Washington University School of Medicine, John Cochran Veterans Affairs Medical Center Edwardsville, IL, United States
Gregory S. Sayuk, MD, MPH1, Neal E. Slatkin, MD2, Nancy Stambler, DrPH3, Robert J. Israel, MD4 1Washington University School of Medicine, John Cochran Veterans Affairs Medical Center, St. Louis, MO; 2University of California Riverside, School of Medicine, Salix Pharmaceuticals, Bridgewater, NJ; 3Progenics Pharmaceuticals, Inc., a subsidiary of Lantheus Holdings, Inc., New York, NY; 4Bausch Health US, LLC, Bridgewater, NJ
Introduction: Opioid-induced constipation (OIC) affects up to 60% of patients using opioids for cancer-related pain. Methylnaltrexone (MNTX) is indicated for the treatment of OIC and does not reduce opioid central analgesia. This post hoc analysis assessed the influence of baseline opioid equivalent dose (OED) on the efficacy and safety of MNTX for OIC patients with severe illness.
Methods: A post hoc analysis was conducted examining pooled data from 3 multicenter, double-blind, randomized, placebo (PBO)-controlled clinical trials of subcutaneous (SC) MNTX in adult patients with OIC and advanced illness. Study 301 (NCT00401362) compared a single SC injection of MNTX 0.15 mg/kg, MNTX 0.30 mg/kg or PBO. Study 302 (NCT00402038) compared SC MNTX 0.15 mg/kg (adjustable to ≥ 0.30 mg/kg beginning on day 9) versus PBO every other day for 14 days. Study 4000 (NCT00672477) compared SC MNTX (8 mg for patients ≥ 38 to < 62 kg; 12 mg for patients ≥ 62 kg) versus PBO every other day for 14 days. Data were stratified by baseline OED (< 80 mg/d [low], 80 to < 150 mg/d [medium], ≥ 150 mg/d [high]). Endpoints of interest included rescue-free laxation (RFL) within 4 hours after the first dose, RFL within 4 hours for ≥ 2 of the first 4 doses (studies 302 and 4000 only), RFL within 24 hours after the first dose, and treatment-emergent adverse events.
Results: A total of 518 patients were included in the low (MTX, n=67; PBO, n=70), medium (MTX, n=55; PBO, n=54), and high (MTX, n=159; PBO, n=113) baseline OED cohorts; 78%–87% across cohorts completed the study. Patients were more likely to have cancer as the primary diagnosis in the higher baseline OED cohorts (low, 55.5%; medium, 58.7%; high, 79.3%). Across cohorts, patients treated with MNTX were more likely than PBO-treated patients to have RFL within 4 hours (56%–65% vs 13%–18%, P < 0.0001), RFL within 4 hours for ≥ 2 of the first 4 doses (52%‒62% vs 4%‒12%, P < 0.0001; Figure), and RFL within 24 hours (67%–75% vs 37%–48%; P < 0.05). The most common gastrointestinal TEAEs, occurring in >5% of patients, were abdominal pain, flatulence, and nausea. No new safety signals were observed.
Discussion: Across the spectrum of baseline OED, MNTX produced RFL responses within 4 and 24 hours in significantly greater proportions of severely ill patients with OIC versus PBO. Most TEAEs were gastrointestinal in nature. MNTX provides effective, safe relief of OIC symptoms while preserving opioid analgesia in patients with advanced illness.
Figure: Figure. The proportion of patients with rescue-free laxation response (responders) within 4 hours after at least 2 of the first 4 doses (ITT population) (Studies 302 and 4000).
Disclosures: Gregory Sayuk: Allergan – Consultant, Speaker's Bureau. Alnylam – Consultant, Speaker's Bureau. GI Health Foundation – Consultant, Speaker's Bureau. Ironwood – Consultant, Speaker's Bureau. Salix Pharmaceuticals – Consultant, Speaker's Bureau. Takeda – Consultant, Speaker's Bureau. Neal Slatkin: Salix Pharmaceuticals, a subsidiary of Bausch Health US. – Employee. Nancy Stambler: Progenics Pharmaceuticals, Inc. a subsidiary of Lantheus Holdings, Inc. – Employee. Robert Israel: Bausch Health US, LLC – Employee.
Gregory S. Sayuk, MD, MPH1, Neal E. Slatkin, MD2, Nancy Stambler, DrPH3, Robert J. Israel, MD4. P1186 - A Pooled Analysis of the Efficacy and Safety of Methylnaltrexone for Opioid-Induced Constipation in Patients With Severe Medical Illness: The Impact of Baseline Opioid Equivalent Dose, ACG 2021 Annual Scientific Meeting Abstracts. Las Vegas, Nevada: American College of Gastroenterology.