Survodutide and Tirzepatide Dash for a Splash with MASH

At the EASL Congress 2024 in Milan, we witnessed quite a splash of new data on both survodutide and tirzepatide for MASH. Friday and Saturday gave us two headline presentations at the meeting and two publications in the New England Journal of Medicine. Lilly pronounced itself “very pleased” with the results of their SYNERGY-NASH study of tirzepatide. Boehringer Ingelheim was less restrained, calling the results with survodutide as a “breakthrough” on fibrosis in MASH.

Jostling for position in the race to meet the need for therapies in MASH is totally understandable, but it’s a little too soon to pick winners. The real winners will be people living with obesity and liver disease if they get better options for medical care.

Survodutide

The survodutide study was a 48-week RCT with its primary endpoint being improvement in MASH with no worsening of fibrosis. Researchers tested three doses: 2.4, 4.8, and 6.0 mg weekly. On the primary endpoint, the results were 47%, 62%, and 43% of patients seeing improvement at those three doses respectively. Only 14% of patients on placebo experienced improvement.

Researcher Daniel Drucker called it a “big win” with “impressive effects on fibrosis.” Boehringer pointed to one of the sub-analyses of liver fibrosis improvement (figure s12 in the NEJM paper) to back their claim of a breakthrough. In that post-hoc analysis, 64.5% of patients on the 6 mg saw improvement in liver fibrosis with no worsening of MASH.

Tirzepatide

The tirzepatide study was similar, 52 weeks, testing weekly 5, 10, and 15 mg doses versus placebo. The primary endpoint was the same. With those three escalating doses, researchers found 44%, 56%, and 62% of patients had an improvement in MASH with no worsening of fibrosis. Only 10% of patients on placebo had improvement.

Drucker called these results “solid,” noting that about half of patients achieved improvement in fibrosis. Lilly did not boast of a breakthrough, instead calling their results on fibrosis encouraging while noting that the study “was not designed to prove that tirzepatide improves fibrosis.”

Caution and Encouragement

We will say that both caution and encouragement are appropriate in viewing these results with survodutide and tirzepatide in MASH. These are merely phase 2 dose-escalation studies. It is clear enough that both of these agents work well for patients with MASH. The effect on fibrosis is tantalizing and it may be that one or both of them will offer a breakthrough.

But the time for real excitement will come when the results of pivotal phase 3 studies emerge – if the results are robust. The need is great and the prospects for improved therapy are indeed encouraging.

Furthermore, confirmation that treating obesity can yield improvements in liver disease will add to the growing realization that weight outcomes are not the sole aim of obesity care. We now know that effective treatment prevents cardiovascular disease events. We are well on our way with indications for preventing chronic kidney disease and reversing sleep apnea.

Helping to resolve or prevent liver disease will do much to fill out the picture.

Click here and here for the NEJM publications, here and here for the press releases. For further reporting click here and here.

Water Drop, photograph by José Manuel Suárez, licensed under CC BY 2.0

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June 9, 2024