Lilly's triple agonist led to high weight loss, reduced knee pain

Eli Lilly's closely watched next-generation weight-loss drug, retratrutide, helped people with obesity and degenerative joint disease lose an average of 23.7% of their body weight and eased knee pain after more than 15 months in a phase 3 study.

The trial hit all primary and key secondary endpoints and showed improvements in cardiovascular risk markers and blood pressure. However, roughly 18% of participants taking the highest tested dose discontinued treatment because of side effects, according to topline data released today.

Lilly's injectable experimental triple hormone (GIP/GLP-1/glucagon) receptor agonist also caused a rare but reported side effect of GLP-1 drugs called dysesthesia, which leads to odd, uncomfortable or even sometimes painful skin sensations.

While most cases were mild and rarely caused patients to stop treatment, this neurological condition showed up in as many as one in five patients taking the highest dose, Lilly reported.

In the TRIUMPH-4 study, 445 adults with obesity and knee osteoarthritis were randomly assigned to receive either 9 or 12 mg of retatrutide or a placebo. Those assigned to retatrutide began treatment at 2 mg weekly and escalated the dose every four weeks in steps until reaching either 9 mg (2, 4, 6 mg) or 12 mg (2, 4, 6, 9 mg).

The co-primary endpoints were reductions in body weight and pain, assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score from baseline to week 68.

Results from the trial show that 12 mg of retatrutide produced an average weight loss of 28.7%, compared with 26.4% for the 9-mg dose and 2.1% for placebo.

Patients receiving the higher dose also saw a 4.4-point reduction in the WOMAC pain score (74.3%), versus 4.5 points (75.8%) for the 9-mg dose and 2.4 points (40.3%) for placebo.

An additional post-hoc analysis showed that 14.1% of patients taking 9 mg retatrutide and 12.0% taking 12 mg experienced complete relief from knee pain by week 68, versus 4.2% in the placebo group.

Adverse events were on par with those seen in other incretin trials, with the most common among retatrutide-treated participants being nausea, diarrhea, constipation, vomiting and decreased appetite, Lilly said.

Dysesthesia was reported in 8.8% (9 mg) and 20.9% (12 mg) of retatrutide patients and 0.7% of those who took a placebo.

Overall, 12.2% of patients taking 9 mg of retatrutide and 18.2% of patients taking 12 mg of retatrutide discontinued treatment due to side effects, compared to 4% of those in the placebo group.

However, Lilly said the dropout rates were closely correlated with the starting BMI of the trial participants and included those who stopped treatment because they felt they were losing too much weight.

Eli Lilly is slated to complete seven more late-stage retatrutide trials next year, including TRIUMPH-1 for obesity and TRIUMPH-2 for obesity and type 2 diabetes, which test a 4 mg maintenance dose.

Alivia Kaylor is a scientist and the senior site editor of Pharma Life Sciences.