Jim Kling

November 01, 2012

LAS VEGAS, Nevada — An investigational peripherally selective, multivalent inhibitor of the mu-opioid receptor improved frequency and quality of bowel movements in chronic pain patients with opioid-induced constipation (OIC), researchers reported here at the American College of Gastroenterology (ACG) 2012 Annual Scientific Meeting and Postgraduate Course.

The drug, TD-1211, is peripherally selective and was designed to alleviate gastrointestinal side effects of other opioid drugs.

"My view is that probably 20% of the patients who are on chronic opioid therapy struggle a great deal with constipation. It significantly impairs their quality of life and limits their function," Lynn Webster, MD, medical director of Lifetree Clinical Research, in Salt Lake City, Utah, who presented the research, told Medscape Medical News.

To identify the proper dose to test in phase 3 trials, the researchers conducted a multicenter, double-blind, parallel-group study of patients with chronic noncancer pain and OIC. Patients continued to take opioid drugs during the trial. The investigators randomly assigned patients to 5-, 10-, or 15-mg TD-1211 or placebo daily. All patients in the TD-1211 arms started with 5 mg of the drug for the first 4 days, and then on day 5, the dose was escalated to the patients' assigned dose for the remainder of the 5-week study.

Patients kept daily diaries to record bowel movement frequency and symptoms. The primary endpoint was the change from baseline in weekly average complete spontaneous bowel movements (CSBMs) over treatment weeks 2 to 5. As a secondary endpoint, the authors examined the change from baseline in weekly average complete and noncomplete spontaneous bowel movements (SBMs) over the same period.

A total of 217 patients enrolled in the study. Placebo-treated patients had an increase of 0.8 CSBMs per week compared with baseline. Patients in the 15-mg TD-1211 group had an increase of 2.5 CSBMs per week (P = .0003), the 10-mg group had an increase of 2.6 (P = .001), and the 5-mg group had an increase of 1.5 (P = .04).

Overall, patients in the placebo group had 1.9 SBMs/week, the TD-1211 5-mg group had 2.7 (P = .07), the 10-mg group had 3.4 (P = .004), and the 15-mg group had 3.7 (P = .0003).

The researchers also conducted a prespecified responder analysis, defined as 3 or more SBMs/week and an increase of at least 1 SBM/week improvement from baseline for at least 3 weeks during weeks 2 to 5 of treatment. By those criteria, 39% of patients in the placebo group were responders, compared with 70% of patients receiving TD-1211 15 mg (P = .002), 61% receiving 10 mg (P = .02), and 59% receiving 5 mg (P = .04).

In the 15-mg group, 75% of patients had an average Bristol Stool Scale score of 2.5 to 5.5 (normal range) at week 5, compared with 49% of the patients receiving placebo (P = .02).

The most common adverse events for TD-1211 included abdominal pain (13% vs 11% for placebo), nausea (9% vs 4%), diarrhea (9% vs 0%), and headache (5% vs 6%). Most gastrointestinal side effects were mild to moderate and resolved within a few days. The researchers saw no evidence of CNS opioid withdrawal or analgesic interference.

"TD-1211 looks to be very effective, and it appears to be dose proportional. Some people are probably going to respond at lower doses, and other people may need to be titrated to a higher dose, but it might be a solution for some folks," Dr. Webster said.

The results are promising, according to Paul Kwo, MD, professor of medicine at Indiana University, in Indianapolis, who moderated the session. "This is a population that needs side-effect-free, adverse-event-free therapies. It can allow management of chronic constipation, and it seemed to be extremely well tolerated, without some of the adverse events we see with some of these therapies for chronic constipation. I certainly hope that larger studies can bear this out and show that this is an effective therapeutic option," Dr. Kwo told Medscape Medical News.

The study was funded by Theravance. Dr. Webster has served on the advisory board, consulted for, or received honoraria from Covidien, Mallinckrodt, Medtronic, Nektar Therapeutics, Pfizer, and Salix. Dr. Kwo has disclosed no relevant financial relationships.

American College of Gastroenterology (ACG) 2012 Annual Scientific Meeting and Postgraduate Course. Abstract 36. Presented October 23, 2012.