Analysts were hoping for a safety profile similar to what was achieved in Phase II but an abnormal sense of touch, called dysesthesia, has emerged in the late-stage TRIUMPH-4 trial.
Eli Lilly’s triple hormone receptor agonist cut body weight by 26.6% on a placebo-adjusted basis and reduced knee osteoarthritis pain by 75%, capping off a trio of wildly successful readouts for the pharma’s obesity pipeline.
BMO Capital Markets dubbed the Thursday readout for retatrutide “a true TRIUMPH”—playing off the trial’s name, TRIUMPH-4. The results are the strongest efficacy reported to date, the firm added.
“These results help to solidify retatrutide’s profile as an even higher efficacy next generation GLP-1+ asset,” BMO wrote Thursday morning.
Lilly’s shares breached the $1,000 mark in pre-market trading Thursday morning, rising 1.5% to $1,008 from $993.64 at close yesterday.
Previously, BMO had been anticipating weight loss of about 20%-23% for retatrutide, which targets GIP, GLP-1 and glucagon, along with 50% pain reduction. This would have put the drug ahead of rival Novo Nordisk’s semaglutide, which scored 42% pain reduction in a previous trial.
But retatrutide went even further, with patients in the Phase III TRIUMPH-4 trial on a 12 mg dose losing an average of 28.7% of their body weight at 68 weeks. The trial featured adults who have obesity or are overweight with knee osteoarthritis.
Adjusted for placebo, the weight loss was 26.6%, according to BMO. In addition to the pain achievement, retatrutide improved measures of physical function, reduced cardiovascular risk and blood pressure.
While the weight loss was significant, Lilly did report a safety signal called dysesthesia in 8.8% and 20.9% of patients on the 9 mg and 12 mg doses, respectively. In the placebo arm, just 0.7% of patients reported this side effect. Dysesthesia is an abnormal sense of touch that causes normal sensations to feel unusual or painful. It’s often a symptom of a larger diseases, such as multiple sclerosis or diabetes.
Analysts were hoping for a safety profile similar to what was achieved in Phase II. Dysesthesia was not reported in Lilly’s earlier mid-stage trial for retatrutide. BMO noted the dysesthesia signal and said the firm will be watching for it in readouts to come and for more detailed data from the TRIUMPH-4 trial. Lilly said that the dysesthesia events did not seem to lead to discontinuation.
Other safety events included typical gastrointestinal symptoms, with nausea rates of 43%, vomiting of 21% and diarrhea of 33%. Lilly reported discontinuation rates of 12.2% and 18.2% across the 9 mg and 12 mg arms, respectively, compared to 4% in the placebo group. Some of these discontinuations were due to “perceived excessive weight loss,” according to Lilly.
“Discontinuation rates appear to highlight the speed and strength of weight loss was excessive for some patients with lower BMI,” BMO wrote. The firm dubbed the discontinuation rates “overall acceptable,” with rates lower in patients with a higher BMI.
Retatrutide has been designed to be more effective than Lilly’s tirzepatide, which is approved for weight loss as Zepbound and diabetes as Mounjaro, Leerink Partners said in a note previewing the readout earlier this month.
It’s unclear if the adverse effect will impact retatrutide’s prospects. Lilly is positioning retatrutide as an option for patients seeking more significant weight loss than what can be achieved with the available GLP-1 therapies. TRIUMPH-4 was not powered to show the maximum weight loss possible, BMO noted.
The Cherry on Top
The retatrutide readout is just one of three major trials that Lilly has read out in recent months, all of them successful. In October, Lilly reported that the oral therapy orforglipron bested AstraZeneca’s Farxiga in a Phase III diabetes trial. The drug, which Lilly plans to submit to the FDA by the end of the year, also beat Novo’s semaglutide at reducing A1C in a head-to-head trial for type 2 diabetes in September.
Truist Securities estimates that Lilly’s weight loss trio of incretin medicines, Mounjaro, Zepbound and orforglipron, could reach $101 billion in peak sales worldwide. Retatrutide could be the cherry on top.
Lilly has six more late-stage studies in the TRIUMPH program underway for retatrutide which are expected to readout by the end of 2026. In total the program, which kicked off in 2023, has enrolled 5,800 people with obesity, obstructive sleep apnea and knee osteoarthritis.
