Review article: evolutionary advances in the delivery of
`aminosalicylates for the treatment of ulcerative colitis
`R. D. COHEN
`
`Clinical Inflammatory Bowel Disease,
`The University of Chicago, Chicago,
`IL, USA
`
`Correspondence to:
`Dr R. D. Cohen, Clinical Inflammatory
`Bowel Disease, The University of
`Chicago, 5841 S. Maryland Avenue.
`MC 4076, Chicago, II. 60637, USA.
`E-mail:
`rcoheneniedicine.bsd.uchicago.edu
`
`Publication data
`Submitted 28 April 2006
`Accepted 25 May 2006
`
`SUMMARY
`
`Ulcerative colitis is a chronic and debilitating disease that involves
`inflammation of the colonic mucosa. Current therapies aim to reduce
`the symptom burden of ulcerative colitis and maintain disease quies-
`cence. The standard first-line treatment for mild-to-moderate ulcerative
`colitis is 5-aminosalicylate therapy, which is available in oral and rectal
`(topical) formulations.
`
`While current 5-aminosalicylate formulations are effective in the
`majority of patients, they are associated with a number of limitations
`including inconvenient dosing regimens and poor patient acceptability,
`which may lead to non-compliance with prescribed therapy. A variety
`of improved delivery mechanisms have been developed in an effort to
`overcome these limitations. Micropellet formulations and high-dose tab-
`lets appear to offer comparable efficacy and tolerability to conventional
`formulations, although any benefit in terms of long-term patient com-
`pliance remains to be proven. Novel methods of delivery, such as those
`using a combination of hydrophilic and lipophilic matrices, designed to
`provide once-daily dosing in a high-strength tablet, may offer a signifi-
`cant improvement in the therapy of active and quiescent ulcerative
`colitis.
`
`This review examines the limitations of current 5-aminosalicylate for-
`mulations and reports on the evolution of novel oral formulations
`designed to overcome these limitations, maximize patient compliance
`during both induction and maintenance of quiescence, and optimize
`overall clinical outcomes.
`
`Aliment Pharmacol Ther 24, 465-474
`
`© 2006 The Author
`Journal compilation © 2006 Blackwell Publishing Ltd
`doi:10.111141365-2036.2006.03010.x
`
`465
`
`SALIXN00012280
`
`Dr. Falk Ex. 2019
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 1
`
`

`
`466 R. D. COHEN
`
`INTRODUCTION
`
`Ulcerative colitis (UC) is a chronic and debilitating dis-
`ease that involves inflammation of the colonic
`mucosa. The disease can affect individuals of any age
`but is most commonly diagnosed in patients aged
`between 15 and 30 years. In the Western world, the
`number of new cases of UC diagnosed each year (inci-
`dence rate) has been estimated to be about seven per
`100 000,1' 2 with over 200 people per 100 000 living
`with UC at any given time.2 UC typically follows a
`relapsing-remitting course and is characterized by the
`symptoms of abdominal pain and bloody diarrhoea.
`Patients also often experience fatigue, weight loss, rec-
`tal bleeding and loss of appetite as well as extracolon-
`ic symptoms including arthritis, inflammation of the
`eye, liver and binary disease, osteoporosis, skin rashes
`and anaemia, all of which considerably diminish qual-
`ity of life (QoL), particularly during the active phase of
`the disease.
`The pathological cause of UC remains unclear. An
`inappropriate and excessive response to dietary trig-
`gers, unidentified infectious agents or the normal colo-
`nic bacterial population:3' 4 by an inadequately
`regulated mucosal immune system are thought to play
`a major pathophysiological role in the chronic inflam-
`mation and manifestation of symptoms of UC.5 In
`addition, there is some indication of a possible genetic
`predisposition to the development of UC.
`Any part of the colon can be affected by UC,
`although left-sided disease is most common. Patients
`with UC almost always have rectal involvement. In as
`many as 55% of patients the disease is limited to this
`region at presentation, defined diagnostically as proc-
`titis.' Approximately 30% of patients present with UC
`extending proximally to the splenic flexure or 60 cm
`from the anal verge, defined as left-sided or distal
`colitis. Only about 15% of patients present with dis-
`ease extending beyond the splenic flexure, which is
`defined as extensive colitis.' However, subsequent
`proximal extension occurs in approximately 35% of
`patients with initial proctitis or left-sided colitis.6
`Current treatments are aimed at reducing the symp-
`tom burden of UC and maintaining disease quiescence.
`The aminosalicylates are, at present, the treatment of
`choice for first-line therapy of mild-to-moderate dis-
`ease, with demonstrated efficacy and safety in patients
`with UC.7' 8 Their action is thought to be predomin-
`antly topical at the site of inflammation within t:he
`colon. The clinical aim, therefore, is to maximize
`
`delivery of t:he active drug, 5-aminosalicylate [5-ASA;
`mesalazine (mesalamine)], to the affected regions
`of the colonic mucosa while minimizing systemic
`absorption.
`The importance of long-term patient compliance
`with 5-ASA therapy in maintaining symptom quies-
`cence has gained increasing recognition in recent
`years. A further benefit of long-term compliance is
`suggested by a number of observational studies that
`have suggested that regular use of 5-ASA is associated
`with an approximate twofold reduction in the risk of
`colorectal cancer development in patients with UC.9' 10
`This is of particular relevance in this disease, as a
`meta-analysis of published studies showed that the
`30-year risk of developing colorectal cancer is 18% in
`patients with UC.1'
`5-Aminosalicylate is available in a number of oral
`and rectal (topical) formulations including tablets,
`micropellets (granules), suppositories and enemas. Sev-
`eral oral formulations have been developed. Sulphasal-
`azine, consisting of a sulphapyridine molecule bonded
`to a 5-ASA molecule, was the first formulation of
`5-ASA shown to be therapeutically effective for the
`treatment of UC. This formulation largely resists gas-
`tric breakdown and systemic absorption until it rea-
`ches the colon, where bacterial azoreductase enzymes
`cleave the bond between the sulphapyridine and
`5-ASA molecules. While sulphasalazine has been
`widely prescribed for the last four decades, due to its
`effectiveness and low cost, it is associated with a num-
`ber of dose-dependent adverse events (including head-
`ache, nausea, dyspepsia and allergy) related to the
`sulphur in the sulphapyridine moiety.12, 13
`A number of new oral 5-ASA formulations also util-
`ize colonic bacteria to release the active drug, but do
`not contain sulphapyridine. Olsalazine (Dipentum;
`Celltech Pharmaceuticals, Inc., Rochester, NY, USA)
`consists of two 5-ASA molecules linked together via
`an azo-bond, while balsalazide (Colazal; Salix Phar-
`maceuticals, Inc., Morrisville, NC, USA) comprises a
`5-ASA molecule azo-bonded to a benzoic acid deriv-
`ative. Other formulations, such as Asacol (Procter Et
`Gamble Pharmaceuticals, Cincinnati, OH, USA), do not
`bond 5-ASA to a carrier molecule, but instead utilize a
`gastro-resistant resin film (e.g. Eudragrit 5) that dis-
`solves at pH values exceeding 7 (equivalent to the pH
`found in the terminal ileum in some individuals) and
`thus are not broken down in the stomach or absorbed
`in the proximal small intestine. Pentasa (Shire US,
`Inc., Wayne, PA, USA) comprises microspheres that
`
`© 2006 The Author, Aliment Pharmocol Ther 24, 465-474
`Journal compilation © 2006 Blackwell Publishing Ltd
`
`SAUXN00012281
`
`Dr. Falk Ex. 2019
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 2
`
`

`
`REVIEW: EVOLUTIONARY ADVANCES IN 5-ASA FORMULATIONS FOR UC 467
`
`contain 5-ASA enclosed within an ethylcellulose semi-
`permeable membrane, which allows pH-independent
`release of the active drug. In contrast to the formula-
`tions described above, Pentasa releases 5-ASA from
`the duodenum to the rectum, and is often used 'off
`label' to treat Crohn's disease in addition to its indica-
`ted use in IJC. Indeed, both the American and British
`Gastroenterology Associations recommend the use of
`high-dose 5-ASA for the first-line treatment of mild
`ileal, ileocolonic or colonic Crohn's disease."' 15
`All the sulphur-free 5-ASA formulations have excel-
`lent and comparable safety profiles. Moreover, a recent
`meta-analysis found no significant difference between
`the current oral formulations in terms of systemic
`exposure.16 However, an almost 1000-fold variation in
`mucosal 5-ASA concentration between formulations
`was observed in a study assessing multiple biopsies
`taken at the same locations throughout patients' lower
`GI tracts, following cessation of 1-week therapy with
`different oral 5-ASA formulations." In a well-
`designed study, with standardized time since last dose
`and standardized biopsy location, mucosal 5-ASA con-
`centration was shown to be inversely correlated with
`endoscopic and histological scores.18 The reported
`large variation in mucosal 5-ASA concentration"
`may, therefore, be a factor in the different efficacies
`reported for the various oral formulations.
`The current delivery mechanisms for 5-ASA have a
`number of limitations. These have been found to
`impact considerably on patient compliance with ther-
`apy, particularly in the long-term periods of disease
`quiescence, and thus overall treatment success. This
`review examines these limitations and reports on the
`evolution of novel formulations designed to overcome
`these problems, maximize patient compliance with
`acute and maintenance therapy and optimize overall
`clinical outcomes.
`
`LIMITATIONS OF CURRENT 5-ASA DELIVERY
`SYSTEMS
`
`Inconvenient and intrusive dosing regimens
`
`The inconvenience of frequent daily dosing, together
`with the number of tablets/capsules required per day,
`have been identified as key factors in reducing patient
`compliance with therapy in UC.19'
`In an early study of compliance to sulphasalazine
`maintenance therapy among patients with inflamma-
`tory bowel disease, regular monitoring of serum sul-
`
`2006 The Author, Aliment Pharmacal Ther 24, 465-474
`Journal compilation © 2006 Blackwell Publishing Ltd
`
`phapyridine levels revealed that a substantial
`proportion of patients failed to take their prescribed
`dose.21 Among 51 outpatients who had been treated
`with sulphasalazine during a recent period of hospital-
`ization, and advised to continue to take a maintenance
`dose during a 6-month follow-up period on leaving
`hospital, serum sulphapyridine levels were consider-
`ably lower during the 6-month follow-up than on dis-
`charge for 21 (41%) patients. Moreover, in 21 of 175
`outpatients prescribed a maintenance dose of sulpha-
`salazine, sulphapyridine was not detected at all during
`a follow-up of up to 4 years.21 Interestingly, when
`questioned, most patients still claimed they took their
`medication as prescribed.
`The reasons for non-compliance with 5-ASA therapy
`are complex. Male gender, single status, full-time
`employment and three-times daily dosing have all
`been identified as independent predictors of non-com-
`pliance.2°' 22 Compliance may be particularly difficult
`to maintain during periods of symptomatic quiescence,
`when there are no symptomatic reminders of the
`underlying chronic disease. In one observational study
`of 94 patients with quiescent UC, 60% failed to adhere
`to their prescribed regimen, with an average consump-
`tion of just 70% of their prescribed dose (based on
`prescriptions filled over at least a 6-month period).22
`A more recent cross-sectional study used direct
`enquiry and monitoring of 5-ASA levels in urine sam-
`ples to assess compliance of 98 outpatients to the
`prescribed maintenance dose of mesalazine. The study
`showed that 43% of patients took <80% of their
`prescribed dose.2° Among a cohort of patients with
`quiescent UC who were asked why they did not take
`their medication as prescribed, 35 (50%) of the
`70 patients who responded said they 'just forgot';
`notably, 21 (30%) said that there were too many pills
`and 14 (20%) did not believe they needed that much
`medicatio n.19
`Rectal formulations of 5-ASA have proven effective
`for patients with distal colitis.23 These formulations
`deliver therapeutic mesalazine concentrations to the
`terminal regions of the colon, which are not ade-
`quately dosed using current oral formulations.24 How-
`ever, such delivery methods are associated with
`leakage as well as problems with retention, burning
`sensation and bloating.25, 26 Rectal formulations
`require patients to retain the formulation for as long
`as possible, which may be difficult during times when
`they are suffering from diarrhoea. Also, rectal formu-
`lations may be particularly intrusive for young adults
`
`SALIXN00012282
`
`Dr. Falk Ex. 2019
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 3
`
`

`
`468 R. D. COHEN
`
`at a time when they are most likely to be establishing
`personal and intimate relationships.
`The inconvenience of current 5-ASA formulations
`and the impact of frequent daily dosing on normal
`activities is likely to play a pivotal role in non-compli-
`ance with prescribed treatment regimens and thereby
`reduce the overall clinical effectiveness of the therapy.
`
`Inadequate treatment of UC
`
`Most patients with UC will experience at least one
`symptomatic relapse following their initial diagnostic
`episode. In a 10-year follow-up of 95 patients receiv-
`ing oral or rectal 5-ASA therapy for a variety of sub-
`types of UC, all patients experienced at least one
`symptomatic relapse following initial diagnosis.27
`Patients with pancolitis and left-sided colitis relapsed
`most quickly, within 2-3 years of diagnosis, while
`those with proctosigmoiditis or proctitis relapsed
`within 9-10 years of diagnosis.27
`While non-compliance with prescribed treatment
`regimen may contribute to symptomatic relapse in a
`proportion of patients, even those who do adhere to
`treatment remain at risk of their disease returning.
`Compliance with 5-ASA medication was monitored for
`up to 2 years in a prospective study of 99 patients
`with quiescent UC.19 Among 40 patients who refilled
`>80% of prescriptions and were thus considered com-
`pliant with therapy, eight (20%) reported a recurrence
`of symptoms.19 These results suggest that patients
`remain at risk despite compliance with treatment.
`
`The impact of non-compliance
`
`Non-compliance with prescribed medication regimens
`is known to affect long-term treatment outcomes28 by
`reducing the efficacy of treatment and, for many
`patients, resulting in a flare-up of the disease and sub-
`sequently reduced QoL. In the University of Chicago's
`study of patients with quiescent UC, compliant patients
`were more likely to remain in remission than non-
`compliant patients (89% vs. 39%; P < 0.001).19 Those
`patients who did not adhere to their prescribed regi-
`men had a fivefold greater risk of recurrence than did
`compliant patients.
`Several studies have shown that the QoL of patients
`with UC is related to the severity of symptoms.29-33
`Patients experiencing a disease flare reported signifi-
`cantly poorer overall QoL than those in symptomatic
`remission.29' 3° Among 160 UC patients with active
`
`disease, all aspects of QoL [as measured by the Inflam-
`matory Bowel Disease Questionnaire (IBDQ)) were sig-
`nificantly lower than for those in symptomatic
`remission." A further, large-scale, multicentre study
`involving 528 patients with UC found that patients
`with active disease of any severity experienced impair-
`ment in their QoL across all domains of the IBDQ and
`that patients with moderate-to-severe disease reported
`the greatest impairment across all domains.29
`A recent cross-sectional study investigated predic-
`tors of disease-specific QoL in patients with UC (n =
`111)?1 All patients completed the IBDQ, the Medical
`Outcomes Study 36-Item Short-Form Health Survey
`(SF-36) and the Illness Perception Questionnaire (IPQ).
`Multivariate regression modelling showed that disease
`activity was the major explanatory variable for each
`of the four IBDQ domains (bowel, systemic, emotional
`and social domains) and for the total IBDQ score. In
`addition, bivariate analyses showed that symptom-
`related disease activity, elements of illness representa-
`tion measured by the IPQ and elements of physical
`and mental health measured by the SF-36 were
`strongly or moderately correlated with disease-specific
`QoL.
`Given that the symptoms of UC are strongly correla-
`ted with health-related QoL, improving compliance
`and thus decreasing the risk of disease flare may be an
`effective strategy to improve QoL.
`
`Optimizing oral 5-ASA delivery to the colon
`
`The limitations of current oral and rectal formulations
`have driven the evolution of 5-ASA therapeutics to
`ensure patient compliance as well as improve delivery
`of active drug to all affected areas of the colon. Recent
`developments include high-dose tablet formulations
`with the hope of improved efficacy, once-daily regi-
`mens of existing formulations in an attempt to sim-
`plify dosing and improve compliance, and novel
`formulations offering more convenient dosing in
`addition to improved drug delivery to the whole
`colon. These new developments are summarized in
`Table 134-4° and discussed in detail below.
`
`Increased dose per tablet and increased daily
`dose
`
`The efficacy of increasing the dose of 5-ASA per tab-
`let, in combination with increasing the dose per day,
`was evaluated in two phase III, randomized, double-
`
`© 2006 The Author, Aliment Pharmocol Ther 24, 465-474
`Journal compilation © 2006 Blackwell Publishing Ltd
`
`SALIXN00012283
`
`Dr. Falk Ex. 2019
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 4
`
`

`
`REVIEW: EVOLUTIONARY ADVANCES IN 5-ASA FORMULATIONS FOR UC 469
`
`Table 1. New developments in 5-aminosalicylate delivery mechanisms for the management of ulcerative colitis
`Formulation (cid:9)
`Key clinical data (cid:9)
`
`References
`
`Mesalazine 800 mg tablets
`(pH-dependent release)
`
`Micropellets
`
`MMX mesalazine (combined
`hydrophilic and
`lipophilic matrices)
`
`Superior overall treatment success with 2 x 800 mg tablets three times
`daily (t.d.s.) vs. 2 x 400 mg tablets t.d.s. for moderate ulcerative colitis;
`no difference between treatment groups for mild disease
`Non-inferiority in terms of clinical remission compared with conventional
`tablet formulation; patients expressed a preference for less frequent
`dosing with micropellet formulation
`2.4 and 4.8 g/day (administered once or twice daily) effective in terms
`of clinical and endoscopic remission with a trend towards better
`sigmoidoscopic improvement at higher dose (4.8 g/day)
`
`Hanauer et al.'"
`
`Raedler et 0.36
`Farup et a1.37
`
`Kamm et al."
`Lichtenstein et al.39
`Prantera et al.'
`
`blind, controlled trials. In the. ASCEND I (n = 268) and
`ASCEND II (n = 286) studies,35 patients were random-
`ized to receive either mesalazine 800 mg tablets
`(2 x 800 mg three times daily [4.8 g/day]), which util-
`ize the same delivery system as the marketed 400 mg
`Asacol tablet, or 400 mg Asacol tablets [2 x 400 mg
`three t:imes daily (2.4 g/day)]. The primary efficacy
`endpoint of both t:rials was 'treatment success', defined
`as either complete remission or an improvement in
`both PGA score and at: least one other clinical param-
`eter, with no worsening in any other clinical param-
`eter compared to baseline.
`In the ASCEND I trial, the primary efficacy analysis
`included patients with mild-to-moderate disease. There
`was no difference between the two doses in terms of
`treatment success (51.3% vs. 55.9% for 2.4 and 4.8
`g/day respectively; P - 0.441) at week 6.35 However,
`a prespecified subgroup analysis of treatment: success
`in patients with moderate disease (n (cid:9)
` 169) revealed a
`difference between the two doses in favour of the
`higher dose (72.4% vs. 57.0% for the 4.8 and 2.4
`g/day dose groups respectively; P = 0.0384)25
`
`In light of these results, the. ASCEND II protocol was
`amended to restrict entry criteria to patients with
`moderat:ely active disease (while the study was still
`blinded and enrolling patients). The authors of the
`ASCEND II t:rial reported that the 4.8 g/day dose was
`superior to the 2.4 g/day dose for t:reat:ment success
`(71.8% vs. 59.2%; P - 0.036) and for time to achieve
`resolution of rectal bleeding (9 days vs. 16 days; P -
`O.0352).35 However, no significant improvements were
`observed for the 4.8 g/day dose over the 2.4 g/day
`dose for any of the other secondary endpoints in the
`study (including proportions of patients with improve-
`ments in st:ool frequency, rectal bleeding, PGA score
`and sigmoidoscopy score).35
`An analysis of combined data from these two trials
`(n - 423) showed that the 4.8 g/day dose provided
`benefits over the 2.4 g/day dose in terms of treatment
`success, improvement in PGA score and sigmoidoscop-
`ic improvement among patients with moderate disease
`(Figure 1)34. However, no additional benefit was seen
`with the 4.8 g/day dose over the 2.4 g/day dose for
`the proportion of patients who achieved remission, or
`
`nAsacol 2.4 g dart t.d.s. (n.223) n Mesalazlne 800 mg tablets 4.8 g dart t.d.s. (n.200)
`
`Figure 1. Treatment success
`rates for the ASCEND I and
`ASCEND II trials (combined
`data) after 6 weeks of treat-
`ment with high-dose Asacol
`tablets [2 x 800 mg t.d.s.
`(4.8 giday)] or conventional
`Asacol tablets (2 x 400 mg
`t.d.s. (2.4 giday)].35 t.d.s., three
`times daily; PGA, Physician's
`Global Assessment; PFA,
`patient functional assessment.
`
`2006 The Author, Aliment Pharmacal Ther 24, 465-474
`Journal compilation © 2006 Blackwell Publishing Ltd
`
`PFA (cid:9)
`Stool frequency Rectal bleeding (cid:9)
`PGA (cid:9)
`Overall
`SIgmoldoscoplc
`treatment Improvement Improvement Improvement Improvement Improvement
`success
`
`• P < 0.05
`
`SALIXN00012284
`
`Dr. Falk Ex. 2019
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 5
`
`(cid:9)
`

`
`470 R. D. COHEN
`
`an improvement in stool frequency, rectal bleeding or
`patient's functioning score (Figure 1).34 No additional
`benefit over 2.4 g/day dose was seen with the 4.8 g/
`day dose in patients with mild disease or mild-to-
`moderate disease in either t:rial. 34'35
`
`Once-daily dosing
`
`Existing formulations
`
`The short-term outcomes of once-daily mesalazine
`(Asacol) vs. conventional dosing (twice or three times
`daily) in maintaining quiescent UC were assessed in a
`pilot feasibility study of 22 patients.41 Patients contin-
`ued to take their prescribed daily dose, but those
`assigned to the once-daily group took a sufficient
`number of tablets to reach this daily dose once a day
`instead of divided doses. After 3 months, all 12
`patients assigned to the once-daily regimen remained
`compliant compared with only seven of the 10
`patients who continued with their conventional dosing
`regimen (P = 0.04; between-group comparison). At
`the 6-month follow-up, the compliance rates for the
`two groups were similar and one patient in each dos-
`ing group had experienced a symptomatic relapse; nei-
`ther of these patients was compliant to the assigned
`regimen.41 Although the conclusions that can be
`drawn from such a small-scale study are limited, these
`results do not indicate any long-term benefit, in terms
`of relapse prevention, from once-daily dosing with
`current oral formulations.
`
`A novel formulation
`
`MMX mesalazine (SPD476, Shire Pharmaceuticals Inc.,
`Wayne, PA, USA) is a once-daily, high-strength (1.2 g
`
`5-ASA/tablet) formulation that combines a pH-
`dependent, gastro-resistant film, to delay initial release
`of the active drug until the terminal ileum, with a ser-
`ies of hydrophilic and lipophilic matrices, designed to
`extend consistent delivery of 5-ASA throughout the
`entire colon.40
`Initial results from two large-scale, double-blind,
`randomized, placebo-controlled phase Ill clinical trials
`have shown MMX mesalazine to be efficacious for
`the induction of remission, sigmoidoscopic improve-
`ment and improvement of symptoms in patients with
`mild-to-moderate UC following 8 weeks once- or
`twice-daily dosing of 2.4 g/day or once-daily dosing
`of 4.8 g/day MMX mesalazine.38' 39 The primary end-
`point for both studies was remission, defined as a
`UC-Disease Activity Index (UC-DAI) score of (cid:9)
`rec-
`tal bleeding and stool frequency scores of 0, and a
`1-point reduction in sigmoidoscopy score from
`baseline.
`In the first study (n - 280), patients received either
`MMX mesalazine 2.4 g/day (1.2 g given twice daily),
`MMX mesalazine 4.8 g/day once daily, or placebo. A
`greater proportion of patients in both MMX mesala-
`zine groups (2.4 and 4.8 g/day) achieved remission
`(34.1% and 29.2% vs. 12.90; P (cid:9)
`0.01), clinical
`improvement (55.7% and 59.6% vs. 25.9%;
`0.001), clinical remission (complete resolution of
`P (cid:9)
`symptoms; 37.5% and 32.6% vs. 18.8%; P
`0.05)
`and improved sigmoidoscopy score (64.8% and 71.9%
`vs. 36.5%; P
`0.01) compared with placebo (Fig-
`ure 2).39 Both the 2.4 g/day and 4.8 g/day dose of
`MMX mesalazine also led to a reduced proportion of
`patients deemed treatment failures (unchanged, wor-
`sened or missing UC-DAI score from baseline) com-
`pared with placebo (28.4% and 24.7% vs. 54.1%;
`0.001).
`P
`
`MMX mesaiazine 2.4 g day' b.d. L MMX mesaiazine 4.8 g day' q.d.s. = Placebo
`
`Remission
`
`Clinical Improvement
`
`Clinical remission
`
`Sigmoidoscopic
`improvement
`
`•P50.001 vs. placebo; -P50.01 vs. placebo; •••P50.05 vs. placebo
`
`Figure 2. Treatment outcomes
`after up to 8 weeks treatment
`with MMX mesalazine 2.4
`g/day (b.d.), MMX mesalazine
`4.8 giday (q.d.s.) or placebo.39
`b.d., twice daily; q.d.s., once
`daily.
`
`© 2006 The Author, Aliment Phormocol Ther 24, 465-474
`Journal compilation © 2006 Blackwell Publishing Ltd
`
`SALIXN00012285
`
`Dr. Falk Ex. 2019
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 6
`
`(cid:9)
`(cid:9)
`(cid:9)
`

`
`REVIEW: EVOLUTIONARY ADVANCES IN 5-ASA FORMULATIONS FOR UC 471
`
`In the second trial, 343 patients were randomized
`to treatment with MMX mesalazine 2.4 g/day or
`4.8 g/day given once daily, Asacol 2.4 g/day (0.8 g
`given three times daily) or placebo.38 Again, a signifi-
`cantly greater proportion of patients receiving either
`dosing regimen of MMX mesalazine achieved remis-
`sion or clinical remission compared with placebo (Fig-
`ure 3). The proportion of patients treated with Asacol
`who achieved either endpoint was not significantly
`superior to placebo. Both MMX mesalazine and Asacol
`produced clinical and sigmoidoscopic improvements
`compared with placebo (P < 0.033). Again, both the
`2.4 g/day and 4.8 g/day dose of MMX mesalazine led
`to a reduced proportion of patients deemed treatment
`failures, compared with placebo (21.4% and 20.0% vs.
`47.7%; P < 0.033).
`In both studies, patients who received MMX mesala-
`zine 4.8 g/day tended toward better sigmoidoscopic
`improvement compared with those who received
`2.4 g/day, consistent with the higher mucosal levels of
`5-ASA and its derivative, N-acetyl 5-ASA, seen with
`4.8 g/day over 2.4 g/day MMX mesalazine.42 The
`once-daily MMX mesalazine dosing schedule offers
`greater convenience and is thus likely to improve
`patient compliance to therapy.
`
`Micropellets
`
`Micropellet formulations of 5-ASA, provided as indi-
`vidual sachets containing granules, have also been
`studied with the aim of providing less frequent dosing
`in an easy-to-swallow formulation.36' 43' 44 Preclinical
`studies have employed pharmacoscintigraphy to ana-
`lyse the colonic availability of 5-ASA released from
`pellets vs. conventional tablets in healthy volunteers.
`
`In these studies, the drug was labelled with a radioact-
`ive tracer, which allows gastrointestinal transit, time
`and region of disintegration of the delivery system,
`and release of the active drug to be determined
`precisely.
`In one study of 14 healthy male volunteers, mesala-
`zine-containing pellets (500 mg) released 5-ASA in
`the same target region (the ileo-caecal region) and in
`a comparable timeframe to mesalazine tablets (Salo-
`falk, 500 mg; Dr Falk Pharma GmbH, Freiburg, Ger-
`many) under fasting conditions.43 Pharmacokinetic
`analyses showed that the plasma area-under-the-curve
`values were significantly lower for the micropellet for-
`mulation than for the tablet formulation, suggesting a
`more prolonged release of 5-ASA,43 although whether
`this equates to increased colonic exposure is unclear,
`as mucosal epithelial cell concentrations were not
`assessed. Similar results were obtained in a study
`comparing mesalazine-containing pellets (1.5 g per
`sachet) with enteric-coated mesalazine tablets (Cla-
`versal, three 500 mg tablets; Merckle GmbH, Ulm,
`Germany) in 24 healthy volunteers." Pharmacokinetic
`analyses revealed comparable systemic exposure fol-
`lowing administration of the two formulations and
`pharmacoscintigraphy showed that for both formula-
`tions active drug was released in the terminal ileum
`and ascending colon. In contrast to the study of Brun-
`ner et al.43 disintegration of the tablet formulations
`took place at a slightly later time point than for the
`micropellet formulation" although, again, it is unclear
`whether there was any relevant difference in the
`extent of colonic exposure as a result.
`The efficacy of mesalazine micropellets [1.5 g per
`sachet, taken twice daily (3 g/day)] and tablets
`(2 x 500 mg tablets, three times daily) in patients
`
`0 MMX mesalazine 2.4 g day-1 q.d.s.
`0 Placebo
`
`II MMX mesalazine 4.8 g dayA q.d.s.
`n Asacol 2.4 g day-1 Its.
`
`100
`
`80 •
`
`Figure 3. Treatment outcomes
`after up to 8 weeks treatment
`with MMX mesalazine 2.4
`giday (q.d.s.), MMX mesala-
`zinc 4.8 g/day (q.d.s.), Asacol
`2.4 g/day (800 mg t.d.s.) or
`placebo.38 q.d.s., once daily;
`t.d.s., three times daily.
`
`© 2006 The Author, Aliment Pharmacal Ther 24, 465-474
`Journal compilation © 2006 Blackwell Publishing Ltd
`
`Remission
`
`Clinical emission
`
`Clinical improvement (cid:9)
`
`*PS0.05 vs. placebo
`
`SIgmoldoscopic
`Improvement
`
`SALIXN00012286
`
`Dr. Falk Ex. 2019
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 7
`
`

`
`Mesalazlne 2 x 500mg tablets t.d.s. (3 g day : n= 178)
`n Mesalazine mlcropellets 1.5 g sachets b.d. (3 g day': n= 179)
`
`472 R. D. COHEN
`
`100 (cid:9)
`
`80
`
`20
`
`Clinical remission
`
`Endoscopic remission
`
`Figure 4. Clinical and endo-
`scopic remission rates among
`adult patients with mild-to-
`moderate ulcerative colitis
`treated with mesalazine tablets
`(2 x 500 mg td.s.) or micro-
`pellets (1.5-g sachet b.d.) for
`up to 8 weeks.36 b.d., twice
`daily; t.d.s., three times daily.
`
`with mild-to-moderate UC (n — 362) have been com-
`pared in a phase II, double-blind, active-controlled
`study.36 The study was designed to show non-inferi-
`ority of the micropellet formulation to tablets in
`terms of clinical remission within 8 weeks. Clinical
`remission was achieved by 67% of patients who
`received the micropellet formulation compared with
`62.9% of patients who received the tablet formula-
`tion (Figure 4), supporting the non-inferiority of the
`micropellet formulation (OR 1.199; 95% CI: 0.758-
`1.897). Compliance was excellent in both treatment
`arms - 96% among patients randomized to the
`micropellet formulation and 98% among those rand-
`omized to the tablet formulation, with similar pro-
`portions of patients rating therapy as 'very good' or
`'good' (74.4% in the micropellet group and 72.9% in
`the tablet group).
`The effects of mesalazine prolonged-release granules
`[one packet four times daily or two packets twice daily
`(4 g/day), Pentasa Sachet] were compared with pro-
`longed-release mesalazine tablets [2 x 500 mg four
`times daily (4 g/day), Pentasa] in 227 patients with
`mild-to-moderate UC.37 Once again, the study was
`designed to confirm the non-inferiority of the granule
`formulation compared with the tablet formulation.
`Both dose regimens of the granule formulation showed
`non-inferiority to mesalazine tablets for change in
`UC-DAI score.37 Both formulations were equally
`effective with comparable improvements in overall
`disease activity. Patient compliance was 97% in all
`three treatment arms although patients preferred
`twice-daily dosing with the granules to tablets taken
`four times daily.37 Whether this preference translates
`into improved longer-term compliance to therapy has
`not yet been reported.
`
`SUMMARY
`
`The current first-line therapy for patients with mild-
`to-moderate UC is 5-ASA therapy, which has been
`shown to be efficacious and well tolerated and is likely
`to remain the mainstay of therapy for this disease.
`Current delivery mechanisms include oral and rectal
`(topical) formulations which, while effective in the
`majority of patients, are associated with a numb