STUDY 303A Phase III, Randomized, Multi-Center, Open-Label, 12 to 14 Month

Extension Study to Evaluate the Safety and Tolerability of Mesalamine Given Once Daily Vs. Twice Daily for the Maintenance of Ulcerative

Colitis in Remission

Study 303: Objectives

Study design

Patient disposition

Definitions

Safety of 8-week acute extension

Efficacy of 8-week acute extension

Safety of 12-month long-term extension

Efficacy of 12-month long-term extension

Summary

Study Design of 303

Open-label, multicenter, phase III study

12–14-month extension of the Lichtenstein et al. and Kamm et al. studies (parent studies)

Two phases

8-week acute extension phase

Patients not in remission at the end of the parent studies

Mesalamine 4.8 g/day (given b.i.d.)

12-month long-term extension phase

Patients in remission at the end of the parent studies or the end of the 8-week acute extension phase

Mesalamine 2.4 g/day (given q.d. or 1.2 g b.i.d.)

Adapted from Kamm et al. Gut 2008;57(7):893-902.

Study 303 End Points1

Primary objective: to assess the long term safety and tolerability of Mesalamine  2.4 g/day over 12 months

Efficacy was not a primary endpoint of Study 303

Secondary objectives included:

Safety in acute extension phase

Time to relapse in long-term extension phase

Patients in remission at 12 months

Patient satisfaction

Adapted from Kamm et al. Poster presented at BSG 20071.

Mild(Score = 1)

Moderate(Score = 2)

Severe(Score = 3)

Rectal bleeding Streaks of blood Obvious blood Mostly blood

Stool frequency 1-2/day > normal 3-4/day > normal > 4/day > normal

Mucosal appearance Erythema

Decreased vascular pattern

Minimal granularity

Friability *

Marked erythema

Friability *

Granularity

Absent vascular pattern

Bleeding minimal trauma

No ulcerations

Ulceration

Spontaneous bleeding

PGA(Physician’s Global Assessment)

Mild Moderate Severe

* Friability moved from Score of 1 to 2

Adapted from Kamm et al. Gastroenterology 2007;132:66–75.

Modified* Ulcerative Colitis-Disease Activity Index

End Point Definitions

Relapse: Withdrawal from the study due to a requirement for alternative treatment (including a dose increase or surgery) for an exacerbation of UC

Remission: Modified UC-DAI score 1, calculated as a score of 0 for rectal bleeding and for stool frequency, a combined Physician’s Global Assessment (PGA) and sigmoidoscopy score of 1, no mucosal friability, and a sigmoidoscopy score reduction of 1 point or more from baseline

Adapted from Kamm et al. 2008;57(7):893-902.

623(Parent Studies)

558 (89.6%)(Rolled over into 303)

312 (56%)(Acute Extension Phase)

246 (44%)(Long-term Extension

Phase)213

225(q.d. Group)

234(b.i.d. Group)

459 (Safety population)(Long-term Extension

Phase)

(68%)

Adapted from:1Kamm et al. Poster presented at BSG 2007.2 Kamm et al. Gut 2008;57(7):893-902.

Patient Disposition1,2

Efficacy Results: 8-Week Acute Extension Phase

8-Week Acute Extension Phase: Efficacy Results

Remission

59.5% of patients in the efficacy population (n=304) achieved remission

Modified UC-DAI score

Mean reduction of 3.9 ± 2.8 points from week 0* to end point

Mean reduction of 5.0 ± 2.7 from parent study baseline to end point

Symptom improvement

65.1% of patients had a score of 0 for stool frequency at end point compared to 7.9% at week 0

80.6% of patients had a score of 0 for rectal bleeding at end point compared to 27.3% at week 0

*Week 0=First study visit of the acute extension phase

Adapted from Lichtenstein GR, et al. Poster presented at ACG, 2007.

(n = 107) (n = 78) (n = 78) (n = 41)

Prior treatment

Up to 8 weeks’ active treatment

Up to 16 weeks’ active treatment

Patients in Remission After Eight Weeks’ Extension Therapy

Num

ber

of

patie

nts

(%

)

Adapted from Lichtenstein et al. Poster presented at ACG 2007.

*Week 0=First study visit of the acute extension phase

8-Week Acute Extension Phase:Sigmoidoscopy Scores

STUDY 303 Acute Extension Phase Conclusions1,2

Mesalamine 4.8 g/day (2.4 g dosed b.i.d.) was well-tolerated in the 8-week acute extension phase

Safety profile similar to that of the parent studies (Lichtenstein et al. and Kamm et al.)

Mesalamine 4.8 g/day for up to 4 months was well-tolerated

Approximately 60% of patients achieved remission, using stringent clinical and endoscopic criteria

Adapted from: 1Lichtenstein et al. Poster presented at APhA 2007.2 Lichtenstein et al. Poster presented at ACG 2007.