Corbus’ from Oral CB1 inverse agonist CRB-913 demonstrates favourable safety profile and emerging evidence of weight loss

Corbus Pharmaceuticals has completed the single ascending dose (SAD) and multiple ascending dose (MAD) Phase 1a study of CRB-913 and the initiation of a Phase 1b dose-range finding study (CANYON-1), with completion expected in the summer of 2026.

CRB-913 is an oral small molecule inverse agonist of the G-protein Coupled Receptor (GPCR) cannabinoid type-1 (CB1). This is a recognized mechanism of action for weight loss, but the first generation of experimental drugs in this class was abandoned due to potential neuropsychiatric adverse event risks. CRB-913 is a highly peripherally restricted CB1 inverse agonist designed to have reduced brain penetration. Pre-clinical models have shown CRB-913 to be 15-fold less brain-penetrant than monlunabant (another experimental CB1 inverse agonist) and to have 50 times lower brain:plasma ratio than rimonabant (an extensively studied first-generation CB1 inverse agonist).

The double-blinded placebo-controlled SAD/MAD Phase 1a study, conducted in the US, assessed the safety, tolerability, and pharmacokinetics (PK) of escalating once-daily doses of CRB-913. The SAD portion of the study (n=64) comprised eight cohorts that received ascending doses of CRB-913 (maximal dose of 600 mg/day) or placebo dosed orally once (2 placebo and 6 CRB-913 per cohort). Seven of the SAD cohorts enrolled healthy participants (mean BMI=28), and one enrolled people with obesity (mean BMI=36). The MAD portion of the study (n=48) comprised four cohorts who received ascending doses of CRB-913 (25 mg, 75 mg or 150 mg) or placebo orally once daily (3 placebo and 9 CRB-913-treated per cohort) over 7 days and followed by a further seven days of continuous, in-clinic observation. Three of the MAD cohorts enrolled healthy participants and one enrolled people with obesity.

No serious treatment-emergent adverse events were reported in the SAD/MAD study. CRB-913 was not associated with GI intolerability. There were no reported cases of nausea, vomiting, or constipation and only a single case of mild diarrhoea.

Daily neuropsychiatric assessments using the Columbia-Suicide Severity Rating Scale (CSSRS), the Patient Health Questionnaire-9 (PHQ-9), and the General Anxiety Disorder-7 (GAD-7) questionnaires remained stable and negative at all time points for all participants. No cases of suicidality, depression, or insomnia were reported in the study.

No neuropsychiatric adverse events were noted in any of the cohorts of non-obese participants. Three adverse events of mild anxiety and one of mild irritability were reported in the obese MAD cohort at 150 mg/day. None of these events was accompanied by suicidality, depression, dysphoria, or insomnia. They were all transient, and symptoms resolved completely without need for medical intervention. The PK profile for CRB-913 was established and was found to be suitable for a once-daily oral dosing.

In the dedicated obese MAD cohort (150 mg QD), all CRB-913-treated participants (n=9), and none in the placebo group (n=3), experienced weight loss. The CRB-913-treated participants achieved a mean 2.9% placebo-adjusted weight loss by Day 14. Individual participant weight loss ranged from 1.3% to 4.3%. Weight loss started early and deepened with time. Notably, several participants treated with CRB-913 reported reduction in food-related thoughts and cravings. Placebo-adjusted weight loss was also seen in healthy, non-obese participants in the 75 mg and 150 mg MAD cohorts.

"We are pleased by the translation of CRB-913 from pre-clinical models to the clinical setting," said Dr Yuval Cohen, Chief Executive Officer of Corbus. "We are encouraged by CRB-913’s potentially class-leading safety and tolerability profile demonstrated in this study. CRB-913’s observed weight loss effect provides further evidence that a markedly peripherally restricted CB1 inverse agonist could offer an attractive orthogonal monotherapy for obesity or combinatory mode of action to the incretin-pathway therapies. We look forward to completing the now-initiated 12-week Phase 1b CANYON-1 obesity study in summer 2026."