TOPLINE:

Monlunabant, a novel cannabinoid receptor 1 (CB1R) inverse agonist, led to significant weight loss compared with placebo in patients with obesity and metabolic syndrome over 16 weeks; however, dose-dependent adverse events resulted in high withdrawal rates.

METHODOLOGY:

• CB1R inverse agonists initially showed promise in the treatment of obesity, but first-generation drugs such as rimonabant were withdrawn due to rare, serious neuropsychiatric side effects.
• Researchers conducted a phase 2a trial in Canada to evaluate the efficacy and safety of monlunabant, a second-generation CB1R inverse agonist that was designed to have limited ability to enter the brain.
• They randomly assigned 242 participants (mean age, 53.5 years; 69% women; mean BMI, 39.7) with obesity and metabolic syndrome to receive monlunabant 10 mg (n = 61), 20 mg (n = 60), 50 mg (n = 60), or placebo (n = 61) once daily for 16 weeks. No lifestyle interventions were provided.
• The primary endpoint was the mean change in body weight from baseline to week 16. The secondary endpoints were mean changes in percentage body weight, waist circumference, lipid profile, and markers of glucose control (A1c, insulin, and C-peptide).
• Safety endpoints included adverse events, serious adverse events, predefined adverse events of special interest, discontinuations due to adverse events, suicidality, depression, anxiety, and vital signs.

TAKEAWAY:

• At week 16, the monlunabant groups showed significantly greater weight loss than the placebo group: least squares mean difference (LSM), -6.4 kg for 10 mg, -6.9 kg for 20 mg, and -8 kg for 50 mg (P < .0001 for all).
• Monlunabant administration also led to a significant reduction in the mean waist circumference compared with placebo (LSM, -3.8 to -5.4 cm).
• Small but significant reductions in A1c were noted across all monlunabant groups compared with placebo (LSM, -0.16% to -0.17%).
• Adverse events, mostly mild-to-moderate gastrointestinal and psychiatric disorders, were dose-dependent, affecting 69% of participants in the 10 mg group, 78% in the 20 mg group, and 92% in the 50 mg group. Early withdrawal due to adverse events also increased as drug dosage increased (13%, 27%, and 42%, respectively).

IN PRACTICE:

“Because the effects on weight loss appear to increase only marginally with higher doses and the adverse events were dose-dependent, there might be a therapeutic window for monlunabant. Further investigation of monlunabant at lower doses and with a close monitoring of adverse events is needed to establish if a safe, effective, and clinically relevant dose range of monlunabant exists,” the authors of the study wrote.

“In a therapeutic landscape now dominated by incretin-based drugs,…future cannabinoid-based approaches should prioritize more reliable peripheral restriction and a nuanced understanding of CB1 signaling mechanisms to minimize adverse effects and improve efficacy,” experts wrote in an accompanying editorial.

SOURCE:

This study, led by Filip K. Knop, MD, Novo Nordisk, Søborg, Denmark, was published online in The Lancet Diabetes & Endocrinology.

LIMITATIONS:

Little information was available about the participants who withdrew from the study. Follow-up of participants was not conducted after treatment discontinuation. Additionally, the study was conducted in a single country and had strict inclusion and exclusion criteria, limiting generalizability of the findings.

DISCLOSURES:

This study was funded by the Novo Nordisk subsidiary Inversago Pharma, which developed monlunabant. Six authors declared being employees or shareholders of Novo Nordisk or Inversago Pharma, with two holding Inversago Pharma stock options. One author is listed as the inventor on a US patent covering monlunabant. Some other authors reported receiving research funding, consulting fees, or honoraria or having other ties with other pharmaceutical companies.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.