Treatment with investigational long-acting amylin, cagrilintide, in people with overweight and obesity, but not diabetes, led to significant reductions in bodyweight and was well tolerated, found a phase II trial by Dr David Lau and colleagues of the University of Calgary Cumming School of Medicine in Canada, in The Lancet.
In the randomised trial, all doses of the novel once-weekly injectable treatment yielded significantly greater weight loss than placebo. 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%
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 said. “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 accompanying commentary by Dr Kishore Gadde of Pennington Biomedical Research Center in Baton Rouge, Louisiana, and David Allison 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 phentermine topiramate and semaglutide in patients with obesity without diabetes.”
Beyond body weight reduction, cagrilintide didn’t appear to have any significant effect on haemoglobin 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 diarrhoea, 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.
Once-weekly cagrilintide for weight management in people with overweight and obesity: a multicentre, randomised, double-blind, placebo-controlled and active-controlled, dose-finding phase 2 trial
Prof David C W Lau, Lars Erichsen, Ann Marie Francisco, Altynai Satylganova, Prof Carel le Roux, Prof Barbara McGowan, Sue Pedersen, Prof Kirsi Pietiläinen, Domenica Rubino, Prof Rachel Batterham
Published in The Lancet on 16 November 2021
Natural amylin is a pancreatic hormone that induces satiety. Cagrilintide is a long-acting amylin analogue under investigation for weight management. We assessed the dose–response relationship of cagrilintide regarding the effects on bodyweight, safety, and tolerability.
We conducted a multicentre, randomised, double-blind, placebo-controlled and active-controlled, dose-finding phase 2 trial at 57 sites including hospitals, specialist clinics, and primary care centres in ten countries (Canada, Denmark, Finland, Ireland, Japan, Poland, Serbia, South Africa, the UK, and the USA). Eligible participants were adults aged at least 18 years without diabetes, with a body-mass index of at least 30 kg/m2 or at least 27 kg/m2 with hypertension or dyslipidaemia. Participants were randomly assigned (6:1) to subcutaneous self-injections of once-weekly cagrilintide (0·3, 0·6, 1·2, 2·4, or 4·5 mg), once-daily liraglutide 3·0 mg, or volume-matched placebo (for six placebo groups).
The trial had a 26-week treatment period, including a dose-escalation period of up to 6 weeks, and a 6-week follow-up period without treatment. Participants and investigators were masked to the assigned study treatment with respect to active versus pooled placebo treatment, but not to different active treatments. The primary endpoint was the percentage change in bodyweight from baseline to week 26, assessed in all randomly assigned participants according to the trial product estimand (assuming all participants were adherent to treatment) and to the treatment policy estimand (regardless of adherence to treatment). Safety was assessed in all participants who received at least one dose of randomised treatment.
Between March 1 and Aug 19, 2019, we randomly assigned 706 participants to cagrilintide 0·3–4·5 mg (100–102 per dose group), 99 to liraglutide 3·0 mg, and 101 to placebo. Permanent treatment discontinuation (n=73 [10%]) occurred similarly across treatment groups, mostly due to adverse events (n=30 [4%]). In total, 29 participants (4%) withdrew from the trial. According to the trial product estimand, mean percentage weight reductions from baseline were greater with all doses of cagrilintide (0·3–4·5 mg, 6·0%–10·8% [6·4–11·5 kg]) versus placebo (3·0% [3·3 kg]; estimated treatment difference range 3·0%–7·8%; p<0·001). Weight reductions were also greater with cagrilintide 4·5 mg versus liraglutide 3·0 mg (10·8% [11·5 kg] vs 9·0% [9·6 kg]; estimated treatment difference 1·8%, p=0·03). Similar weight loss reductions were observed with the treatment policy estimand. The most frequent adverse events were gastrointestinal disorders (eg, nausea, constipation, and diarrhoea) and administration-site reactions. More participants receiving cagrilintide 0·3–4·5 mg had gastrointestinal adverse events compared with placebo (41%–63% vs 32%), primarily nausea (20%–47% vs 18%).
Treatment with cagrilintide in people with overweight and obesity led to significant reductions in bodyweight and was well tolerated. The findings support the development of molecules with novel mechanisms of action for weight management.
The Lancet article – Once-weekly cagrilintide for weight management in people with overweight and obesity: a multicentre, randomised, double-blind, placebo-controlled and active-controlled, dose-finding phase 2 trial (Open access)
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