Naloxegol Shows Promise in Relieving Opioid-Induced Constipation
- On September 16, 2014, the U.S. Food and Drug Administration approved Movantik (naloxegol), an oral treatment for opioid-induced constipation in adults with chronic non-cancer pain.
The investigational oral medication naloxegol was more effective than placebo in relieving opioid-induced constipation in two phase III trials published in the June 19 New England Journal of Medicine.
“The therapeutic gain over placebo for naloxegol 25-mg/day was 10% to 15% in the two trials,” said lead author William Chey, MD, Professor of Internal Medicine, Director of the GI Physiology Laboratory, and Co-Director of the Michigan Bowel Control Program, University of Michigan Health System, Ann Arbor, Mich.
“This trial was unique in that it also identified and enrolled patients who had tried and failed other laxatives for their opioid-induced constipation prior to enrollment,” Dr. Chey said. “The benefits were maintained in this group of laxative refractory patients,” he noted.
“Treatment of opioid-induced constipation is challenging; most patients are not satisfied with their commonly used laxatives,” commented Ashok K. Tuteja, MD, gastroenterologist and Associate Professor of Internal Medicine, University of Utah Health Care, Salt Lake City. Naloxegol appears to be safe and effective,” he said.
Naloxegol is an investigational peripherally-acting mu-opioid receptor antagonist (PANORA) that is designed to limit the effects of opioids on the gastrointestinal tract without impacting opioid receptors in the brain. The U.S. Food and Drug Administration accepted the New Drug Application for naloxegol in November 2013.
Studies Involved Over 1,300 Patients
The phase III studies, KODIAC-04 (n=652) and KODIAC-05 (n=700), were both 12-week, multicenter, randomized, double-blind, placebo-controlled trials. Patients with noncancer pain and opioid-induced constipation were randomized to 12.5-mg and 25-mg doses of naloxegol once daily. The studies were supported by AstraZeneca.
The primary endpoint was the 12-week response rate (≥3 spontaneous bowel movements per week, and an increase from baseline of ≥1 spontaneous bowel movements for ≥9 of 12 weeks and for ≥3 of the final 4 weeks per week).
The response rate was significantly higher in the 25-mg naloxegol groups (39.7%-44.4%) than in the placebo groups (29.3%-29.4%). In a subpopulation of patients with inadequate response to laxatives, response rates also were significantly higher in the 25-mg naloxegol groups (46.8%-48.7% vs. 28.8%-31.4%). In KODIAC-04, but not KODIAC-05, response rates were significantly higher in the 12.5-mg group than in the placebo group (42.6% vs. 28.8%).
Naloxegol also was linked to improvements in time to the first spontaneous bowel movement, mean number of days per week with one or more spontaneous bowel movements, number of weekly spontaneous bowel movements, severity of straining, and stool consistency.
How Might Naloxegol Fit Into the Treatment Paradigm?
“There are no head-to-head comparisons between the different PAMORAs, so it is impossible to make direct comparisons between the drugs; but (efficacy) data from these trials with naloxegol were as good or better than has been reported with other drugs in this class,” Dr. Chey said.
“(Because of) price and formulary availability, these drugs are likely to be reserved for patients who have failed over-the-counter laxatives—for this reason, the inclusion of patients who had previously failed laxatives and the finding of clinical benefit with naloxegol in this population is important,” Dr. Chey said.
“The response rate of 10% to 15% with naloxegol is moderate, but is comparable to other drugs for the treatment of constipation, including opioid-induced constipation in non-cancer patients,” Dr. Tuteja commented. “This highlights that action on mu receptors is one of the several mechanisms by which opioids cause constipation,” Dr. Tuteja said, adding that large-scale, long-term safety studies are needed to validate these findings and determine which patients are likely or unlikely to respond to this medication.
Large-scale, long-term safety studies are needed to validate these findings and determine which patients are likely or unlikely to respond to this medication,” Dr. Tuteja said. “If approved by the FDA, this will be the second oral drug for the treatment of non-cancer opioid-induced constipation. The first of agent—lubiprostone—improves constipation by acting on chloride channels but not affecting specific opioid receptors),” Dr. Tuteja said.
“In general, the drug was well tolerated—the most common side effects were abdominal pain and diarrhea,” Dr. Chey noted. These side effects were mild-to-moderate in severity and were more common in the 25-mg group.
The mean daily opioid doses and pain scores remained unchanged during the study. Thus, “the peripheral action of naloxegol was evident by not causing opioid withdrawal or worsening of pain,” Dr. Tuteja commented.
Severe adverse events were rare and were evenly distributed between the study groups. There was one major cardiovascular adverse event in the 25-mg treatment group, one in the 12.5-mg treatment group, and two in the placebo group.