CB-5945 (Formerly ADL5945), a Potent Orally Bioavailable Peripheral Opioid Receptor Antagonist, Improves Bowel Motility With a Low Incidence and Severity of Gastrointestinal Adverse Effects in a Dose-dependent Manner; Results of 2 Phase 2 Trials in Patients with Opioid-induced Constipation

Opioids are a mainstay for managing chronic pain, however central and peripheral adverse effects often limit their utility. Mu opioid receptor (MOR) binding is primarily responsible for opioid-induced constipation (OIC) and gastrointestinal (GI) symptoms; the delta OR (DOR) may also play a similar role. CB-5945, a MOR and DOR antagonist, is under development for the treatment of OIC and associated abdominal symptoms in patients on chronic opioid therapy for persistent noncancer
pain.
Randomized, double-blind, placebo-controlled, Phase 2 studies compared CB-5945 dosed once- (0.25mg QD) or twice-daily (0.1mg BID and 0.25mg BID) with placebo based on spontaneous bowel movement (SBM) change over treatment weeks 1-4. Other endpoints included overall SBM responders (patient with ≥3SBMs/week and ≥1 SBM/week from baseline for 3 of 4 weeks), opioid consumption, pain scores, and adverse events (AEs). 131 patients (BID) and 81 patients (QD) were randomized. Mean OIC duration ranged from 3.4-6.9 years; back pain was the most common pain condition. Mean SBM change from baseline was 1.44 (placebo BID), 1.40 (placebo QD), 1.96 (0.1mg BID), 2.58 (0.25mg QD), and 3.42 (0.25mg BID), with a mean treatment difference change of 0.51 (P=0.2979), 1.18 (P=0.0118), and 1.98 (P=0.0003) in the 0.1-mg BID, 0.25-mg QD, and 0.25-mg BID groups, respectively.

Significant, clinically-meaningful improvement in SBM frequency was observed after CB-5945 treatment, with the 0.25-mg BID dose demonstrating the most favorable benefit-to-risk profile.
Phase 3 trials are planned.

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