Naldemedine (Symproic, Shionogi Inc) is more effective than placebo in relieving opioid-induced constipation (OIC) in advanced cancer patients and does not interfere with the analgesic effect from opioid treatment, phase 3 clinical trials indicate.
“COMPOSE-4 and COMPOSE-5 are especially notable, because they are, to our knowledge, the first phase III clinical trials to evaluate the efficacy and safety of an oral PAMORA for OIC specifically in patients with cancer,” lead author Nobuyuki Katakami, MD, PhD, Institute of Biomedical Research and Innovation Hospital, Kobe, Japan, and colleagues write.
Naldemedine, which is a peripherally acting mu-opioid receptor antagonist (PAMORA), is approved in the United States for use in patients receiving opioids who have chronic non-cancer-related pain and constipation.
Competing products have not been proven to work in cancer patients or are not oral formulations, observe the Japanese authors.
“[Our] results highlight the utility of once-daily oral naldemedine 0.2 mg taken with or without food as an effective treatment option for patients with OIC and cancer,” the authors conclude.
The study was published online October 2 in the Journal of Clinical Oncology.
COMPOSE-4 was a randomized, double-blind, placebo-controlled trial designed to evaluate the efficacy and safety of once-daily oral naldemedine 0.2 mg given for 2 weeks in comparison with placebo in a total of 193 cancer patients with OIC.
Ninety-seven patients received active therapy, and 96 others received placebo.
The primary endpoint of the trial was the proportion of patients who responded to treatment with three or more spontaneous bowel movements (SMBs) per week as well as an increase of at least 1 SBM per week from baseline.
At the end of the 2-week treatment period, 71.1% of patients who received naldemedine reached the primary endpoint, compared with 34.4% of the patients who received placebo (P < .0001), a difference of 36.8% in the proportion of responders to study drug in favor of active therapy, investigators report.
Mean frequency of SBMs per week from baseline was also significantly greater in the naldemedine group, at 5.16 SBMs per week vs 1.54 for control patients (P < .0001).
Furthermore, patients who received naldemedine reported more SBMs with complete bowel evacuation, at 2.76 SBMs per week, compared with 0.71 SBMs per week for patients who received placebo (P < .0001).
Patients who received naldemedine were also more likely to report SBMs without straining, at 3.85 SBMs per week, compared with 1.17 SBMs per week for the patients who received placebo (P = .0005).
A significantly higher proportion of naldemedine-treated patients, at 44.3%, experienced a treatment-emergent adverse event (TEAE), compared with 26% for patients who received placebo (P = .01). The most common TEAE was diarrhea, reported by 19.6% of patients receiving naldemedine, vs 7.3% of those taking placebo.
As the investigators explain, naldemedine works by blocking the action of opioids at opioid receptors within the enteric nervous system, thus possibly restoring gastrointestinal tract function, which in turn could promote diarrhea.
TEAEs also caused more of the patients taking naldemedine to discontinue treatment, at approximately 10%, compared to 1% of the patients taking placebo.
Mean Clinical Opioid Withdrawal Scale scores were similar between the two treatment groups.
“Given the opposing pharmacology of naldemedine and opioids, a main safety concern is the possibility of precipitation of symptoms of opioid withdrawal,” the study authors observe.
They found no differences between the two groups with respect to signs or symptoms of opioid withdrawal, nor was there any apparent reduction in opioid-mediated analgesia in the naldemedine group.
“Together, these findings…confirm that minimal amounts of, if any, naldemedine cross the blood-brain barrier and stimulate opioid receptors in the CNS [central nervous system],” the investigators conclude.
COMPOSE-5 was an open-label, single-arm extension study of COMPOSE-4 during which patients enrolled in COMPOSE-4 could continue to receive active treatment.
The main objective of COMPOSE-5 was to continue to evaluate the safety of naldemedine.
A total of 131 patients who finished the randomized, double-blind portion of the clinical trial program received open-label naldemedine.
As was seen in COMPOSE-4, the most common TEAE was diarrhea, reported by 18.3% of patients taking the drug in COMPOSE-5.
Approximately 3% of patients in COMPOSE-5 required a dose reduction during the study. The rate of TEAEs that caused treatment discontinuation was 9.2% in both trials.
The study was funded by Shionogi & Co Ltd, Osaka, Japan. Dr Katakami has participated in the speakers’ bureaus for AstraZeneca, Eli Lilly, Pfizer, Taiho Pharmaceutical, Ono Pharmaceutical, Novartis, and Chugai Pharmaceutical. He also receives research funding from MDS, Astellas Pharma, AstraZenca, Eisai, Ono Pharmaceutical, Amgen, Shionogi Pharma, Daiichi Sankyo, Chugai Pharmaceutical, Eli Lilly, Boehringer Ingelheim, Bristol-Myers Squibb, Mariushi Pharma, and Merck Serono.
J Clin Oncol. Publsihed online October 2, 2017. Abstract
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