1. TEGASEROD PROGRAM FUNCTIONAL DYSPEPSIA
Sam O. Sue, MD
VP/Clinic Research Development
Global Medical Advisor
East Hanover, NJ USA
NOVARTIS PHARMACEUTICALS CORPORATION
Advisory Board Meeting 01/24/03 (Version final) V4

2. Functional Dyspepsia
Recurrent upper Abnominal Discomfort without identifiable cause
Often meal related epigastric discomfortBloating, Early Satiety, Fullness
20 to 30% Gastro Consults
Advisory Board Meeting 01/24/03 (Version final) V4

3. Tegaserod Mechanistic Properties
Tegaserod accelerates Gastric Emptying - Volunteers
Tegaserod normalizes delayed Gastric Emptying - FD
Tegaserod improves post meal Gastric accommodation
Merz, M. et al Clinical Pharmacology Report, Novartis oct 99
Earnest, D. et al submitted Gastro - DDW 2003
Jack, J. et al UEGW 2002 (references?)
Advisory Board Meeting 01/24/03 (Version final) V4

4. Functional Dyspepsia Phase II Studies
4 DBPC dose finding studies (D )
Patient Population: FD > 3 months duration
Treatment : 8 weeks
Gastric emptying status
0.5 mg
2 mg
6 mg
12 mg
NGE
BID (D2202) x x x
TID (D2204) x x x
DGE (+NGE)
BID (D2201) x x x
TID (D2203) x x x
Advisory Board Meeting 01/24/03 (Version final) V4

5. Touch-Tone Dyspepsia Assessment (IVRS) Daily (first week) and Weekly
Study Design
Tegaserod bid/tid
Tegaserod bid/tid
Screening
Baseline
Tegaserod bid/tid
Placebo
1 week
2 weeks
8 weeks
Endoscopy Scintigraphy
Random- ization
Touch-Tone Dyspepsia Assessment (IVRS)
Daily
Daily (first week) and Weekly
Advisory Board Meeting 01/24/03 (Version final) V4

6. FD: Efficacy Assessments
Primary:
Satisfactory relief of meal related stomach problems (IVRS): Yes/No
Daily (last week baseline, first week treatment)
Weekly (remainder of treatment)
Secondary:
Daily severity of (4-pt scale, IVRS):
early satiety, postprandial fullness, postprandial bloating in the stomach region, stomach pain, nausea, vomiting
Quality of Life
Generic (MOS SF-36)
Disease specific (Nepean)
Advisory Board Meeting 01/24/03 (Version final) V4

7. Secondary Efficacy Assessments
Weekly: • most bothersome symptom
Daily: • early satiety
• postprandial fullness
• postprandial bloating in the stomach region
• nausea
• epigastric/stomach pain
• vomiting (yes/no)
Daily discomfort scale
0 = none (not present)
1 = mild (awareness of the symptom but easily tolerated)
2 = moderate (discomfort sufficient to interfere with
normal activities such as work and sleep)
3 = severe (incapacitating with inability to perform
Advisory Board Meeting 01/24/03 (Version final) V4

8. Disease characteristics at Baseline Most bothersome symptoms (Pooled ITT)
40%
37%
35%
30%
Postprandial bloating
25%
21%
19%
Postprandial fullness
Percent of patients
20%
Epigastric/Stomach Pain
15%
10%
10%
Early Satiety
10% 2%
Nausea 5%
Vomiting 0%
Advisory Board Meeting 01/24/03 (Version final) V4

9. Responder Rates for Satisfactory Relief Responder: Satisfactory relief at least 50% or 75% of the weeks during treatment period
40%
 5.6%
 11.8%
30% *
Responders (pooled ITT)
20%
10%
37.6%
40.6%
37.5%
35.3%
36.4%
26.3%
24.5%
31.9%
29.2%
24.8%
24.6%
21.7%
22.7%
10.9%
12.6%
13.8%
24.5%
14.6% 0%
BID
TID
BID
TID
 50%
 75%
Placebo BID (n=125)
T 0.5 mg bid (n=69)
T 2 mg bid (n=120)
T 6 mg bid (n=119)
T 12 mg bid (n=55)
Placebo TID (n=95)
T 0.5 mg tid (n=94)
T 2 mg tid (n=94)
T 6 mg tid (n=89)
Advisory Board Meeting 01/24/03 (Version final) V4

10. Gastric Retention (%) of Meal at 4 hours post meal (DGE-ITT)
* “normal” gastric retention rate at 4 hours is 6.3%
T24
T18
T12 T6
Placebo
Advisory Board Meeting 01/24/03 (Version final) V4

11. Summary of Tolerability (D2201-2204)
Most frequent adverse event is diarrhea
Dose dependent increase in frequency irrespective of gastric emptying status
Leading rarely to discontinuation, highest in 6 mg TID with 9%
More frequent in males
Diarrhea not well defined and frequency possibly overestimated
Advisory Board Meeting 01/24/03 (Version final) V4

12. CONFIDENTIAL
Conclusions
Baseline severity and gastric emptying status were significant covariates for all symptoms. Other “less important” covariates include age and hp status.
For fullness, satiety, and bloating, the medium doses, i.e. 2 tid, 6 bid and 6 tid showed positive treatment effects at most weeks. The best treatment effects were around 0.1 (improvement over placebo).
“Baseline severity and gastric emptying status were significant covariates for all symptoms. Other “less important” covariates include age and hp status.”
Advisory Board Meeting 01/24/03 (Version final) V4

13. Conclusions (cont.)
Better treatment responses were observed in some patient subgroups, e.g.
Female patients tended to be more responsive with medium doses for most symptoms;
GE normal patients responded better at 6 mg bid while GE delayed responded better at 6 mg tid.
Less severe patients responded better at 6 mg bid, but not at other doses.
Advisory Board Meeting 01/24/03 (Version final) V4