EX-99.1 2 a13-11872_1ex99d1.htm EX-99.1

Exhibit 99.1

 

Poster 376

APS2013, New Orleans, LA

 rvickery@theravance.com

 

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

 

Introduction

 

·             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.

 

Methods

 

·             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.

 

Results

 

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.

 

Demographics

 

·             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.

 

OIC

 

·             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.

 

Efficacy

 

·             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 Conclusions

 

·             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.

 

References

 

(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.