Nearly two decades after the FDA rejected the first-in-class drug, a resurgence of CB1 receptor inhibitors is underway, with companies like Novo Nordisk, Corbus Pharmaceuticals, and Skye Bioscience conducting clinical trials for obesity treatments. These new therapies aim to improve safety profiles by targeting peripheral receptors, unlike the first-generation drugs that caused significant neuropsychiatric side effects.
A Second Chance for CB1 Inhibitors
Yuval Cohen, CEO of Corbus, noted the comeback nature of this drug class, recalling the initial excitement around CB1 receptor antagonists in 2006 before the FDA's rejection of rimonabant due to severe psychiatric side effects. Rimonabant, initially approved in Europe, blocked endocannabinoid receptors in the brain to suppress appetite but led to increased depression, anxiety, and suicidality. The FDA deemed it unapprovable in 2006, and European regulators withdrew it from the market in 2008.
Cohen stated that the stigma surrounding rimonabant led to the abandonment of the mechanism of action by other pharmaceutical companies.
Targeting Peripheral Receptors
Novo Nordisk, Corbus, and Skye are now focusing on developing safer CB1 inhibitors that do not cross the blood-brain barrier. These peripherally restricted drugs, such as Skye’s nimacimab, Corbus’s CRB-913, and Novo’s monlunabant, aim to reduce neuropsychiatric effects by targeting CB1 receptors in peripheral tissues like adipose tissue, liver, muscles, and the GI tract, according to Skye CEO Punit Dhillon.
Phase Ib studies of nimacimab reported no serious adverse events, with Dhillon highlighting the absence of neuropsychiatric effects or depression. However, Phase IIa results from monlunabant showed mild to moderate neuropsychiatric side effects such as anxiety, irritability, and sleep disturbances, though no serious adverse events were reported. Patients treated with monlunabant experienced an average weight loss of 15 lbs after 16 weeks, compared to 1.5 lbs for the placebo group.
Mechanism of Action and Combination Therapies
CB1 receptors, described by Cohen as "amazing little engines," activate appetite and promote food intake, fat storage, and energy storage. CB1-targeting drugs act as inverse agonists, reversing this process to reduce hunger and promote fat conversion to energy. This metabolic rewiring can improve insulin sensitivity, glucose tolerance, and lipid profiles, Dhillon explained.
Louis Aronne from Weill-Cornell Medical College noted that cannabinoid pathways are integral to leptin signaling, which regulates fat storage. Peripherally acting drugs could sensitize the body to leptin, facilitating fat release from fat cells and suppressing appetite.
Skye is currently evaluating nimacimab in combination with Wegovy in a Phase II study. Dhillon believes that combining CB1 inhibitors with GLP-1s could provide synergistic benefits by addressing both caloric restriction and metabolic pathway re-establishment.
Preclinical testing of Corbus’ CRB-913 with GLP-1 medications like Wegovy, Zepbound, and liraglutide in mice with diet-induced obesity showed enhanced reductions in body weight, body fat, liver triglycerides, liver fat deposits, insulin resistance, and leptinemia. Cohen suggests that combining CB1-targeting drugs with incretin-targeting drugs could lead to greater weight loss, particularly in populations who cannot or do not want to use GLP-1 drugs, need a higher degree of weight loss, or want to maintain weight loss achieved with GLP-1 drugs.
Aronne added that combining a CB1-targeting drug with a GLP-1 medicine could allow for lower doses of GLP-1s, potentially reducing gastrointestinal side effects and improving medication adherence.
The Future of Obesity Treatment
Aronne envisions obesity treatment moving towards early intervention, similar to hypertension management. The trials of nimacimab, monlunabant, and CRB-913 will determine whether CB1 inhibitors will play a role in this evolving treatment landscape. Cohen emphasized the potential for a complete change in mindset around this mechanism if the data are positive.
