Full Press Release Details
APS2013, New Orleans, LA
TD-1211 Demonstrates Tolerability and Clinical Activity Following Multiple Treatment
Administration Strategies in Patients with Opioid-Induced Constipation
Neil Singla(1), Daniel Canafax(2), Angela Kang(2), Yu-Ping Li(2), Ullrich Schwertschlag(2), Lynn Webster(3), and Ross Vickery(2)
(1) Lotus Clinical Research, Inc., Pasadena, CA; (2) Theravance, Inc., South San Francisco, CA; (3) Lifetree Clinical Research, Inc., Salt Lake City, UT
Opioid analgesics such as morphine continue to play a critical role in chronic cancer and non-cancer pain control.(1) Despite their effectiveness, opioids have significant drawbacks, notably the development of analgesic tolerance and physical dependence, sedation, respiratory depression and bowel dysfunction.(2)
Opioid-induced constipation (OIC) is common, affecting up to 80% of patients receiving opioids for chronic non-cancer pain.(3)
TD-1211 is an investigational, peripherally selective, mu-opioid receptor antagonist designed to alleviate gastrointestinal side effects of opioid therapy without affecting analgesia.
TD-1211 was assessed in a Phase 2, single-blind exploratory study in 95 adult patients with OIC.
The safety and tolerability of various doses, dosing strategies and dose escalations of TD-1211, as well as efficacy results, from this study are reported here.
A single-blind, multi-center, six-cohort study was conducted in chronic non-cancer pain patients with OIC, defined as <5 spontaneous bowel movements (SBMs) over a 2-week baseline period and at least one additional symptom of constipation in at least 25% of the bowel movements.
The first four cohorts received an oral dose of TD-1211 5mg once daily for either 4 days (Cohorts 1 and 2) or 2 days (Cohorts 3 and 4), followed by an increase in daily dose to either 10mg or 15mg for two weeks. Cohort 5 received 2mg once daily and cohort 6 received 2.5mg q6h for two weeks without dose escalation (Figure 1).
For at least 14 days prior to Day 1, patients were on a stable chronic opioid regimen, with a total daily dose of >30mg morphine equivalent units (MEU).
Patients were required to stop laxatives and bowel regimens, except protocol-permitted rescue bisacodyl use, throughout the study.
Electronic diaries collected frequency, timing, and symptoms of bowel movements; use of laxatives and opioids; and daily pain scores.
The primary study objective was to evaluate the safety and tolerability of TD-1211 5mg once daily as an initiation dose, for 4 or 2 days, escalated to 10mg or 15mg once daily as maintenance therapy for 2 weeks.
Additional study objectives were to examine the tolerability and effects of a TD-1211 2mg qd dose and a TD-1211 2.5mg q6h dose administered for two weeks; and to assess the efficacy of TD-1211 10mg and 15mg doses.
Patient baseline characteristics
95 patients were enrolled, 16 patients per cohort, except Cohort 6 which enrolled 15 patients.
12 (12.6%) patients terminated study early; 6 due to adverse events (AEs); 2 each for physician decision and withdrawal by subject; and 1 each for other and protocol deviation.
Mean age was 48.0 years (range = 22.0 to 65.0) and was similar across cohorts.
55.8% of patients were female and 78.9% were white.
Mean baseline daily oral opioid dose ranged across cohorts from 93 to 170 MEU, with the lowest and highest doses being 30 and 745 MEU, respectively.
During the baseline period, 55% of patients used bisacodyl, and bisacodyl was not used more than 3 days by any patient.
Mean baseline SBMs/week was 0.9 to 1.7; mean baseline complete spontaneous bowel movements (CSBMs)/week was 0.1 to 0.6.
Figure 1: Study Schematic
Table 1: Adverse Events Reported in > 5% of Patients
| TD-1211 | |||||||||||||||
| Safety | Cohort 1 | Cohort 2 | Cohort 3 | Cohort 4 | Cohort 5 | Cohort 6 | All TD-1211 | ||||||||
| Population | (n=16) | (n=16) | (n=16) | (n=16) | (n=16) | (n=15) | (N=95) | ||||||||
| Any AEs, n (%) | 7 (43.8) | 11 (68.8) | 9 (56.3) | 8 (50.0) | 3 (18.8) | 6 (40.0) | 44 (46.3) | ||||||||
| Gastrointestinal Disorders | 5 (31.3) | 7 (43.8) | 6 (37.5) | 4 (25.0) | 3 (18.8) | 6 (40.0) | 31 (32.6) | ||||||||
| Abdominal Distension | 2 (12.5) | 1 (6.3) | 0 | 1 (6.3) | 0 | 1 (6.7) | 5 (5.3) | ||||||||
| Abdominal Pain | 1 (6.3) | 1 (6.3) | 3 (18.8) | 3 (18.8) | 2 (12.5) | 4 (26.7) | 14 (14.7) | ||||||||
| Diarrhea | 0 | 2 (12.5) | 3 (18.8) | 0 | 1 (6.3) | 0 | 6 (6.3) | ||||||||
| Flatulence | 0 | 2 (12.5) | 2 (12.5) | 1 (6.3) | 0 | 3 (20.0) | 8 (8.4) | ||||||||
| Nausea | 1 (6.3) | 3 (18.8) | 3 (18.8) | 1 (6.3) | 0 | 1 (6.7) | 9 (9.5) | ||||||||
| Nervous System Disorders | 2 (12.5) | 2 (12.5) | 4 (25.0) | 0 | 0 | 1 (6.7) | 9 (9.5) | ||||||||
| Headache | 2 (12.5) | 2 (12.5) | 2 (12.5) | 0 | 0 | 0 | 6 (6.3) |
Table 2: GI-Related Adverse Events; 4-Day and 2-Day Initiation Periods
| TD-1211 | |||||||||||||
| Combined | Combined | ||||||||||||
| Cohort | Cohort 2 | 1 & 2 | Cohort 3 | Cohort 4 | 3 & 4 | ||||||||
| Safety Population | 1 (n=16) | (n=16) | (n=32) | (n=16) | (n=16) | (n=32) | |||||||
| 4-Day Initiation Period | 2-Day Initiation Period | ||||||||||||
| Any GI-related AEs of interest, n (%) | 1 (6.3) | 2 (12.5) | 3 (9.4) | 3 (18.8) | 3 (18.8) | 6 (18.8) | |||||||
| Abdominal Pain | 0 | 1 (6.3) | 1 (3.1) | 3 (18.8) | 3 (18.8) | 6 (18.8) | |||||||
| Diarrhea | 0 | 0 | 0 | 2 (12.5) | 0 | 2 (3.1) | |||||||
| Nausea | 1 (6.3) | 1 (6.3) | 2 (6.3) | 2 (12.5) | 1 (6.3) | 3 (9.4) | |||||||
| Vomiting | 0 | 0 | 0 | 1 (6.3) | 0 | 1 (3.1) |
Figure 2: Spontaneous Bowel Movements
Intent to Treat Population (ITT) - observed cases TMP = treatment maintenance period.
Figure 3: Complete Spontaneous Bowel Movements
Intent to Treat Population (ITT) - observed cases. TMP = treatment maintenance period.
Primary study objective
TD-1211 was generally well tolerated at all dose levels tested (Table 1) .
Initiating treatment with TD-1211 5mg for 4 days resulted in fewer GI-related AEs (Table 2).
Escalating TD-1211 to 10mg versus 15mg did not produce unexpected AEs or events of greater severity (Table 1).
Secondary tolerability and safety objectives
The majority of treatment-related GI AEs were associated with initiation of treatment, resolved within a few days, and were mild or moderate in severity.
No treatment-emergent serious adverse events (SAEs) were reported.
There were no reports of central opioid withdrawal.
No clinically significant laboratory, ECG, or vital sign abnormalities were observed.
Study 0076 was not powered to show statistical differences between the various doses of TD-1211.
TD-1211 10mg and 15mg mean change from baseline at Week 2 in SBM frequency ranged from 3.3 to 5.4.
TD-1211 10mg and 15mg mean change from baseline at Week 2 in CSBM frequency ranged from 2.8 to 4.4.
TD-1211 2mg demonstrated minimal activity with a mean increase from baseline at Week 2 of 1.8 SBMs and 0.7 CSBMs
TD-1211 2.5mg q6h was clinically active with a mean increase from baseline at Week 2 of 4.3 SBMs and 4.5 CSBMs.
TD-1211 was generally well-tolerated at dose levels up to 15mg. Majority of GI AEs resolved within a few days, and all GI AEs resolved without sequelae.
There were no treatment-emergent SAEs.
Initiation of dosing at 5mg before escalating to 10mg or 15mg resulted in fewer GI-related AEs.
No evidence of centrally-mediated opioid withdrawal.
TD-1211 10mg and 15mg administered orally once a day demonstrated a clinically meaningful response at Week 2.
These results support further development of a 5mg treatment initiation dose followed by maintenance therapy at up to 15mg qd.
(1) Walsh, T.D. (2000). Seminars in Oncology, 27, 45-63.
(2) Walsh, T.D. (1990). J. Pain Symptom Manage., 5, 362-367.
(3) Holzer, P. (2012). Current Pharmaceutical Design, 18, 6010-6020.