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The investigational long-acting amylin analogue cagrilintide (AM833) helped people with overweight or obesity, but no diabetes, shed pounds in a phase II trial.

In the randomized trial, all doses of the novel once-weekly injectable treatment yielded significantly greater weight loss than placebo, reported David C.W. Lau, MD, of the University of Calgary Cumming School of Medicine in Canada, and colleagues in

Estimated mean reduction in body weight from baseline to week 26 was as follows:

• Cagrilintide 0.3 mg: 6.0%
• Cagrilintide 0.6 mg: 6.8%
• Cagrilintide 1.2 mg: 9.1%
• Cagrilintide 2.4 mg: 9.7%
• Cagrilintide 4.5 mg: 10.8%
• Placebo: 3.0%

The highest dose of cagrilintide also yielded significantly greater weight loss than 3.0-mg liraglutide (Saxenda). This equated to an average weight loss of 11.5 kg (25.4 lb) in the 4.5-mg cagrilintide arm versus 9.6 kg (21.2 lb) in the 3.0-mg liraglutide arm.

The researchers also pointed out that the decline in body weight seen with cagrilintide hadn't even reached a plateau yet by week 26.

"This is the first study to investigate the effect of ascending doses of cagrilintide for weight management," Lau's group pointed out. "Before this study, cagrilintide was shown to promote weight loss in a dose-dependent manner in preclinical studies and one clinical trial."

As a long-acting, acylated amylin analogue, cagrilintide acts as a satiety signal in the brain; it also slows gastric emptying and suppresses the post-prandial glucagon response to meals.

"Given its novel mechanism of action and the known heterogeneity of response to currently approved pharmacotherapies, cagrilintide presents an opportunity to expand the range of existing pharmacotherapies for weight management," the researchers wrote.

This agent could also be investigated in combination with other agents with other mechanisms of action, they added. It has already been tested in a phase I trial in combination with 2.4 mg of semaglutide (Wegovy) for 20 weeks, which yielded a weight loss of more than 17%.

An by Kishore M. Gadde, MD, of Pennington Biomedical Research Center in Baton Rouge, Louisiana, and David B. Allison, PhD, of Indiana University School of Public Health-Bloomington, compared the novel agent with other agents.

In post-approval studies, short-acting amylin analogue pramlintide (SymlinPen), at higher doses injected three times daily, yielded about a 2.8% greater weight loss than placebo over a 16-week period.

"The weight loss achieved with cagrilintide in Lau and colleagues' study is clinically significant, greater than that achieved with pramlintide, and deserves further examination in longer duration trials," Gadde and Allison wrote.

Also, they noted, "placebo-subtracted 26-week weight loss with cagrilintide, assuming it is durable over longer duration, appears to be greater than that observed with orlistat and naltrexone-bupropion, approximately the same as that with liraglutide, and less than with and semaglutide in patients with obesity without diabetes."

Beyond body weight reduction, cagrilintide didn't appear to have any significant effect on hemoglobin A1c (HbA1c) or fasting glucose. However, there was a drop in fasting insulin concentrations across all treatment groups by week 26.

Drops in triglycerides and very-low-density cholesterol were significantly greater with the two highest doses of cagrilintide versus placebo, but they were similar to those with liraglutide.

All treatment groups also saw greater improvements in Three-Factor Eating Questionnaire Revised 18-item version 2 scores, marked by greater cognitive restraint with eating, emotional eating, and uncontrolled eating.

Adverse events were more common with cagrilintide than placebo but similar to liraglutide. Overall, 4% of participants withdrew from the trial. The most commonly reported adverse events were GI-related -- nausea, constipation, and diarrhea -- along with administration-site reactions.

Conducted across 57 international sites, the phase II dose-finding study enrolled a total of 706 participants at least 18 years old. Females could not have childbearing potential (postmenopausal or premenopausal with documented hysterectomy, etc.). All had either obesity, defined as a BMI of at least 30, or overweight with a BMI of at least 27 plus hypertension or dyslipidemia. Diabetes, defined as an HbA1c of 6.5% or higher, was grounds for exclusion. Also, any patients with prior or planned obesity treatment with surgery or a weight loss device were excluded.

Patients randomized 6:1 to any dose of cagrilintide were started on 0.3 mg (for a final dose of 0.3 mg) or 0.6 mg (for all other doses) per week at randomization, which was escalated incrementally every 2 weeks until reaching the final dose.

All participants also received diet and physical activity counseling.

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