AM833 plus semaglutide safe, leads to greater weight loss in obese/overweight individuals

14 Apr 2021 bởiStephen Padilla
AM833 plus semaglutide safe, leads to greater weight loss in obese/overweight individuals

The combination of long-acting amylin analogue AM833 (at all tested doses) and glucagon-like peptide-1 receptor agonist semaglutide (2.4 mg) is well tolerated and shows an acceptable safety profile, with pharmacokinetics data supporting once-weekly dosing, according to a study presented at the virtual conference of the Endocrine Society (ENDO 2021).

In addition, the combination of AM833 1.2, 2.4, or 4.5 mg plus semaglutide resulted in greater weight loss compared with placebo plus semaglutide, the researchers, led by Lone B. Enebo, Ph D, from Novo Nordisk, reported.

This randomized, double-blind, placebo-controlled, phase I trial investigated the safety, tolerability, pharmacokinetics, 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) plus semaglutide vs placebo plus semaglutide in obese or overweight individuals.

The trial lasted for 20 weeks and included a 16-week escalation period followed by a 4-wek treatment period at target dose and a 5-week follow-up. Men and women of nonchildbearing potential, aged 18–55 years, with body mass index (BMI) of 27–39.9 kg/m2 were eligible for this study.

The number of adverse events (AEs) from baseline to follow-up was the primary endpoint. Secondary ones were pharmacokinetic parameters (area under the curve [AUC] 0-168 h [AUC0-168], maximum concentration [Cmax], half-life [t1/2], and time to Cmax [tmax]).

Enebo and colleagues separately analysed the changes in body weight (exploratory endpoint) for AM833 0.16−2.4 mg plus semaglutide (vs pooled placebo) and AM833 4.5 mg plus semaglutide (vs matched placebo) due to a different semaglutide dose escalation regimen used in this treatment arm.

Ninety-six participants were randomized, of whom 95 were exposed to treatment (mean age 40.6 years, body weight 95.7 kg, BMI 32.1 kg/m2, 59 percent male) and 80 (83 percent) completed the trial. [ENDO 2021, abstract P02-2]

The number of AEs were significantly lower in the AM833 (0.16–4.5 mg) plus semaglutide arm than in the pooled placebo plus semaglutide arm (37–89 vs 132, respectively). Most AEs were mild or moderate, and the proportion of individuals with one or more AEs was comparable across treatment groups.

Nearly one-third of all AEs were gastrointestinal (GI) disorders (207 of 566), mainly nausea, dyspepsia, and vomiting. More participants in the AM833 1.2–4.5 mg plus semaglutide arm reported GI AEs compared with those in the placebo plus semaglutide arm. Injection site reactions (n=72) were the second most common AEs, all of which were mild and not dependent on AM833 dose.

Exposure to AM833 was proportional to dose for both AUC0-168 and Cmax and had no impact on semaglutide exposure and elimination. AM833 0.16−4.5 mg t1/2 ranged from 159–195 h and median tmax ranged from 24–72 h.

At week 20, body weight changes from baseline with AM833 1.2 and 2.4 mg plus semaglutide were greater than with pooled placebo plus semaglutide (–15.7 percent and –17.1 percent vs –9.8 percent, respectively; p<0.001) and with AM833 4.5 mg plus semaglutide vs matched placebo plus semaglutide (–15.4 percent vs –8.0 percent; p<0.01).