Novo Nordisk announced results from a Phase IIa trial of monlunabant, its oral weight loss drug acquired in the $1 billion Inversago Pharmaceuticals acquisition last year. While the trial met its primary endpoint, questions remain about finding the optimal balance between efficacy and safety, causing investor concern.
The company's stock price dropped by more than 6% following the data announcement on September 19, falling from $134.88 to a low of $126.13 the next day, reflecting market uncertainty about the drug's future.
Trial Results Show Promise but Raise Dosing Questions
The Phase IIa study (NCT05891834) evaluated the efficacy and safety of monlunabant, a small molecule oral cannabinoid receptor 1 (CB1) inverse agonist, at once-daily doses of 10mg, 20mg, and 50mg compared to placebo.
All treatment arms achieved statistically significant weight loss. The 10mg cohort lost an average of 7.1kg compared to just 0.7kg in the placebo group. However, researchers observed limited additional weight reduction at higher doses, raising questions about the optimal dosing strategy.
Martin Holst Lange, Novo Nordisk's Executive Vice-President and Head of Development, acknowledged the challenges: "The Phase IIa results indicate the weight-lowering potential of monlunabant and that further work is needed to determine the optimal dosing to balance safety and efficacy."
Safety Profile Requires Further Investigation
The trial revealed dose-dependent adverse events that will need careful consideration in future studies. The most common side effects were gastrointestinal, with the vast majority being mild to moderate in severity.
More concerning were the mild to moderate neuropsychiatric side effects observed in the treatment arm, including anxiety, irritability, and sleep disturbances. These effects were also dose-dependent, though no serious neuropsychiatric adverse events were reported.
This safety profile is particularly important given the history of CB1 receptor antagonists. Previous drugs in this class were withdrawn from the market due to psychiatric side effects, making the safety profile of monlunabant a critical focus for further development.
Strategic Importance for Novo Nordisk's Obesity Portfolio
Monlunabant represents an important strategic addition to Novo Nordisk's obesity treatment portfolio, which is currently dominated by its highly successful GLP-1 receptor agonist semaglutide (marketed as Wegovy for obesity and Ozempic for type 2 diabetes).
As an oral small molecule with a different mechanism of action, monlunabant could potentially address different patient populations or be used in combination therapies. The oral administration route also offers convenience advantages over injectable treatments.
"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," Lange emphasized.
Next Steps in Development
To address the questions raised by the Phase IIa results, Novo Nordisk plans to initiate a Phase IIb trial in obesity next year. This study will aim to determine the optimal dosing regimen that maximizes weight loss while minimizing side effects.
The company is also exploring monlunabant's potential in other indications. A separate Phase IIa trial (NCT05514548) is currently investigating the drug in patients with diabetic kidney disease, potentially broadening its therapeutic applications.
Market Context and Competitive Landscape
The mixed results come at a time of intense competition in the weight loss drug market. While Novo Nordisk and Eli Lilly dominate with their injectable GLP-1 receptor agonists, pharmaceutical companies are racing to develop oral alternatives that could capture significant market share.
The $1 billion acquisition of Inversago Pharmaceuticals in August 2023 highlighted Novo Nordisk's commitment to expanding its obesity treatment options beyond its current portfolio. However, the recent trial results suggest that realizing the full potential of this investment may require additional research and development efforts.
Industry analysts will be closely watching the planned Phase IIb trial to assess whether monlunabant can overcome the dosing challenges identified in the current study and emerge as a viable addition to the obesity treatment landscape.
