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Adding an investigational long-acting amylin analogue to semaglutide was both safe and effective for weight management, according to a phase Ib randomized controlled trial.

Of six different doses of once-weekly subcutaneous cagrilintide (AM833) tested, certain doses plus 2.4 mg of the GLP-1 receptor agonist semaglutide resulted in significantly greater weight loss compared with semaglutide alone, reported Lone B. Enebo, PhD, of Novo Nordisk in Søborg, Denmark, and colleagues.

The findings were presented at the virtual European Congress on Obesity and also published in .

Specifically, the researchers found that three doses of cagrilintide -- 1.2 mg, 2.4 mg, and 4.5 mg -- in conjunction with once-weekly subcutaneous 2.4-mg semaglutide yielded significant weight loss from baseline through the end of treatment (week 20):

• 1.2-mg cagrilintide: 15.7% drop in body weight from baseline
• 2.4-mg cagrilintide: 17.1% drop
• 4.5-mg cagrilintide: 15.4% drop

In comparison with placebo plus semaglutide, 1.2 mg, 2.4 mg, and 4.5 mg of cagrilintide plus semaglutide all resulted in significantly greater estimated treatment differences for change in baseline body weight.

Doses of 0.16 mg (8.3% drop in baseline body weight), 0.30 mg (10% drop), and 0.60 mg (10.6% drop) of cagrilintide plus 2.4-mg semaglutide all yielded slightly greater drops in baseline body weight versus placebo plus semaglutide, although the differences weren't statistically significantly.

Across the board, glycemic parameters showed improvement in all treatment groups regardless of the cagrilintide dose.

These findings built upon a previous , initially presented at the 2020 virtual ObesityWeek, which met its primary endpoint showing a 10.8% weight loss at week 26 with 4.5-mg cagrilintide compared with a 3% weight loss with placebo.

Novo Nordisk also recently published findings of the STEP clinical program, demonstrating that once-weekly 2.4-mg semaglutide plus lifestyle management resulted in a significant drop in body weight after 68 weeks of treatment versus lifestyle intervention alone.

This dose of semaglutide has yet to be FDA approved, although Novo Nordisk in December 2020. In December 2017, the agent was first approved in 0.5-mg and 1-mg injectable dosing sold under the trade name Ozempic, which is indicated for type 2 diabetes and risk reduction of major cardiovascular events, including heart attack, stroke, and death, in adults with type 2 diabetes with known heart disease. Subsequently, in September 2019, an oral form of semaglutide was approved in 7-mg and 14-mg tablets, sold under the trade name Rybelsus, likewise indicated for type 2 diabetes.

Cagrilintide works as a long-acting acylated amylin analogue that has agonistic effects on amylin and calcitonin receptors. Amylin is a glucoregulatory pancreatic hormone that's secreted along with insulin, involved in delaying of gastric emptying, as well as suppressing the release of postprandial glucagon.

This trial recruited 285 adults ages 18 to 55 with a body mass index of 27 to 39.9 from the Altasciences Clinical Kansas site in Overland Park. Of this group, 96 were randomly assigned to treatment, averaging about 16 participants in each of the six cohorts. Using a 3:1 randomization, an average of 12 participants were assigned to each of the six cagrilintide plus semaglutide groups, with each group compared with six different groups of four participants assigned to placebo plus semaglutide.

The six groups receiving cagrilintide were started on initial doses of 0.01, 0.02, 0.04, 0.08, 0.16, and 0.45 mg each, which were escalated every 4 weeks until final doses were achieved by week 16. Cagrilintide and placebo were administered via a NovoPen4 durable device on the right side of the abdomen, while semaglutide was administered with a PDS290 pre-filled pen-injector on the left side.

The trial did not include any lifestyle intervention, and participants were instructed to maintain their typical level of physical activity throughout the trial.

As for safety, combination treatment was generally well tolerated. As expected with a GLP-1 receptor agonist, the majority of treatment-related adverse events were gastrointestinal disorders, including nausea, decreased appetite, vomiting, dyspepsia, and diarrhea. Among the 566 treatment-emergent adverse events reported, 207 were gastrointestinal-related, evenly spread across cagrilintide doses.

Overall, the majority of adverse events were mild or moderate, and only two participants in the combination treatment group experienced events leading to withdrawal.

"The key point with combinations is the need to be more effective than monotherapy at a reasonable price in terms of both adverse events and cost," pointed out Sara Becerril, PhD, and Gema Frühbeck, MD, PhD, both of the University of Navarra in Pamplona, Spain, in an .

Because this phase Ib trial was mainly designed for safety, the weight loss efficacy findings should be interpreted "with caution," they noted.

Ultimately, any lingering efficacy questions will only be answered with additional long-term trials.

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