S497 Naloxegol Accelerates Time to First Spontaneous Bowel Movement (SBM) and Complete SBM (CSBM) With Predictable Efficacy in Patients With Extreme Opioid-Induced Constipation (OIC): A Pooled Analysis of Two Phase 3 Trials

Abstract

Introduction: In a pooled analysis of two phase 3 trials, naloxegol, a peripherally acting mu-opioid receptor antagonist (PAMORA), demonstrated rapid onset and predictable efficacy in relieving OIC symptoms in subjects taking opioids for chronic non-cancer pain (KODIAC 4/5 [N=1337]; NCT01309841/NCT01323790). For a proportion of patients, symptoms of OIC are severe, resulting in < 1 SBM/week. The objective of this analysis was to characterize the initial onset and maintenance of response in subjects with extreme OIC at baseline. Methods: Data were pooled from the two phase 3 trials; extreme OIC was defined as < 1 SBM and < 1 complete SBM (sense of complete evacuation) (CSBM) per week; 380 subjects (28.4% of the overall population) met these criteria. Data were analyzed to characterize the time to and predictability of initial response within 48 hours of the first dose of naloxegol (12.5mg/25mg). The time to 1st post-dose SBM & CSBM without rescue medication for naloxegol vs placebo (PBO) during the 12-week treatment period was analyzed via the Cox proportional hazard model; treatment effect was analyzed via the hazard ratio (HR). The median time to 1st post-dose SBM & CSBM was derived via the Kaplan-Meier (KM) method. Onset of action was measured by the proportion of patients achieving a SBM and CSBM from 4hrs to 48hrs following the initial dose, which reflects a clinically relevant timeframe. Results: The time to first SBM and CSBM was significantly shorter for naloxegol (12.5mg/25mg) vs PBO (all P< 0.05); the corresponding HRs all favored naloxegol over PBO (all P< 0.001), indicating an approximate twofold reduction in the time to 1 st SBM and CSBM for the naloxegol groups vs PBO (Table). The median times to 1st SBM were 6.3hrs (25mg), 22.9hrs (12.5mg), and 55.8hrs (PBO). The median times to 1st CSBM were 75.8hrs (25mg), 74.0hrs (12.5mg), and 263.8hrs (PBO). The KM curves showed clear separation of naloxegol treatments from PBO for the 1st SBM and CSBM. Higher proportions of patients achieved a SBM and CSBM by ≤4hr, ≤6hr, ≤8hr, ≤12hr, ≤24hr, and ≤48hr for the naloxegol groups vs PBO (Figure). Conclusion: Consistent with the overall phase 3 data, naloxegol (12.5mg/25mg) demonstrates rapid and clinically relevant onset of action and predictable dose-dependent efficacy in subjects with extreme OIC.Figure 1.: Patients with Extreme OIC. A. Kaplan-Meier Curve for Time to the First Post-Dose SBM; B. Kaplan-Meier Curve for Time to the First Post-Dose CSBM; C. Onset of Action Within the First 48 Hours Post-Initial Dose for a SBM. D. Onset of Action within the First 48 Hours Post-Initial Dose for a CSBM.Table 1.: Patients with Extreme OIC: The Median Time To 1st SBM and 1st CSBM During the 12-Wk Treatment Period (KODIAC 4/5 Studies; ITT Population)