Sima Ahadieh, Master of Science: No financial relationships to disclose
Objectives: This model-based meta-analysis (MBMA) aimed to evaluate the longitudinal weight loss by amylin receptor (AMYR) agonists alone and in combination with glucagon-like peptide-1 receptor (GLP-1R) agonists using literature data.
Methods: This was an expansion to an existing meta-analysis presented previously [1] and included six additional randomized controlled studies for AMYR agonists cagrilintide, pramlintide, and the combination of cagrilintide and semaglutide (a GLP-1R agonist). The primary endpoint was the percent change from baseline (%CFB) in body weight in obese patients. The same model structure was maintained for placebo, drug, and covariate effects: the total treatment effect included both placebo and drug effects; drug effects were characterized by mechanism-specific Emax models and drug-specific ED50s; reversed exponential models plateaued with respect to time were used to describe the longitudinal placebo response and drug effects; the type 2 diabetes population was included as a covariate on maximum weight loss; a durability function was employed to capture the loss of placebo effect over time. In this analysis, additional Emax and onset rate constants were assessed for the AMYR agonist class along with drug-specific ED50s, and an interaction factor was estimated for the combination of AMYR and GLP-1R agonists. Simulations using the final model were conducted to predict the placebo-corrected %CFB in body weight at different time points and ratios of long- vs. short-term drug effects, with mean and 95% confidence intervals (CI) for each treatment.
Results: The estimated mean Emax for AMYR agonists were 12.2%, and smaller than the mean Emax of 19.5% for GLP-1R agonists. The onset rate constants for drug effects were similar between AMYR and GLP-1R agonists. The interaction factor for the combination was estimated to be 0.77 times the sum of the Emax effects of AMYR and GLP-1R agonists. The model predicted mean placebo corrected weight loss %CFB at 72 weeks for cagrilintide 2.4 mg, semaglutide 2.4 mg, and the combination of cagrilintide/semaglutide 2.4/2.4 mg as -9.58% [-8.31; -10.9], -12.6% [-11.6; -13.5], and -17.1% [-16.6; -17.7], respectively. The predicted ratios of long- vs. short-term drug effects were consistent for AMYR agonists alone and in combination with GLP-1R agonists, with values of 2.2 for Week 12/Week 4, 1.5 for Week 26/12, and 1.2 for Week 72/Week 26. An interactive shiny app was developed for assessing analysis results.
Conclusions: AMYR agonists alone demonstrated lower efficacy but similar onset in weight loss compared to GLP-1R agonists. The combination of AMYR and GLP-1 agonists resulted in a less than additive effect in weight loss. Long-term efficacy may be predicted from short-term weight loss for AMYR agonists alone and in combination with GLP-1R agonists.
Citations: [1] Ahadieh S, Ravva P, and Ahn JE, “A Longitudinal Model-based Meta-Analysis (MBMA) of Body Weight in Obesity Trials”, American Conference on Pharmacometrics 15, Phoenix, AZ (2024)
