The Danish pharma giant’s latest obesity product, a cannabinoid CB1 receptor blocker, was linked to mild to moderate neuropsychiatric side effects in a Phase 2 clinical trial. While its prospect showed promise in addressing obesity, some trial participants experienced unwanted side-effects such as mood swings and mild cognitive changes. The company is closely monitoring these symptoms as it prepares for further trials. Despite these concerns, the company says its CB1 receptor blocker continues to offer hope for patients struggling with obesity.

The following article originally appeared in Fierce Biotech.

Novo Nordisk’s $1 billion bet that it had found a cannabinoid CB1 receptor blocker that could reduce weight while avoiding the psychiatric effects that capsized Sanofi’s Acomplia faces questions after the company revealed mid-stage headline results.

The Danish Big Pharma gained its CB1 receptor blocker, now known as monlunabant, as part of the acquisition of Canada’s Inversago in a vague deal that Novo described at the time as being worth “up to” $1.07 billion inclusive of milestone payments.

Announcing the deal in August of 2023, Novo said monlunabant had already demonstrated weight loss in a phase 1b trial. But the fresh push into the CB1 modality brought back memories of Sanofi’s Acomplia, which was withdrawn from the European market by regulators in 2009 after studies linked the drug to a doubling of the risk of psychiatric disorders. The product never won approval in the U.S.

In this morning’s readout from Novo's phase 2 trial of monlunabant in 243 people with obesity and metabolic syndrome, it seems the CB1 receptor blocker may face some familiar problems.

“Reporting of mild to moderate neuropsychiatric side effects, primarily anxiety, irritability, and sleep disturbances, was more frequent and dose-dependent with monlunabant compared to placebo,” Novo acknowledged in the Sept. 20 release.

The company stressed that “no serious adverse events were reported in relation to neuropsychiatric side effects.”

The most common adverse events were gastrointestinal, the pharma noted, with “the vast majority being mild to moderate and dose-dependent.”

The weight loss shown by monlunabant, while “statistically significant,” was also nothing special considering the current treatment landscape. The lowest once-daily dose, at 10 mg, achieved a reduction in body weight of 7.1 kg over 16 weeks from a baseline weight of 110.1 kg—equivalent to a weight loss of 6.4%.

While it’s important to be cautious of like-for-like comparisons of separate trials, a 2.4 mg dose of Novo’s blockbuster obesity drug Wegovy has been shown to induce 5% weight loss after just 12 weeks. That drug is given as an injection, whereas an oral option could be viewed as a favorable alternative for many with obesity.

The company has another oral bet. Earlier this month, Novo showed that its amylin and GLP-1 receptor co-agonist had produced 13.1% weight loss in 12 weeks.

Novo noted in this morning’s release that the higher doses of monlunabant it evaluated, namely 20 mg and 50 mg, only induced “limited additional weight loss” over the 10 mg dose.

While the uninspiring weight loss numbers coupled with neuropsychiatric side effects may appear to put a dent into Novo’s post-Wegovy obesity strategy, the company was clear in the release that it will continue to evaluate the CB1 blocker. A larger phase 2b obesity trial is slated to begin next year and will assess “the safety profile of monlunabant over a longer duration in a global population.”

“The phase 2a results indicate the weight-lowering potential of monlunabant and that further work is needed to determine the optimal dosing to balance safety and efficacy,” Martin Holst Lange, EVP and Head of Development at Novo, explained in the release.

“Obesity is a complex disease with a significant unmet need, and as an oral small molecule having a new mechanism of action, monlunabant is one of the novel projects in our pipeline with the potential of treating obesity,” he added.

The pharma's stock had dropped 5.7% to $127.10 as of 10:25 am ET on Friday morning.

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