Although opioids are widely used for managing chronic pain, central and peripheral adverse events (AEs) are common. Unlike other adverse effects, opioid-induced constipation (OIC), a predominantly peripheral effect, persists for the duration of therapy and may lead to pain management disruptions. Gastrointestinal mu opioid receptor (MOR) binding is primarily responsible for OIC, although contribution from enteric delta opioid receptors (DOR) is likely. CB-5945, a MOR and DOR antagonist, is under development for OIC and associated abdominal symptoms in patients on chronic opioid therapy for noncancer pain.
CB-5945 0.25 mg and 0.1 mg twice daily (BID) were evaluated in a randomized, double-blind, placebo-controlled, Phase 2 study. The primary endpoint was change in spontaneous bowel movements (SBMs) over 4 weeks. Other endpoints included overall SBM responders (patient with ≥ 3 SBMs/week and ≥ 1 SBM/week from baseline for 3 of 4 weeks), spontaneous complete BMs (SCBMs), opioid consumption, pain scores, trough plasma – concentrations, and treatment-emergent AEs (TEAEs).
131 patients were randomized (mean age = 50 years). Mean OIC duration ranged from 3.4-5.7 years, baseline mean morphine equivalent total daily dose was 248-273 mg, and back pain was the most common pain condition. Mean SBM change from baseline was 1.44 (placebo BID), 1.96 (0.1 mg BID), and 3.42 (0.25 mg BID), with treatment difference changes of 0.51 (P = 0.2979) and 1.98 (P = 0.0003) in the 0.1-mg and 0.25-mg groups, respectively. 26% (placebo), 28% (0.1 mg BID), and 56% (0.25 mg BID; P = 0.005) of patients were overall responders.
Mean treatment difference change in SCBMs was 0.18 (P = 0.1634; 0.1 mg BID) and 1.45 (P = 0.0013; 0.25 mg BID). There were no clinically-relevant changes in opioid consumption, pain scores, nor evidence of CNS effects. Mean steady state CB-5945 trough concentrations were 264.4 pg/mL (0.1 mg BID) and 572.8 pg/mL (0.25 mg BID). The most commonly reported AE was upper respiratory tract infection (placebo, 14%; 0.1mg, 7%; 0.25 mg,7%). The proportion of patients with ≥ 1 GI TEAEs was < 10% across groups with the lowest proportion in the 0.25-mg BID dose (placebo, 9.3%; 0.1 mg, 7.0%; 0.25 mg, 4.4%). The vast majority were rated as mild with none rated as severe.
Clinically meaningful, statistically significant improvement in SBM frequency with a highly favorable GI tolerability was observed after CB-5945 0.25mg BID treatment.
Phase 3 trials are planned with this dose.