosis was present in 43% of participants at baseline and 57% had F3 fibrosis.