Salix Pharmaceuticals, Inc. (cid:9)
`MPUC3003 Clinical Study Report (cid:9)
`
`CONFIDENTIAL Encapsulated Mesalamine Granules
`Final: 11 October 2007
`
`1. TITLE PAGE
`
`A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial to
`Evaluate the Use of Mesalamine Pellet Formulation 1.5G QD to Maintain
`Remission from Mild to Moderate Ulcerative Colitis
`
`Name of Test/Investigational Drug: (cid:9)
`
`Indication Studied: (cid:9)
`Phase of Study: (cid:9)
`Protocol Number: (cid:9)
`
`Encapsulated Mesalamine Granules (eMG)
`(formerly referred to as Encapsulated
`Mesalamine Pellets [MP])
`Maintenance of remission of ulcerative colitis
`Phase 3
`MPUC3003
`
`Study Initiation (First Subject, First Visit)
`Date: (cid:9)
`Study Completion (Last Subject, Last
`Visit) Date: (cid:9)
`Date of Study Report: (cid:9)
`
`20 December 2004
`
`26 April 2007
`11 October 2007
`
`Study Sponsor: (cid:9)
`
`Name of Sponsor Signatory: (cid:9)
`
`Salix Pharmaceuticals, Inc
`1700 Perimeter Park Drive
`Morrisville, North Carolina, USA 27560
`Tel: (919) 862-1000 and Fax: (919) 862-1095
`
`William P. Forbes, PharmD
`Vice President, Research and Development &
`Chief Development Officer
`Salix Pharmaceuticals, Inc.
`1700 Perimeter Park Drive
`Morrisville, NC 27560
`
`This study was conducted in accordance with the International Conference on Hannonisation
`Guidelines for Good Clinical Practice, the ethical principles that have their origin in the
`Declaration of Helsinki, and Title 21 of the United States Code of Federal Regulations
`Sections 50, 56, and 312.
`
`Confidential Information—Subject to Protective Order (cid:9)
`
`SALIX00043192
`Dr. Falk Ex. 2027
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 1
`
`

`
`Salix Pharmaceuticals, Inc. (cid:9)
`MPUC3003 Clinical Study Report (cid:9)
`
`CONFIDENTIAL Encapsulated Mesalamine Granules
`Final: 11 October 2007
`
`Name of Sponsor Company: Salix Pharmaceuticals, Inc.
`Name of Finished Product: Encapsulated Mesalamine Granules (eMG) (formerly referred to as Mesalamine
`Pellets [MP])
`Name of Active Ingredient: Mesalamine
`The primary efficacy endpoint was the proportion of ITT subjects who remained
`Efficacy Results:
`relapse-free after 6 months of treatment. The eMG treatment group had a larger
`proportion of relapse-free subjects (78.9%) when compared with subjects treated
`with placebo (58.3%) at Month 6/EOS. This difference between the two treatments
`was statistically significant (p < 0.001) using a CMH test, demonstrating that eMG
`QD was more effective than placebo in maintaining remission of UC in subjects
`participating in this study. A supplementary post hoe analysis of the primary
`endpoint on the ITT population, using a chi-square test, produced a similar result
`(p < 0.001).
`
`Primary Efficacy Endpoint
`
`®eMG (cid:9) q Placebo
`.......................................................................................................................................................................................................................
`I (cid:9)
`ITT Population (cid:9)
`PP Population
`(N= 305; P < 0.001) (cid:9)
`(N= 293, P=0.001)
`
`789 (cid:9)
`
`785 (cid:9)
`
`90.0 (cid:9)
`
`80.0
`
`700f-
`
`600 (cid:9)
`
`-
`50.0
`
`U)
`
`40.0
`
`30.0
`
`20.0
`
`10.0
`
`58.3
`
`
`
`41.7 (cid:9)
`
`40.9
`
`21.1 (cid:9)
`
`21.5
`
`- (cid:9)
`
`0.0 (cid:9)
`
`.;-
`
`' (cid:9)
`
`-- (cid:9)
`Successes (cid:9)
`
`-~ --
`
`Failures (cid:9)
`Successes (cid:9)
`Month 61EOS Treatment Outcome
`
`-- (cid:9)
`
`r- -
`
`Failures
`
`The primary efficacy analysis was repeated as a sensitivity test using the PP
`population. Again, the eMG treatment group had a larger proportion of relapse-free
`subjects when compared with subjects treated with placebo (78.5% vs. 59.1%,
`p = 0.001).
`
`The effectiveness of eMG QD was further supported by the results of the secondary
`endpoints.
`
`o (cid:9)
`
`The number and proportion of subjects at each level of change from baseline
`in the revised Sutherland DAI rectal bleeding component score at
`Month 6/EOS revealed a statistically significant difference (p = 0.008) in
`favor of the eMG group.
`
`o (cid:9) A greater proportion of placebo subjects had an increased mucosal
`appearance score at Month 6IEOS, although this difference in the change
`from baseline was not statistically significant (p = 0.098) using a C.MH test
`
`Confidential Information—Subject to Protective Order
`
`SALIX00043197
`Dr. Falk Ex. 2027
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 2
`
`(cid:9)
`(cid:9)
`

`
`Salix Pharmaceuticals, Inc. (cid:9)
`MPUC3003 Clinical Study Report
`
`CONFIDENTIAL Encapsulated Mesalamine Granules
`Final: 11 October 2007
`
`Name of Sponsor Company: Salix Pharmaceuticals, Inc.
`Name of Finished Product: Encapsulated Mesalamine Granules (eMG) (formerly referred to as Mesalamine
`Pellets [MP])
`Name of Active Ingredient: Mesalamine
`controlling for country. However, a statistically significant difference
`between the treatment groups (p= 0.035) was noted using a chi-square test.
`
`Efficacy Results
`(continued):
`
`Safety Results:
`
`o (cid:9)
`
`The number and proportion of subjects at each level of change from baseline
`in the revised Sutherland DAI physician's rating of disease activity
`component score at Month 6/EOS revealed a statistically significant
`difference (p = 0.005) in favor of the eMG group.
`
`® (cid:9) A larger proportion (70.3% vs. 53.1%; p = 0.003) of subjects receiving eMG
`versus placebo were classified as treatment successes (maintaining the revised
`Sutherland DAI score of < 2 with no individual component of the revised
`Sutherland DAI > 1 and rectal bleeding = 0).
`
`® (cid:9) A smaller mean change (0.9 vs. 2.0; p = 0.001) from baseline was observed in
`the eMG group compared with placebo group in the revised Sutherland DAI
`total score.
`
`® (cid:9) A higher probability of remaining relapse-free was observed in the eMG
`group, (77%; 95% Cl: 0.71, 0.83) compared with the placebo group (56%;
`95% CI: 0.46, 0.67) over the 6 month course of the study.
`
`® (cid:9)
`
`The number and proportion of subjects at each level of change from baseline
`in the revised Sutherland DAI stool frequency component score at
`Month 6/EOS revealed a statistically significant difference (p = 0.005) in
`favor of the eMG group.
`
`Encapsulated mesalamine granules administered 1.5 g QD over 6 months for the
`maintenance of remission of ulcerative colitis were safe and well tolerated in this
`study. Exposure to eMG was longer (mean = 142.8 days) than placebo (mean = 118.2
`days).
`
`The safety results are summarized here:
`
`® (cid:9)
`
`The percentage of subjects experiencing any TEAE was essentially
`identical between the eMG and placebo groups (64.1% eMG, 63.8%
`placebo) and most TEAEs were mild or moderate in intensity.
`
`• (cid:9) Ulcerative colitis flare was more than twice as common in the placebo
`group (26.6%) compared with the eMG group (11.2%). Headache, a
`known side effect of mesalamine, was slightly more common in the eMG
`group (11.2%) than in the placebo group (7.4%).
`
`® (cid:9)
`
`• (cid:9)
`
`There were no deaths during the study and only 4 SAES (2 in each study
`group); 1 subject in the placebo group experienced an SAE of UC
`considered to be possibly related to study drug.
`
`A smaller percentage of subjects in the eMG group prematurely
`discontinued the study due to a TEAS (15.0%) compared with subjects in
`the placebo group (27.7%).
`
`Confidential Information—Subject to Protective Order
`
`SALIX00043198
`Dr. Falk Ex. 2027
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 3
`
`(cid:9)
`(cid:9)
`

`
`Salix Pharmaceuticals, Inc. (cid:9)
`MPUC3003 Clinical Study Report (cid:9)
`
`CONFIDENTIAL Encapsulated Mesalamine Granules
`Final: 11 October 2007
`
`IR 1 (cid:9)
`
`(I (cid:9)
`
`1 , Wit I
`
`S . (cid:9)
`
`I ,,
`
`13.1. Discussion
`
`The results of this randomized placebo controlled trial demonstrated that eMG 1.5 g taken QD was
`effective, safe, and well-tolerated for the maintenance of remission of UC over a 6 month period. A
`statistically significant (p < 0.001) larger proportion of subjects in the eMG group (78.9%)
`maintained remission at Month 6/EOS compared with subjects in the placebo group (58.3%). The
`effectiveness of eMG QD was further demonstrated by a larger number of subjects maintaining a
`DAI rectal bleeding component score of 0 at Month 6/EOS (p = 0.008) as compared with placebo.
`
`The effectiveness of eMG QD was also supported by the results of other secondary analyses. The
`number and proportion of subjects at each level of change from baseline at Month 6/EOS in the
`revised Sutherland DAI component scores of physician's rating of disease activity (p = 0.005) and
`stool frequency (p = 0.005) showed a statistically significant difference between treatment groups
`in favor of the eMG group. Additionally a larger proportion (70.3% vs. 53.1%; p = 0.003) of
`subjects receiving eMG versus placebo were classified as treatment successes (maintaining the
`revised Sutherland DAI score of < 2 with no individual component of the revised Sutherland DAI
`> 1 and rectal bleeding = 0). Moreover, the eMG group had a statistically significant smaller mean
`change from baseline in Sutherland DAI total score (p = 0.001) at Month 6/EOS accompanied by a
`significantly (p <0,001) lower risk of relapse than the placebo group.
`
`A smaller proportion of subjects in the eMG group had an increased mucosal appearance score at
`Month 6/EOS, but there was no statistically significant difference in the change from baseline
`(p = 0.098) using a CMH test controlling for country. However, a post hoc, supplemental analysis
`conducted using a chi-square test did reveal a statistically significant difference between the
`treatment groups (p= 0.035).
`
`Encapsulated mesalamine granules were well tolerated; most TEAEs were mild or moderate in
`intensity, and the percentage of subjects experiencing any TEAE was essentially identical between
`the eMG and placebo groups (64.1% eMG, 63.8% placebo). However, fewer GI-related TEAEs
`were noted in the eMG group than in the placebo group (37.9% vs. 47.9%). Most notably, less than
`half the proportion of subjects (11.2%) treated with eMG experienced a ulcerative colitis flare
`compared with subjects in the placebo group (26.6%), further demonstrating the effectiveness of
`eMG in maintaining remission. This trend was also evident among subjects who discontinued due
`to AE, with a greater than 2-fold larger proportion of subjects treated with placebo discontinuing
`due to UC (24.5% vs. 9.7%).
`
`Although it is difficult to compare the results of clinical trials for the maintenance of remission of
`UC due to different measures of success, the 78.9% of subjects in the eMG 1.5 g QD group who
`remained relapse free is similar to the 65.5% of subjects who remained relapse free when treated
`
`117
`
`Confidential Information—Subject to Protective Order (cid:9)
`
`SALIX00043308
`Dr. Falk Ex. 2027
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 4
`
`(cid:9)