P139 OLORINAB, A PERIPHERALLY RESTRICTED, HIGHLY SELECTIVE AGONIST OF THE CANNABINOID RECEPTOR TYPE 2 FOR THE MANAGEMENT OF VISCERAL PAIN IN INFLAMMATORY BOWEL DISEASE (IBD) – PRECLINICAL AND EARLY CLINICAL DEVELOPMENT

Abstract

Introduction: Abdominal pain is common and persistent in patients with IBD. Available anti-inflammatory treatments often fail to relieve pain despite disease remission. Cannabinoid receptor agonists have shown efficacy in visceral pain, but development has been limited by psychotropic effects mediated by the cannabinoid receptor type 1. Olorinab is a peripherally restricted, highly selective agonist of the cannabinoid receptor type 2 (CB2 receptor). Herein is an overview of preclinical efficacy, clinical safety, and pharmacokinetics (PK) data from early studies. Methods: Male Sprague Dawley rats (6-7 weeks old) were randomly assigned to study groups. Colitis was induced using 12 mg 2,4,6-trinitrobenzene sulfonic acid in 35% ethanol applied rectally. Control or colitis rats were given oral olorinab (3 or 30 mg/kg) or vehicle twice daily for 5 days, starting 1 day before colitis induction. Visceral hypersensitivity was measured in vivo as visceromotor responses (VMR) to colorectal distension (CRD; 0-80 mm Hg). In 2 double-blind, placebo-controlled, Phase 1 studies, healthy young adult male and female volunteers were randomized to receive either a single ascending dose (SAD; 10-400 mg) or multiple ascending doses (MAD; 50-200 mg 3 times daily [TID] for 10 days) of oral olorinab or placebo. Safety, tolerability, and PK were evaluated. Results: Olorinab-treated colitis rats had reduced VMR to CRD versus vehicle-treated colitis rats (VMR normalized to control levels, p < 0.001, n = 9/group). Olorinab was generally well tolerated as 1 dose up to 400 mg and in multiple doses up to 200 mg TID. In the SAD study, 45% (19/42) of olorinab and 21% (3/14) of placebo subjects reported adverse events (AEs; most mild). Most common AEs in olorinab subjects were dry mouth, somnolence, diarrhea, dizziness, and headache, mostly at the highest doses. In the MAD study, 26% (7/27) of olorinab and 33% (3/9) of placebo subjects reported AEs (all mild). Most common AEs in olorinab subjects were headache and nausea. Olorinab exposure increased during single and multiple doses less than dose proportionally. The mean Tmax was ∼1.5 hours, and mean t1/2 was 3.11-4.23 hours with single doses up to 400 mg. In the MAD study plasma steady state occurred within 4 days. Conclusions: The peripherally restricted CB2 receptor agonist, olorinab, showed preclinical efficacy in a rat model of colitis-induced visceral hypersensitivity. In healthy volunteers, olorinab was safe and well tolerated without psychotropic AEs. These preclinical and early clinical safety data support the continued clinical development of olorinab for the treatment of visceral pain associated with IBD. A randomized Phase 2a, open-label, 8-week study to assess the tolerability, PK, and efficacy of olorinab (25 or 100 mg TID) in patients with quiescent Crohn’s disease experiencing pain has been implemented.