A drug that Novo Nordisk acquired to expand its prospects in metabolic disorders has failed a mid-stage clinical trial in diabetic kidney disease. The results also showed signs of a neuropsychiatric side effect that could crimp plans to develop this pill in other metabolic indications, including obesity.
The Phase 2b results for the drug, monlunabant, were tucked into Novo Nordisk’s report of full-year 2024 financial results released Wednesday. The company said the once-daily pill did not meet the main goal of showing statistically significant improvement on the measure of certain compounds in urine that are indicative of kidney disease. The most common adverse events were gastrointestinal, and the company said the vast majority of them were mild to moderate. But Novo Nordisk also noted mild-to-moderate neuropsychiatric side effects that were more frequent in patients who received the study drug.
Neuro effects are a risk for monlunabant and others in its drug class, which targets cannabinoid receptor type 1 (CB1). This receptor, found mainly in the central nervous system but also in some peripheral organs and tissues, regulates various physiological processes, including appetite. Targeting it for obesity was validated by rimonabant (brand name Acomplia), a Sanofi drug approved in Europe in 2006. But hitting CB1 receptors in the brain led to psychiatric effects. Those complications led Sanofi to withdraw the product from the market in 2008.
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Monlunabant, formerly INV-202, came from Novo Nordisk’s 2023 acquisition of Inversago Pharma. The Canadian company designed this small molecule to preferentially target CB1 receptors in the gastrointestinal tract, liver, kidneys, and pancreas. The M&A deal followed Inversago’s report of Phase 1 data showing clinically significant weight loss.
Last September, Novo Nordisk reported Phase 2 obesity study results showing statistically significant weight loss at 16 weeks across all three doses tested. While gastrointestinal side effects were mild to moderate, the results also showed mild-to-moderate neuropsychiatric effects such as anxiety, irritability, and sleep disturbances. Novo Nordisk said these effects were more frequent in those who treated with the study drug compared to those who received a placebo.
At the time of the trial readout, Martin Lange, executive vice president and head of development at Novo Nordisk, said the results indicate the drug’s weight-lowering potential, adding that more work is needed to determine the optimal dose to balance safety and efficacy. But the signs of neuropsychiatric effects for monlunabant, despite a design intended to avoid such problems, leaves other companies with an opportunity to show differentiation with their peripherally restricted CB1-targeting drugs.
Skye Bioscience aims to drug CB1 with nimacimab. As a large molecule that does not easily penetrate the blood brain barrier, this antibody should avoid sparking the neuropsychiatric side effects observed with small molecules that target CB1, Skye Chief Development Officer Tu Diep told MedCity news last year. A Phase 2 test of the Skye drug in obesity is expected to yield data later this year.
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Meanwhile, Corbus Pharmaceuticals is developing what it describes as a next-generation peripherally restricted CB1 receptor agonist. In preclinical research presented at the Obesity Week 2024 conference in November, Corbus reported that brain levels of its drug, CRB-913, were 15-fold lower compared to monlunabant that was administered to mice at the same dose. Corbus expects to begin a Phase 1 test of its drug in the first quarter of 2025.
In Novo Nordisk’s report of third quarter 2024 financial results, the company said it expected to begin a larger Phase 2b obesity test for monlunabant in 2025. The goal of this study is to further investigate the dosing and safety profile of the drug over a longer period of time in a global population. Regarding monlunabant’s mid-stage failure in kidney disease, Novo Nordisk said Wednesday that it is evaluating this drug for further clinical development in this indication.
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