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.
The safety profile was consistent with that expected from radiotherapy/temozolomide plus bevacizumab. The increased AE incidence with bevacizumab did not impact patients' ability to receive standard-of-care treatment or to undergo further surgery.
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