In a midstage trial, Eli Lilly’s star diabetes and weight loss drug tirzepatide showed promise in fatty liver disease, a difficult-to-treat condition that doesn’t yet have an FDA-approved therapy.
Tirzepatide, known under the brand names Mounjaro and Zepbound, helped 74% of overweight or obese adults with metabolic dysfunction-associated steatohepatitis (MASH) clear MASH with no worsening of liver scarring, or fibrosis, after 52 weeks, Lilly reported alongside its fourth-quarter earnings results on Tuesday.
The result comes from a high dose of tirzepatide, 15 mg, given under the skin once per week in the phase 2 SYNERGY-NASH trial. For the 10-mg and 5-mg doses, the clearance rates were 63.1% and 51.8%, respectively, according to a presentation. All doses came significantly above the 12.6% rate seen in the placebo group.
The midstage trial win gives the Lilly GLP-1/GIP dual agonist a big boost—not that it needed it given its huge success in diabetes and obesity. MASH, until recently known as nonalcoholic steatohepatitis (NASH), still has no FDA-approved treatment despite the fact that it affects an estimated 115 million people worldwide.
Madrigal Pharmaceuticals’ resmetirom appears poised to end the MASH therapy drought, with an FDA decision on that prospect expected by March 14. And tirzepatide’s data look very competitive.
In the phase 3 MAESTRO-NASH trial, resmetirom, at 100 mg, led to MASH resolution without any worsening of fibrosis in 30% of patients, compared with 10% for placebo, after 52 weeks.
The Lilly phase 2 trial is a bit different in that it enrolled patients with stage 2 or 3 MASH, whereas the Madrigal phase 3 study also included a small group of patients with earlier-stage disease. The Lilly study only enrolled patients who had a body mass index of at least 27kg/m2, whereas the Madrigal trial didn’t require a patient to be overweight.
Tirzepatide’s latest phase 2 win adds to a positive sign reported back in 2021. In a sub-study of the phase 3 SURPASS-3 trial, tirzepatide led to a greater reduction in liver fat content compared with Novo Nordisk’s basal insulin Tresiba in patients with Type 2 diabetes.
But perhaps resmetirom and Tresiba are not considered tirzepatide’s equal rivals. The Lilly GLP-1/GIP drug is competing most directly with Novo’s GLP-1 med semaglutide—known commercially as Wegovy and Ozempic—across multiple indications.
In a phase 2 trial conducted in patients with stage 1 to 3 MASH, semaglutide, when given at 0.4-mg once-daily dose, helped 59% of patients achieve MASH resolution with no worsening of fibrosis, versus 17% for placebo.
At that time, semaglutide failed to show a significant advantage on reducing fibrosis.
Now, tirzepatide appears to have fallen into the same pattern. Despite the massive anti-MASH effect, tirzepatide only showed what Lilly called a “clinically meaningful” result in terms of decrease in fibrosis by at least one stage.
During a conference call Tuesday, Lilly’s chief scientific officer Dan Skovronsky, M.D., Ph.D., said the phase 2 study was not designed to be statistically powered to evaluate improvement in fibrosis.
Previously, in MAESTRO-NASH, 26% of patients who took Madrigal’s resmetirom at the 100-mg dose achieved at least one stage of fibrosis improvement, with no worsening on a steatohepatitis activity score. That was significantly better than the 14% seen in the control group.
Still, Skovronsky seems less concerned about the fibrosis marker.
“I don’t know what the reversibility of fibrosis is with a metabolic agent,” Skovronsky said of a potential SYNERGY-NASH readout during the Evercore ISI HealthCONx Conference in November, according to a Leerink Partners transcript. “I am confident that we can reduce fat and that can reduce inflammation. Probably we should be able to see a reduction in progression of fibrosis. But in terms of regression or reversal [of] fibrosis, that feels like a higher bar to regression.”
MASH is just one disease on a long list of indications that Lilly and Novo are trying to tap into with their respective GLP-1 drugs. Besides SYNERGY-NASH, Leerink analysts in January highlighted five other tirzepatide trial readouts to watch this year.
The SURMOUNT-OSA trial will show how tirzepatide performs in obese patients with obstructive sleep apnea. Lilly’s SUMMIT study in heart failure with preserved ejection fraction (HFpEF) could also report an outcome this year. Last year, Novo's semaglutide already succeeded in nondiabetic obese HFpEF patients in the phase 3 STEP-HFpEF trial.
Lilly's SURMOUNT-1 weight loss trial in obesity will produce results from a long-term follow-up, as well. Further, the SURPASS-CVOT trial pits tirzepatide against Lilly’s own GLP-1 drug Trulicity on cardiovascular outcomes, and Leerink analysts expect the newer med to show superiority.
Last but not least, the SURMOUNT-5 head-to-head weight loss trial between tirzepatide and semaglutide bears a primary completion date in November and could therefore yield a top-line announcement by the end of this year.