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STUDY 303

STUDY 303. A Phase III, Randomized, Multi-Center, Open-Label, 12 to 14 Month Extension Study to Evaluate the Safety and Tolerability of MMX Mesalamine Given Once Daily Versus Twice Daily for the Maintenance of Ulcerative Colitis in Remission. Objectives. Study Design Patient Disposition

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STUDY 303

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  1. STUDY 303 A Phase III, Randomized, Multi-Center, Open-Label, 12 to 14 Month Extension Study to Evaluate the Safety and Tolerability of MMX Mesalamine Given Once Daily Versus Twice Daily for the Maintenance of Ulcerative Colitis in Remission

  2. 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

  3. MMX Mesalamine 2.4 and 4.8 g/day is Effective for the Induction of Remission • Lichtenstein et al.1 and Kamm et al.2 studies: Two double-blind,placebo-controlled, phase III studies evaluating the efficacy and tolerability of MMX mesalamine; • Both studies demonstrated MMX mesalamine 2.4 g/day (given q.d. or 1.2 g b.i.d.) and 4.8 g/day (given q.d.) to be efficacious and well tolerated for the induction of remission in patients with active, mild-to-moderate UC. Adapted from: 1ichtenstein et al. ClinGastroenterolHepatol 2007;5:95–102. 2Kamm et al. Gastroenterology 2007;132:66–75.

  4. Study Design of 303 • Open-label, multicentre, phase III study • 12- to 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 • MMX mesalamine 4.8 g/day (2.4 g 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 • MMX mesalamine 2.4 g/day (2.4 g q.d. or 1.2 g b.i.d.) Adapted from Kamm et al. Gut. 13 February 2008. [Epub ahead of print]

  5. Study 303: End points1 • Primary objective: to assess the long-term safety and tolerability of MMX mesalamine 2.4 g/day over 12 months • Efficacy was not a primary end point 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 1Adapted from Kamm et al. BSG 2007.

  6. Modified* UC-Disease Activity Index * Friability moved from Score of 1 to 2 Adapted from Kamm et al. Gastroenterology 2007;132:66–75.

  7. Modified* UC-Disease Activity Index * Friability moved from Score of 1 to 2 Adapted from Kamm et al. Gastroenterology 2007;132:66–75.

  8. 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. Gut 13 February 2008. [Epub ahead of print]

  9. Patient Disposition1,2 623 (Parent Studies) 558 (89.6%) (Rolled over into 303) 312 (56%) ( Acute Extension Phase) 246 (44%) (Long-term Extension Phase) 213 (68%) 459 (Safety population) (Long-term Extension Phase) 234 (b.i.d. group) 225 (q.d. group) Adapted from: 1Kamm et al. BSG 2007.2Kamm et al. Gut. 13 February 2008. [Epub ahead of print]

  10. Demographic and Clinical Characteristics: Long-term Extension Phase Adapted Kamm et al. Gut. 13 February 2008. [Epub ahead of print]

  11. Safety Results: 8-Week Acute Extension Phase

  12. 8-Week Acute Extension Phase: Treatment-Related Adverse Events in ≥1% of Patients *NOS=not otherwise specified ** Investigations=laboratory parameter abnormalities

  13. Efficacy Results: 8-Week Acute Extension Phase

  14. Up to 16 weeks’ active treatment Up to 8 weeks’ active treatment (n = 78) (n = 41) (n = 78) (n = 107) Prior treatment Placbo MMX mesalamine 2.4 g/day MMX mesalamine 4.8 g/day pH-dependent, delayed-release mesalamine 2.4 g/day*

  15. 8-Week Acute Extension Phase: Sigmoidoscopy Scores Number of patients (%) *Week 0=First study visit of the acute extension phase • Adapted from Lichtenstein et al. ACG 2007.

  16. Study 303: Acute Extension Phase Conclusions1,2 • MMX mesalamine4.8 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.) • MMX 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. APhA 2007.2 Lichtenstein et al. ACG 2007.

  17. Safety Results: 12-Month Long-term Extension Phase

  18. 12-Month Long-term Extension Phase: Treatment-Related Adverse Events Experienced by 1% of Subjects Adapted from Kamm et al. Gut 13 February 2008. [Epub ahead of print]

  19. Eighteen patients (3.9%) experienced 22 serious adverse events (SAEs) 21/22 considered unrelated to treatment Angina pectoris Pulmonary edema Ulcerative colitis Chronic hepatitis Lung abscess Pneumonia Electric shock Abnormal liver function test Cerebral infarction Aggravated depression Menometrorrhagia Ovarian cyst COPD exacerbation 12-Month Long-term Extension Phase: Serious Adverse Events1,2 *Some SAEs were experienced more than once during the long-term extension phase Adapted from Kamm et al. Gut 13 February 2008. [Epub ahead of print]

  20. Efficacy Results: 12-Month Long-term Extension Phase

  21. 12-Month Long-term Extension Phase: Remission Rates According to Dose 80 72.3 68.5 67.8 70 64.4 60 Long-term extension efficacy 50 (q.d. n=219; b.i.d. n=232) Patients (%) 40 Patients meeting strict remission criteria at baseline (q.d. n=171; b.i.d. n=191) 30 20 10 0 2.4 g/day (q.d.) 2.4 g/day (1.2 g b.i.d.) Adapted from Kamm et al. Gut 13 February 2008. [Epub ahead of print]

  22. Prevention of Relapse • Of the 220 patients who achieved remission following 816 weeks’ acute therapy, 218 entered the maintenance phase; • At the end of this 12-month maintenance phase, 89.9% (196/218) of patients who had achieved remission during 8–16 weeks of acute therapy were relapse-free.

  23. 12-Month Long-term Extension Phase: Time to Relapse (patients in remission at baseline) • At 12 months, the proportion of patients who had not relapsed was 88% in the 2.4 g/day q.d. group and 92% in the 2.4 g/day (1.2 g b.i.d.) group 100 80 60 40 20 0 2.4 g/day b.i.d. 2.4 g/day q.d. Proportion not relapsing (%) Log-rank P value = 0.1716 0 50 100 150 200 250 300 350 400 450 Time since start of treatment (days) Adapted from Kamm et al. DDW 2007.

  24. 12-Month Long-term Extension Phase:Patient Satisfaction • Patients completed a questionnaire at 6 months or at the end of the study if patient withdrew earlier • Scoring was on a 5-grade scale • Extremely dissatisfied to extremely satisfied • Results • 152 patients completed the questionnaire • 79 from q.d. group, 73 from b.i.d. group • Overall satisfaction with medication (somewhat or extremely satisfied) • 98.7% in q.d. group • 95.9% in b.i.d. group • Adapted from Wilson L. SGNA 2007.

  25. Overall Efficacy - Remission • Combining data from all three studies, 56.6% (196/346) of the patients who started MMX mesalamine therapy achieved remission and were maintained relapse-free over 14–16 months therapy; • This proportion was similar irrespective of whether patients started on 2.4 g/day (58.1%; 100/172) or 4.8 g/day (55.2%; 96/174).

  26. Study 303: Overall Conclusions • 4.8 g/day (2.4 g dosed b.i.d.) was well-tolerated in the 8-week acute phase • Its safety profile was similar to that of the parent studies • 2.4 g/day (dosed q.d. or as 1.2 g b.i.d.) was well-tolerated in the 12-month maintenance phase • No signals of long-term safety concerns were observed • ~ 90% of patients did not relapse during 12 month’s treatment with 2.4 g/day • The vast majority of patients were satisfied with treatment during maintenance phase • Was well tolerated for 12-16 months and was similar to that of other mesalamine products

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