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`Review article: Increasing the dose of oral
`mesalazine therapy for active ulcerative colitis
`does not improve remission rates
`
`Article (PDF Available) in Alimentary Pharmacology & Therapeutics 26(9):1179-86 · December 2007 with
`22 Reads
`DOI: 10.1111/j.1365-2036.2007.03471.x · Source: PubMed
`
`1st Alan V. Safdi
`15.32 · Ohio Gastroenterology & Liver Instit...
`
`2nd Russell Cohen
`43.1 · University of Chicago
`
`Abstract
`
`Oral mesalazine (mesalamine, 5-aminosalicylic acid) formulations are effective in the treatment of active
`ulcerative colitis. All formulations contain the same active drug but differ with regard to mechanisms to
`deliver the drug to the colon. Patients who fail to respond to initial therapy are often administered higher
`doses of the same formulation. To review published trials of oral mesalazine formulations in treating active
`ulcerative colitis and to examine the effect of dose escalation on remission rates. Increasing the doses of
`oral mesalazine formulations does not result in higher remission rates, although increasing the doses of
`some formulations has been effective in increasing symptomatic improvement and/or response to
`treatment. Because oral mesalazine formulations do not demonstrate a significant dose response with
`regard to induction of remission of active ulcerative colitis, simple dose escalation may not be the most
`effective course for patients who fail to respond to initial mesalazine treatment.
`
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`Full-text (PDF)
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`Available from: Alan V. Safdi, Oct 12, 2015
`
`https://www.researchgate.net/publication/5900396_Review_article_Increasing_the_dose_o...
`
`8/25/2016
`
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`Review article: Increasing the dose of oral mesalazine therapy for active ulcerative colitis ...
`
`Page 2 of 11
`
`Alimentary Pharmacology
`
`Therapeutics
`
`Review article: increasing the dose of oral mesalazine therapy for
`active ulcerative colitis does not improve remission rates
`A. V. SAFDI* & R. D. COHEN
`
`*Greater Cincinnati Gastroenterology
`Associates, Cincinnati, OH, USA;
`Department of Medicine, Section of
`Gastroenterology, University of
`Chicago, Chicago, IL, USA
`
`Correspondence to:
`Dr A. V. Safdi, Greater Cincinnati
`Gastroenterology Associates, 2925
`Vernon Place, Suite 100, Cincinnati,
`OH 45219, USA.
`E-mail: gialan@aol.com
`
`Publication data
`Submitted 9 January 2007
`First decision 19 January 2007
`Resubmitted 18 July 2007
`Second decision 27 July 2007
`Resubmitted 7 August 2007
`Third decision 7 August 2007
`Resubmitted 16 August 2007
`Accepted 16 August 2007
`
`S UMMA RY
`
`Background
`Oral mesalazine (mesalamine, 5-aminosalicylic acid) formulations are
`effective in the treatment of active ulcerative colitis. All formulations
`contain the same active drug but differ with regard to mechanisms to
`deliver the drug to the colon. Patients who fail to respond to initial
`therapy are often administered higher doses of the same formulation.
`
`Aim
`To review published trials of oral mesalazine formulations in treating
`active ulcerative colitis and to examine the effect of dose escalation on
`remission rates.
`
`Results
`Increasing the doses of oral mesalazine formulations does not result in
`higher remission rates, although increasing the doses of some formula-
`tions has been effective in increasing symptomatic improvement and or⁄
`response to treatment.
`
`Conclusions
`Because oral mesalazine formulations do not demonstrate a significant
`dose response with regard to induction of remission of active ulcerative
`colitis, simple dose escalation may not be the most effective course for
`patients who fail to respond to initial mesalazine treatment.
`
`Aliment Pharmacol Ther 26, 1179–1186
`
`ª 2007 The Authors
`
`2007 Blackwell Publishing Ltd
`Journal compilation
`doi:10.1111/j.1365-2036.2007.03471.x
`
`ª
`
`1179
`
`https://www.researchgate.net/publication/5900396_Review_article_Increasing_the_dose_o...
`
`8/25/2016
`
`GeneriCo, Flat Line Capital
`Exhibit 1054 Page 2
`
`

`
`Review article: Increasing the dose of oral mesalazine therapy for active ulcerative colitis ...
`
`Page 3 of 11
`
`1180 A . V . S A F D I A N D R . D . C O H E N
`
`INT RODUCTION
`
`Mesalazine (mes alamine), or 5-ami nosalicylic acid (5-
`ASA), is an effective therapy for the induction and
`maintenance of remiss ion in patients with ulcerative
`colitis (UC),
`a chronic inflammatory disease of the
`colonic mucosa. Because the drug acts topically, the
`goal of therapy is to maximize 5-ASA delivery to
`the
`colon.
`However, because 5-ASA is
`readily
`absorbed by the upper gastrointestinal (GI) tract, vari-
`ous strategies have been developed to delay 5-ASA
`release until the drug reaches the colon. Although all
`oral 5-ASA formulations contain the same active drug,
`mechanisms to deliver the drug directly to the colon
`differ. These diffe rences in drug delivery may account
`for variability in efficac y and tolerability among
`different formulations.
`Oral 5-ASA formulations available in the United
`(Pentasa;
`States include controlled-release capsules
`Shire US Inc, Wayne, PA, USA), which release 5-ASA
`slowly throughout
`the length of
`the GI
`tract; pH-
`dependent dela yed-release tablets
`(Asacol; Procter &
`Gamble Pharmaceuticals Inc, Cincinnati, OH, USA) and
`(Lialda; Shire US Inc),
`multimatrix mesalazine tablets
`both of which employ an enteric coating that dissolves
`when sustained pH reaches 7 or higher in the terminal
`ileum and colon; and azo-bonded prodrugs, in which
`bacterial azoreduction in the colon releases 5-ASA
`from a carrier molecule (Figure 1). Azo-bonded 5-ASA
`prodrugs include sulfasalazine (Azulfidine; Pfizer Inc,
`New Y ork, NY, USA and generics), in which 5-AS A is
`bonded to a sulfa moiety; olsalazine (Dipentum; Pfizer
`Inc), which consists of two 5-ASA molecules bonded
`(Colazal; Salix Pharmaceu-
`together; and balsala zide
`ticals Inc, Morrisville, NC, USA), which utilizes the
`inert carrier molecule 4-aminobenzoyl- -alanine.
`Oral 5-ASA formulatio ns are effective first-line
`treatments for active, mild-to-moderate UC, but many
`patients fail
`to achieve remission following initial
`5-ASA therapy, and as a consequence, have their 5-
`However, dose escalation of
`ASA doses increase d.
`many formulations increases the potential for systemic
`absorption of 5-ASA without a clear or consistent
`benefit in efficacy. Because oral 5-ASA formulations
`differ in mechanism of drug delivery, switching unre-
`sponsive pa tients to another formulation may be an
`alternative to simply increasing the dose.
`This article
`will review published clinical trials evaluating the effi-
`cacy of increasing the 5-ASA dose of each oral formu-
`lation in treating active UC.
`
`Figure 1. Mesalazine, or 5-aminosalicylic acid (5-ASA), is
`readily absorbed by the gastrointestinal (GI) tract, so
`strategies have been developed to delay drug release until
`the agent reaches the colon. Controlled-release mesalazine
`(1) releases 5-ASA slowly throughout the GI tract, where
`20% to 30% of the dose is absorbed before reaching the
`colon. pH-Dependent mesalazine formulations (2) rely on
`an enteric coating that dissolves when pH levels reach 7
`or higher in the terminal ileum, and 21% to 28% of the
`5-ASA dose is absorbed prior to reaching the colon.
`Azo-bonded 5-ASA prodrugs (3) rely on anaerobic bacte-
`ria in the colon to enzymatically release active drug and
`deliver 99% of the dose directly to the colon.
`
`INDUCTION OF REMISSION
`
`Studies evaluating oral 5-ASA formulations in the
`treatment of active UC apply various scoring systems
`and disease activity indices to determine efficacy and
`the induction of remission; thus, direct comparison of
`studies employ ing different efficacy endpoints is chal-
`lenging.
`Some trials employ relati vely strict defini-
`tions of remission, involving complete symptom relief
`and endoscopic assessment of
`the colonic mucosa;
`others do not report remission rates but consider clini-
`cal response achieved if symptoms are relieved with-
`out endoscopic assessment or if clinical improvement
`in symptom severity or physician’s global assessment
`
`ª 2007 The Authors,
`Journal compilation
`
`Aliment Pharmacol Ther 26,
`1179–1186
`2007 Blackwell Publishing Ltd
`ª
`
`https://www.researchgate.net/publication/5900396_Review_article_Increasing_the_dose_o...
`
`8/25/2016
`
`GeneriCo, Flat Line Capital
`Exhibit 1054 Page 3
`
`

`
`Review article: Increasing the dose of oral mesalazine therapy for active ulcerative colitis ...
`
`Page 4 of 11
`
`R E V I E W : E F F I C A C Y O F D O S E E S C A L A T I O N F O R U L C E R A T I V E C O L I T I S 1181
`
`(PGA) is attained. Despite these differences in study
`design, the benefit of 5-ASA dose escalation may be
`evaluated by comparing efficacy results between treat-
`ment dosing arms within individual trials. However,
`⁄
`many trials are limited by the relatively small numbers
`of patients enrolled in each treatment arm.
`
`Controlled-release mesalazine
`
`In a dose-ranging clinical trial evaluating controlled-
`release mesalazine in 374 patients with mildly to mod-
`erately active UC, remission (defined as complete relief
`of symptoms after 8 weeks) was achieved by 21%, 29%,
`and 29% of patients who received mesalazine 1 g day,
`⁄
`2 g ⁄
`day, and 4 g day, respectively, compared with 12%
`⁄
`of patients who received placebo (Table 1). When clin-
`ical improvement (defined as any improvement from
`baseline in PGA score after 8 weeks) was used as an
`endpoint, improvement was achieved by 71%, 79%, and
`84% of patients who received 1 g day, 2 g day, and
`⁄
`⁄
`4 g ⁄ day, respectively, compared with 54% of patients
`who received placebo. For both endpoints, efficacy dif-
`ferences among the three mesalazine doses were not sig-
`
`nificant ( -values not reported).P
`
`pH-Dependent delayed-release mesalazine
`
`Several clinical trials have been conducted to evaluate
`the efficacy of pH-dependent delayed-release mesal-
`azine doses between 1.6 g day and 4.8 g day in the
`⁄
`⁄
`treatment of active UC (Table 1). In a study of 87
`patients with mildly to moderately active UC, complete
`response (defined as relief of all symptoms after
`6 weeks) was achieved by 9% and 24% of patients
`who received pH-dependent mesalazine 1.6 g day and
`⁄
`4.8 g day, respectively, compared with 5% of patients
`⁄
`who received placebo. A partial response (defined as
`improvement
`in
`symptoms
`from baseline) was
`achieved by 18% and 50% of patients who received
`the 1.6-g day and 4.8-g day doses, respectively, com-
`⁄
`⁄
`pared with 13% of patients who received placebo.
`Although the difference in partial
`response rates
`between the 4.8-g day dose and placebo was consid-
`⁄
`
`ered significant ( < 0.0001), differences in efficacyP
`results between the two mesalazine doses were not sig-
`
`nificant ( -values not reported).P
`In a dose-ranging study of 131 patients with mildly
`to moderately active UC,
`the rates of
`remission
`(defined as complete resolution of symptoms, with a
`score of 0 for all assessments) after 6 weeks were
`
`ª 2007 The Authors,
`Journal compilation
`
`Aliment Pharmacol Ther 26,
`1179–1186
`2007 Blackwell Publishing Ltd
`ª
`
`equal (14%) between patients who received pH-depen-
`dent
`delayed-release mesalazine
`1.6 g day
`and
`⁄
`2.4 g day, compared with 5% of patients who received
`⁄
`Improvement (defined as reduction in PGA
`placebo.
`score and in at least one other component score, with
`no score increased in severity) after 6 weeks was
`achieved by 29% and 35% of patients who received
`the 1.6-g day and 2.4-g day doses, respectively, com-
`⁄
`⁄
`pared with 18% of patients who received placebo. The
`efficacy of each mesalazine dose was significantly
`greater than that of the placebo group (
`0.03), but
`P £
`differences between the two doses were not significant
`
`( -values not reported).P
`A third dose-ranging study of pH-dependent mesal-
`azine was conducted to establish the safety and effi-
`cacy of an investigational 800-mg mesalazine tablet
`Among 110 patients
`and the higher 4.8-g day dose.
`⁄
`with mild UC, overall
`improvement
`(defined as
`improvement in PGA score and in at least one other
`component score, with no score increased in severity)
`after 6 weeks was achieved by 40% and 33% of
`patients who
`received
`pH-dependent mesalazine
`2.4 g day and 4.8 g day,
`
`respectively ( = 0.410).P
`⁄
`⁄
`Among 254 patients with moderate UC, overall
`improvement was achieved by 59% and 72% of
`patients who received the 2.4-g day and 4.8-g day
`⁄
`⁄
`doses,
`
`respectively ( = 0.036). Complete remissionP
`(defined as complete resolution of symptoms, normal
`endoscopy assessment, functional assessment of ‘gen-
`erally well,’ and PGA score of 0) after 6 weeks was
`achieved by 18% and 20% of patients with moderate
`UC who received the 2.4-g day and 4.8-g day doses,
`⁄
`⁄
`
`respectively ( -value not reported). Complete remissionP
`among patients with mild disease was not reported.
`
`pH-Dependent multimatrix mesalazine
`
`Dose-ranging studies have been performed with mul-
`timatrix mesalazine, a mesalazine formulation that
`also employs pH-dependent drug release (Table 1). In a
`pilot study of 38 patients with mildly to moderately
`active UC, re mission [defined as UC Disease Activity
`Index (UC-DAI) score of 1, with scores of 0 for rectal
`£
`bleeding and stool frequency and at least a 1-point
`reduction from baseline in sigmoidoscopy score] after
`8 weeks was attained by 0%, 31%, and 18% of
`patients who
`received multimatrix mesalazine
`1.2 g day, 2.4 g day, and 4.8 g day,
`respectively.
`⁄
`⁄
`⁄
`The differences in remission rates among treatment
`
`groups were not significant ( = 0.130).P
`
`https://www.researchgate.net/publication/5900396_Review_article_Increasing_the_dose_o...
`
`8/25/2016
`
`GeneriCo, Flat Line Capital
`Exhibit 1054 Page 4
`
`

`
`Review article: Increasing the dose of oral mesalazine therapy for active ulcerative colitis ...
`
`Page 5 of 11
`
`1182 A . V . S A F D I A N D R . D . C O H E N
`
`Table 1. Efficacy of increasing oral mesalazine dose in active ulcerative colitis (UC)
`
`Study
`
`
`
`Treatment dosage ( )n
`
`Treatment duration
`
`Endpoints and results
`
`Controlled-release mesalazine
`Hanauer et al.
`
`8 weeks
`
`Remission*
`
`Clinical improvement
`
`Sninsky et al.
`
`6 weeks
`
`21%
`29%
`29%
`12%
`
`
`
`
`71%
`79%
`
`84%
`
`54%
`
`6 weeks
`
`Complete response*
`
`Partial response
`
`
`
`9%
`24%
`5%
`Remission*
`
`
`
`
`14%
`14%
`5%
`
`18%
`50%
`
`13%
`Clinical improvement
`
`29%
`
`35%
`
`18%
`Overall improvementà
`
`40%
`33%
`Overall improvementà
`
`6 weeks
`
`6 weeks
`
`Complete remission*
`
`18%
`20%
`
`59%
`72%§
`
`8 weeks
`
`Remission
`
`pH-Dependent mesalazine
`Schroeder et al.
`
`1 g ⁄ day (92)
`2 g ⁄ day (97)
`4 g ⁄ day (95)
`Placebo (90)
`
`1.6 g day (11)
`⁄
`4.8 g day (38)
`⁄
`Placebo (38)
`
`Hanauer et al.
`(Mild UC)
`
`Hanauer et al.
`(Moderate UC)
`
`Multimatrix mesalazine
`D’Haens et al.
`
`1.6 g day (44)
`⁄
`2.4 g day (43)
`⁄
`Placebo (44)
`
`2.4 g day (52)
`⁄
`4.8 g day (58)
`⁄
`
`2.4 g day (130)
`⁄
`4.8 g day (124)
`⁄
`
`1.2 g day (13)
`⁄
`2.4 g day (14)
`⁄
`4.8 g day (11)
`⁄
`
`Kamm et al.
`
`8 weeks
`
`2.4 g day (84)
`⁄
`4.8 g day (85)
`⁄
`Placebo (86)
`
`Lichtenstein et al.
`
`8 weeks
`
`Olsalazine
`Meyers et al.
`
`2.4 g day (88)
`⁄
`4.8 g day (89)
`⁄
`Placebo (85)
`
`0.75 g day (14)
`⁄
`1.5 g day (15)
`⁄
`3.0 g day (14)
`⁄
`Placebo (19)
`
`0%
`31%
`18%
`Remission
`
`40%
`àà
`41%
`àà
`22%
`Remission
`
`34%**
`29%**
`13%
`
`Clinical improvement
`
`61%§§
`65%§§
`40%
`Clinical improvement
`
`
`
`
`56%
`60%
`26%
`
`21 days
`
`Clinical improvement
`
`29%
`27%
`50%
`16%
`
`ª 2007 The Authors,
`Journal compilation
`
`Aliment Pharmacol Ther 26,
`1179–1186
`2007 Blackwell Publishing Ltd
`ª
`
`https://www.researchgate.net/publication/5900396_Review_article_Increasing_the_dose_o...
`
`8/25/2016
`
`GeneriCo, Flat Line Capital
`Exhibit 1054 Page 5
`
`

`
`Review article: Increasing the dose of oral mesalazine therapy for active ulcerative colitis ...
`
`Page 6 of 11
`
`R E V I E W : E F F I C A C Y O F D O S E E S C A L A T I O N F O R U L C E R A T I V E C O L I T I S 1183
`
`Table 1. continued
`
`Study
`
`
`
`Treatment dosage ( )n
`
`Treatment duration
`
`Endpoints and results
`
`Balsalazide
`Levine et al.
`
`8 weeks
`
`Remission
`
`Improvement in PGA
`
`2.25 g day (35)
`⁄
`6.75 g day (35)
`⁄
`Mesalazine 2.4 g day (36)
`⁄
`
`20%
`23%
`19%
`
`51%
`74%***
`62%
`
`PGA, physician’s global assessment.
`< 0.05 vs. placebo; Defined as an improvement in PGA score and in at least
`* Defined as complete symptom resolution;
` P
`à
`one other component score, with no score increased in severity; §
`= 0.036; Defined as 3-point decrease from baseline in
`P
`‡
`UC-Disease Activity Index score; **
`
`0.009 vs placebo;.
`
`< 0.001 vs placebo;.
`0.010 vs. placebo; §§
`0.006
`P £
` P
`àà P £
`P £
`vs. placebo.;
`Positive dose-response relationship,
`= 0.04; ***
`= 0.03 vs. 2.25 g day.
`P
`P
`⁄
`
`A study of 341 patients with mildly to moderately
`active UC reported that remission (defined as modified
`UC-DAI score of 1, with scores of 0 for rectal bleed-
`£
`ing and stool frequency and at least a 1-point reduc-
`tion from baseline in sigmoidoscopy score) after
`8 weeks was achieved by 40% and 41% of patients
`who received multimatrix mesalazine 2.4 g day and
`⁄
`4.8 g day, respectively, and by 33% of patients who
`⁄
`received pH-dependent delayed-release mesalazine
`In this study, 22% of patients
`(Asacol) 2.4 g day.
`⁄
`who received placebo achieved remission. Clinical
`improvement (defined as a decrease of at least 3 points
`from baseline in modified UC-DAI score) was attained
`by 61% and 65% of patients who received the 2.4-
`g day and 4.8-g day doses, respectively, compared
`⁄
`⁄
`with 56% of patients who received pH-dependent
`delayed-release mesalazine. Clinical improvement was
`achieved by 40% of patients who received placebo.
`For both remission and improvement, both multima-
`trix mesalazine doses were significantly more effective
`than placebo (
`0.01), but differences between the
`P £
`two doses were not clinically or statistically significant
`
`( -values not reported).P
`In a separate study of 262 patients with mildly to
`moderately active UC, remission (defined as a modified
`UC-DAI score of 1, with scores of 0 for rectal bleed-
`£
`ing and stoo l frequency, no mucosal friability, and at
`least a 1-point reduction from baseline in sigmoidos-
`copy score) after 8 weeks was achieved by 34% and
`29% of patients who received multimatrix mesalazine
`
`2.4 g day and 4.8 g day ( = 0.485),P
`respectively,
`⁄
`⁄
`compared with 13% of patients who received pla-
`Clinical improvement (defined as a decrease of
`cebo.
`
`ª 2007 The Authors,
`Journal compilation
`
`Aliment Pharmacol Ther 26,
`1179–1186
`2007 Blackwell Publishing Ltd
`ª
`
`at least 3 points from baseline in modified UC-DAI
`score) was attained by 56% and 60% of patients who
`
`received the 2.4-g day and 4.8-g day doses ( -valueP
`⁄
`⁄
`not
`reported),
`respectively, compared with 26% of
`patients in the placebo group. Similar to the previous
`study, for both remission and improvement, both mul-
`timatrix mesalazine doses were superior to placebo
`(
`0.009), but differences between the two doses
`P £
`were not clinically or statistically significant.
`
`Azo-bonded 5-ASA prodrugs
`
`Azo-bonded prodrugs rely on bacterial activity in the
`colon to enzymatically release 5-ASA at the site of
`inflammation. Azo-bonded sulfasalazine is an effective
`first-line treatment
`for mild-to-moderate UC,
`but
`dose-related adverse events affect up to 50% of
`patients and substantially limit
`its clinical useful-
`In response to the poor tol erability of sul-
`ness.
`fasalazine,
`the
`non-sulfa
`azo-bonded
`prodrugs
`olsalazine and balsalazide have been developed and
`evaluated in clinical trials (Table 1).
`A dose-ranging study of olsalazine in 62 patients with
`active UC intolerant of sulfasalazine reported that
`improvement (defined as reduction in global clinical
`colitis activity and or reduction in overall sigmoido-
`⁄
`scopic score from baseline) after 21 days was achieved
`by 29%, 27%, and 50% of patients who received olsala-
`zine 0.75 g day, 1.5 g day, and 3.0 g day, respectively,
`⁄
`⁄
`⁄
`compared with 16% of patie nts who received placebo.
`A positive dose-response relationship with regard to
`improvement rates was established among the three
`olsalazine doses, but remission rates were not reported.
`
`https://www.researchgate.net/publication/5900396_Review_article_Increasing_the_dose_o...
`
`8/25/2016
`
`GeneriCo, Flat Line Capital
`Exhibit 1054 Page 6
`
`

`
`Review article: Increasing the dose of oral mesalazine therapy for active ulcerative colitis ...
`
`Page 7 of 11
`
`1184 A . V . S A F D I A N D R . D . C O H E N
`
`In a clinical trial comparing the efficacy of two
`doses of azo-bonded balsalazide with pH-dependent
`delayed-release m esalazine in 106 patien ts with mildly
`to moderately active UC, remission (defined as normal
`stool frequency, no blood in the stool, PGA score of
`‘quiescent,’ and sigmoidoscopy score of mild or nor-
`mal) after 8 wee ks was reported in 20% and 23% of
`patients who received balsalazide 2.25 g day and
`⁄
`
`6.75 g day ( = 0.771), respectively, compared withP
`⁄
`19% of patients who received pH-dependent mesal-
`(It should be noted that 6.75 g of
`azine 2.4 g day.
`⁄
`balsalazide contains 2.4 g of active 5-ASA and is thus
`an equimolar dose with regard to the mesalazine com-
`parator arm.) The 6.75-g day balsalazide dose was
`⁄
`superior
`to the 2.25-g day balsalazide dose
`in
`⁄
`improvement of individual UC symptoms after 8 weeks
`(
`0.030), including rectal bleeding, stool frequency,
`P £
`sigmoidoscopy score, and PGA.
`
`D IS CUSS ION
`
`Oral 5- ASA formulations are effective for inducing
`and maintaining remission in patie nts with UC, but
`clinical studies have shown no clear or consistent
`benefit of increases above the standard re commended
`dose of 2.4 g day (or the appropriate equimolar dose
`⁄
`of a prodrug formulation) for induction of remission.
`Significant dose-related increase s
`in efficacy were
`reported when improvement or partial response was
`but not when more
`used as an endpoint,
`rigorous definitions of remission were applied. This
`lack of a clear dose-response relationship across all
`agents may reflect an upper limit to effective 5-ASA
`doses,
`above which little
`therapeutic benefit
`is
`observed. Alternatively, this may reflect the ‘satura-
`tion’ of a drug delivery system, when doses above a
`certain level are no longer delivered efficiently to
`the colon.
`Although the higher doses of oral mesalazine were
`well tolerated in these studies, it is, ho wever, impor-
`tant to note that higher mesalazine doses are associ-
`ated with increased systemic absorption of 5-ASA.
`In comparative studies of mesalazine agents, 5-ASA
`plasma levels after administration of pH-dependent,
`delayed-release mesalazine were observed to be 4.5
`times higher than those observed after administration
`of
`equimolar
`doses
`of
`azo-bonded
`bals alazide
`(740 ng mL vs. 160 ng mL, respectively;
`= 0.018).
`P
`⁄
`⁄
`Mesalazine agents are generally safe and associated
`with broad therapeutic windows, but higher systemi c
`
`levels of 5-ASA increase the risk of systemic adverse
`events, such as renal disease.
`The most desirable treatment for UC is one that pro-
`duces consistent efficacy rates by maximizing 5-ASA
`levels in the colonic mucosa and minimizing systemic
`absorption. When more 5-ASA is delivered intact to
`the colon, more active drug is available to control
`demonstrated
`colonic inflammation. Hussain et al.
`that
`increasing the dose of pH-dependent delayed-
`release mesalazine from 2.4 g day to 4.8 g day did
`⁄
`⁄
`not increase colonic mucosal concentrations of 5-AS A.
`More active drug reaches the colonic mucosa when it
`is delivered by an azo-bonded formulation than by a
`pH-dependent formulation. For example, 72% of the
`5-ASA in pH-dependent delayed-release mesalazine
`reaches the colon intact, while 99% of 5-ASA in the
`azo-bonded prodrug balsalazide is delivered to the
`Additionally, azo-bonded balsalazide
`colon intact.
`has been shown to achieve 96% greater colonic muco-
`sal
`concentrations of 5-ASA than pH-dependent
`delayed-release mesalazine.
`Furthermore, pH-dependent mesalazine may not
`release the full dose of 5-ASA when it reaches the
`and GI
`colon. Variable tablet dissolution rates
`have been demonstrated. Nota-
`tract pH levels
`bly, a study of 39 healthy volunteers reported that
`pH levels did not reach 7 in any section of the GI
`tract in 25% of participants.
`In addition, pH levels
`among patients with UC may be lower than those
`observed in healthy individuals, and a small study
`of six patients with UC found that colonic pH levels
`tended to be lowest
`in individuals with the most
`Other
`small
`studies documented
`active disease.
`wide variations in colonic pH levels in patients with
`; this variance suggests that if a sufficiently
`UC
`high pH level
`is not achieved in the colon, pH-
`dependent delayed-release mesalazine
`tablets may
`dissolve incomplete ly and fail
`to release the full
`dose of 5-ASA at the site of inflammation. In fact,
`whole
`and
`partial
`pH-dependent
`delayed-release
`mesalazine tablets have been detected in the stools
`and of healthy volunteers par-
`of patients with UC
`ticipating in a clinical trial.
`A pH-dependent delivery mechanism may be ineffi-
`cient in the treatment of UC, for reasons that include
`the degree of systemic absorption of 5-ASA associated
`with pH-dependent mesalazine and the evidence sug-
`gesting incomplete tablet dissolution in healthy indi-
`viduals and patients with UC. Azo-bonded 5-ASA
`prodrugs, which deliver virtually all of the 5-ASA dose
`
`ª 2007 The Authors,
`Journal compilation
`
`Aliment Pharmacol Ther 26,
`1179–1186
`2007 Blackwell Publishing Ltd
`ª
`
`https://www.researchgate.net/publication/5900396_Review_article_Increasing_the_dose_o...
`
`8/25/2016
`
`GeneriCo, Flat Line Capital
`Exhibit 1054 Page 7
`
`

`
`Review article: Increasing the dose of oral mesalazine therapy for active ulcerative colitis ...
`
`Page 8 of 11
`
`R E V I E W : E F F I C A C Y O F D O S E E S C A L A T I O N F O R U L C E R A T I V E C O L I T I S 1185
`
`directly to the site of colonic inflammation, are an
`alternative to using higher doses of pH-dependent
`mesalazine formulations
`in patie nts who do not
`respond to initial therapy. In fact, a preliminary open-
`label study demonstrated that among 59 patie nts with
`UC who failed to achieve clinical remission by week 8
`of
`treatment with
`pH-dependent
`delayed-release
`mesalazine 2.4 g day, 61% of patients achieved remis-
`⁄
`sion after being switched to azo-bonded balsalazide
`6.75 g day
`(an equimolar mesalazine
`dose)
`for
`⁄
`Because no oral 5-ASA formulation clearly
`8 weeks.
`demonstrates a significant dose response regarding
`
`induction of UC remission, patients who do not
`respond to initial 5-ASA treatment may not bene-
`fit
`from simply increasing the dose of
`the initial
`formulation.
`
`ACKNOWLEDGEMENTS
`
`Declaration of personal interests: Dr. Cohen and Dr.
`Safdi have served as speakers and consultants for
`Salix.
`: Supportfunding interests
`
`for
`Declaration of
`preparation of the manuscript was provided by Salix
`Pharmaceuticals, Inc.
`
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