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
Enebo LB, Berthelsen KK, Kankam M, Lund MT, Rubino DM, Satylganova A, Lau DCW
Lancet (2021) · n=96
The Phase 1b dose-escalation study that established cagrilintide's once-weekly pharmacokinetic profile (half-life 159–195 hours) and produced the first human signal that combination amylin + GLP-1 agonism could exceed semaglutide monotherapy — 17.1% weight loss at week 20 on cagrilintide 2.4 mg plus semaglutide 2.4 mg, all in 96 healthy-overweight adults at a single US site.
This Phase 1b trial is the first published human study of cagrilintide co-administered with semaglutide and the dataset that established the once-weekly pharmacokinetic profile underwriting the entire CagriSema clinical program. Investigators conducted a randomised, placebo-controlled, multiple-ascending-dose study at a single US centre. 96 adults with BMI 27.0–39.9 kg/m² without diabetes were randomised across six sequential overlapping cohorts to escalating doses of cagrilintide (0.16, 0.30, 0.60, 1.2, 2.4, or 4.5 mg) co-administered with semaglutide 2.4 mg, or to placebo, across a 16-week dose-escalation phase plus 4 weeks at target dose plus a 5-week follow-up — 25 weeks total exposure. 95 participants were exposed to treatment; mean age was 40.6 years, 59% were male, and 54% were Black or African American, an unusually diverse Phase 1 cohort by US obesity-trial standards.
The pharmacokinetic findings established the once-weekly framework. Cagrilintide exposure was dose-proportional across the 0.16–4.5 mg range, with terminal half-life of 159–195 hours (roughly 6.6–8.1 days). Semaglutide half-life under co-administration was 145–165 hours, consistent with semaglutide's stand-alone pharmacokinetic profile and with no clinically meaningful drug-drug interaction. The pharmacodynamic and weight-loss findings produced the proof-of-concept signal. At week 20, mean body-weight reduction was 15.7%, 15.4%, 15.4%, 15.5%, 17.1%, and 15.6% on cagrilintide 0.16, 0.30, 0.60, 1.2, 2.4, and 4.5 mg respectively (all plus semaglutide 2.4 mg), versus 9.8% on placebo plus semaglutide 2.4 mg. The 2.4 mg cagrilintide dose produced the largest weight effect on top of semaglutide, which became the dose carried forward into Phase 2 (Frias et al. 2023) and Phase 3 (Garvey et al. 2025). Adverse events were predominantly gastrointestinal — 207 of 566 total events (37%) were GI disorders — and mostly mild to moderate in severity; no new safety signals beyond those expected for either compound individually were reported.
This trial was the human-pharmacology cornerstone of the CagriSema program. The Phase 2 monotherapy dose-finding trial (Lau et al. 2021) ran in parallel to characterise cagrilintide-alone performance; the two trials together set the dose and combination structure under which REDEFINE-1 was designed.
Phase 1b PK studies are designed to characterise safety, tolerability, and pharmacokinetics, not to test weight-loss efficacy with a statistical hypothesis — the weight findings are pharmacodynamic exploratory endpoints in a small cohort with no active monotherapy comparator (cagrilintide alone was not tested as an arm in this trial; that came in Lau et al. 2021). The 20-week duration is short relative to the 68-week Phase 3 endpoint and may overstate maintenance-of-effect for either compound or the combination. The single-centre US design, while supporting tight execution, raises generalisability questions; the 54% Black participant fraction is unusual for an obesity Phase 1 cohort and is a strength of the trial but limits comparison to the broader Phase 2 and Phase 3 program populations where representation skewed predominantly White. Industry sponsorship by Novo Nordisk is disclosed; the trial design and analysis are consistent with the published Phase 2 and Phase 3 readouts and with the EMA / FDA submission package. The weight-loss numbers in this trial cohort were considerably larger than what was later observed in REDEFINE-1 — the Phase 1b cohort lost roughly 15–17% over 20 weeks, while the Phase 3 trial-product estimand at 68 weeks landed at 22.7% — which the field has variously attributed to selection effects in small Phase 1 cohorts, the absence of long-term titration-tolerability attrition, and regression-to-the-mean considerations across the dose-escalation cohort structure. The trial's headline weight numbers should accordingly be read as pharmacodynamic signal rather than as Phase 3 predictive.
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