Skye Bioscience comments on monlunabant Phase 2 top-line data

Skye Bioscience (SKYE) providing a statement regarding a recent announcement by Novo Nordisk (NVO) on Phase 2a top-line data with monlunabant, Novo’s small-molecule oral cannabinoid receptor inverse agonist. “We are encouraged to see that monlunabant met its primary endpoint and demonstrated at least a 6% placebo-adjusted weight loss at 16 weeks, which we see as broadly supportive of the mechanism of action for inhibition of peripheral CB1 receptors and its role in weight loss,” said Punit Dhillon, Skye’s CEO. “The observation of dose-dependent neuropsychiatric side effects in this study was unfortunate, however, this highlights a key distinction between our large-molecule CB1 inhibitor and known small-molecule CB1 inhibitors currently in development. Nimacimab, a monoclonal antibody being developed by Skye, has demonstrated minimal accumulation of drug in the brain in preclinical non-human primate studies, and in our limited data set from the Phase 1 MAD study in non-alcoholic fatty liver disease, importantly, no neuropsychiatric adverse events were observed.” “In pharmacodynamic models, the key advantages of nimacimab’s peripheral restriction from the brain have been underscored,” said Chris Twitty, Skye’s Chief Scientific Officer. “Modeling of Phase 1 pharmacokinetic and preclinical biodistribution data demonstrate* that both nimacimab and monlunabant have sufficient peripheral exposure to exceed their respective IC90 thresholds to inhibit CB1 signaling. However, as expected for a small molecule, monlunabant has reported notable leakage into the brain, leading to central exposure exceeding the IC75 concentration at all doses tested in the Phase 2a study. We believe these data demonstrate a critical challenge faced by current CB1 small molecules in development, which lack adequate restriction from the brain and an increased potential for neuropsychiatric side effects.” Dhillon added, “It is clear that with increased restriction from the brain, nimacimab provides a potential clear safety advantage over a small molecule approach. In addition, nonclinical studies have shown the predominant role of peripherally-driven CB1 inhibition in achieving weight loss and metabolic gains versus centrally-driven CB1 inhibition. To support our hypothesis, Skye has developed a murine mouse model expressing the human variant of the CB1 receptor, which will allow us to evaluate the effects on weight loss with nimacimab in a diet-induced obesity murine model. We expect to share results from these studies in the near future.” Skye launched its Phase 2 trial of nimacimab in obesity in August 2024. This trial, which is the first to also assess a GLP-1/CB1 inhibitor combination, is expected to report interim weight loss data in Q2 2025 and top-line data in Q4 2025.