Skye Bioscience presents PK, PD model on CB1 inhibitors

Skye Bioscience (SKYE) presented a clinical pharmacokinetic, PK, and pharmacodynamic, PD, model that underscores the fundamental relationship between biodistribution and efficacy of CB1 inhibitors at the annual European Congress on Obesity meeting. This model demonstrated that achieving strong peripheral CB1 inhibition is sufficient to achieve efficacy, including weight loss. In contrast, blocking CB1 in the brain, which is associated with neuropsychiatric side effects, is not enough on its own to achieve weight loss. Published clinical PK and potency data coupled with Phase 2 and Phase 3 efficacy data from Novo Nordisk’s monlunabant and Sanofi’s rimonabant, respectively, as well as Phase 1 data from nimacimab were used to develop a model to determine whether peripheral CB1 inhibition alone is sufficient for weight loss, or if central inhibition is also required for optimal efficacy. The results showed that central inhibition of CB1 alone was not sufficient for weight loss with P2 data for monlunabant, and demonstrated that increasing drug levels in the brain did not improve efficacy. Relatedly, monlunabant’s Ph2 dose range established that all doses achieved significant peripheral inhibition, resulting in significant but similar weight loss.