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Tirzepatide was superior to placebo for MASH resolution

Results from Eli Lilly and Company’s SYNERGY-NASH that evaluated the investigational use of tirzepatide in adults with biopsy-proven metabolic dysfunction-associated steatohepatitis (MASH) with stage 2 or 3 fibrosis, showed 51.8%, 62.8% and 73.3% of participants taking 5mg, 10mg and 15mg, respectively, achieved an absence of MASH with no worsening of fibrosis on liver histology, compared to 13.2% of participants on placebo at 52 weeks of treatment, meeting the study's primary endpoint. The data were presented at the European Association for the Study of the Liver (EASL) Congress 2024 and simultaneously published in The New England Journal of Medicine (NEJM).

SYNERGY-NASH was a multicentre, double-blind, randomised, placebo-controlled phase 2 study evaluating the efficacy and safety of tirzepatide at various doses in adults with biopsy-confirmed metabolic dysfunction-associated steatohepatitis (MASH), previously referred to as nonalcoholic steatohepatitis (NASH), with stage 2 or 3 fibrosis.

The trial randomised 190 participants to receive tirzepatide 5mg, 10mg, 15mg or placebo, administered subcutaneously once weekly for 52 weeks. The primary endpoint was MASH resolution without worsening of fibrosis at 52 weeks. Secondary endpoints included fibrosis improvement without worsening of MASH. 

In a secondary endpoint, the efficacy estimand showed 59.1%, 53.3% and 54.2% of participants taking 5mg, 10mg and 15mg, respectively, achieved a 1-stage or greater fibrosis improvement without worsening of MASH compared to 32.8% of participants on placebo.

Evaluation of additional secondary endpoints showed tirzepatide was associated with improvements in body weight, blood markers of liver injury, and biomarkers of liver fat, inflammation and fibrosis. While the phase 2 study was not designed to prove that tirzepatide improves fibrosis, the study results showed the potential for a clinically meaningful treatment effect across all doses.

"MASH is the second most common contributor to liver transplantation in the U.S., highlighting the need for novel therapies1," said Dr Rohit Loomba, chief of the division of gastroenterology and hepatology at University of California San Diego School of Medicine. "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."

Results of the treatment-regimen estimand analysis (below) were consistent with those observed with the efficacy estimand:

*p values for the secondary endpoint are nominal and not adjusted for multiple comparisons.

The overall safety profile of tirzepatide in SYNERGY-NASH was similar to that observed in the previously reported SURMOUNT and SURPASS trials. The most commonly reported adverse events in SYNERGY-NASH were gastrointestinal-related (nausea, diarrhoea, decreased appetite, constipation and weight loss) and generally mild to moderate in severity.

"Lilly is very pleased with the degree of MASH resolution observed in the SYNERGY-NASH study, and we are encouraged by the improvement of fibrosis observed," said Dr Jeff Emmick, senior vice president, product development, Lilly. "MASH is expected to impact more than 19 million adults in the US by 2039 and based on the study results, we believe tirzepatide may have the potential to help people living with this disease."

Lilly is engaged with regulatory authorities on the next steps for tirzepatide for the treatment of MASH.

The findings were reported in the paper, ‘Tirzepatide for Metabolic Dysfunction–Associated Steatohepatitis with Liver Fibrosis’, published in NEJM. To access this paper, please click here (log-in is required)


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