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Axelopran Phase 2B Study Demonstrates a Sustained Increase in Bowel Movement Frequency

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Axelopran Phase 2B Study Demonstrates a Sustained Increase in Bowel Movement Frequency Axelopran Phase 2b Study Demonstrates a Sustained Increase in Bowel Movement Frequency in Patients Regardless of Duration of Opioid-Induced Constipation Poster #406 Ross Vickery, PhD1, Lynn Webster, MD2, Yu-Ping Li, PhD1, Neil Singla, MD3, and Daniel Canafax, PharmD1 APS 2014, Tampa, FL 1 Theravance, Inc., South San Francisco, CA; 2 CRI Lifetree, Inc., Salt Lake City, UT; 3 Lotus Clinical Research, Inc., Pasadena, CA [email protected] Introduction Results . Opioid analgesics such as morphine continue to play a critical role in Patient baseline demographics Figure 1: Baseline and Weeks 2-5 Average Figure 3: Pre-Specified SBM Responder Analysis by Table 3: GI-Related Adverse Events Occurring 1 chronic cancer and non-cancer pain control. Despite their effectiveness, . As shown in Table 1, baseline characteristics were similar for Complete Spontaneous Bowel Movements (CSBMs) Duration of OIC Group in at Least 2 Patients in Any Group opioids have significant drawbacks, notably the development of analgesic all treatment groups in the overall population as well as the by Duration of OIC Group Overall <5 Years >=5 Years Safety Population Axelopran tolerance and physical dependence, sedation, respiratory depression and short and long duration of OIC groups. (n=201) (n=102) (n=99) All 2 100 Placebo 5 mg 10 mg 15 mg bowel dysfunction. Subjects were on a representative spectrum of opioids. Baseline Week 2-5 Average Axelopran (N=54) (N=56) (N=53) (N=52) Overall <5 Years >=5 Years Overall <5 Years >=5 Years (N=161) Opioid-induced constipation (OIC) is common, affecting up to 80% of . Daily opioid doses ranged from 30-1740 oral MEU. (n=201) (n=102) (n=99) (n=188) (n=92) (n=96) No. of Patients and 3 80 11 13 15 14 42 patients receiving opioids for chronic non-cancer pain. Back pain was the most commonly reported reason for chronic 4 Percentage with GI (20.4%) AEs (23.2%) (28.3%) (26.9%) (26.1%) . Axelopran (formerly TD-1211) is an investigational, peripherally selective, opioid use. s r e 6 7 6 8 21 d Abdominal n 60 multivalent mu-opioid receptor antagonist designed to alleviate o Mean and range of OIC duration in the study were 6.0 years . p Pain (11.1%) (12.5%) (11.3%) (15.4%) (13.0%) s k e e e R t 1 2 3 2 7 W Abdominal gastrointestinal side effects of opioid therapy without affecting analgesia. n and 0.2 - 39.3 years, respectively. / e S c r 40 Pain Upper (1.9%) (3.6%) (5.7%) (3.8%) (4.3%) M e B . Safety and efficacy results, including the primary and key secondary P S 2 Table 1: Patient Baseline Demographics by C 4 6 4 14 Diarrhea 0 endpoints, from a 5-week, Phase 2b study in chronic non-cancer pain Duration of OIC (7.1%) (11.3%) (7.7%) (8.7%) 4 20 3 1 2 1 4 OIC patients have been previously reported. Flatulence Overall Population Axelopran (5.6%) (1.8%) (3.8%) (1.9%) (2.5%) . Since OIC is not prone to tolerance and patients can experience OIC for 2 4 8 3 15 Placebo 5 mg 10 mg 15 mg 38.5% 58.5% 61.2% 70.2% 33.3% 47.8% 54.2% 60.7% 44.0% 66.7% 68.0% 84.2% 0 Nausea (3.7%) (7.1%) (15.1%) (5.8%) (9.3%) the duration of opioid therapy, patients were divided into short and long (N=54) (N=55) (N=53) (N=53) Placebo 5mg 10mg 15mg Placebo 5mg 10mg 15mg Placebo 5mg 10mg 15mg 0.2 0.1 0.3 0.2 0.1 0.2 0.3 0.2 0.3 0.0 0.4 0.2 0.8 1.5 2.6 2.5 1.0 2.1 2.6 1.8 0.7 1.2 2.6 3.6 0 1 4 1 5 Program: E:\SCE\LOCAL\SANDBOX_18097361_373648726125054\Biostat\td-1211\OIC\0084\csr\programs\g_responders_comb_hxoic.sas Run by wabanadmin on 21APR14 17:43 0 duration of OIC groups (<5 and ≥5 years) to explore if OIC duration Mean Age (years) 47.6 48.3 49.2 48.9 Vomiting Placebo 5mg 10mg 15mg EA population. Missing weekly data were imputed as non-responder. (1.9%) (7.1%) (1.9%) (3.1%) impacts axelopran treatment response. Female Gender 28 37 32 30 Program: E:\SCE\LOCAL\SANDBOX_17562614_166803471615908\Biostat\td-1211\OIC\0084\csr\programs\g_chg_wk_csbm_comb_hxoic.sas Run by wabanadmin on 09APR14 22:57 EA population; no imputation Responder definition: ≥3 SBMs per week and an increase of ≥ 1 SBM per week Efficacy Endpoints by Baseline Opioid Dose (con’t) BMI Mean (kg/m2) 28.3 27.8 27.8 28.1 from baseline for ≥3 weeks over Weeks 2-5 Using a pre-specified responder definition, there Duration of OIC (yrs) 5.5 6.4 6.7 5.3 . was a dose-response relationship between responder Duration of OIC <5 years Methods Axelopran Figure 2: Baseline and Weeks 2-5 Average Table 2: Mean (SD) Change from Baseline in rate and axelopran dose for the overall population Placebo 5 mg 10 mg 15 mg Spontaneous Bowel Movements (SBMs) by Duration Weeks 2-5 Weekly Average CSBMs and SBMs . A 5-week, double-blind, randomized, multi-center, placebo-controlled, (N=28) (N=24) (N=25) (N=32) and both OIC duration groups (Fig. 3). Mean Age (years) 45.7 47.5 48.8 47.9 of OIC Group by Baseline Opioid Use parallel-group study was conducted in chronic non-cancer pain patients Female Gender 17 16 15 17 Baseline Week 2-5 Average Tolerability and Safety with OIC, defined as ≤5 spontaneous bowel movements (SBMs) over a Mean (SD) Change from Baseline in Mean (SD) Change from Baseline in Overall <5 Years >=5 Years Overall <5 Years >=5 Years BMI Mean (kg/m2) 27.9 27.4 27.8 28.3 . Axelopran was generally well tolerated, with overall 2-week baseline period and at least one additional symptom of (n=201) (n=102) (n=99) (n=188) (n=92) (n=96) Weekly Average CSBMs Weekly Average SBMs 5.1 constipation in at least 25% of the bowel movements. Duration of OIC (yrs) 2.1 2.2 2.0 2.4 treatment emergent adverse events (TEAEs) similar 5mg 10mg 15mg 5mg 10mg 15mg Placebo Placebo between axelopran and placebo and gastrointestinal . For the first 4 days of dosing, patients randomized to axelopran received Axelopran Axelopran Axelopran Axelopran Axelopran Axelopran Duration of OIC ≥5 years Axelopran 4 (GI) TEAEs predominant (Table 3). 5mg daily and on Day 5, remained at 5mg or were dose-escalated to 10mg Placebo 5 mg 10 mg 15 mg k e e 1.5 (2.2) 2.6 (2.4) 2.5 (3.3) 2.7 (2.2) 3.4 (2.7) 3.7 (3.0) (N=26) (N=31) (N=28) (N=21) W The majority of GI-related AEs were associated with . or 15mg daily for the remainder of the treatment period. Patients randomized / 0.8 (1.4) 1.9 (1.8) S Overall (n=46) (n=47) (n=45) (n=46) (n=47) (n=45) M to placebo received placebo for all 5 weeks. Mean Age (years) 49.7 48.9 50.3 49.5 B (n=50) (n=50) treatment initiation, mild-to-moderate, and resolving S p=0.0413 p=0.0010 p=0.0003 p=0.0739 p=0.0038 p=0.0003 . For at least 14 days prior to Day 1, patients were on a stable chronic opioid Female Gender 11 21 17 13 2 within a few days. <5 yrs regimen, with a total daily dose of ≥30mg morphine equivalent units (MEU). BMI Mean (kg/m2) 28.8 28.2 27.7 27.8 1.0 (1.6) 2.1 (2.9) 2.6 (2.4) 1.8 (2.4) 1.6 (1.7) 2.8 (2.6) 3.0 (2.7) 2.9 (2.4) . No treatment-related serious adverse events (SAEs) OIC (n=25) (n=18) (n=22) (n=27) (n=25) (n=18) (n=22) (n=27) . Patients were required to stop laxatives and bowel regimens, except Duration of OIC (yrs) 9.2 9.7 10.9 9.9 duration were reported. protocol-permitted rescue bisacodyl use, throughout the study. Modified Intent to Treat Population ≥5 yrs . No clinically significant laboratory, ECG, or vital sign 1.2 1.2 1.1 1.2 1.2 1.3 1.2 1.1 1.2 1.0 1.0 1.3 1.9 2.7 3.4 3.7 1.6 2.8 3.0 2.9 2.3 2.7 3.8 4.9 0.7 (1.3) 1.2 (1.4) 2.6 (2.4) 3.6 (4.2) 2.3 (1.8) 2.7 (2.0) 3.8 (2.7) 4.9 (3.5) . Electronic diaries collected frequency, timing, and symptoms of bowel 0 OIC (n=25) (n=28) (n=25) (n=18) (n=25) (n=28) (n=25) (n=18) abnormalities were observed. Placebo 5mg 10mg 15mg duration movements; use of laxatives and opioids; daily pain scores; and satisfaction/ Program: E:\SCE\LOCAL\SANDBOX_17562575_236458569230274\Biostat\td-1211\OIC\0084\csr\programs\g_chg_wk_sbm_comb_hxoic.sas Run by wabanadmin on 09APR14 22:57 EA population; no imputation EA population; no imputation. P-values were based on a mixed-effect model repeated measures with baseline quality of life metrics. Efficacy Endpoints by Duration of OIC Group as covariate. Primary efficacy endpoint was the change from baseline in weekly average .
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