Eli Lilly and Company announced groundbreaking positive topline results from the Phase 3 TRIUMPH-4 clinical trial, confirming its investigational drug, retatrutide, delivered weight loss results that exceeded prior expectations while also providing substantial relief from the pain and functional limitations associated with knee osteoarthritis.
The data position retatrutide as a first-in-class weekly injectable that activates three hormone receptors (GIP, GLP-1, and glucagon) as a potential market leader with efficacy surpassing currently approved dual-agonist therapies.
Trial Highlights: Weight Loss and Pain Relief
The 68-week, randomized, double-blind, placebo-controlled TRIUMPH-4 study evaluated retatrutide in adults with obesity or overweight and knee osteoarthritis, but without diabetes. Both tested doses (9 mg and 12 mg) successfully met all co-primary and key secondary endpoints.
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Key Efficacy Results (Highest Dose – 12 mg)
- Massive Weight Reduction: Participants taking the highest 12 mg dose of retatrutide lost an average of 28.7% of their initial body weight by week 68. For the average patient in the trial, this translated to a weight loss of up to 71.2 pounds.
- Osteoarthritis Pain Relief: The drug showed a significant impact on pain, reducing Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain scores by up to an average of 75.8%.
- Pain-Free Status: A post-hoc analysis revealed that more than one in eight patients on retatrutide (up to 14.1% on the 9 mg dose) were completely free of knee pain at the end of the 68-week period, compared to only 4.2% on placebo.
In addition to the highest dose, the 9 mg dose also showed robust efficacy, achieving an average weight reduction of 26.4% of body weight. Analysts noted that the magnitude of weight loss seen with retatrutide exceeded “bull case” forecasts for the drug.
Metabolic and Cardiovascular Benefits
Beyond the co-primary endpoints of weight loss and pain reduction, the trial showed significant improvements in key secondary endpoints related to overall cardiometabolic health:
- Improved Cardiovascular Markers: Retatrutide treatment reduced established cardiovascular risk markers, including non-HDL cholesterol, triglycerides, and high-sensitivity C-reactive protein (hsCRP).
- Blood Pressure: At the highest dose, retatrutide lowered systolic blood pressure by an average of 14.0 mmHg.
- Physical Function: The treatment significantly improved measures of physical function, highlighting the impact of reduced weight and pain on patient mobility.
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Safety and Discontinuation Rates
The safety profile for retatrutide was generally consistent with the incretin class of drugs, though the higher doses saw increased rates of adverse events (AEs) leading to discontinuation.
- Common Adverse Events: The most frequently reported adverse events in the retatrutide arms (9 mg and 12 mg, respectively) were gastrointestinal in nature: nausea (38.1% and 43.2%), diarrhea (34.7% and 33.1%), and constipation (21.8% and 25.0%).
- Discontinuation: Discontinuation rates due to AEs were 12.2% for the 9 mg dose and 18.2% for the 12 mg dose, compared to 4.0% for placebo. Lilly noted that these rates were highly correlated with lower baseline Body Mass Index (BMI) and included discontinuations due to “perceived excessive weight loss.”
- New Safety Signal: A new safety signal, dysesthesia (an unpleasant, abnormal sense of touch or sensation on the skin), was observed in up to 20.9% of patients on the 12 mg dose, though it was generally mild and rarely led to discontinuation.
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