PII-006 - PHARMACODYNAMIC MODELS AS EARLY PREDICTORS OF WEIGHT LOSS EFFICACY IN EARLY-PHASE CLINICAL RESEARCH

C. Dehn¹, E. Ridolfi²; ¹Evolution Research Group, New Providence, NJ, United States of America, ²Evolution Research Group (ERG), New Providence, NJ, United States of America.

Background: In early-phase clinical trials, study durations and drug exposures are brief, making it difficult to observe early signals of efficacy from endpoints such as weight loss that require time for measurable change to occur. Identifying pharmacodynamic (PD) models that can predict efficacy as surrogates for weight loss could streamline drug development and accelerate decision-making processes.

Methods: A broad literature search was conducted to identify potential PD models that could serve as early indicators of efficacy in early-phase development of weight-loss therapies. The search revealed several promising methodologies, including circulating, behavioral, and body composition biomarkers. Relevant studies were analyzed based on their ability to detect signals predicting weight-loss efficacy, even before significant weight changes occurred.

Results: 1. Blood Ketones: Elevated blood ketones, particularly β-hydroxybutyrate, were identified as markers of enhanced fat oxidation. Studies showed significant increases in ketones within one to two weeks of ketogenic interventions, correlating with long-term weight loss.
2. Indirect Calorimetry: Changes detected by indirect calorimetry were shown to precede measurable weight loss. These metabolic shifts were observed in response to pharmacologic interventions and dietary changes.
3. Universal Eating Monitor (UEM): Early-phase studies demonstrated that behavioral changes in food intake and satiety measured via UEM were associated with the appetite-suppressing effects of weight-loss therapies.
4. Gut Hormones: Modulation of gut hormones such as GLP-1 and PYY was predictive of reduced caloric intake and subsequent weight loss in early phase trials.
5. Body Composition: Techniques like DEXA and MRI detected reductions in fat mass and changes in body composition with as little as two to four weeks of exposure to weight-loss therapies, even before overall weight loss was measurable.

Conclusion: Pharmacodynamic models offer valuable early-phase indicators of weight-loss efficacy. Incorporating these markers into early-phase clinical trials can accelerate the identification of effective weight-loss therapies by providing early signals of therapeutic efficacy before significant weight loss is observed.