Lilly's retatrutide clears 2 more trials, FDA filing set for Q1 2027

Eli Lilly & Co.'s experimental triple-agonist retatrutide met primary endpoints in two Phase 3 obesity trials, delivering weight loss of as much as 22.6% in patients with severe obesity and cardiovascular disease and 20.8% in those with type 2 diabetes.

"Across five positive Phase 3 studies, retatrutide has shown powerful efficacy, and we believe it could be an important future tool in the management of cardiometabolic health," Kenneth Custer, executive vice president and president of Lilly Cardiometabolic Health, said in a statement.

In TRIUMPH-2, which enrolled 1,152 adults with obesity or overweight and type 2 diabetes, patients on the highest 12-milligram weekly dose lost an average of 49.6 pounds, or 20.8% of body weight, over 80 weeks, compared with 9.3 pounds, or 4%, for placebo. The same dose reduced A1C by 1.5 percentage points from a baseline of 7.7%. In TRIUMPH-3, which studied 1,949 adults with severe obesity — a baseline BMI of 40.4 — and established cardiovascular disease, the 12-milligram dose produced average weight loss of 55.8 pounds, or 22.6%, versus 7.7 pounds, or 3.2%, for placebo.

The results complete a five-study Phase 3 package that positions retatrutide as a potential successor to Lilly's blockbuster Zepbound (tirzepatide), which targets two metabolic hormones. Retatrutide activates receptors for GIP, GLP-1 and glucagon — a triple mechanism that has produced the highest weight-loss efficacy seen in the class. Lilly plans to submit a biologics license application to the US Food and Drug Administration in the first quarter of 2027, with additional submissions globally.

Safety and cardiovascular data

Gastrointestinal side effects were the most common adverse events across both trials, consistent with the GLP-1 drug class. In TRIUMPH-2, diarrhea occurred in 33.6% of patients on the 12-milligram dose versus 13.2% on placebo, nausea in 28% versus 8%, and vomiting in 15.7% versus 4.2%. Discontinuation rates due to adverse events reached 11.6% on the 9-milligram dose and 7.7% on 12 milligrams, compared with 4.9% for placebo.

In TRIUMPH-3, major adverse cardiovascular events occurred less frequently than anticipated in both arms. In a pre-specified analysis, the hazard ratio for MACE-5 — a composite of all-cause death, heart attack, stroke, heart failure event or coronary revascularization — was 0.82 (95% confidence interval: 0.55 to 1.22) for retatrutide versus placebo. However, the narrower MACE-3 composite of cardiovascular death, heart attack and stroke showed a hazard ratio of 1.12 (95% CI: 0.64 to 1.96), meaning patients on retatrutide had a 12% higher risk of those three events, though the result was not statistically significant. The drug did meaningfully reduce several cardiovascular risk factors: triglycerides fell 37%, non-HDL cholesterol dropped 16.5%, systolic blood pressure declined 9.3 millimeters of mercury, and high-sensitivity C-reactive protein, a marker of inflammation, decreased 51.2%.

Market implications

The data package gives Lilly a potential competitive edge over Novo Nordisk A/S, whose Wegovy (semaglutide) targets only GLP-1 and whose experimental CagriSema has shown weight loss in the 15% to 23% range depending on the patient population. Retatrutide's 22.6% result in severe obesity with comorbidities — a notoriously difficult-to-treat group — suggests the triple agonist could capture a meaningful share of the obesity market, which analysts project will exceed $100 billion in annual sales by the end of the decade. Investors will watch for the FDA's acceptance of the BLA filing in early 2027 and any label expansions for obstructive sleep apnea and knee osteoarthritis pain, where retatrutide has also shown positive Phase 3 results.

This article is for informational purposes only and does not constitute investment advice.