Eli Lilly has surpassed analysts’ highest hopes for the efficacy of retatrutide, linking the triple agonist to 28.7% weight loss and a 75.8% reduction in pain scores in patients with obesity and knee osteoarthritis. But the blowout efficacy was offset by a higher discontinuation rate than in an earlier retatrutide study.
Like Lilly’s diabetes and obesity drugs Mounjaro and Zepbound, retatrutide is an agonist of GLP-1 and GIP. Retatrutide also adds a third hormone, glucagon, to the mix to serve people who need effects beyond those driven by Lilly’s existing duo of injectable obesity blockbusters. The Big Pharma ran the phase 3 Triumph-4 trial to compare two doses of retatrutide to placebo in 445 people with obesity or who are overweight and have knee osteoarthritis.
After 68 weeks of once-weekly injections, patients on the higher 12-mg dose of retatrutide lost an average of 28.7% of their body weight, though this was specific to those who stayed on the study and did not drop out. The percentage reflects average weight loss of 71.2 pounds from a baseline of 248.5 lbs. Patients on the 9-mg dose lost 26.4%, or 64.2 lbs, of their body weight.
The rate dropped for the highest dose, which saw patients lose an average of 23.7% of their body weight at 68 weeks, when including those who discontinued treatment.
Weight loss was one of two co-primary endpoints, both of which the trial met. The other co-primary endpoint looked at change in an osteoarthritis pain score. Lilly reported about a 75% reduction in pain scores on both retatrutide doses, compared to a 40% decline in the placebo group.
The weight loss and pain data beat the bull case that BMO Capital Markets analysts laid out in a note to investors last week. BMO analysts’ best-case scenario was 25% weight loss and a 60% reduction on the pain score. The analysts compared the figures to the 22.5% weight loss on Lilly’s dual agonist after 72 weeks and the 42% reduction in the pain score in a trial of Novo Nordisk’s rival GLP-1 drug semaglutide.
In another pre-readout note, Guggenheim Securities analysts predicted Lilly would report “lower but still robust weight loss” compared to other retatrutide trials. Lilly reported weight loss of up to 24.2% at Week 48 of a phase 2 trial.
While efficacy exceeded the BMO analysts’ bull case, the positive news was tempered by the safety and tolerability results. An adverse event profile that was consistent with that seen in phase 2 was the other part of the BMO analysts’ bull case.
In the phase 3 trial, 18.2% of patients discontinued the high dose of retatrutide because of adverse events. The rate was lower on the low dose, 12.2%, but still well above the 4% discontinuation rate in the placebo arm. Up to 16% of patients discontinued retatrutide because of adverse events in phase 2. Around 1 in 5 patients on the 12-mg dose saw the unusual side effect of dysesthesia, an unpleasant feeling on the skin. Lilly said it was mild for most patients, rarely a cause for stopping treatment.
Lilly said Triumph-4 discontinuation rates were highly correlated with baseline body mass index (BMI). The rates included discontinuations for perceived excessive weight loss. Limiting the analysis to patients with a BMI of 35 or higher at baseline, thereby excluding people with overweight and class 1 obesity, cut the rates to 8.8% and 12.1% for the low and high doses, respectively, compared to 4.8% with placebo.
BMO analysts predicted Lilly’s share price could rise 5% to 10% if the data met their bull case, a big swing for a near-trillion-dollar company. With the discontinuation rate offsetting the efficacy, shares in Lilly rose 1% to $1,004 in early premarket trading.
Lilly expects to complete seven more retatrutide trials in obesity and Type 2 diabetes next year. The schedule of planned data drops includes results in patients who received a 4-mg maintenance dose of the once-weekly triple hormone receptor agonist.