Phase III Trials: Naloxegol Improves Opioid-Induced Constipation in Pain Patients
FDA approval decision expected in September
The New England Journal of Medicine has published the results from two pivotal phase III studies — KODIAC-4 and KODIAC-5 — of naloxegol (AstraZeneca/Nektar Therapeutics), an investigational treatment for opioid-induced constipation (OIC).
Opioids play an important role in chronic pain relief by binding to mu-receptors in the brain, but they also bind to mu-receptors in the bowel. That is why patients taking opioids for chronic pain can develop OIC. In fact, the incidence of OIC varies and has been reported to be as high as 81% in patients taking opioids.
Naloxegol is a peripherally acting mu-opioid receptor antagonist (PAMORA) studied in adult patients with chronic non-cancer pain who are experiencing OIC.
The primary endpoint data from the KODIAC-4 and KODIAC-5 studies showed that more OIC patients treated with naloxegol 25 mg had a consistent response of increased spontaneous bowel movements (SBMs) through 12 weeks of treatment compared with those given placebo (KODIAC-4: 44% vs. 29%, respectively; P = 0.001; KODIAC-5: 40% vs. 29%, respectively; P = 0.021). The 12.5-mg dose in KODIAC-5 did not show statistical significance for the primary endpoint.
The most commonly reported adverse events with naloxegol were gastrointestinal (GI) in nature (i.e., abdominal pain, diarrhea, nausea, vomiting, flatulence) and appeared to be dose-related, occurring more commonly in the 25-mg group. Most adverse events were mild to moderate in severity and occurred shortly after the initiation of naloxegol.
A new drug application for naloxegol was accepted by the FDA in November 2013. The Prescription Drug User Fee Act (PDUFA) date is September 16, 2014.
Movantik is the drug’s proposed proprietary name.
On June 11–12, 2014, the FDA convened its Anesthetic Analgesic Drug Products Advisory Committee (AADPAC) to review the PAMORA class of drugs. The committee voted that the FDA should not require cardiovascular outcomes trials for this drug class, which includes naloxegol. After a clarification of the vote, most of the committee members suggested continued post-approval data collection for cardiovascular safety.
Naloxegol has been designed to block the binding of opioids to opioid receptors in the GI tract without affecting opioid receptors in the brain. In the phase III clinical studies, the drug was administered as a once-daily tablet.
Source: Nektar Therapeutics; June 19, 2014.