Tirzepatide Shows Improvements in MASH Without Worsening Fibrosis

Tirzepatide (Zepbound; Eli Lilly) showed that 51.8%, 62.8%, and 73.3% of individuals with biopsy-proven metabolic dysfunction-associated steatohepatitis (MASH) achieved an absence of MASH with no worsening fibrosis for liver histology for the 5 mg, 10 mg, and 15 mg dosages, respectively, according to results from the SYNERGY-NASH phase 2 study.^1,2

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"MASH is the second most common contributor to liver transplantation in the US, highlighting the need for novel therapies," Rohit Loomba, MD, MHSc, chief of the division of gastroenterology and hepatology at University of California San Diego School of Medicine, said in a news release. "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."¹

The trial was a multicenter, double-blind, randomized, placebo-controlled study conducted at 130 sites in 10 countries. Investigators included individuals aged 18 to 8 years old with a body mass index between 27 and 50, with or without diabetes. Treatment was randomized 1:1:1:1 with either tirzepatide 5 mg, 10 mg, 15 mg, or the placebo. All dosages were injected subcutaneously once weekly for 52 weeks, according to the study authors. A liver biopsy was performed at the end of the 52-week period, which were evaluated by central pathologists.²

The primary end point included resolution of MASH without worsening fibrosis at week 52, and the secondary end points included decrease in at least 1 fibrosis stage, decrease of at least 2 points in the Non-Alcoholic Fatty Liver Disease (NAFLD) activity score with a reduction of at least 1 point in 2 activity score components, and changes in liver fat content, according to the study authors.²

A total of 165 individuals finished the trial, with 161 completing the trial regiment and 157 having the liver biopsy results evaluated. The demographic and clinical characteristics were generally similar, with approximately 86% being White and 12% being Asian, and 36% identified as Hispanic or Latinx. The mean age was 54.4 years and a total of 57% were women and 58% had type 2 diabetes.²

Investigators found that, for the key secondary end point, 55% in the 5 mg, 51% in the 10 mg, and 51% in the 15 mg group all had an improvement in at least 1 fibrosis stage without worsening MASH compared with 30% in the placebo group. They found that the reductions were more apparent with individuals who had stage F3 fibrosis compared with F2 fibrosis. There were no effects observed for the percentage of individuals with a decrease of at least 2 fibrosis stages without worsening of MASH, increase of at least 1 fibrosis stage, or absences of fibrosis, according to the study authors.²

There was a decrease of at least 2 points in NAFLD activity score with a reduction of at least 1 point in at least 2 activity score components in approximately 72% to 78% of the 3 tirzepatide groups compared with 37% for the placebo group. Further, steatosis score occurred in 62% to 75% compared with 32%, lobular inflammation score in 61% to 62% compared with 36%, and hepatocellular ballooning score in 77% to 82% compared with 54%, respectively.²

Adverse events (AEs) were reported in approximately 92% of patients in all tirzepatide groups and in 83% of the placebo group, with the most commonly reported AEs for tirzepatide being gastrointestinal events (mostly mild to moderate in severity). Discontinuation due to AEs occurred in approximately 4% in each group. Serious AEs were reported in approximately 6% of each group, according to the investigators.²

Eli Lilly will work with regulatory agencies for the next steps for the drug for the treatment of MASH.¹

References

1. Lilly's tirzepatide was superior to placebo for MASH resolution, and more than half of patients achieved improvement in fibrosis at 52 weeks. News release. Eli Lilly. June 8, 2024. Accessed June 11, 2024. https://investor.lilly.com/news-releases/news-release-details/lillys-tirzepatide-was-superior-placebo-mash-resolution-and-more

2. Loomba R, Hartman ML, Lawitz EJ, et al. Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis. N Engl J Med. Published online June 8, 2024. doi:10.1056/NEJMoa2401943