Safety, tolerability, pharmacokinetics, and pharmacodynamics of concomitant administration of multiple doses of cagrilintide with semaglutide 2•4 mg for weight management: a randomised, controlled, phase 1b trial

Cagrilintide is a long-acting amylin analogue, and semaglutide 2•4 mg is a glucagon-like peptide-1 analogue. Both the drugs have been investigated as options for weight management. Lone B Enebo and colleague published a study in The Lancet journal under the title “Safety, tolerability, pharmacokinetics, and pharmacodynamics of concomitant administration of multiple doses of cagrilintide with semaglutide 2•4 mg for weight management: a randomized, controlled, phase 1b trial”. The summary of this paper is given below:

Objective:

To investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of cagrilintide and semaglutide in combination.

Method:

This is a randomized, placebo-controlled, multiple ascending doses, phase 1b trial. A healthy individual between 18–55 years of age with a body-mass index of 27•0−39•9 kg/m² was recruited from a single center in the USA. Six sequential overlapping cohorts were included in the trial. Eligible participants in each cohort were randomly assigned in a 3:1 ratio to receive a once-weekly subcutaneous cagrilintide or matched placebo, in combination with a once-weekly subcutaneous semaglutide 2•4 mg, independent of lifestyle interventions. In each cohort, the doses of each drug were co-escalated, and in 4-week intervals to the desired dose over 16 weeks is achieved. Investigators, participants, and the sponsor were masked to assigned treatment.

The primary outcome was a number of treatment-emergent adverse events. Secondary pharmacokinetic endpoints assessed maximum concentration [Cmax] of cagrilintide and semaglutide from the day of last dose (week 19) to end of treatment (week 20); exploratory pharmacokinetic endpoints were time to Cmax, half-life, plasma clearance, and volume of distribution of both drugs. Exploratory pharmacodynamic endpoints were changes in body weight, hormones, and glycaemic parameters. Safety, pharmacokinetic, and pharmacodynamic endpoints were investigated in all participants who were exposed to at least one dose of the study drug. This study is now complete and registered with ClinicalTrials.gov, NCT03600480.

Findings:

This combination treatment with cagrilintide 0•16–4•5 mg and semaglutide 2•4 mg for 20 weeks was well tolerated in overweight and obese patients. There were no unexpected safety concerns arisen apart from mild to moderate cases of gastrointestinal disorders, nausea, and vomiting which are known effects of semaglutide and cagrilintide. Greater mean weight reduction was found with cagrilintide in combination with semaglutide (2•4 mg) without lifestyle interventions as compare to cagrilintide alone. There were frequent reports of decreased appetite and increased satiety with cagrilintide and semaglutide in participants.

Limitation:

The study was not designed to assess weight reduction; it was investigated as an exploratory endpoint. Hence, the data should be interpreted with caution. Secondly, the short duration of the trial might have restricted the efficacy and safety of this combination treatment. A longer trial to assess sustained weight loss should be conducted. Due to the less sample size, findings might not be generalized. Subjects with high cardiovascular risk and BMI of 40 kg/m2 were excluded from the trial because of potential complications that could act as confounding factors. Lastly, the covid-19 pandemic has affected the trial visits converting them into outpatient visits.

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