EX-99.1 2 a08-14726_1ex99d1.htm EX-99.1

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