New drug enhances GLP-1 weight loss without extra added effects, trial finds

Nimacimab significantly enhanced weight loss when combined with GLP-1 therapy without adding side effects, according to mid-stage clinical trial results involving 136 adults.

The experimental drug targets the body’s endocannabinoid system differently from existing weight-loss medications, offering a potential new approach to treating obesity when used alongside drugs such as semaglutide.

Participants given both drugs lost an average of 13.2 per cent of their body weight over 26 weeks, compared with 10.25 per cent for those on semaglutide alone — a statistically significant difference of nearly 3 per cent.

Skye Bioscience’s CBeyond study tested the first-in-class monoclonal antibody, which blocks CB1 receptors involved in appetite regulation and fat storage. The CB1 receptor is part of the endocannabinoid system, which helps control hunger, metabolism and fat accumulation. When these receptors become overactive, they can promote weight gain.

“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, past president of The Obesity Society and clinical adviser to Skye Bioscience, the drug’s developers.

“Equally important, although the sample size is small, nimacimab achieved this without neuropsychiatric or additive gastrointestinal adverse events. I believe these results warrant further evaluation of the therapeutic potential of this novel CB1 inhibitor.”

Previous CB1-blocking drugs were abandoned because of psychiatric side effects such as anxiety and depression. Nimacimab has been engineered to stay outside the brain, potentially avoiding the problems that affected earlier drugs targeting this pathway.

In the 26-week trial, adults with overweight or obesity were randomly assigned weekly injections of nimacimab, semaglutide (the active ingredient in Wegovy), both drugs together, or placebo.

When used alone, nimacimab produced modest results — participants lost 1.5 per cent of their body weight compared with 0.26 per cent for placebo, a difference that was not statistically significant. Researchers said exposure to the 200 mg dose was lower than expected, suggesting higher doses may prove more effective.

“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, the company’s chief medical officer.

Pharmacokinetic data describe how the body absorbs, distributes, metabolises and eliminates a drug, helping determine optimal dosing.

“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.”

The most striking results came from the combination therapy. All participants receiving both drugs lost more than 5 per cent of their body weight, compared with 85 per cent of those on semaglutide alone. Two-thirds of the combination group lost more than 10 per cent, versus 50 per cent with semaglutide alone.

Importantly, the combination produced a healthier lean-to-fat mass ratio, indicating weight loss came primarily from fat reduction rather than muscle loss — addressing a concern that some GLP-1 drugs may cause skeletal muscle wastage.

Weight loss was still ongoing at the end of the 26-week study, suggesting further reductions could occur with longer treatment.

Safety findings were encouraging across all treatment groups. No neuropsychiatric side effects — such as anxiety, depression or insomnia — were reported with nimacimab, either alone or combined with semaglutide.

Gastrointestinal side effects, a leading cause of discontinuation with GLP-1 therapies, did not increase when nimacimab was added to semaglutide. These typically include nausea, vomiting, diarrhoea and constipation.

The overall discontinuation rate was 27 per cent, with only 3.7 per cent of participants dropping out due to adverse events — most of them in the placebo group.

“Gastrointestinal side effects remain a leading cause of discontinuation with obesity therapies,” said Sean Wharton, director of the Wharton Medical Clinic and a clinical adviser to Skye Bioscience.

“It was notable that nimacimab did not increase GI adverse events while adding clinically meaningful weight loss in combination with semaglutide. In my view, a next study with higher nimacimab dosing is the logical step to fully define its role in clinical practice.”

“With our preclinical data, toxicology safety margin, and PK modelling, we believe we have a path to support higher dosing, and we are evaluating the next stage of development to optimise dosing in potential future clinical trials,” Arora said.

Participants from the Phase 2a study are continuing in a 26-week extension trial, with results expected in early 2026. This will provide data on the longer-term efficacy and safety of the combination approach.

GLP-1 drugs such as semaglutide mimic a hormone that regulates appetite and blood sugar. While highly effective for weight loss, some studies have raised concerns about side effects including kidney injury, skeletal muscle loss and gastrointestinal issues.

A combination therapy that enhances weight loss without compounding side effects could address a major unmet need in obesity treatment, where many patients struggle with the tolerability of current medications.