Safety and Tolerability of Concomitant Administration of Multiple-Dose AM833 With Semaglutide 2.4 MG for Weight Management

Background: Combining weight management medications with different modes of action may provide more effective treatment options for people with obesity. Subcutaneous (sc) AM833, a long-acting amylin analog, and sc semaglutide 2.4 mg, a glucagon-like peptide-1 receptor agonist, are both under clinical development for weight management. Methods: This was a randomized, double-blind, placebo-controlled, phase 1 trial to investigate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of concomitant administration of six ascending doses of weekly AM833 (0.16, 0.3, 0.6, 1.2, 2.4, or 4.5 mg) + semaglutide vs placebo + semaglutide in subjects with overweight or obesity. The 20-week trial included a 16-week escalation period followed by a 4-week treatment period at target dose and a 5-week follow-up. Eligible subjects were male or female of non-childbearing potential, aged 18–55 years, with BMI 27−39.9 kg/m(2). The primary endpoint was number of adverse events (AE) from baseline to follow-up. Secondary endpoints included PK parameters (area under the curve [AUC] 0–168 h [AUC(0-168)], maximum concentration [C(max)], half-life [t(1/2)] and time to C(max) [t(max)]). Changes in body weight (exploratory endpoint) were analyzed separately for AM833 0.16−2.4 mg + semaglutide (vs pooled placebo) and AM833 4.5 mg + semaglutide (vs matched placebo) due to a different semaglutide dose escalation regimen used in this treatment arm. Results: Of 96 subjects randomized, 95 were exposed to treatment (59% male; mean age 40.6 years, body weight 95.7 kg, BMI 32.1 kg/m(2)) and 80 (83%) completed the trial. The number of AEs ranged from 37–89 with AM833 (0.16–4.5 mg) + semaglutide and 132 with pooled placebo + semaglutide. Most AEs were mild or moderate and the proportion of subjects with ≥1 AE was similar across treatment arms. About one-third of all AEs were gastrointestinal (GI) disorders (n=207 of 566), primarily nausea, dyspepsia, and vomiting. A greater proportion of subjects reported GI AEs with AM833 1.2–4.5 mg + semaglutide vs placebo + semaglutide. The second most common AEs were injection site reactions (n=72), all mild and not dependent on AM833 dose. Exposure to AM833 was proportional to dose for both AUC(0-168) and C(max), and did not affect semaglutide exposure and elimination. AM833 0.16−4.5 mg t(1/2) ranged from 159–195 h and median t(max) ranged from 24–72 h. At week 20, body weight changes from baseline with AM833 1.2 and 2.4 mg + semaglutide were greater vs pooled placebo + semaglutide (−15.7% and −17.1% vs −9.8%, respectively; p<0.001) and with AM833 4.5 mg + semaglutide vs matched placebo + semaglutide (−15.4% vs −8.0%; p<0.01). Conclusion: Treatment with AM833 at all tested doses + semaglutide was generally well tolerated with an acceptable safety profile. PK data support once-weekly dosing. The combination of AM833 1.2, 2.4, or 4.5 mg + semaglutide led to greater weight loss compared with placebo + semaglutide.