FDA Approves Movantik for the Treatment of Opioid-induced Constipation

The US Food and Drug Administration (FDA) today approved Movantik (naloxegol), an oral peripherally acting mu-opioid receptor antagonist, for the treatment of opioid-induced constipation (OIC) in adults with chronic non-cancer pain.

Movantik, developed by Nektar Therapeutics and AstraZeneca Plc, was approved based on data from two clinical trials that tested safety and efficacy in a total of 1,352 participants who had taken opioids for at least four weeks for non-cancer related pain and who had OIC. Participants were randomized to receive once-daily Movantik 12.5 mg or 25 mg or placebo for 12 weeks.

The FDA reported that “results of the first trial showed that 44 percent of participants receiving 25 mg of Movantik and 41 percent of participants receiving 12.5 mg of Movantik experienced an increase in bowel movements per week, compared to 29 percent of participants receiving placebo. The second trial showed similar results.”

The most commonly reported side effects associated with Movantik were abdominal pain, diarrhea, headache and flatulence.

Results from the studies (KODIAC-4 and KODIAC-5) were published in June 2014 in the New England Journal of Medicine. According to a news release summarizing results from the trials, the primary endpoint in both studies was percentage of OIC responders over 12 weeks of treatment vs. placebo.

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.

Naloxegol 25 mg 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).”

Additional study results 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)

Investigators reported that there was 1 major adverse cardiovascular event in the 25 mg treatment arm, 1 in the 12.5 mg treatment arm, and 2 in the placebo arm of the trials.

Back in June 2014, a majority of the members of the FDA’s Anesthetic and Analgesic Drug Products Advisory Committee voted that the FDA should not require cardiovascular outcomes trials for peripherally acting mu-opioid receptor antagonists. However, “following a clarification of the vote, the majority of the Committee suggested continued post-approval data collection for cardiovascular safety,” according to a statement released at the time by AstraZeneca, which will distribute Movantik.

As a condition of approval, the FDA announced it is requiring a postmarketing study to further evaluate the potential risk of cardiovascular adverse events in patients taking Movantik.