Eli Lilly’s retatrutide posts Phase 3 gains across obesity, type 2 diabetes, knee osteoarthritis pain and sleep apnea

Eli Lilly and Company (NYSE: LLY) said its investigational obesity drug retatrutide produced substantial improvements across multiple obesity-related conditions in two pivotal Phase 3 trials. In results announced June 6, Lilly reported that retatrutide reduced body weight while also lowering measures of knee osteoarthritis pain and moderate-to-severe obstructive sleep apnea severity in one study, and improving blood sugar control and weight in a second study in adults with type 2 diabetes.

Retatrutide is a once-weekly, first-in-class “triple hormone receptor agonist” that activates receptors for glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon. Lilly said the company is still studying the molecule and that it is investigational and legally available only to participants in its clinical trials.

For the TRIUMPH-1 program, Lilly described a Phase 3, 80-week, randomized, double-blind, placebo-controlled “master trial” that included obesity and two nested basket trials focused on knee osteoarthritis pain and obstructive sleep apnea. The study enrolled 2,339 participants randomized to retatrutide 4 mg, 9 mg, 12 mg, or placebo. Lilly said retatrutide met primary endpoints for each basket at 80 weeks, with the company describing average weight loss of 64.4 pounds (25.9%) for the 9 mg dose and 70.3 pounds (28.3%) for the 12 mg dose.

Lilly said the same TRIUMPH-1 data showed “meaningful improvements” beyond weight. In participants with knee osteoarthritis, retatrutide reduced Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale scores by up to 4.3 points (73.1%) from a baseline of 6.0. In participants with moderate-to-severe obstructive sleep apnea, Lilly said retatrutide reduced the apnea-hypopnea index (AHI) by up to 36.1 events per hour (60.6%), from a baseline of 58.6. Lilly also reported a pre-specified extension for participants with baseline body mass index (BMI) of at least 35, with those continuing on the 12 mg dose through 104 weeks losing an average of 85.0 pounds (30.3%).

In a separate Phase 3 trial, TRANSCEND-T2D-1, Lilly said retatrutide improved A1C and supported weight loss in adults with type 2 diabetes. The 40-week, randomized, double-blind, placebo-controlled study enrolled 537 participants randomized to retatrutide 4 mg, 9 mg, 12 mg, or placebo. Lilly said retatrutide met its primary endpoint and key secondary endpoints at 40 weeks, with average A1C reductions of up to 2.0% from a baseline of 7.9%. Lilly reported that up to 90% of participants taking retatrutide achieved A1C below 7.0%, and up to 85% reached A1C at or below 6.5%, with up to 46% achieving A1C below 5.7%.

Lilly said TRANSCEND-T2D-1 participants also experienced weight loss, including an average loss of up to 36.6 pounds (16.8%) for the 12 mg dose at 40 weeks, with Lilly stating weight loss had not yet plateaued at that time. The company also reported reductions in several cardiovascular risk factors in both trials, including decreases in triglycerides, non-HDL cholesterol, systolic blood pressure, and waist circumference, though it did not provide longer-term cardiovascular outcomes in this announcement.

Lilly said the adverse events seen in TRIUMPH-1 and TRANSCEND-T2D-1 were generally consistent with other incretin-based therapies. In TRIUMPH-1, common events included nausea, diarrhea, constipation, vomiting, and upper respiratory tract infections, while Lilly reported incidences of dysesthesia and urinary tract infections as well. The company said discontinuation rates due to adverse events were 4.1%, 6.9%, and 11.3% across retatrutide doses in TRIUMPH-1, and 2.2%, 4.5%, and 5.1% across doses in TRANSCEND-T2D-1, versus 4.9% and 0.0% with placebo, respectively.