Exhibit 99.1
TD-5108, a Selective 5-HT4 Agonist, Is Consistently Better Than Placebo Regardless of Response Definition in Patients with Chronic Constipation
Michael
R Goldberg(1), Yu-Ping Li(1), Kenneth Pitzer(1), John F Johanson(2), Allen W
Mangel(3), Michael M Kitt(1)
1. Clinical Pharmacology, Theravance, Inc., South San Francisco, CA, USA,
2. University of Illinois College of Medicine, Rockford, IL, USA, 3. RTI-Health
Solutions, Research Triangle, NC, USA
TD-5108 is a highly selective, full agonist at the human 5-HT4 receptor. Multiple response definitions were pre-specified in a Phase 2 dose-ranging clinical trial of TD-5108 in patients (pts) with chronic idiopathic constipation (CIC). TD-5108 was consistently better than placebo in response rates across response definitions.
Methods: This double-blind, randomized, PBO-controlled, parallel-group, multicenter trial enrolled 401 adult pts (age 18-64 years) at 48 U.S. sites. Eligible pts (<3 spontaneous bowel movements [SBM]/week [wk] during a 2-wk baseline) were randomized to receive TD-5108 15, 30, or 50 mg, or PBO once daily for 4 wks. Bowel function and clinical symptoms were recorded using a daily interactive voice response system and a range of response definitions were applied to the comparison with placebo.
Results: Treatment groups were balanced for baseline characteristics. The average (avg) numbers of SBM and complete SBM (CSBM) at baseline were 1.2 and 0.25/wk, respectively. Analyses of the response definitions are summarized below (n=number of patients treated for at least 7 days). Response rates using each definition were significantly greater than placebo for all TD-5108 doses. The lowest PBO response rates (< 10%) were seen with definitions that incorporated CSBM frequency > 3/wk; these response definitions were also associated with the greatest differences between TD-5108 and PBO—5-fold or greater.
Conclusion: In this study in pts with CIC treated for 4 wks, the percent response to TD-5108 was greater than that to placebo regardless of response definition. The most robust differentiation of responses to TD-5108 vs PBO was achieved with response definitions incorporating > 3CSBM/wk.
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PBO |
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15 mg |
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30 mg |
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50 mg |
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Max Fold Difference from |
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% with > 1 SBM/wk increase in Wk 4 |
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45% |
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82% |
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63% |
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76% |
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1.82 |
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% with an avg of >3 SBM/wk and an avg increase of > 1 SBM/wk |
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43% |
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75% |
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66% |
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64% |
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1.74 |
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% with >3 SBM/wk in Wk 4 |
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41% |
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78% |
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60% |
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72% |
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1.90 |
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% with > 1 CSBM/wk increase in Wk 4 |
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29% |
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59% |
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45% |
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54% |
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2.03 |
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% with > 1 SBM/wk increase for all 4 wks |
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25% |
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69% |
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49% |
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71% |
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2.84 |
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% with >3 SBM/wk for all 4 wks |
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22% |
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60% |
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42% |
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61% |
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2.77 |
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% with > 1 CSBM/wk increase for all 4 wks |
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13% |
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42% |
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30% |
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39% |
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3.23 |
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% with >3 CSBM/wk in Wk 4 |
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9% |
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48% |
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27% |
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37% |
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5.33 |
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% with an avg of >3 CSBM/wk and an avg increase of > 1 CSBM/wk |
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7% |
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44% |
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30% |
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35% |
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6.29 |
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% with >3 CSBM/wk for all 4 wks |
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5% |
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27% |
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19% |
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21% |
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5.40 |
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