TD-1211 phase 2b study demonstrates increased bowel movement frequency and constipation-related symptom improvement in patients with opioid induced constipation (OIC)

Background: TD‐1211 is an investigational, peripherally selective, multivalent inhibitor of the mu‐opioid receptor designed with the goal of alleviating gastrointestinal side effects of opioid therapy without affecting analgesia. A 5‐week, double‐blind, parallel‐group study in 217 chronic non‐cancer pain OIC patients evaluated the safety and efficacy of 3 oral doses of TD‐1211 compared to placebo. Methods: For the first 4 days of dosing, patients randomized to TD‐1211 received 5mg and on Day 5, remained at 5mg or were dose‐escalated to 10mg or 15mg for the remainder of the treatment period. Patients randomized to placebo received placebo for all 5 weeks. The primary efficacy endpoint was the change from baseline in weekly average complete spontaneous bowel movements (CSBMs) over treatment weeks 2‐ 5. A key secondary endpoint was change from baseline in weekly average SBMs over the same period. Other previously unreported constipation‐related symptom endpoints included rectal pain, straining, and Constipation Symptom Global Assessment (CSGA). Results: The mean increase from baseline for placebo‐treated patients was 0.8 CSBMs/wk vs. 2.5 (p= 0.0003), 2.6 (p=0.001), and 1.5 (p=0.04) for TD‐1211 15mg, 10mg, and 5mg, respectively. The mean increase from baseline for placebo‐treated patients was 1.9 SBMs/wk vs. 3.7 (p= 0.0003), 3.4 (p=0.004), and 2.7 (p=0.07) for TD‐1211 15mg, 10mg, and 5mg, respectively. The percentage of SBMs reported as requiring 'quite a bit' or 'extreme' straining decreased from a baseline range of 58‐70% to 9%, 11%, and 19% at week 5 for TD‐1211 15mg, 10mg, and 5mg, respectively, compared to 36% for placebo (p‐values ,0.05). The percentage of SBMs associated with 'severe' or 'very severe' rectal pain decreased from a baseline range of 21‐46% to 5%, 7% and 11% at week 5 for TD‐1211 15mg, 10mg, and 5mg, respectively, compared to 19% for placebo (p‐values ,0.05). The baseline CSGA scores indicated 0‐4% of patients having 'none' or 'mild' symptoms, which improved to 57%, 48%, and 44% for TD‐1211 15mg, 10mg, and 5mg, respectively, at the end of treatment, compared to 22% for placebo (p‐values ,0.05 at the top two doses). The most common adverse events (AEs) reported for TD‐1211 were abdominal pain (13% for TD‐1211 vs. 11% for placebo), nausea (9% vs. 4%), diarrhea (9% vs. 0%), and headache (5% vs. 6%). The majority of treatmentrelated, gastrointestinal AEs were associated with treatment initiation, resolved within a few days, and were mild to moderate. There was no evidence of CNS opioid withdrawal or analgesic interference. Conclusions: TD‐1211 increased CSBM and SBM frequency and improved measures of straining, rectal pain, and overall constipation symptoms in OIC patients.