As GLP-1 drugs further cement themselves as standard-of-care treatments for obesity, Skye Bioscience is looking to try a different tactic. Based on past research showing a cannabinoid receptor 1 (CB1) inhibitor led to weight loss — although later abandoned due to neuropsychiatric side effects — the biotech has refined the approach to ensure its monoclonal antibody (mAb) nimacimab is only peripherally active.Now, Skye is moving its negative allosteric modulating mAb into the Phase II CBeyond study, where its weight-loss potential will be tested alone and in combination with Novo Nordisk’s obesity stalwart Wegovy (semaglutide). The biotech thinks nimacimab has the potential to avoid the gastrointestinal (GI) adverse events associated with GLP-1 receptor agonists, as well as the depressive symptoms seen with an earlier, failed CB1 inhibitor. Study designCBeyond will randomise 80 individuals with obesity or overweight and a weight-related co-morbidity to receive a weekly injection of nimacimab or placebo. The trial is also enrolling a separate 40-patient cohort to evaluate nimacimab in combination with Wegovy, versus the GLP-1 plus placebo. Study participants will receive treatment for 26 weeks, and then be evaluated for an additional 13 weeks to evaluate the degree of weight loss associated with both interventional arms. Interim data are due in the second quarter of 2025, CEO Punit Dhillon told FirstWord, and top-line data should be ready by the end of that year.Cannabinoid biology According to Dhillon, Sanofi’s first-generation CB1 inhibitor rimonabant showed consistent weight-loss capabilities, but was scrapped due to the neuropsychiatric side effects. Nimacimab, on the other hand, is peripherally restricted, which could help ensure the mAb reaches key receptors in the GI tract, adipose tissue, the kidneys, liver and pancreas — all of which collectively promote inflammatory, fibrotic and metabolic diseases. Blocking CB1 with nimacimab “has the potential to limit or even reverse pathologies associated with these organs,” Dhillon said. He further explained that due to the mAb’s differentiated mechanism of action, it could boost “sustainable weight loss with higher ‘quality’ outcomes with respect to fat mass loss/muscle preservation, GI tolerability,” noting that up to 40% of weight loss associated with GLP-1s is due to muscle loss.Instead of just being a competitor to the established drugs, Dhillon said that combining nimacimab with Wegovy in CBeyond could “drive additive or potentially synergistic effects due to their orthogonal mechanisms… including potential improvements in GI tolerability.”Skye isn’t the only company with a CB1 programme in its pipeline. Novo Nordisk has INV-202, an oral CB1 inverse agonist, in a Phase II trial for weight loss. According to ClinicalTrials.gov, the study is expected to conclude in March. The obesity leader gained the asset last year through its takeout of Inversago, who stands to receive up to $1.1 billion if certain milestones are met.