Novo's CB1 Drug Aids Weight Loss, Safety and Efficacy Uncertain

Novo Nordisk's considerable $1 billion investment into the Canadian biotech firm Inversago Pharma aims to enhance its portfolio of obesity medications. This ambition hinges on addressing the safety issues associated with their new drug, monlunabant.

Novo Nordisk recently announced that their oral small molecule drug, monlunabant, demonstrated significant weight loss in a Phase 2a clinical trial. Monlunabant is a CB1 inverse agonist acquired through the takeover of Inversago Pharma in August 2023. The trial revealed that all once-daily doses of monlunabant successfully achieved statistically significant weight reduction from the baseline compared to a placebo. Despite this, the higher doses did not produce the expected extent of weight loss.

During the 16-week trial, participants on the lowest dose of 10 mg of monlunabant lost an average of 7.1 kg, while those on the placebo lost only 0.7 kg. However, at the higher doses of 20 mg and 50 mg, the additional weight loss observed was minimal. This outcome did not generate much enthusiasm in the market, resulting in a 4.3% drop in Novo Nordisk's US shares ($NVO) on Friday morning. Shares of Corbus Pharmaceuticals ($CRBP) plummeted by 63%, as investors viewed Novo’s trial results as indicative of potential challenges for Corbus’ own pipeline asset, which is set to begin a Phase 1 study next year. Corbus had seen a 755% increase in its shares year-to-date, making it one of the top-performing biotech stocks of 2024 until this point.

TD Cowen analyst Michael Nedelcovych expressed disappointment over the efficacy and safety results, suggesting that while Novo sees a future for the drug, its potential has been somewhat reduced. Novo Nordisk plans to progress to a Phase 2b study in the coming year, which will involve a larger patient group and an extended testing period. Monlunabant, also known as INV-202, is additionally being evaluated for diabetic kidney disease, with a recent trial completion noted in the federal trials database.

Historically, the first generation of CB1 drugs faced significant safety issues in the 2000s, with one such drug being withdrawn in Europe due to concerns over suicidality and never reaching the US market. However, Novo Nordisk, alongside other pharmaceutical companies like Corbus and Skye Bioscience, aims to develop CB1 drugs that minimize brain penetration, thereby avoiding severe side effects associated with earlier versions.

Former Inversago CEO François Ravenelle previously indicated that the new approach targets the biological mechanisms more precisely while avoiding brain areas to prevent depressive mood disorders linked to first-generation CB1 drugs. Despite this, monlunabant's safety profile remains a concern. Novo Nordisk reported that side effects such as anxiety, irritability, and sleep disturbances were more common and dose-dependent compared to the placebo. These side effects were generally mild to moderate in severity.

Gastrointestinal issues were the most frequently reported adverse events in the Phase 2a study, with most being mild to moderate. According to Martin Holst Lange, Novo Nordisk's head of development, the Phase 2a results highlight the potential of monlunabant in reducing weight. However, he emphasized that further research is needed to determine the optimal dosing to balance safety and efficacy.