Comparative effects of central and peripheral PDE10A inhibition on weight gain following semaglutide cessation in diet-induced obese mice

Abstract

Obesity is a chronic disease of disordered energy balance for which durable weight management remains an unmet need. The rise in use of anorectic therapies, such as incretin analogues, now particularly highlights the need for therapies which maintain weight loss after cessation of effective pharmacotherapy. Phosphodiesterase 10A (PDE10A) inhibition increases energy expenditure and promotes white adipose tissue browning in preclinical models, providing a mechanistic rationale for its therapeutic application. Two complementary studies in male diet-induced obese C57BL/6J mice were conducted to evaluate its pharmacological activity. In a 21-day dose-response study, BEN-8744, an orally bioavailable, peripherally-restricted, PDE10A inhibitor, significantly attenuated body weight gain relative to vehicle at all doses tested. In a 40-day weight maintenance study, mice pre-treated with semaglutide were switched to vehicle-only, BEN-8744, the brain-penetrant PDE10A inhibitor mardepodect or continued semaglutide. Mardepodect was comparable to continued semaglutide, significantly suppressing food intake and weight gain. BEN-8744 showed numerically less gain than vehicle but this difference did not reach statistical significance. Contrary to mardepodect treatment, BEN-8744 also did not significantly improve glucose tolerance or serum insulin. These findings establish BEN-8744 as pharmacologically active through a food-intake-independent mechanism consistent with increased energy expenditure, but indicate that its efficacy is modest relative to additional central PDE10A inhibition. Central PDE10A target engagement is essential for a sustained anti-obesity effect.