Cagrilintide combined with semaglutide is safe and effective for weight management
Obesity is a chronic disease associated with the development of multiple diseases, such as type 2 diabetes, cardiovascular disease, cancer, osteoarthritis, chronic back pain, and asthma. Despite the high incidence of obesity-related diseases, there are few treatment options available for weight management worldwide, including drug therapy. Combining obesity drugs with different mechanisms of action may be beneficial for obese or overweight patients and provide an effective treatment option for weight management.
Cagrilintide is a long-acting amylin analog that has agonist effects on both natural amylin and calcitonin receptors. Semaglutide is a glucagon-like peptide-1 (GLP-1) analog that has been approved for the treatment of type 2 diabetes and is being studied for weight management. The Lone B Enebo team of Novo Nordisk in Denmark studied the safety, tolerability, pharmacokinetics, and pharmacodynamics of different doses of cagrilintide combined with semaglutide 2.4 mg for weight management.
In this randomized, placebo-controlled, multiple-dose escalation, phase 1b trial, researchers enrolled participants aged 18 to 55 years with a body mass index of 27.0 to 39.9 kg/m² and other healthy individuals. The trial included 6 consecutive overlapping cohorts, in each of which participants were randomly assigned (3:1) to receive once-weekly subcutaneous injections of cagrilintide (0.16, 0.30, 0.60, 1.2, 2.4, or 4.5 mg) or matching placebo in combination with once-weekly subcutaneous injections of semaglutide 2.4 mg without lifestyle intervention. In each cohort, the doses of cagrilintide and semaglutide were co-escalated every 4 weeks to the desired dose for 16 weeks, and participants were treated at the target dose for 4 weeks and then followed for 5 weeks.
The primary endpoint was the number of treatment-emergent adverse events from baseline to the end of follow-up. Secondary pharmacokinetic endpoints evaluated from the last dose (week 19) to the end of treatment (week 20) were the area under the plasma concentration-time curve from 0 to 168 hours (AUC0-168h) and the maximum concentration [Cmax] of cagrilintide and semaglutide; exploratory pharmacokinetic endpoints were half-life, time to reach Cmax [tmax], plasma clearance, and volume of distribution of cagrilintide and semaglutide; exploratory pharmacodynamic endpoints were changes in body weight, glycemic parameters, and hormones.
From July 25, 2018, to December 17, 2019, 96 eligible participants were randomly assigned to cagrilintide (0.16-2.4 mg group, n=12; 4.5 mg group, n=11) or placebo (n=24) in combination with 2.4 mg semaglutide, of which 95 treated participants were included in the safety and full analysis data sets. The mean age of the participants was 40.6 years, 56 of the 95 participants (59%) were male, and 51 (54%) were black or African American. Of the 566 adverse events reported in 92 subjects, 207 (37%) were gastrointestinal disorders, including 71 subjects taking 0.16-4.5 mg cagrilintide, of which 69 (97%) experienced adverse events, and 24 subjects taking placebo, of which 23 (96%) experienced adverse events. Most adverse events were mild to moderate in severity, and the proportion of participants experiencing one or more adverse events was similar in each treatment group. Exposure was proportional to cagrilintide dose and did not affect semaglutide exposure or elimination.
At cagrilintide 0.16-4.5 mg, AUC0-168h ranged from 926 to 24271 nmol×
h/L, and Cmax ranged from 6.14 to 170 nmol/L. At 2.4 mg of semaglutide, the AUC0-168h ranged from 12757 to 15305 nmol×h/L, and the Cmax ranged from 96.4 to 120 nmol/L. The half-life of cagrilintide 0.16 to 4.5 mg was 159 to 195 h, and the median tmax was 24 to 72 h. The half-life of semaglutide 2.4 mg was 145 to 165 h, and the median tmax was 12 to 24 h. The plasma clearance and distribution volume of cagrilintide and semaglutide were similar in all treatment groups. At week 20, the mean percentage weight loss in the cagrilintide 1.2 mg and 2.4 mg groups was greater than that in the placebo group (15.7% in the cagrilintide 1.2 mg group, 17.1% in the cagrilintide 2.4 mg group, and 9.8% in the placebo group (1-5); the estimated treatment differences were -6.0% and -7.4% in the cagrilintide 1.2 mg and 2.4 mg groups, respectively, compared with the placebo group; glycemic parameters improved in all treatment groups, regardless of cagrilintide dose. Hormonal changes were similar in all treatment groups.
The results of the study showed that the combination of cagrilintide and semaglutide 2.4 mg was well tolerated and had an acceptable safety profile. Larger and longer trials are needed in the future to fully evaluate the efficacy and safety of this treatment combination.
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