Skye Bioscience Discusses Monlunabant Phase 2 Data, Reaffirms Nimacimab Development Plan

Skye Bioscience, Inc., a biopharmaceutical company currently in the clinical stages, has shared insights in light of Novo Nordisk's recent announcement about the top-line results from their Phase 2a trial of monlunabant, a small-molecule oral cannabinoid receptor (CB1) inverse agonist. According to Punit Dhillon, CEO and Chairman of Skye, these findings are encouraging as they support the mechanism of action for peripheral CB1 receptor inhibition in promoting weight loss. Monlunabant achieved at least a 6% placebo-adjusted weight loss at 16 weeks, meeting its primary endpoint. However, the study also noted dose-dependent neuropsychiatric side effects, which distinguish small-molecule CB1 inhibitors from Skye's large-molecule approach.

Skye's nimacimab, a monoclonal antibody, has shown minimal drug accumulation in the brain according to preclinical studies on non-human primates and Phase 1 multiple ascending dose (MAD) studies in non-alcoholic fatty liver disease (NAFLD). Importantly, there were no observed neuropsychiatric adverse events among the participants (N=62). Chris Twitty, Skye's Chief Scientific Officer, highlighted that nimacimab's peripheral restriction from the brain offers significant safety advantages. The pharmacokinetic and preclinical biodistribution data indicate that nimacimab and monlunabant have sufficient peripheral exposure to inhibit CB1 signaling. However, monlunabant has shown notable leakage into the brain, leading to central exposure and potential neuropsychiatric side effects.

Nimacimab’s ability to restrict brain exposure presents a potential safety advantage over small-molecule approaches. Nonclinical studies underscore that peripheral CB1 inhibition plays a predominant role in achieving weight loss and metabolic benefits. To validate this, Skye has created a murine mouse model that expresses the human CB1 receptor, allowing the evaluation of nimacimab's effects on weight loss in a diet-induced obesity model. Results from these studies are anticipated soon.

Skye initiated a Phase 2 trial of nimacimab for obesity in August 2024. This trial is unique as it also explores a combination of nimacimab and a GLP-1/CB1 inhibitor. Interim weight loss data from this trial is expected in Q2 2025, with top-line data anticipated in Q4 2025.

Nimacimab's potency and pharmacokinetics have been modeled using both Phase 1 clinical data and non-human primate biodistribution data. This model predicts robust peripheral exposure with minimal central exposure, thereby potentially reducing neuropsychiatric side effects. Conversely, monlunabant’s model, based on Phase 1 clinical data and preclinical biodistribution data, indicates sufficient peripheral inhibition but significant brain exposure, consistent with reported neuropsychiatric adverse events.

The therapeutic index of nimacimab appears to be wider compared to small-molecule CB1 inhibitors, allowing for higher dosing flexibility while maintaining low central levels. Nimacimab has shown favorable tolerability in Phase 1 clinical data, further supporting its potential broader therapeutic index.

Monlunabant achieved approximately 6% weight loss at 16 weeks, which is consistent with historical benchmarks for CB1 inhibitors and supports the target of an 8% placebo-adjusted weight loss at 26 weeks in Skye’s current Phase 2 study of nimacimab. However, monlunabant also exhibited central nervous system exposure and related neuropsychiatric side effects across its trials, unlike nimacimab, which has shown no such issues in its trials.

Nimacimab’s differentiation lies in its non-competitive inhibition of CB1 signaling. Unlike small molecules that target the orthosteric site of CB1, nimacimab binds to an allosteric site, allowing it to inhibit CB1 signaling without competing with natural ligands. This mechanism ensures a better pharmacokinetic/pharmacodynamic relationship even with higher endocannabinoid levels.

Nimacimab is a first-in-class humanized monoclonal antibody that inhibits CB1 signaling peripherally as an inverse agonist and antagonist. It has demonstrated potential in addressing obesity, chronic kidney disease, and metabolic dysfunction-associated steatohepatitis (MASH) due to its anti-fibrotic, anti-inflammatory, and metabolic actions. Skye Bioscience aims to develop next-generation molecules targeting G-protein coupled receptors to improve metabolic health, with nimacimab being a key candidate in their clinical trials.