Written By: Pallavi Sahane BPharm
Reviewed By: Pharmacally Editorial Team
A new randomized, double-blind, placebo-controlled Phase 2b trial evaluating monlunabant an oral CB1 receptor inverse agonist has demonstrated statistically significant weight loss in adults with obesity and metabolic syndrome. The study, published in The Lancet Diabetes & Endocrinology in October 2025, was sponsored by Inversago Pharma (a Novo Nordisk company) and conducted across multiple research centers in Canada, with 243 participants enrolled.
About the Monlunabant
Monlunabant, also known as INV-202 or NN9440, is an oral, peripherally selective CB1 receptor inverse agonist being developed by Novo Nordisk following its acquisition of Inversago Pharma. It aims to retain the metabolic efficacy of first-generation CB1 blockers while avoiding their neuropsychiatric risks by restricting central nervous system penetration.
Monlunabant acts on peripheral cannabinoid type 1 (CB1) receptors located primarily in adipose tissue, liver, skeletal muscle, and the gastrointestinal tract. Inhibiting these receptors improve insulin sensitivity, decrease lipogenesis, and enhance energy expenditure. By minimizing central CB1 activity through its limited brain exposure, monlunabant is designed to achieve substantial metabolic effects, such as weight loss and lipid profile improvement, without mood-related side effects.
About Obesity and Metabolic Syndrome
Obesity and metabolic syndrome are interrelated conditions characterized by excess adiposity, insulin resistance, dyslipidemia, and hypertension. Collectively, they increase the risk of cardiovascular disease, type 2 diabetes, and all-cause mortality. Current anti-obesity treatments including GLP-1 receptor agonists have shown major benefits, but the need for oral, multi-pathway solutions remains high.
Clinical Evidence
The 16-week Phase 2b trial (ClinicalTrials.gov NCT05891834) randomized adults with obesity and metabolic syndrome to receive once-daily oral monlunabant at doses of 10 mg, 20 mg, or 50 mg, or placebo. The trial employed a double-blind, parallel-group design, ensuring treatment allocation concealment from participants, investigators, and sponsors.
The primary endpoint was mean change in body weight from baseline to week 16 compared with placebo. Secondary endpoints included waist circumference, fasting plasma glucose, and lipid profile improvements. Safety was monitored across all treatment arms.
Results
At week 16, participants receiving monlunabant displayed dose-dependent, statistically significant weight reduction versus placebo. Results showed:
10 mg: −6.4 kg vs. placebo
20 mg: −6.9 kg vs. placebo
50 mg: −8.0 kg vs. placebo
The placebo group observed an average weight reduction of only 0.7 kg. About 76% of trial participants completed the study, with higher discontinuation rates in higher-dose arms.
Safety Profile
Adverse events were primarily mild to moderate and correlated with dose increase. The most common events included nausea, anxiety, irritability, diarrhea, and sleep disturbances. Gastrointestinal events were frequent but transient. Neuropsychiatric side effects, although milder than those seen with past CB1 blockers, were more common in the higher-dose (50 mg) group. Importantly, no deaths or serious treatment-related adverse events were recorded, supporting a promising tolerability signal.
Key Expert Opinions
According to Filip K. Knop, the study’s lead investigator from Novo Nordisk, “Monlunabant achieved meaningful weight loss across all doses with a manageable safety profile, but careful dose selection will be key for long-term use”.
Martin Lange, Executive Vice President at Novo Nordisk, remarked that while CB1 antagonism remains a compelling mechanism, “balancing efficacy against neuropsychiatric tolerability will determine its real-world potential”.
This Phase 2a study solidifies monlunabant’s promise as a new therapeutic pathway for obesity and metabolic syndrome management. Building upon its Phase 2a success, Novo Nordisk is expected to advance this candidate into late-stage trials, seeking an oral, peripherally targeted option in the expanding global obesity drug market.
References
Prof Filip K Knop et al, Efficacy and safety of monlunabant in adults with obesity and metabolic syndrome: a double-blind, randomised, placebo-controlled, phase 2a trial, The Lancet Diabetes and Endocrinology, Volume 13, Issue 11p911-923November 2025