Skye Bioscience has reported topline results from its Phase 2a CBeyond study evaluating the peripherally acting CB1 inhibitor nimacimab in adults with overweight or obesity, showing clinically meaningful additional weight loss when combined with semaglutide, but not when used alone at the tested dose.

In the 26-week randomised, placebo- and active-controlled trial, nimacimab 200 mg monotherapy did not achieve the primary endpoint of weight loss versus placebo, recording a mean placebo-subtracted reduction of 1.26% (p=0.27). Preliminary pharmacokinetic data suggested lower than expected drug exposure, leading the company to consider higher dosing for future studies.

In contrast, the combination of nimacimab 200 mg with semaglutide achieved a statistically significant and clinically meaningful additional reduction in body weight compared with semaglutide alone (-13.2% vs -10.25%, p=0.0372). The effect did not plateau at 26 weeks, indicating potential for further weight loss with extended dosing.

“The 200 mg monotherapy arm provided important pharmacokinetic insight, showing that lower-than-expected drug exposure may have limited the observed effect and informing the dose-ranging strategy we are developing,” said Puneet Arora, chief medical officer of Skye Bioscience. “At the same time, the combination of nimacimab with semaglutide produced a clinically meaningful additional weight loss that exceeded semaglutide alone, with a favourable tolerability profile even in patients who achieved the highest exposure levels.”

Nimacimab, a monoclonal antibody designed to block peripheral CB1 receptors without crossing the blood–brain barrier, demonstrated placebo-like tolerability as monotherapy and in combination. Rates of gastrointestinal adverse events were similar across arms, and no neuropsychiatric adverse events were reported. The overall discontinuation rate was 27%, with only 3.7% of participants stopping due to adverse events.

“This is the first clinical study to show that the combination of a CB1 inhibitor and a GLP-1 therapeutic can drive clinically meaningful additional weight loss beyond a GLP-1 drug alone,” said Louis Aronne, clinical advisor to Skye and past president of The Obesity Society. “Although the sample size is small, nimacimab achieved this without neuropsychiatric or additive gastrointestinal adverse events.”

Sean Wharton, clinical advisor and director at Wharton Medical Clinic, added: “Gastrointestinal side effects remain a leading cause of discontinuation with obesity therapies. It was notable that nimacimab did not increase GI adverse events while adding clinically meaningful weight loss in combination with semaglutide.”

The CBeyond study enrolled 136 adults with a mean BMI of approximately 36.8 kg/m². Participants were randomised to receive nimacimab, placebo, semaglutide alone, or the combination for 26 weeks, with an ongoing 26-week extension assessing higher-dose nimacimab (300 mg).

Skye said it believes multiple factors support further evaluation at higher doses, including favourable safety margins and dose-dependent effects observed in preclinical models. Data from the extension phase are expected in the first quarter of 2026, with detailed 26-week findings to be presented at ObesityWeek in November.