Exploratory Literature Meta‐Analysis to Characterize the Relationship Between Early and Longer Term Body Weight Loss for Antiobesity Compounds

Abstract

The presented analysis was performed to characterize the relationship between treatment-related early (week 4) and longer term (3-6 months) weight loss to understand the potential utility of 4-week proof-of-mechanism studies in the early decision-making process during clinical development of new antiobesity compounds. A regression-based meta-analysis was performed leveraging publically available clinical outcomes data to (1) characterize the within-trial relationship between treatment-related early and longer term body weight loss and (2) identify and quantify key covariate effects on this relationship. Data from 89 randomized clinical trials with 209 treatment arms, representing observations from 54 461 patients and 9 treatments, were available for the meta-analysis. Results indicated that (1) there is a correlation between treatment-related early and longer term body weight loss (r > 0.9), (2) baseline body weight influences the relationship between early and longer term weight loss, whereas comorbidity such as type 2 diabetes mellitus, class of drugs including GLP-1 analogues and the antiobesity compounds lorcaserin or phentermine/topiramate showed no significant effects on this relationship. The model was externally evaluated with data from the investigational compound beloranib, for which longer term weight loss could be successfully predicted based on early response data. Based on these results, the identified strong relationship between treatment-related early and longer term weight loss appears to be independent of mechanism of action. Thus, findings from this analysis can optimize design of clinical studies and facilitate development of new anti-obesity compounds.

Translational Modeling to Guide Study Design and Dose Choice in Obesity Exemplified by AZD1979, a Melanin‐concentrating Hormone Receptor 1 Antagonist

“…53 The inferred average EI reduction of 14% over 1 year is in agreement with predictions by Rahmandad 19 who expressed BW loss in terms of body mass index units (11-14% EI reduction required; assuming body mass index of 35 kg/m2, and interpolating between reported body mass index changes of 1 and 5 units). Furthermore, the relationship between BW loss after 4 weeks with BW loss after 23-26 weeks presented in the metaanalysis of obesity studies by Plock et al 54 compares reasonably well with the inferred relationship in our analysis mainly concerning patients with diabetes, given that different patient populations were considered. Both the analysis on the active arms and the analysis on placebo-corrected data suggested the same required EI reduction of 14% for a 10% BW loss over 1 year, adding confidence to the derived estimate.…”

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“…Longitudinal MBMA models describing the time course of efficacy of drugs within or across therapeutic classes within the context of a disease progression modeling framework have been developed across several therapeutic areas. Examples include rheumatoid arthritis, psoriasis, osteoporosis, menopausal hot flashes, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, obesity, diabetes, and Alzheimer's disease . These typically invoke a common structural model of time course of efficacy with the drug effect described as an additional term over the placebo effect and the time course of disease progress.…”