STUDY%20303

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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

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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

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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. Clin
Gastroenterol Hepatol 2007595102. 2Kamm et
al. Gastroenterology 20071326675.
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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
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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.
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Modified UC-Disease Activity Index
Mild(Score 1) Moderate(Score 2) Severe(Score 3)
Rectal bleeding Streaks of blood Obvious blood Mostly blood
Stool frequency 1-2/day gtnormal 3-4/day gtnormal gt 4/day gtnormal
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(Physicians Global Assessment) Mild Moderate Severe
Friability moved from Score of 1 to 2
Adapted from Kamm et al. Gastroenterology
20071326675.
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Modified UC-Disease Activity Index
Mild(Score 1) Moderate(Score 2) Severe(Score 3)
Rectal bleeding Streaks of blood Obvious blood Mostly blood
Stool frequency 1-2/day gtnormal 3-4/day gtnormal gt 4/day gtnormal
Mucosal appearance Erythema Decreased vascular pattern Minimal granularity Marked erythema Friability Granularity Absent vascular pattern Bleeding minimal trauma No ulcerations Ulceration Spontaneous bleeding
PGA(Physicians Global Assessment) Mild Moderate Severe
Friability moved from Score of 1 to 2
Adapted from Kamm et al. Gastroenterology
20071326675.
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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 Physicians 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
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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
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Demographic and Clinical Characteristics
Long-term Extension Phase
MMX Mesalamine 2.4 g/day (q.d.) (n225) MMX Mesalamine 2.4 g/day (1.2 g b.i.d.) (n234)
Male, 47.1 48.7
Mean age, years 42.4 42.6
Diagnosis, Newly diagnosed 14.2 14.5
No. relapses in last 2 years, 0-2 3-6 7 60.0 33.8 1.8 61.5 35.0 2.1
Left-sided disease, 77.8 76.5
Adapted Kamm et al. Gut. 13 February 2008. Epub
ahead of print
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Safety Results 8-Week Acute Extension Phase
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8-Week Acute Extension Phase Treatment-Related
Adverse Events in 1 of Patients
Adverse event Patients, (n312) n ()
Total 27 (8.7)
Gastrointestinal disordersVomiting NOS Nausea UC aggravated Diarrhea NOS 15 (4.8) 4 (1.3) 4 (1.3) 3 (1.0) 3 (1.0)
Investigations 7 (2.2)
Nervous system disorders Headache 7 (2.2) 4 (1.3)
NOSnot otherwise specified
Investigationslaboratory parameter abnormalities
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Efficacy Results 8-Week Acute Extension Phase
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Up to 16 weeks active treatment
Up to 8 weeks active treatment
(n 78)
(n 78)
(n 41)
(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

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8-Week Acute Extension Phase Sigmoidoscopy
Scores
Number of patients ()
Week 0First study visit of the acute extension
phase
Adapted from Lichtenstein et al. ACG 2007.
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Study 303 Acute Extension Phase Conclusions1,2

• MMX 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.)
• 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.
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Safety Results 12-Month Long-term Extension
Phase
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12-Month Long-term Extension Phase
Treatment-Related Adverse Events Experienced by
?1 of Subjects
MMX Mesalamine 2.4 g/day (q.d.) (n225) MMX Mesalaine 2.4 g/day (1.2g b.i.d.)(n234)
Patients with any treatment-related adverse events n () 25 (11.1) 22 (9.4)
Abdominal pain (nos) 3 (1.3) 2 (0.9)
Ulcerative colitis aggravated 4 (1.8) 1 (0.4)
Diarrhea 3 (1.3) 2 (0.9)
Abdominal pain upper 1 (0.4) 3 (1.3)
Adapted from Kamm et al. Gut 13 February 2008.
Epub ahead of print
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12-Month Long-term Extension Phase Serious
Adverse Events1,2

• 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

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
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Efficacy Results 12-Month Long-term Extension
Phase
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12-Month Long-term Extension Phase Remission
Rates According to Dose
Adapted from Kamm et al. Gut 13 February 2008.
Epub ahead of print
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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 816 weeks of acute therapy were
  relapse-free.

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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.
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12-Month Long-term Extension PhasePatient
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.
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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 1416 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).

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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
  months 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