Cagrilintide

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

Summary

Background

Natural amylin is a pancreatic hormone that induces satiety. Cagrilintide is a long-acting amylin analogue currently being investigated for weight management. This study assessed the dose–response relationship of cagrilintide concerning its effects on body weight, safety, and tolerability.

Methods

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 across ten countries: Canada, Denmark, Finland, Ireland, Japan, Poland, Serbia, South Africa, the UK, and the USA. Participants were adults aged 18 years or older without diabetes, having a body-mass index of at least 30 kg/m² or at least 27 kg/m² with hypertension or dyslipidaemia. They 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. The trial included a 26-week treatment period with dose-escalation up to 6 weeks, and a 6-week follow-up period without treatment. Participants and investigators were masked regarding active vs. pooled placebo treatment, but not to different active treatments. The primary endpoint was the percentage change in body weight from baseline to week 26. Safety was assessed in all participants who received at least one dose of randomised treatment. This trial is registered with ClinicalTrials.gov (NCT03856047) and is closed to new participants.

Findings

Between March 1 and August 19, 2019, we 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%) was similar across treatment groups, mainly due to adverse events (n=30, 4%). A total of 29 participants (4%) withdrew from the trial. 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]) compared with 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 compared with 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 (nausea, constipation, diarrhoea) and administration-site reactions. More participants receiving cagrilintide 0.3–4.5 mg experienced gastrointestinal adverse events compared with placebo (41%–63% vs 32%), primarily nausea (20%–47% vs 18%).

Interpretation

Treatment with cagrilintide in individuals with overweight and obesity resulted in significant reductions in body weight and was well tolerated. These findings support the development of molecules with new mechanisms of action for weight management.

Funding

Novo Nordisk A/S.

Introduction

Obesity is a widespread, complex, progressive chronic condition associated with long-term complications, such as type 2 diabetes, cancer, hypertension, and cardiovascular disease, which reduce quality of life and life expectancy. Additionally, obesity increases the risk of severe COVID-19 outcomes, including hospitalization, intensive care admission, and mortality.

Modest weight loss (5%–10%) provides health benefits, reducing the risk of type 2 diabetes and cardiometabolic disease. More significant weight loss (≥10%) can improve complications such as obstructive sleep apnea and knee osteoarthritis. Most chronic weight management guidelines recommend a step-wise approach starting with lifestyle interventions, followed by adjunct pharmacotherapy if sufficient weight loss isn’t achieved. Despite obesity's prevalence and associated risks, few approved pharmacotherapy options are available, with modest efficacy (3%–9% weight loss relative to placebo at 1 year). Results from the global phase 3 Semaglutide Treatment Effect in People with Obesity (STEP) trial showed considerable weight loss with the new-generation GLP-1 receptor agonist semaglutide 2.4 mg, leading to its US FDA approval for weight management in June 2021. Given obesity’s heterogeneity and varied treatment responses, exploring novel molecules with different action mechanisms might provide effective therapeutic options.

Amylin, a pancreatic β-cell hormone co-secreted with insulin in response to nutrient intake, functions as a satiety signal, acting on the brain’s homeostatic and hedonic regions. It slows gastric emptying, suppresses post-prandial glucagon response, and regulates appetite and food choices through receptors in the hindbrain and other brain regions. Cagrilintide, a long-acting, acylated amylin analogue, reduces food intake and body weight dose-dependently. This study assessed the dose–response relationship of cagrilintide regarding its effects on body weight, safety, and tolerability of ascending doses of subcutaneous cagrilintide once weekly in participants with overweight or obesity. It also compared changes in waist circumference and cardiometabolic parameters with cagrilintide, placebo, and the GLP-1 receptor agonist liraglutide 3.0 mg, approved for weight management.

Study Design and Participants

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). 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.

Results

Between March 1 and August 19, 2019, we screened 886 participants and randomly assigned 706 to treatment: cagrilintide 0.3–4.5 mg (100–102 participants per dose group), liraglutide 3.0 mg (99 participants), or volume-matched placebo (101 participants). All randomly assigned participants were exposed to trial product and included in the full and safety analysis sets. 73 participants (10%) permanently discontinued treatment and 29 (4%) withdrew from the trial. Of those who completed the trial, weight loss was more significant with all doses of cagrilintide compared to placebo, and greater with cagrilintide 4.5 mg versus liraglutide 3.0 mg. Gastrointestinal disorders were the most common adverse events.

Discussion

Cagrilintide is the first long-acting amylin analogue to be investigated for weight management. In this study, treatment with cagrilintide for 26 weeks in participants with overweight or obesity, as an adjunct to lifestyle interventions, led to dose-dependent, clinically relevant reductions in body weight and waist circumference. The 7.8% mean weight loss achieved with cagrilintide 4.5 mg at week 26 was significant compared to the placebo. The findings support the potential of novel amylin analogues like cagrilintide for effective weight management.

Conclusion

The phase 2 trial results indicate that once-weekly cagrilintide can significantly reduce body weight in individuals with overweight and obesity. The treatment was well tolerated, although gastrointestinal side effects were common. Continued exploration of cagrilintide and other novel molecules with different mechanisms of action could provide effective alternatives for weight management and broaden therapeutic options for obesity treatment.