Patients dosed with an experimental Skye Bioscience obesity did not lose enough weight to meet the goals of a mid-stage study, dealing a setback to the biotech’s bid to revive a class of medicines once written off due to safety risks. Those complications did not emerge in the clinical trial, which Skye executives say suggest the drug may yet prove successful with higher dosing.
The Skye drug, nimacimab, is an antibody designed to block CB1, a receptor whose physiological roles include regulating appetite. San Diego-based Skye is evaluating the weekly injectable drug in a 136-patient Phase 2a study. The preliminary results reported Monday show participants who received Skye’s nimacimab as a monotherapy lost an average 1.52% of their body weight after 26 weeks compared to 0.26% weight loss for the placebo arm — not enough to be statistically significant.
The combination of the study drug with Novo Nordisk’s Wegovy was better, achieving a clinically meaningful average 13.2% loss in weight compared to 10.25% in the arm that received Wegovy and a placebo. While these results fell short of statistical significance, weight loss did not plateau at 26 weeks, which the company said indicates patients could continue to lose more weight with longer dosing.
Skye shares opened Monday at $1.81 each, down nearly 62% from Friday’s closing price.
CB1 has both clinical and regulatory validation from Sanofi, which received European approval in 2006 for rimonabant, an oral small molecule inhibitor of the target. While targeting CB1 in the gastrointestinal tract can help patients lose weight, this receptor is also found in the central nervous system. Rimonabant hit these receptors in the brain, leading to suicidal ideation in some patients. In 2008, Sanofi withdrew the drug from the market.
Skye designed nimacimab to be peripherally restricted, blocking CB1 in gastrointestinal tract but avoiding the CNS. In an interview last year, Chief Development Officer Tu Diep explained that as an antibody, nimacimab is too large to penetrate the blood-brain barrier — which should avoid causing the complication risks observed with rimonabant. In the Phase 2a results, Skye said nimacimab alone and in combination with Wegovy showed a clean safety profile. Not only were there no additional gastrointestinal side effects, there were also no neuropsychiatric adverse events reported.
Patients who completed the 26-week study were eligible to enroll in a 26-week extension study. Enrollment is complete and Skye expects data will be available in the first quarter of next year. More detailed results from the initial 26-week period will be presented next month during the ObesityWeek conference in Atlanta.
The 200 mg, once-weekly dose was based on modeling from Phase 1 testing suggesting significant peripheral exposure of the drug but little to no exposure in the brain, Skye said in an investor presentation. The company said preclinical data and modeling of the nimacimab’s pharmacokinetics (PK) — how the body interacts with the drug throughout its exposure in the body — indicate the drug’s potential at higher doses.
“With our preclinical data, toxicology safety margins, and PK modeling, we believe we have a path to support higher dosing, and we are evaluating the next stage of development to optimize dosing in potential future clinical trials,” Chief Medical Officer Puneet Arora said in the Skye announcement.
Skye is trying to set itself apart in a small group of companies working to revive CB1 inhibition as a way to treat obesity. Novo Nordisk’s 2023 acquisition of Inversago Pharma brought a lead program, now called monlunabant, that is an oral small molecule inhibitor of CB1. While this drug has mid-stage data showing statistically significant weight loss, results showed neuropsychiatric effects. Corbus Pharmaceuticals’ CRB-913 is also a peripherally restricted oral small molecule inhibitor of CB-1; the company expects to begin a Phase 1b dose-ranging study in the fourth quarter of this year.
Skye said in the investor presentation it will focus on a combination strategy with Wegovy while continuing to evaluate higher doses of nimacimab as a monotherapy. The company will also assess nimacimab’s potential as a maintenance treatment for patients who have achieved target weight loss with a GLP-1 weight loss drug. In the clinical trial results so far, nimacimab did not increase the frequency or severity of gastrointestinal side effects that are a common reason cited for discontinuing treatment. That could give the Skye drug a safety and tolerability advantage over chronic use of GLP-1 drugs.
For Skye to proceed with higher dosing of nimacimab as a monotherapy, William Blair analyst Andy Hsieh said it is imperative to reduce the patient dosing burden, which is currently two injections, 100 mg per syringe. Hsieh is more intrigued by the Skye drug’s potential use in combination with Wegovy. The results show that the two drugs together led to a 13% placebo-adjusted weight loss, which was within the double-digit range that Skye had set and showed separation from treatment with Wegovy alone, he said in a note sent to investors.
“We are disappointed by the clinical setback of nimacimab,” Hsieh wrote. “However, we are hopeful that with higher doses (such as 600 mg or 1,000 mg per week), nimacimab could show more substantial monotherapy activity and accentuate its ability to be combined with Wegovy.”
Photo: Peter Dazeley, Getty Images
