Eli Lilly metabolic disorder medication tirzepatide, already approved in type 2 diabetes and weight management, now has early clinical data indicating it can also help patients with a fatty liver disease that so far has no FDA-approved drug therapies.
In a Phase 2 clinical trial, Lilly said that at 52 weeks, 74% of participants who received the highest dose of tirzepatide achieved an absence of nonalcoholic steatohepatitis (NASH) with no worsening of the liver fibrosis that is a hallmark of this chronic liver disease. By comparison, 12.6% of participants given a placebo met this main study goal. Lilly reported these preliminary results Tuesday in its announcement of fourth quarter 2023 financial results.
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Tirzepatide is a peptide designed to mimic incretins, or gut hormones, by binding to and activating two targets: the GLP-1 and GIP receptors. By mimicking the role of naturally found gut hormones, these drugs, called incretin mimetics, are intended to spark metabolic effects that include regulating both blood sugar and appetite. Lilly’s injectable drug is marketed as Mounjaro in type 2 diabetes and as Zepbound in chronic weight management. Ongoing clinical research for tirzepatide includes NASH, which some in the metabolic disorders field, including Lilly, are starting to call metabolic dysfunction-associated steatohepatitis, or MASH.
Tirzepatide’s MASH study is designed to evaluate three doses of the once-weekly injectable drug. The estimated enrollment is 196 participants. The preliminary results show that all three doses met the main goal of absence of NASH/MASH with no worsening of liver fibrosis. Disease severity is classified into four stages, stage 4 being liver cirrhosis. A key secondary study goal was to show a decrease in fibrosis by at least one stage with no worsening of MASH. On this measure, Lilly reported “clinically meaningful” results across the three doses of its drug. The adverse effects reported in the study were consistent with other tests of the drug. Known side effects of incretin mimetics include nausea, diarrhea, vomiting, and stomach pain.
In a research note sent to investors Tuesday, Leerink Partners analyst Thomas Smith said tirzepatide’s MASH resolution is competitive with other drug candidates, including Akero Therapeutics’ drug candidate, efruxifirmen. Cross-trial comparisons are tricky, but in Akero’s Phase 2b results, 76% of patients who received efruxifirmen achieved resolution compared with 15% of those given a placebo.
Smith acknowledged tirzepatide showed only clinically meaningful results for the study’s key secondary goal of fibrosis improvement. But he said the magnitude in benefit achieved in MASH resolution and the strong trend on fibrosis improvement could translate into statistically significant benefit in a larger Phase 3 study.
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The first FDA approval in MASH could come next month. Madrigal Pharmaceuticals faces a March 14 target date for a regulatory decision on its drug candidate, a once-daily oral small molecule called resmetirom. Smith said incretin drugs such as tizepatide may find use addressing some aspects of the MASH, but added it’s unlikely these drugs are a silver bullet or functional cure for MASH patients with advanced fibrosis. Long term, Leerink Partners expects multiple drugs and drug combinations will become the standard of care in this metabolic disorder.
“Based on this view, we believe there is a disconnect between near-term perception (likely to drive weakness today) and fundamental reality, and that the size of the potential market and nature of the disease provide ample opportunity for multiple winners among companies developing NASH therapeutics,” Smith said.
William Blair analyst Andy Hsieh wrote in a research note that MASH resolution and fibrosis improvement are surrogate endpoints for longer term measures of the disease, such as the rates of liver transplant and liver-related hospitalizations. Fibrosis improvement is thought to be the more relevant of the two endpoints. Therapies with robust results across both measures, along with the convenience of daily dosing and better tolerability, will likely achieve the most significant uptake in MASH, Hsieh said. He added that Viking Therapeutics’ VK2809, an oral drug that addresses the same targets as Madrigal’s drug candidate, could become a competitive alternative, if approved.
Tirzepatide (Mounjaro) won its first approval in 2021 as a treatment for type 2 diabetes. It quickly became a blockbuster seller for Lilly, and is now second in revenue behind only Trulicity, an older diabetes drug that also binds to and activates the GLP-1 receptor. In the fourth quarter of 2023, Mounjaro achieved $2.2 billion in revenue, topping the $1.7 billion in sales for Trulicity. But for the full year, Trulicity remains Lilly’s top drug with $7.4 billion in revenue versus $5.1 billion for Mounjaro. Zepbound, which won its FDA approval this past November for chronic weight management, generated $175.8 million in revenue before the end of 2023.
Photo: Craig F. Walker/The Boston Globe, via Getty Images
