Novo tries a new trick on an old obesity target

Novo Nordisk will buy Inversago Pharma and its cannabinoid receptor modulating drugs for up to $1 billion. The deal stands to bolster Novo’s cardiometabolic ambitions—if clinical trial data keeps showing that Inversago’s molecules can overcome safety concerns that previously sank the drug class.

“This is a comeback for this biology,” says Inversago CEO François Ravenelle. “The data really supports that this biology, that was kind of thrown in the trash can, can really help patients who are obese and diabetic.”

Cannabinoid receptor type 1 (CB1) is a G-protein-coupled receptor (GPCR) that’s embedded in the surface of cells. It responds to endocannabinoids, including the tetrahydrocannabinol (THC) in marijuana. Just as pot use causes “the munchies,” drug developers had hoped that CB1 blockers could suppress appetite and help treat obesity.

In 2006, Sanofi secured European approval of a CB1 blocker, rimonabant, for weight loss. But regulators pulled the drug in 2008 because it also triggered serious psychiatric problems, including depressive disorders that could lead to suicide. The US Food and Drug Administration never approved it.

Inversago and Novo are betting that next-generation CB1 blockers can harness the class’s cardiometabolic benefits without the side effects. Whereas rimonabant acts in and outside the brain and spinal cord, Inversago’s lead compound, INV-202, is a bigger, more polar molecule that does not cross the blood-brain barrier very well. This quality should sidestep the neuropsychiatric side effects that shuttered rimonabant, Ravenelle says.

Rimonabant was also an “unbiased” CB1 blocker, modulating two pathways downstream of the CB1 GPCR. INV-202, in contrast, is “biased” and modulates only one of these pathways, a preference that could provide safety benefits.

Inversago licensed the drug from the US National Institutes of Health, where it was originally called MRI-1891.

In Inversago’s recent Phase Ib trial of INV-202 in 37 adults, people who received a once-daily pill lost on average 3.3% of their body weight after 28 days. Placebo recipients gained 0.5%. A Phase II trial of the drug is now ongoing in diabetic kidney disease, where it might delay the deterioration of kidney function.

Novo transformed the obesity drug market in 2021 when FDA approved its weight loss drug Wegovy (semaglutide). This injectable biologic mimics a hormone that is released by the gut to control appetite. Weekly doses of Wegovy can help patients shed up to 15% of their body weight when administered for over a year with diet and exercise. The drug also reduces the risk of major heart issues by 20%, according to recent trial results. Novo is on track to sell over $4 billion of Wegovy in 2023, just in the US.

Eli Lilly and Company’s Mounjaro (tirzepatide), which mimics another gut hormone, might offer even greater weight-loss potential.

But CB1 blockers promise other benefits, says Donna Ryan, a past president of the World Obesity Federation. “I don’t see this as a stand-alone obesity drug,” Ryan says. The overall effects of CB1 blockers on cardiometabolic health—including lipid levels—could make them useful for various chronic diseases. “That’s the public health challenge of the 21st century,” she says.