Salix Pharmaceuticals, Inc. (cid:9)
`IvIPUC3004 Clinical Study Report (cid:9)
`
`CONFIDENTIAL Encapsulated Mesalamine Granules
`Final: 26 October 2007
`
`al. (cid:9)
`
`M v,
`
`PHARNIACuUTtCA.LS, INC.
`(}AvANcc T`IE iYMu .N l IN
`
`CLINICAL STUDY REPORT
`
`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
`MPUC3004
`
`Study Initiation (First subject, first visit)
`Date: (cid:9)
`Study Completion (Last subject, last visit)
`Date: (cid:9)
`Date of Study Report: (cid:9)
`
`24 December 2004
`
`08 August 2007
`26 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 Harmonisation
`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)
`
`SALIX00048657
`Dr. Falk Ex. 2028
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 1
`
`

`
`Salix Pharmaceuticals, Inc. (cid:9)
`MPUC3004 Clinical Study Report
`
`CONFIDENTIAL Encapsulated Mesalamine Granules
`Final: 26 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 (79.9%) when compared with subjects treated with
`placebo (66.7%) at Month 6/EOS. This difference between the two treatments was
`statistically significant (p = 0.029) using a CIVIH test, demonstrating that eMG was
`more effective than placebo in maintaining remission of UC in subjects participating
`in this study.
`
`Primary Efficacy Endpoint
`
`00 (cid:9)
`
`80
`
`70 (cid:9)
`
`60
`
`50
`
`a W. 40
`
`n (cid:9)
`
`30
`
`20
`
`10
`
`®,MG (cid:9) q Placebo
`...................................................................................................................................................................................................................
`1 (cid:9)
`ITT Population (cid:9)
`PP Population
`)N'257, P = 0.029) (cid:9)
`(N = 247P = 0.034)
`
`79.9
`
`80.1 (cid:9)
`
`68.7 (cid:9)
`
`
`
`67.4
`
`i (cid:9)
`
`33.3 (cid:9)
`
`32.6
`
`20.1 fl (cid:9)
`19.9 fl
`i±.LL._I_H.
`
`Success (cid:9)
`
`Failure (cid:9)
`
`Success (cid:9)
`
`Failure
`
`Month 6 Treatment Outcome
`
`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 (80.1% vs. 67.4%,
`p = 0.034).
`
`The effectiveness of eMG was further supported by the results of 2 exploratory
`secondary endpoint analyses:
`
`• (cid:9) A larger proportion of eMG subjects met the 3 criteria of maintaining a
`revised Sutherland DAI < 2 with no individual component > 1 and rectal
`bleeding = 0 at Month 6/EOS, compared with subjects receiving placebo
`(72.05 vs. 58.1%, p = 0.039).
`
`• (cid:9)
`
`The eMG group had a lower risk of relapse than the placebo group over the
`6 month course of the study (hazard ratio = 0.57, p = 0.024).
`The following additional secondary endpoints demonstrated differences between the
`eMG and placebo groups but did not reach statistical significance:
`
`o (cid:9) A larger proportion of eMG subjects had no increase in the rectal bleeding
`subscore of the revised Sutherland DAI from baseline to Month 6/EOS
`(84.7% vs. 75.3%).
`
`Confidential Information—Subject to Protective Order (cid:9)
`
`SALIX00048662
`Dr. Falk Ex. 2028
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 2
`
`(cid:9)
`(cid:9)
`(cid:9)
`

`
`Salix Pharmaceuticals, Inc. (cid:9)
`IVIPUC3004 Clinical Study Report (cid:9)
`
`CONFIDENTIAL Encapsulated Mesalamine Granules
`Final: 26 October 2007
`
`Name of Sponsor Company: SalixPharmaceuticals, Inc.
`Name of Finished Product: Encapsulated Mesalamine Granules (eMG) (formerly referred to as Mesalamine Pellets
`MP])
`Name of Active Ingredient: Mesalamine
`® (cid:9) A larger proportion of eMG subjects had no increase in the mucosal
`appearance subscore of the revised Sutherland DAI from baseline to Month
`6/EOS (79.2% vs. 74.1%).
`
`® (cid:9) A larger proportion of eMG subjects had no increase in the physician's
`rating of disease subscore of the revised Sutherland DAI from baseline to
`Month 6/EOS (84.8% vs. 75.3%).
`
`® (cid:9)
`
`The eMG group showed a smaller mean change in the revised Sutherland
`DAI total score from baseline to Month 6/EOS (0.7 vs. 1.2).
`
`• (cid:9) A larger proportion of eMG subjects had no increase in the stool frequency
`subscore of the revised Sutherland DAI from baseline to Month 6/EOS
`(82.9% vs. 76.3%).
`
`Safety Results:
`
`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. Mean exposure to eMG was longer (147.84 days) than placebo (133.90 days).
`
`The safety results are summarized below:
`
`• (cid:9)
`
`The percentage of subjects experiencing any TEAE was lower in the eMG
`group compared with the placebo group (eMG: 53.4% vs. placebo: 63.7%)
`and most TEAEs were mild or moderate in intensity.
`
`• (cid:9) Ulcerative colitis flare was twice as common in the placebo group (22.0%)
`compared with the eMG group (10.6%). Headache, a known side effect of
`mesalamine, was more common in the eMG group (10.6%) than in the
`placebo group (7.7%).
`
`• (cid:9)
`
`• (cid:9)
`
`® (cid:9)
`
`• (cid:9)
`
`There were no deaths during the study.
`
`Five serious adverse events (SAEs) in 4 subjects (2 subjects in each study
`group) were reported. None of the SAEs were considered to be possibly
`related to study drug.
`
`The percentage of subjects that prematurely withdrew from the study due to
`a TEAE was similar between the treatment groups (eMG: 5.5%, placebo:
`6.6%).
`
`Few events related to hepatic, renal, and pancreatic function, which are a
`potential concern with mesalamine administration, were observed.
`
`In summary, eMG 1.5 g taken once per day for up to 6 months was safe and well
`tolerated; the safety profile did not differ in any clinically meaningful way from that
`of placebo.
`
`The table below also presents an overall summary of safety.
`
`Confidential Information—Subject to Protective Order
`
`SALIX00048663
`Dr. Falk Ex. 2028
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 3
`
`(cid:9)
`

`
`Salix Pharmaceuticals, Inc. (cid:9)
`NIPUC3004 Clinical Study Report (cid:9)
`
`CONFIDENTIAL Encapsulated Mesalamine Granules
`Final: 26 October 2007
`
`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
`treatment period. A larger proportion of subjects in the eMG group (79.9%) maintained
`remission at Month 6/EOS compared with the placebo group (66.7%). This difference was
`statistically significantly (p = 0.029). A sensitivity analysis of the primary endpoint using the
`PP population gave nearly identical results, with 80.1% of eMG-treated subjects remaining
`relapse-free compared with 67.4% of placebo-treated subjects (p = 0.034).
`
`The effectiveness of eMG taken QD was further supported by the results of the exploratory
`secondary analyses. Analysis of the number and proportion of subjects maintaining the revised
`Sutherland DAI < 2 with no individual component of the revised Sutherland DAI > 1 and rectal
`bleeding = 0 at Month 6/EOS revealed a statistically significant (p = 0.039) difference between
`treatment groups, with 72.0% of eMG subjects classified as treatment successes compared with
`58.1% of placebo subjects. Moreover, the eMG group had a statistically significantly lower risk
`of relapse than the placebo group (hazard ratio = 0.57, p = 0.024).
`
`The results of the remaining exploratory secondary analyses were also in favor of the eMG
`group. A larger percentage of eMG subjects, compared with placebo, had a change from
`baseline < 0 in their rectal bleeding score, mucosal appearance score, physician's rating of
`disease activity score, and stool frequency score. Encapsulated mesalamine granule subjects
`also had a lower mean change from baseline in their revised Sutherland DAI total score when
`compared with placebo. However, these results were not statistically significant.
`
`Encapsulated mesalamine granules were safe and well tolerated; most TEAEs were mild or
`moderate in intensity. The system organ class with the most frequently reported TEAEs was
`GI System Disorders. Fewer subjects receiving eMG reported GI-related TEAEs than subjects
`receiving placebo (eMG: 32.3% vs. placebo: 45.1%). Most notably a trend toward prolonged
`relapse status in the eMG group was evidenced by the proportion of subjects who experienced a
`UC flare; UC flare was twice as common in the placebo group (eMG: 10.6%; placebo: 22.0%).
`This trend was also apparent in the proportion of subjects who withdrew prematurely from the
`study because of lack of efficacy (eMG: 15.2% vs. placebo: 23.7%).
`
`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 79.9% of subjects in the eMG group who
`remained relapse free is similar to the 65.5% of subjects who remained relapse free when
`treated with another mesalamine-based drug (Asacol®, Proctor and Gamble Pharmaceuticals) at
`
`121
`
`Confidential Information—Subject to Protective Order (cid:9)
`
`SALIX00048777
`Dr. Falk Ex. 2028
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 4