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.
| | PBO
(n=98) | | 15 mg
(n=95) | | 30 mg
(n=91) | | 50 mg
(n=84) | | Max Fold Difference from
PBO | |
| | | | | | | | | | | |
% with > 1 SBM/wk increase in Wk 4 | | 45% | | 82%
p<0.001 | | 63%
p=0.028 | | 76%
p<0.001 | | 1.82 | |
| | | | | | | | | | | |
% with an avg of >3 SBM/wk and an avg increase of > 1 SBM/wk | | 43% | | 75%
p<0.001 | | 66%
p<0.002 | | 64%
p<0.004 | | 1.74 | |
| | | | | | | | | | | |
% with >3 SBM/wk in Wk 4 | | 41% | | 78%
p<0.001 | | 60%
p=0.015 | | 72%
p<0.001 | | 1.90 | |
| | | | | | | | | | | |
% with > 1 CSBM/wk increase in Wk 4 | | 29% | | 59%
p<0.001 | | 45%
p=0.033 | | 54%
p=0.002 | | 2.03 | |
| | | | | | | | | | | |
% with > 1 SBM/wk increase for all 4 wks | | 25% | | 69%
p<0.001 | | 49%
p=0.002 | | 71%
p<0.001 | | 2.84 | |
| | | | | | | | | | | |
% with >3 SBM/wk for all 4 wks | | 22% | | 60%
p<0.001 | | 42%
p=0.007 | | 61%
p<0.001 | | 2.77 | |
| | | | | | | | | | | |
% with > 1 CSBM/wk increase for all 4 wks | | 13% | | 42%
p<0.001 | | 30%
p=0.010 | | 39%
p<0.001 | | 3.23 | |
| | | | | | | | | | | |
% with >3 CSBM/wk in Wk 4 | | 9% | | 48%
p<0.001 | | 27%
p=0.004 | | 37%
p<0.001 | | 5.33 | |
| | | | | | | | | | | |
% with an avg of >3 CSBM/wk and an avg increase of > 1 CSBM/wk | | 7% | | 44%
p<<0.001 | | 30%
p<0.001 | | 35%
p<0.001 | | 6.29 | |
| | | | | | | | | | | |
% with >3 CSBM/wk for all 4 wks | | 5% | | 27%
p<0.001 | | 19%
p=0.006 | | 21%
p=0.002 | | 5.40 | |
