Tirzepatide for the treatment of metabolic dysfunction-associated steatohepatitis with liver fibrosis: results of the SYNERGY-NASH phase 2 trial

How efficacious and safe was tirzepatide, a dual agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like-peptide-1 receptors, in treating non-cirrhotic metabolic dysfunction-associated steatohepatitis (MASH) with significant liver fibrosis?

Method: SYNERGY-NASH (NCT04166773) was a multicenter, double-blind, randomized, placebo (PBO)-controlled Phase 2 dose-finding trial in patients with biopsy-confirmed MASH, stage 2 or 3 fibrosis and a nonalcoholic fatty liver disease activity score (NAS)≥4. Participants (n=190) were randomly assigned 1:1:1:1 to receive once-weekly s.c. tirzepatide (5 mg, 10 mg or 15 mg) or PBO for 52 weeks. The primary endpoint was MASH resolution without worsening of fibrosis at 52 weeks. Secondary endpoints included fibrosis improvement by≥1 stage without worsening of MASH and a reduction in NAS by≥2 points with≥1 point reduction in at least 2 NAS components. Efficacy results were analyzed with the intent to treat population using multiple imputation for missing data.

Results: End-of-treatment liver biopsies were available for 157 participants. The proportion of participants who achieved MASH resolution without worsening of fibrosis was 9.8% for PBO, 43.6% for tirzepatide 5 mg, 55.5% for tirzepatide 10 mg and 62.4% for tirzepatide 15 mg (differences vs. PBO 33.8-52.6%; p<0.001 for all doses). Among 155 participants who completed the study on treatment with evaluable biopsies, the primary endpoint was achieved by 51.8%, 62.8%, and 73.3% for tirzepatide 5 mg, 10 mg and 15 mg, respectively, compared with 13.2% for PBO (p<0.001 for all doses). The proportion who achieved≥1-stage fibrosis improvement without worsening of MASH was 29.7% for PBO, 54.9% for tirzepatide 5 mg, 51.3% for tirzepatide 10 mg and 51.0% for tirzepatide 15 mg (differences vs. PBO 21.3-25.2%; p<0.05 for all doses). A reduction in NAS by≥2 points was achieved by 71.7% to 78.3% of participants across the three tirzepatide dose groups and by 36.7% with PBO (p<0.001 for all doses). Body weight was reduced by up to 17.3% with tirzepatide. Liver enzymes and liver fat decreased, and serum as well as imaging biomarkers of liver inflammation and fibrosis significantly (p<0.01) improved in the tirzepatide groups vs. PBO. Adverse events with tirzepatide were mostly gastrointestinal, and mild to moderate in severity.

Conclusion: In this Phase 2 study of patients with MASH and significant fibrosis, tirzepatide treatment for 52 weeks was more effective than placebo in achieving MASH resolution without worsening of fibrosis. Fibrosis also improved with tirzepatide treatment but without an apparent dose-response effect. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for treatment of non-cirrhotic MASH.