title: A phase 2, double-blind, randomized, placebo-controlled, dose-escalation study to evaluate the efficacy, safety, and tolerability of naloxegol in patients with opioid-induced constipation.
abstract: Naloxegol (previously known as NKTR-118) is a peripherally acting μ-opioid receptor antagonist engineered using polymer conjugate technology in development as an oral, once-daily agent for the treatment of opioid-induced constipation (OIC). Eligible patients with OIC (n=207), defined as <3 spontaneous bowel movements (SBMs) per week with accompanying symptoms, on a stable opioid regimen of 30-1000 mg/day morphine equivalents for ≥ 2 weeks were randomized to receive 4 weeks of double-blind placebo or naloxegol (5, 25, or 50mg) once daily in sequential cohorts after a 1-week placebo run-in. The primary end point, median change from baseline in SBMs per week after week 1 of drug administration, was statistically significant for the 25- and 50-mg naloxegol cohorts vs placebo (2.9 vs 1.0 [P=0.0020] and 3.3 vs 0.5 [P=0.0001], respectively). The increase in SBMs vs placebo was maintained over 4 weeks for naloxegol 25mg (3.0 vs 0.8 [P=0.0022]) and 50mg (3.5 vs 1.0 [P<0.0001]). Naloxegol was generally well tolerated across all dosages. The most frequent adverse events (AEs) were abdominal pain, diarrhea, and nausea. Most AEs at 5 and 25mg/day were mild and transient. Similar AEs occurred with increased frequency and severity in the 50-mg cohort. There was no evidence of a statistically significant increase from baseline in pain, opioid use for the 25- and 50-mg cohorts, or centrally mediated opioid withdrawal signs and/or symptoms with naloxegol. These data demonstrate that once-daily oral naloxegol improves the frequency of SBMs compared with placebo and is generally well tolerated in this population of patients with OIC.
authors.affiliation: CRI Lifetree Research, Salt Lake City, UT, USA Genentech Inc., San Francisco, CA, USA Nektar Therapeutics, San Francisco, CA, USA Oakland, CA, USA AstraZeneca Pharmaceuticals, Wilmington, DE, USA.
authors.forename: Lynn
authors.initials: L
authors.lastname: Webster
authors.forename: Sunita
authors.initials: S
authors.lastname: Dhar
authors.forename: Michael
authors.initials: M
authors.lastname: Eldon
authors.forename: Lorianne
authors.initials: L
authors.lastname: Masuoka
authors.forename: Jaakko
authors.initials: J
authors.lastname: Lappalainen
authors.forename: Mark
authors.initials: M
authors.lastname: Sostek
mesh_terms: D000328:Adult; D000701:Analgesics, Opioid / Q000009:adverse effects; D015331:Cohort Studies; D003248:Constipation / Q000139:chemically induced / Q000188:drug therapy* / Q000523:psychology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007391:International Cooperation; D008297:Male; D008875:Middle Aged; D009270:Naloxone / Q000008:administration & dosage*; D009292:Narcotic Antagonists / Q000008:administration & dosage*; D011788:Quality of Life; D011795:Surveys and Questionnaires; D013997:Time Factors
chemical_list: D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D009270:Naloxone
keywords: Constipation; NKTR-118; Naloxegol; Naloxol; Naloxone; Opioid