Active Development Portfolio for Obesity Pharmacotherapy: An Analysis of Data from the ClinicalTrials.gov Registry

INTRODUCTION. The success of incretin receptor agonists has changed the standard of obesity pharmacotherapy and has stimulated both the development of incremental innovations based on existing medicinal products and the search for substances with fundamentally new mechanisms of action. Given the rapid diversification of the development portfolio, its systematic monitoring is required to forecast therapeutic horizons and to prepare the healthcare system in advance for the introduction of new approaches.

AIM. To perform a comprehensive analysis of the active portfolio of clinical developments in obesity pharmacotherapy in terms of the distribution across clinical trial phases, the types of molecular targets, the assessment of comorbidity outcomes, and the completeness of pharmacological profile disclosure.

MATERIALS AND METHODS. Data from the ClinicalTrials.gov registry were analyzed. Of 726 records of the active development portfolio, 475 active interventional studies of anti-obesity medicinal products covering 210 active substances were selected.

RESULTS. The study revealed a structural asymmetry of the portfolio: radical innovations accounted for 7.6% (16 substances) and incremental innovations for 21.0% (44), while the mechanism of action of 44.8% (94) was not disclosed. A translational barrier was identified: non-incretin medicinal products had not passed beyond phase II of clinical trials, whereas phases III–IV were dominated by agonists of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors, as well as by amylin analogues. Radical targets address the loss of muscle mass (activin type II receptor inhibitors) and the recurrence of obesity, as well as modulation of independent axes of body weight regulation: the central axis (a monoamine oxidase B inhibitor), the endocannabinoid axis, and the hepatic axis (RNA interference targeting the INHBE gene). Incremental innovations are represented by monoand multiagonists of the GLP-1, GIP, and glucagon receptors, as well as by amylin and GLP-1 co-agonists. A paradigm shift was observed: in 18.7% (89) of the studies, comorbidity outcomes served as the primary endpoint (cardiovascular outcomes, 25.8%; carbohydrate metabolism outcomes, 24.7%). The leading sponsors of late-phase developments were Eli Lilly and Novo Nordisk (90 studies). More than half of the studies (245) were concentrated in the United States. The Chinese segment (117 studies) focused on scaling up validated approaches without creating fundamentally new targets; at the same time, 26 of the 94 substances with an undisclosed mechanism of action (27.7%) are being developed under the lead sponsorship of Chinese organizations.

CONCLUSIONS. The identified translational barrier determines the medium-term prospects of obesity pharmacotherapy: in the coming years, the clinical armamentarium will be expanded primarily with multiagonists of the incretin axis and amylin analogues, whereas the need for medicinal products that preserve muscle mass and prevent obesity recurrence will remain unmet. The shift of focus toward comorbidity outcomes (the concept of obesity as a multisystem disease) requires the healthcare system to prepare for the integration of multi-target medicinal products into the standards of care for cardiovascular and metabolic complications. The high proportion of candidates with an undisclosed mechanism of action hampers comprehensive horizon scanning and strategic planning.

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