Novo Obesity Drug Shows Mild to Moderate Neuropsychiatric Side Effects in Phase 2

Novo Nordisk has made a significant investment of $1 billion in a cannabinoid CB1 receptor blocker, monlunabant, aiming to achieve weight reduction without the psychiatric side effects that led to the downfall of Sanofi's Acomplia. This investment came through the acquisition of Canada's Inversago in a deal valued up to $1.07 billion, including milestone payments. Announced in August 2023, the acquisition included monlunabant, which had already shown weight loss potential in a phase 1b trial.

The latest phase 2 trial results, however, have raised some concerns about monlunabant. Conducted with 243 participants suffering from obesity and metabolic syndrome, the trial revealed that neuropsychiatric side effects such as anxiety, irritability, and sleep disturbances were more frequent and dose-dependent in those taking monlunabant than in those receiving a placebo. Although these side effects were mild to moderate and no serious neuropsychiatric adverse events were reported, the finding echoes the issues that plagued Acomplia, which was withdrawn from the European market in 2009 due to psychiatric risks.

The study also highlighted gastrointestinal issues as the most common adverse events, again described as mild to moderate and dose-dependent. Despite achieving statistically significant weight loss, the results were not particularly impressive in the context of current treatment options. The 10 mg dose of monlunabant led to a 7.1 kg reduction in body weight over 16 weeks from a baseline of 110.1 kg, equating to a 6.4% weight loss.

Comparing this to Novo's other obesity treatments, a 2.4 mg dose of the injectable drug Wegovy has shown a 5% weight loss after just 12 weeks. While monlunabant offers the convenience of an oral drug, which can be appealing to many with obesity, other oral candidates in Novo’s pipeline, like the amylin and GLP-1 receptor co-agonist, have delivered more significant results with a 13.1% weight loss in 12 weeks.

Moreover, higher doses of monlunabant (20 mg and 50 mg) did not yield substantial additional weight loss over the 10 mg dose. Despite these uninspiring results and the neuropsychiatric side effects, Novo Nordisk remains committed to evaluating monlunabant further. A larger phase 2b trial is planned for next year to assess its safety profile over a more extended period in a global population.

Martin Holst Lange, EVP and Head of Development at Novo, stated that the phase 2a results demonstrate monlunabant's weight-lowering potential, emphasizing the need for further research to find the optimal dosing balance between safety and efficacy. He acknowledged the complexity of obesity as a disease with considerable unmet needs, expressing confidence in monlunabant as an oral small molecule with a new mechanism of action, which could be a valuable addition to their obesity treatment pipeline.

Despite the promising aspects of monlunabant, the mixed phase 2 results have had an immediate impact on Novo’s stock, which dropped 5.7%, reaching $127.10 by mid-morning on the day of the announcement. The company remains focused on its long-term strategy to combat obesity through innovative treatments, showcasing a commitment to overcoming the challenges posed by side effects and less-than-expected weight loss outcomes.