With the obesity numbers for Eli Lilly’s retatrutide already stacking up nicely, the company has rounded out its pitch for the triple agonist with top-line data on its ability to lower blood sugar levels and reduce weight in patients with Type 2 diabetes.
The headline results, which Lilly reported Thursday, appear competitive with the GLP-1 drugs already on the market for diabetes.
After 40 weeks of treatment, 4-mg, 9-mg and 12-mg doses of retatrutide—an agonist of GLP-1, GIP and a third hormone, glucagon, aka triple G—demonstrated average reductions in A1C of 1.7%, 1.9% and 1.9%, respectively, when accounting for all patients in the trial. These results hit the study’s primary endpoint, the company said in a March 19 press release.
When it came to the key secondary endpoint of weight loss, participants on the 12-mg dose of retatrutide lost an average of 36.6 pounds, or 16.8% of their body weight, when only assessing patients who received treatment as intended—known as an efficacy estimand. When stretching out the analysis to cover all patients who started on the 12-mg regimen, the average weight loss was reduced slightly to 15.3% (33.3 pounds).
No plateauing of weight loss was identified by the 40-week mark, according to Lilly.
With the caveat that cross-trial comparisons are an imperfect tool, Novo in February reported that Type 2 diabetes patients who received CagriSema—a combination of Wegovy’s ingredient semaglutide and experimental amylin receptor agonist cagrilintide—charted average efficacy estimand weight loss of 14.2% after 68 weeks. On A1C, CagriSema reduced patients’ blood sugar by 1.9% on average.
When asked by Fierce Biotech how Lilly sees retatrutide lining up against the growing list of obesity competitors, a spokesperson for the Big Pharma pointed out there have “been no head-to-head studies to-date comparing retatrutide with other incretins, and it is not appropriate to draw conclusions from cross-trial comparisons due to differences in study designs and patient populations.”
Back in December, 12 mg retatrutide was linked to an efficacy estimand weight loss of 28.7%—and a 75.8% reduction in pain scores—in a phase 3 trial of the triple agonist in patients with both obesity and knee osteoarthritis.
While the weight loss in this morning’s diabetes trial is noticeably lower than in the December phase 3 study, Lilly’s spokesperson explained that losing weight is often harder for this patient population due to underlying metabolic factors.
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Lilly’s Type 2 diabetes study for retatrutide enrolled 537 participants. Apart from the A1C and weight loss endpoints, the Transcend-T2D-1 trial also looked at measures like change from baseline in triglycerides, fasting serum glucose, non-HDL cholesterol and systolic blood pressure, as well as the specific thresholds of patients who achieved certain A1C reductions and weight loss levels.
The plan is to submit retatrutide to regulators before the end of the year as a treatment for obesity, with a diabetes filing to follow in 2027, a spokesperson told Fierce.
Lilly is counting on next-generation incretin medicines like retatrutide—as well as its oral GLP-1 orforglipron—to eventually pick up the torch from its current diabetes and obesity mainstays Mounjaro and Zepbound, both of which are underpinned by Lilly’s dual GIP/GLP-1 receptor agonist tirzepatide.
“For many people with type 2 diabetes, it is a struggle to achieve both A1C control and weight loss, since obesity has historically been harder to treat for those with type 2 diabetes,” Kenneth Custer, Ph.D., president of Lilly Cardiometabolic Health, said in the release.
“With triple agonist retatrutide, we set out to make a molecule that could help patients achieve substantial A1C reduction and weight loss,” Custer added. “These results support the remarkable potential of this novel molecule for people living with type 2 diabetes, with up to 2% A1C improvement and nearly 17% weight loss in 40 weeks of treatment.”
Retatrutide may have exceeded predictions with its obesity data back in December, but that blowout efficacy was offset by a higher discontinuation rate, 18.2%, than expected by analysts.
It was a better story this morning, with discontinuation rates from adverse events at the 12-mg dose at 5.1%. At this dose, the most common adverse events were nausea (26.5%), diarrhea (22.8%) and vomiting (17.6%), according to this morning’s release, all common side effects from these types of medicines.
While about 21% of patients in the 12-mg cohort of December’s obesity trial experienced dysesthesia—an unpleasant feeling on the skin—this level was down to 4.4% in today’s diabetes study.
Lilly’s new retatrutide data also appeared to stand up against the A1C reductions and weight loss charted by the current crop of approved GLP-1s for diabetes.
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In the data included in Ozempic’s FDA-approved label, the drug at the 1-mg dose helped patients reduce their A1C by 1.6% from a baseline of 8.1% at 30 weeks and enabled them to lose an average of 4.7 kilograms (a little more than 10 pounds).
Mounjaro’s FDA label clocks an average A1C reduction of 1.8% from baseline after 40 weeks. Patients on the drug lost between 6.3 and 7.8 kilograms, or between 14 and 17 pounds, according to the label.
Elsewhere, a new commercial GLP-1 challenger has emerged in China by way of Pfizer and its local partner Sciwind Biosciences, which recently scored approval for their drug ecnoglutide under the respective diabetes and obesity brand names Xianyida and Xianweiying.
Phase 3 data on ecnoglutide point to 2.2% to 2.6% A1C reductions at the highest, 1.2-mg, dose tested, versus 0.6% to 1.09% reductions on placebo, plus an average weight reduction of 3.21 kilograms (about seven pounds) at that dose.
