Lilly plans phase 2b NASH trial of dual GIP, GLP-1 agonist

Eli Lilly
Lilly also showed reducing the starting dose and extending the dose-escalation period improved tolerability. (Eli Lilly)

Eli Lilly is planning to test its closely watched diabetes drug tirzepatide in a phase 2b nonalcoholic steatohepatitis (NASH) trial. The expansion is driven by midphase Type 2 diabetes data suggesting the dual GIP and GLP-1 receptor agonist improves markers associated with NASH.

Lilly turned heads last year with phase 2b data linking tirzepatide, also known as LY3298176, to steep reductions in body weight and blood sugar in patients with poorly controlled Type 2 diabetes. At the annual Scientific Sessions of the American Diabetes Association (ADA) in San Francisco, Lilly shared further analyses of the data and how they have shaped its plans for tirzepatide.

"We believe we're in a good position and are very pleased with what we've seen thus far with tirzepatide. We know that weight reduction has also been shown to have an effect in NASH, and we also understand that insulin resistance is a contributing factor in the development of NASH. With tirzepatide, we certainly see reduction in weight, but from a mechanism perspective, we see additional improvements in insulin sensitivity and lipid and fat metabolism that we think could have an improvement in NASH," Brad Woodward, Lilly's global development leader for incretins, said. 

The analysis of NASH patients enrolled in the Type 2 diabetes trial linked higher doses of tirzepatide to statistically significant changes in markers associated with the liver disease, compared to placebo and Trulicity. Tirzepatide failed to outperform both the control arms against all the NASH markers, but the apparent effect of the drug on keratin-18, pro-c3, adiponectin and ALT provided Lilly with the encouragement to target the disease. The markers offer insights into fibrosis and other processes.

Lilly plans to further assess the effect of tirzepatide on NASH patients in a phase 2b trial starting later this year. The trial will move Lilly into an indication adjacent to its core focus for tirzepatide on diabetes, a condition that is associated with a higher risk of developing NASH.

In recent months, Lilly has kicked off a series of phase 3 trials in Type 2 diabetes. Lilly used ADA to share more assessments of the data that supported its decision to start the late-phase program and the design of the trials.

The assessments included a look at data from a phase 2 trial that informed Lilly’s approach to dosing in the pivotal program. In the phase 2, Lilly showed reducing the starting dose and extending the dose-escalation period resulted in a lower rate of gastrointestinal adverse events than in the phase 2b that read out last year. 

In the phase 2b, 40% of patients who received the highest dose suffered from nausea. The rates of diarrhea and vomiting were 32% and 26%, respectively. In the dose escalation trial, 46% of subjects suffered from at least one of the gastrointestinal side effects. 

The data failed to win over all observers. Evercore's Umer Raffat told investors the "titration trial didn't deliver a clear answer on how to manage tolerability" of the highest 15 mg dose, adding that he thinks "10 mg remains the commercially relevant dose." Credit Suisse analysts expressed similar reservations, noting that the dose-escalation trial saw "fairly meaningful rates of nausea, vomiting and diarrhea."