Naldemedine, a peripherally acting μ-opioid receptor antagonist (PAMORA), will be commercially available later this year, offering a new treatment option for opioid-induced constipation in adults with chronic noncancer pain.1 The drug was approved by the US Food and Drug Administration (FDA) March 23, 2017, based on data from the COMPOSE program (ClinicalTrials.gov identifier: NCT01928953), which included a couple 12-week trials (COMPOSE-1 and COMPOSE-2) and a single 52-week trial (COMPOSE-3).1 The results of the 12-week trials were recently published in the Lancet Gastroenterology & Hepatology and demonstrate a consistent and adequate safety and efficacy profile for naldemedine.2
“To date, despite the mandate by the FDA for two replicate trials to adequately support the efficacy of a new drug for the treatment of opioid-induced constipation, no PAMORA has consistently shown significant efficacy at the therapeutic dose intended for all patients in both trials. To our knowledge, [our program is] the first report of consistent efficacy for the treatment of opioid-induced constipation with a PAMORA at a therapeutic dose suitable for all patients, irrespective of renal function,” wrote the study authors.2
Collectively, COMPOSE-1 and COMPOSE-2 included >1000 patients (aged 18-80 years) treated in outpatient settings throughout 7 countries, including the United States. All patients had stable opioid regimens and were receiving opioids ≥3 months. Patients’ baseline characteristics were similar between study cohorts, and the study population was reported to be representative of the typical chronic noncancer pain population with opioid-induced constipation.
During the study, patients were randomly assigned to take orally a 0.2 mg naldemedine treatment or placebo once daily with or without food. Patients kept an electronic diary in which they recorded their daily medication use and bowel function via a questionnaire. Patients were not allowed to use laxatives during the study, except as a rescue medication if they had not experienced a bowel movement in 72 hours. The primary efficacy endpoint was proportion of responders. Patients were deemed responders if they had ≥3 spontaneous bowel movements (SBMs) per week and an increase from baseline of at least 1 SBM per week for that week (a positive response week) for at least 9 weeks of the 12-week treatment period (>3 of which were in the last 4 weeks).
Both studies met the primary endpoint, with the naldemedine groups showing a significantly higher percentage of responders vs placebo. In COMPOSE-1, 47.6% of naldemedine-treated patients (130 of 273) were responders vs 34.6% of placebo-treated patients (94 of 272), indicating a 13.0% difference (95% CI, 4.8-21.3; P =.002). In COMPOSE-2, 52.5% of naldemedine-treated patients (145 of 276) were responders vs 33.6% of placebo-treated patients (92 of 274), indicating an 18.9% difference (95% CI, 10.8-27.0; P <.0001).
Several secondary endpoints, which were evaluated while the study was underway to provide additional data on clinical efficacy, were also improved with naldemedine. These included mean increase in SBMs per week from baseline to the last 2 weeks of treatment (P <.0001), mean increase in SBMs with complete evacuations per week from baseline to the last 2 weeks (P <.0001), and mean increase in SBMs without straining per week from baseline to last 2 weeks compared with placebo (COMPOSE-1, P =.0003; COMPOSE-2, P =.0011). Improvements in these measures started at week 1 and remained durable throughout the study, indicating naldemedine treatment might also alleviate the symptomatic burden of opioid-induced constipation.
Overall, naldemedine was well tolerated. In COMPOSE-1 and COMPOSE-2, treatment-related adverse events affected approximately 22% and 20% of naldemedine-treated patients, respectively, vs 17% and 11% of placebo-treated patients, respectively. Differences in adverse events between treatment groups was attributed largely to increased gastrointestinal disorders in patients receiving naldemedine, with abdominal pain, diarrhea, nausea, and gastroenteritis being most common. “Gastrointestinal side-effects are expected with naldemedine because of its mechanism of action, which reverses the effect of opioids on μ-opioid receptors in the gastrointestinal tract,” the researchers wrote.
Summary and Clinical Applicability
Naldemedine was approved by the FDA as a schedule II controlled substance because of its structural similarity to naltrexone; however, the medication is currently finishing review by the US Drug Enforcement Administration to remove the controlled substance classification. A decision is anticipated this summer, and the drug is expected to be commercially available later this year. The drug will be comarketed with Purdue Pharma LP.
Limitations and Disclosures
COMPOSE-1 and COMPOSE-2 presented several limitations, most notably, the reliance on patient-reported data and the short treatment period (12 weeks). However, results of COMPOSE-3 (ClinicalTrials.gov identifier: NCT01965652) are expected to be published soon and will provide data for up to 52 weeks of treatment. This study also seeks to assess the benefits of using laxatives in combination with naldemedine.
The COMPOSE program was funded by naldemedine’s manufacturer, Shionogi & Co. Although company employees were involved in the studies, the study authors attest there was no inappropriate influence by management on the studies’ design, data interpretation, or authoring of the final clinical report.2
- FDA approves Symproic® (naldemedine) once-daily tablets C-II for the treatment of opioid-induced constipation in adults with chronic non-cancer pain [news release]. http://www.purduepharma.com/news-media/2017/03/fda-approves-symproic-naldemedine-once-daily-tablets-c-ii-for-the-treatment-of-opioid-induced-constipation-in-adults-with-chronic-non-cancer-pain. Published March 23, 2017. Accessed June 26, 2017.
- Hale M, Wild J, Reddy J, Yamada T, Ferreora JCA. Naldemedine versus placebo for opioid-induced constipation (COMPOSE-1 and COMPOSE-2): two multicentre, phase 3, double-blind, randomised, parallel-group trials [published online May 30, 2017]. Lancet Gastroenterol Hepatol. doi: 10.1016/S2468-1253(17)30105-X