AstraZeneca has announced that the New England Journal of Medicine (NEJM) has published results of two pivotal Phase III studies - KODIAC-4 and KODIAC-5 of naloxegol, 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 as high as 81%* in patients taking opioids. Naloxegol, which has the potential to be the first FDA approved once-daily oral treatment for patients with OIC, is a peripherally-acting mu-opioid receptor antagonist (PAMORA) studied in adult patients with chronic non-cancer pain experiencing OIC.
**Primary endpoint data from the KODIAC-4 and -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 to placebo [44% vs. 29% (p=0.001 KODIAC-4) and 40% vs. 29% (p=0.021 KODIAC-5)]. The 12.5 mg dose in KODIAC-5 did not show statistical significance for the primary endpoint.
The 25 mg dose also demonstrated a higher response rate through 12 weeks of treatment compared to placebo in patients with laxative inadequate response (LIR), a secondary endpoint. Results for an additional secondary endpoint showed that patients taking naloxegol 25 mg in the KODIAC-4 and KODIAC-5 studies were likely to have a first post-dose spontaneous bowel movement 25-30 hours sooner than placebo, respectively (median six and 12 hours for naloxegol 25 mg compared to 36 and 37 hours for placebo, in studies KODIAC-4 and -5, respectively).
"An estimated 235 million prescriptions for opioids are written in the US each year, of which 20% are for chronic pain. For patients taking prescription opioids for chronic pain, constipation is one of the most common and bothersome side effects, and these patients can experience sub-optimal relief from laxatives," said William Chey, MD, AGAF, FACG, FACP, Professor of Medicine at the University of Michigan Health System. "These results demonstrated the potential for naloxegol, if approved, to be a new treatment option as the studies showed rapid and sustained improvement for these patients, without compromising their pain management over the course of the trials."
The Phase III studies, KODIAC-4 (n=652) and KODIAC-5 (n=700), were 12-week, multicenter, randomised, double blind, placebo-controlled pivotal trials that evaluated 12.5 mg and 25 mg doses of naloxegol, administered once-daily.
Additional results from the KODIAC-4 and KODIAC -5 clinical trials published in NEJM included:
- The number of SBMs per week increased with naloxegol 25 mg treatment over 12 weeks, with both studies showing an improvement in treatment effect versus placebo
- Improvements in straining, stool consistency, and frequency of days with complete SBMs were observed with naloxegol 25 mg (both studies)
- The most commonly reported adverse effects with naloxegol were gastrointestinal in origin (abdominal pain, diarrhea, nausea, vomiting, flatulence) and appeared to be dose-ordered, occurring more commonly in the 25 mg group. Most adverse events were mild to moderate in severity and occurred shortly after initiation of naloxegol
- There was 1 major adverse cardiovascular event (MACE) in the 25 mg treatment arm, 1 in the 12.5 mg treatment arm and 2 in the placebo arm
A New Drug Application (NDA) for naloxegol was accepted by the US Food and Drug Administration on 19 November 2013. MOVANTIK((TM)) is the proposed proprietary name for naloxegol. On 11-12 June 2014, the FDA convened the Anesthetic Analgesic Drug Products Advisory Committee (AADPAC) to review the class of peripherally acting opioid receptor antagonists. The Committee voted that the FDA should not require cardiovascular outcomes trials for the PAMORA class of drugs which includes MOVANTIK. Following a clarification of the vote, the majority of the Committee suggested continued post-approval data collection for cardiovascular safety. The Prescription Drug User Fee Act (PDUFA) date set by the FDA for MOVANTIK is 16 September 2014.
MOVANTIK is also under regulatory review with health agencies in the European Union and Canada.