Next-generation obesity drugs are testing combination approaches intended to lead to greater weight reduction and one of them, an experimental Eli Lilly medication that hits three targets, now has data from a late-stage study showing dramatic loss of body weight over the course of 80 weeks.
The headline number from these preliminary results posted Thursday is an average 28.3% absolute weight reduction, or a little more than 70 pounds, which unsurprisingly came from the highest dose three doses tested of the experimental drug, retatrutide. The knock on obesity drugs is that they only work if patients keep taking them — and side effects lead a lot of patients to stop taking them. That’s what could make the results for the lowest dose important. At this dose, discontinuation of retatrutide was lower than the placebo group.
Like Lilly’s blockbuster obesity drug Zepbound, retatrutide is also an engineered peptide. In addition to targeting and activating the GLP-1 and GIP receptors hit by Zepbound, retatrutide activates a third target called the glucagon receptor. In some circles, this triple combo goes by the shorthand “GGG” or “triple-G.”
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The latest results come from a Phase 3 study that enrolled 2,339 patients with obesity or overweight and at least one weight-related comorbidity, but not diabetes. These participants were randomly assigned to receive one of three doses of retatrutide or a placebo. Patients assigned to receive the study drug started with a 2 mg once-weekly dose and increased dosage every four weeks until reaching the target dose. By allowing the body to gradually adjust to the drug, this step dosing is intended to mitigate side effects, such as gastrointestinal problems.
All three retatrutide doses handily beat a placebo assessed on the main goal of measuring weight loss at 80 weeks. The study drug also met key secondary goals, such as measures of waist circumference. Lilly said the most common adverse events included nausea, diarrhea, constipation, vomiting — all common side effects of obesity drugs. But Lilly’s triple combination drug introduces some new ones: urinary tract infections and dysesthesia, which is a physical sensation of burning, itching, or pain.
Lilly characterized the urinary tract infections and dysesthesia as mild to moderate, adding that most of these cases resolved during treatment. Despite these side effects, the drugmaker said many patients stayed on treatment. The discontinuation rate was 11.3% for the high dose and 6.9% for the middle dose. The 4.1% discontinuation rate for the lowest dose, 4 mg, was better than the 4.9% discontinuation reported in the placebo group. Leerink Partners analyst David Risinger noted that the low discontinuation rate for the 4 mg dose required just a single escalation step and yet was still able to deliver 19% weight loss at the 80-week mark.
“We view retatrutide’s (GGG) combination of best-in-class weight loss with a manageable tolerability profile — particularly at the 4 mg dose with only one escalation step — as raising the bar for future novel obesity drug developers,” Risinger said.
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Analysts at William Blair take a more cautious view in a research note, pointing to higher incidences of vomiting in the middle -and high-dose cohorts. The analysts added that investors might have been looking for greater weight loss than the drug showed in the trial. For context, they said the dual-mechanism of Zepbound led to 5% to 6% greater weight loss compared to Novo Nordisk’s Wegovy, which offers the single mechanism of activating GLP-1 receptors. Based on that comparison, many investors expected a similar increase in weight reduction for retatrutide. Acknowledging the caveats of cross-trial comparisons, the William Blair analysts said retatrutide appears to offer an additional 3% weight loss compared with Zepbound. The bank still sees a future for retatrutide, but mainly for those with high body mass indexes (BMIs) needing a more powerful drug.
“Taken together, we believe retatrutide is positioned well within the ultra-high potency category of anti-obesity medications,” the analysts said. “However, given the tolerability profile, it will likely be limited to individuals at the higher end of the BMI spectrum. For the majority of patients living with obesity, we believe that Zepbound will continue to serve as the go-to medication, due to its balanced efficacy and tolerability profile.”
Lilly said more detailed results from this study will be presented in June during the American Diabetes Association Scientific Sessions meeting in New Orleans. This study is part of a broader program evaluating retatrutide in more than 5,800 clinical trial participants. The first data readout last December was from a trial evaluating the drug in patients with knee osteoarthritis. Other trials are assessing the drug’s effect on other weight-related conditions, such as obstructive sleep apnea, back pain, and fatty liver disease. By the end of this year, Lilly expects to have data from seven total Phase 3 tests of retatrutide.
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