mesalamine with mmx™ technology for the treatment of ulcerative colitis

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Drug Profile 10.1586/17474124.2.3.299 © 2008 Expert Reviews Ltd ISSN 1747-4124 299 www.expert-reviews.com Mesalamine with MMX™ technology for the treatment of ulcerative colitis Expert Rev. Gastroenterol. Hepatol. 2(3), 299–314 (2008) Stefan Schreiber , Michael A Kamm and Gary R Lichtenstein Author for correspondence Institute for Clinical Molecular Biology, Center for Conservative Medicine, Schittenhelmstr. 12, 24105, Kiel, Germany Tel.: +49 431 597 2350 Fax: +49 431 597 1842 [email protected] Mesalamine with MMX Multi Matrix System ® technology (hereafter referred to as MMX mesalamine) is an oral, high-strength (1.2 g/tablet), once-daily formulation of 5-aminosalicylic acid used for the treatment of ulcerative colitis. This new formulation has been designed to provide delayed and prolonged 5-aminosalicylic acid release throughout the colon. In recent clinical studies, MMX mesalamine (taken as a once-daily dose of 2.4 or 4.8 g) effectively induced clinical remission and mucosal healing versus placebo in patients with active, mild-to- moderate ulcerative colitis. Once remission was achieved, MMX mesalamine effectively maintained disease remission in the majority of patients for at least 12 months. In this paper, we comprehensively review the results of studies exploring the clinical pharmacology, efficacy and safety of MMX mesalamine in patients with ulcerative colitis, and examine the implications of these findings on clinical practice. KEYWORDS: 5-aminosalicylic acid • adherence • induction • maintenance • mesalamine • mucosal healing • MMX Multi Matrix System • remission • ulcerative colitis Ulcerative colitis (UC) is a chronic, idio- pathic, inflammatory disease of the colon characterized by an unpredictable relaps- ing–remitting course [1], in which phases of active inflammation interchange with phases of almost symptom-free remission. Approxi- mately 50% of patients with UC have a relapse in any given year [2], which is why ade- quate maintenance therapy is of great impor- tance. However, some patients develop perma- nent symptoms without ever achieving a symptom-free interval. Typically, continuous inflammatory changes in the colonic mucosa begin just above the anal verge and spread proximally [3]. The inflammation, which in severe disease leads to ulceration and sponta- neous hemorrhage, can be confined to the rec- tum (proctitis) or extend beyond the splenic flexure throughout the colon (pancolitis) [4]. Proctitis, proctosigmoiditis and left-sided coli- tis are the most common presentations of UC, accounting for 60–80% of all new cases [4]. The signs and symptoms of UC are fairly het- erogeneous, and depend on the severity and location of the disease. Symptoms of UC can vary in their frequency and severity, however, they typically include bloody diarrhea, abdomi- nal cramps and left-lower abdominal pain, fecal urgency and weight loss [3]. Extraintestinal com- plications (e.g., arthropathy, cutaneous condi- tions, ocular inflammation, hepatic and renal disorders, and bone loss) are also not uncom- mon [101]. Long-standing UC, particularly if not subjected to maintenance treatment, is an important risk factor for the development of colonic adenocarcinoma [5]. This risk is particu- larly high if UC is associated with the presence of primary sclerosing cholangitis [5]. Current estimates suggest that the global incidence rate of UC ranges from 0.5 to 24.5 cases per 100,000 individuals [6]. While the highest incidence is reported in industrialized countries in North America, and Northern and Western Europe, recent studies indicate that the incidence has now started to plateau or decrease in many of these Westernized countries [6,7]. Conversely, in developing nations in Eastern Europe, South America, and Asia, where the rate of UC has been traditionally low, the inci- dence is rising progressively in line with indus- trial development and urbanization [6]. Little is known about the epidemiology of UC in

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Page 1: Mesalamine with MMX™ technology for the treatment of ulcerative colitis

Drug Profile

10.1586/17474124.2.3.299 © 2008 Expert Reviews Ltd ISSN 1747-4124 299www.expert-reviews.com

Mesalamine with MMX™ technology for the treatment of ulcerative colitisExpert Rev. Gastroenterol. Hepatol. 2(3), 299–314 (2008)

Stefan Schreiber†, Michael A Kamm and Gary R Lichtenstein†Author for correspondenceInstitute for Clinical Molecular Biology, Center for Conservative Medicine, Schittenhelmstr. 12, 24105, Kiel, GermanyTel.: +49 431 597 2350Fax: +49 431 597 [email protected]

Mesalamine with MMX Multi Matrix System® technology (hereafter referred to as MMXmesalamine) is an oral, high-strength (1.2 g/tablet), once-daily formulation of 5-aminosalicylicacid used for the treatment of ulcerative colitis. This new formulation has been designed toprovide delayed and prolonged 5-aminosalicylic acid release throughout the colon. In recentclinical studies, MMX mesalamine (taken as a once-daily dose of 2.4 or 4.8 g) effectivelyinduced clinical remission and mucosal healing versus placebo in patients with active, mild-to-moderate ulcerative colitis. Once remission was achieved, MMX mesalamine effectivelymaintained disease remission in the majority of patients for at least 12 months. In this paper,we comprehensively review the results of studies exploring the clinical pharmacology, efficacyand safety of MMX mesalamine in patients with ulcerative colitis, and examine theimplications of these findings on clinical practice.

KEYWORDS: 5-aminosalicylic acid • adherence • induction • maintenance • mesalamine • mucosal healing • MMX Multi Matrix System • remission • ulcerative colitis

Ulcerative colitis (UC) is a chronic, idio-pathic, inflammatory disease of the coloncharacterized by an unpredictable relaps-ing–remitting course [1], in which phases ofactive inflammation interchange with phasesof almost symptom-free remission. Approxi-mately 50% of patients with UC have arelapse in any given year [2], which is why ade-quate maintenance therapy is of great impor-tance. However, some patients develop perma-nent symptoms without ever achieving asymptom-free interval. Typically, continuousinflammatory changes in the colonic mucosabegin just above the anal verge and spreadproximally [3]. The inflammation, which insevere disease leads to ulceration and sponta-neous hemorrhage, can be confined to the rec-tum (proctitis) or extend beyond the splenicflexure throughout the colon (pancolitis) [4].Proctitis, proctosigmoiditis and left-sided coli-tis are the most common presentations of UC,accounting for 60–80% of all new cases [4].The signs and symptoms of UC are fairly het-erogeneous, and depend on the severity andlocation of the disease. Symptoms of UC canvary in their frequency and severity, however,

they typically include bloody diarrhea, abdomi-nal cramps and left-lower abdominal pain, fecalurgency and weight loss [3]. Extraintestinal com-plications (e.g., arthropathy, cutaneous condi-tions, ocular inflammation, hepatic and renaldisorders, and bone loss) are also not uncom-mon [101]. Long-standing UC, particularly ifnot subjected to maintenance treatment, is animportant risk factor for the development ofcolonic adenocarcinoma [5]. This risk is particu-larly high if UC is associated with the presenceof primary sclerosing cholangitis [5].

Current estimates suggest that the globalincidence rate of UC ranges from 0.5 to24.5 cases per 100,000 individuals [6]. While thehighest incidence is reported in industrializedcountries in North America, and Northern andWestern Europe, recent studies indicate that theincidence has now started to plateau or decreasein many of these Westernized countries [6,7].Conversely, in developing nations in EasternEurope, South America, and Asia, where therate of UC has been traditionally low, the inci-dence is rising progressively in line with indus-trial development and urbanization [6]. Little isknown about the epidemiology of UC in

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Africa, Latin America and Australasia due to a lack of data.Worldwide, the reported prevalence of UC ranges from 100to 200 cases per 100,000 individuals [2].

In terms of treatment, both US and European evidence-basedguidelines recommend the anti-inflammatory agent 5-amino-salicylic acid (ASA) for the first-line treatment of inflammatorysymptoms in patients with active, mild-to-moderate UC, andfor maintenance of remission [2,8]. The efficacy of 5-ASA inpatients with UC has been proven in multiple studies in boththe acute and maintenance settings [9,10]. Furthermore, theresults of retrospective studies suggest that regular use of 5-ASAis associated with a reduced risk of colonic adenocarcinomacompared with no 5-ASA use [11].

5-aminosalicylic acid is a topical treatment that is believed to actdirectly on the inflamed colonic mucosa [12]. The precise mecha-nism of action of 5-ASA is not completely understood. A numberof routes by which an anti-inflammatory effect is mediated at thecolonic mucosa have been proposed. These include the inhibitionof: prostaglandin synthesis (via inhibition of COX); chemotacticleukotriene synthesis (via inhibition of lipoxygenase) [13]; IL-1 syn-thesis [14,15]; and NF-κB activation by TNFα [16] and IL-1 [17].Additionally, it is thought that 5-ASA may act as a biological anti-oxidant by gathering oxygen free radicals [18]. Recently, 5-ASA hasbeen shown to exert a therapeutic effect via interaction with thePPAR-γ [19], a transcription factor that is involved in the colonicmucosal inflammation of patients with UC [20], by acting as asynthetic ligand at the PPAR-γ binding site [19].

5-aminosalicylic acid is applied either through direct rectalapplication or by a process of deferred release from an oral for-mulation designed not to release the active drug before it reachesa designated portion of the gastrointestinal (GI) tract (e.g., theileocecal region). There are a variety of 5-ASA delivery systemson the market, including both oral and rectal formulations. Forsome patients (e.g., those with active, mild-to-moderate exten-sive colitis), oral 5-ASA therapies (tablets, capsules, sachets andsuspensions) are preferable to rectal formulations (suppositories,and liquid, gel or foam enemas) since, from clinical experience,it is perceived that they are better tolerated and have a morepractical, ‘patient-friendly’ application. However, rectal formula-tions may be preferable in certain patients, such as those withlimited disease (i.e., active, mild-to-moderate proctitis, or distaldisease where they may be given in combination with oral5-ASA [2,8]). Indeed, in patients with extensive disease a com-bination of oral and rectal mesalamine has shown increasedefficacy over oral mesalamine alone [21]. Systemic steroids,immunosuppressant drugs (thiopurines, methotrexate andciclosporin), and the anti-TNF biologic agent infliximab arerecommended as second- or third-line therapy, when patientshave not responded to 5-ASA, or when there is more severe dis-ease [2,8]. It should be noted that the potential for serious sideeffects with these drugs is higher than with 5-ASA [22–24], andthe evidence base for the use of immunosuppressant drugs is notas extensive as for 5-ASA therapies. If pharmacologic therapiesare ineffective, surgical intervention may be required.

Overview of the marketIntroduction to oral 5-aminosalicylatesOf the oral 5-ASA formulations, sulfasalazine (e.g., Azulfidine®

and Azulfidine® EN-tabs® [Pharmacia & Upjohn Company,NY, USA]) was the first to come to market. Sulfasalazine (a5-ASA prodrug [102] that is metabolized to 5-ASA and sulfapyrid-ine in the colon by intestinal bacteria) was developed in the1940s, initially as a treatment for rheumatoid arthritis, and is stillprescribed today for the treatment of mild-to-moderate UC [25,26].The original concept behind the drug was that 5-ASA would actas a carrier for the antibiotic sulfapyridine moiety. By creating alarge molecule with an azo-bond between the two chemical enti-ties, the resulting compound became nonabsorbable. It was sub-sequently shown that the therapeutically effective chemical entitywas not sulfapyridine but 5-ASA [27].

Although sulfasalazine is clearly effective [9,10], the drug is oftenpoorly tolerated, with side effects that include hypersensitivityreactions, headache, nausea, vomiting, dyspepsia and anorexia [8].These side effects, which limit the utility of the drug, are attrib-uted to the sulfapyridine moiety of the sulfasalazine molecule. Ina recent meta-analysis of seven induction-of-remission trials, sul-fasalazine was shown to be significantly less well tolerated thannewer nonsulfa-containing oral 5-ASA therapies (odds ratio:0.38; 95% confidence interval [CI]: 0.25–0.57 [10]). Sulfasala-zine was also associated with a significantly higher proportion ofwithdrawals due to adverse events (AEs; odds ratio: 0.34; 95%CI: 0.19–0.63 [10]).

Over the past few decades, several nonsulfa-containing oral5-ASA formulations have been introduced (TABLE 1) [102], whichhave a better tolerability profile than sulfasalazine (permittingthe use of higher therapeutic doses) and distinct delivery char-acteristics [9,10]. To date, the most widely used nonsulfa-con-taining oral therapies are the delayed-release, pH-dependentmesalamine formulations (e.g., Asacol®, Mesasal®, Salofalk®,Claversal®, Ipocol® and Mesren®; TABLE 1). These delayed-release formulations utilize a pH-sensitive outer film, such asEudragit® L or S (Röhm GmbH & Co. KG, Pharma Polymers,Darmstadt, Germany), that dissolves when the pH within theGI tract reaches 6–7 or higher, such as within the terminalileum/colon (Eudragit S-coated tablets, release at pH ≥ 7) ordistal jejunum/proximal ileum (Eudragit L-coated tablets,release at pH ≥ 6) [102]. In addition to these therapies, there isalso a time-dependent, controlled slow-release, ethylcellulose-coated, microsphere formulation of mesalamine (Pentasa®;TABLE 1). The pH-independent release of 5-ASA from Pentasabegins in the duodenum and continues into the inflamed areasof the lower intestines [25,28,29]. Finally, there are the diazo-bonded prodrug formulations (olsalazine and balsalazide),which, like sulfasalazine, utilize the commensal flora to release5-ASA into the colon [25,28,29,102]. The binding of 5-ASA to acarrier molecule (another 5-ASA molecule in the case of olsala-zine, or a benzoic acid derivative in the case of balsalazide)allows the tablet to resist breakdown in the stomach and delays

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systemic absorption until the drug reaches the colon. Once inthe colon, bacterial azoreductase enzymes cleave the bondbetween the two molecules to release active 5-ASA.

The results of controlled trials and large meta-analyses have con-firmed the efficacy and favorable safety profile of oral 5-ASA thera-pies for both the symptomatic treatment of patients with active,mild-to-moderate UC, and maintenance of remission in patientswith quiescent disease [9,10]. While the results of some studies sug-gest potential advantages for one nonsulfa 5-ASA therapy overanother [28–33], the evidence for superiority is inconclusive, and it isgenerally accepted that most oral formulations have broadly similarefficacy. Rather, the efficacy of treatment within individual patientsmay be more influenced by factors such as patient adherence (dis-cussed later), variability in luminal pH (particularly important forpH-dependent formulations), altered GI transit time, delayed gas-tric emptying associated with food intake, and variability inmucosal 5-ASA concentrations [34–38]. With these factors to con-sider, it may be necessary for physicians to try more than oneformulation if an initial trial results in a suboptimal response.

Patient adherence to oral 5-aminosalicylatesAs with many treatments for chronic diseases, the overall effec-tiveness of 5-ASA therapy is highly dependent on patient adher-ence. The results of several community-based studies indicate

that adherence to 5-ASA is often poor (as low as 40% [39])among patients with UC, with the worst rates reported inpatients with quiescent disease [36,39–42]. The causes of non-adherence are multifactorial, but include the number of pillsand frequency of dosing [36,41,43,45]. This is important from aprescribing perspective, as many conventional oral 5-ASA ther-apies require multiple daily dosing (three- or four-times daily)and consumption of a large number of tablets or capsules (typi-cally up to 12/day) due to their low 5-ASA content. Importantly,reduced treatment efficacy resulting from poor adherence to5-ASA can lead to a significantly increased risk of disease relapseand deterioration in patient quality of life [40,45–48]. Nonadher-ence may also increase an individual patient’s risk of malig-nancy, as regular 5-ASA use has been shown to reduce the riskof colorectal cancer compared with no 5-ASA use in patientswith UC [11].

New oral 5-aminosalicylate formulationsOwing to adherence issues, several new oral 5-ASA formula-tions have been developed with the aim of reducing pill bur-den, lowering dosing frequency, and/or improving ease andconvenience of administration (TABLE 2) [49,103–106]. The first ofthese new formulations is the high-dose pH-dependent, delayed-release mesalamine tablet (Procter & Gamble Pharmaceuticals,

Table 1. Traditional nonsulfa-containing oral 5-ASA formulations.

Drug Recommended daily dose for induction therapy (given as divided doses)

Manufacturer

pH-dependent, delayed-release

Asacol® 400-mg tablet Up to 12 tablets Procter & Gamble Pharmaceuticals, Cincinnati, OH, USA

Claversal® 250- and 500-mg tablets

Six (250-mg) tablets or three (500-mg) tablets Merckle GmbH, Ulm, Germany

Mesasal® 250- and 500-mg tablets

Six (250-mg) tablets or three (500-mg) tablets GlaxoSmithKline, Mississauga, Ontario, Canada

Salofalk® 250- and 500-mg tablets

Six (250-mg) tablets or three (500-mg) tablets Dr Falk Pharma GmbH, Freiburg, Germany and Axcan Pharma, Mont St. Hilaire, Quebec, Canada

Mesren® 400-mg tablet Up to 12 tablets Teva UK Ltd, Runcorn, Cheshire, UK; Schering-Plough UK, Welwyn Garden City, Hertfordshire, UK

Ipocol® 400-mg tablet Up to 12 tablets Lagap SA, Vezia, Switzerland

Time-dependent, controlled slow-release

Pentasa® 250- and 500-mg tablets or capsules

Up to 16 (250-mg) or eight (500-mg) tablets or capsules

Ferring Pharmaceuticals, Copenhagen, Denmark; Shire Pharmaceuticals Inc., Wayne, PA, USA

Diazo-bonded prodrug formulations

Dipentum® (olsalazine) 250-mg capsule/500-mg tablet

Up to 12 capsules or six tablets Pharmacia AB, Stockholm, Sweden

Colazal®/Colazide®

(balsalazide) 750-mg capsuleUp to nine capsules Salix Pharmaceuticals, Inc., Morrisville, NC, USA

ASA: Aminosalicylic acid.Data from [102].

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OH, USA) [50,51]. With a dose strength of 800 mg, only threetablets are required (in contrast to the usual six required withthe standard 400 mg tablet) when taking the approved2.4 g/day dose for the treatment of mild-to-moderately activeUC; the three-times daily dosing schedule remainsunchanged. The development of the high-dose tablet hasallowed investigation of the efficacy of pH-dependent,delayed-release mesalamine at an increased dose of 4.8 g/dayin two large Phase III, randomized, double-blind trials(Assessing the Safety and Clinical Efficacy of a New Dose of5-Aminosalicylate Acid [ASCEND] I and II) [50,51]. Inpatients with moderate disease severity only the 4.8 g/daydose of pH-dependent, delayed-release mesalamine (2 × 800 mgthree-times daily) was shown to be superior to the 2.4 g/daydose (2 × 400 mg three-times daily) in terms of treatment suc-cess (a composite primary end point defined as either com-plete remission [resolution of symptoms, a patient functionalassessment of ‘generally well,’ a Physician’s Global Assessment(PGA) score of 0 and normal endoscopic findings] or a clini-cal response to therapy [improvement in baseline PGA scoreand at least one other assessment, with no worsening), andimprovement in PGA in patients with moderate UC [50,51].However, the 4.8 g/day dose did not improve treatment suc-cess versus the 2.4 g/day dose, nor did it provide any addi-tional benefit over the lower dose for any end point inpatients with mild disease [50,51]. Consequently, for patientswith mild UC it is not yet clear whether the 4.8 g/day dose ofpH-dependent, delayed-release mesalamine provides addi-tional clinically meaningful benefit over the standard2.4 g/day dose. Generally, a dose response has yet to be shownfor 5-ASA formulations, however a three-dose trend between1, 2 and 4 g/day has been observed during an 8-week study ofpatients receiving Pentasa [52].

Second, mesalamine micropellet sachets (Claversal micro-pellets, Salofalk granules and Pentasa sachet prolonged-releasegranules; TABLE 2) have been introduced with the aim of pro-viding less frequent (higher strength) dosing in an easy-to-swallow formulation. In healthy volunteer studies, Claversalmicropellets and Salofalk granules have been shown to havesimilar (but not identical) release characteristics to their corre-sponding tablet formulations [53,54]. Moreover, two clinicalnoninferiority studies of Claversal micropellets and Pentasasachet prolonged-release granules, respectively, have demon-strated equivalent therapeutic efficacy versus the same dailydose of multiple corresponding tablets in patients with active,mild-to-moderate UC [55,56].

Finally, the newest 5-ASA therapy to become available is amesalamine formulation using MMX Multi Matrix System®

(MMX™ [Cosmo Technologies Ltd., Wicklow, Ireland]) tech-nology (hereafter referred to as MMX mesalamine), a noveltherapy designed to provide delayed and prolonged 5-ASArelease throughout the colon. The remainder of this article pro-files the clinical pharmacology, efficacy and safety of MMXmesalamine in patients with UC.

Introduction to MMX mesalamineMMX mesalamine is a new, oral, high-strength formulationof 5-ASA designed for once-daily administration. MMXmesalamine delayed-release tablets are manufactured byCosmo SpA (Milan, Italy), and marketed by Shire Pharma-ceuticals Inc. (under license from Giuliani SpA, Milan, Italy)under the trade names of Lialda™ in the USA and thePacific Rim, and Mezavant™ in the European Union andCanada (except in the UK and Ireland, where it is known asMezavant™ XL).

Table 2. New nonsulfa-containing oral 5-aminosalicylic acid formulations.

Drug 5-ASA dose Recommended daily regimen for induction therapy*

Manufacturer

Claversal® micropellets 1.5 g per sachet Two sachets taken as two divided doses

Merckle GmbH, Ulm, Germany

Pentasa® prolonged-release granules

1 g per packet Four packets taken as two or four divided doses

Ferring Pharmaceuticals Inc., Copenhagen, Denmark; Shire Pharmaceuticals Inc., Wayne, PA, USA

Salofalk® Granu-Stix® granules

0.5, 1.0 or 1.5 g per sachet

Threes 1.0 g sachets or three 0.5 g sachets taken as three divided doses

Dr Falk Pharma GmbH, Freiburg, Germany and Axcan Pharma, Mont St Hilaire, Quebec, Canada

Asacol® high-dose tablet

0.8 g per tablet Six tablets taken as three divided doses

Procter & Gamble Pharmaceuticals, Cincinnati, OH, USA

MMX mesalamine (Lialda™)‡

1.2 g per tablet Two or four tablets once-daily Cosmo SpA (Milan, Italy), marketed by Shire Pharmaceuticals, Inc., Wayne, PA, USA, under license from Giuliani, SpA, Milan, Italy

*Or daily regimen equivalent to currently recommended regimen for induction therapy.‡Also known as Mezavant™ XL in the UK and Ireland, and as Mezavant™ elsewhere.ASA: Aminosalicylic acid.Data from [49,103–106].

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Unlike other nonsulfa 5-ASA therapies, MMX mesalamine uti-lizes MMX technology [57,58]. As reported by Tenjarla et al. [58],MMX technology comprises hydrophilic and lipophilic excipi-ents (polymer matrices) enclosed within a pH-dependent,gastroresistant, enteric coating (FIGURE 1). The gastroresistantcoating delays initial release of 5-ASA (which is containedwithin the tablet core) until the pH is 7.0 or higher (usuallyencountered within the terminal ileum). As the gastroresistantcoating disintegrates, the hydrophilic excipients interact withthe GI fluids, and cause the tablet to swell (much like a spongeexposed to water) and form an outer viscous gel mass. The vis-cous gel mass is designed to slow diffusion of the drug fromthe tablet core into the colonic lumen. As the tablet and itssurrounding gel mass progress through the colon, the pieces ofthe gel mass gradually break away from the core, releasing5-ASA. The lipophilic excipients slow the penetration of theintestinal fluids into the tablet core, which reduces the rate ofdissolution of 5-ASA, and thereby prolongs its release. Thismethod of sustaining gradual 5-ASA release distinguishesMMX mesalamine from other oral 5-ASA formulations thathave no such mechanism for prolonging release of 5-ASA oncethe tablet enters the colon.

ChemistryEach MMX mesalamine delayed-release tablet contains 1.2 g ofmesalamine (5-ASA), which has the chemical name 5-amino-2-hydroxybenzoic acid (C7H7NO3) and a molecular weight of153.14 Da (FIGURE 2) [49]. MMX mesalamine delayed-release tab-lets are ellipsoidal in shape with a red–brown coating and a whitecore. In addition to the active drug, the tablets also contain theinactive ingredients sodium carboxymethylcellulose, carnaubawax, stearic acid, silica (colloidal hydrated), sodium starch glyco-late (type A), talc, magnesium stearate, methacrylic acid co-poly-mer types A and B, triethylcitrate, titanium dioxide, red ferricoxide and polyethyleneglycol 6000 [49].

Pharmacokinetics & pharmacodynamicsPharmacokineticsSince 5-ASA therapies act topically at the level of the colonicmucosa, pharmacokinetic (PK) studies of these agents havemuch less clinical relevance than those of systemically activedrugs. Nevertheless, the PK characteristics of MMX mesala-mine have been investigated in two open-label, healthy volun-teer studies. In the first of these studies, the PK profile of MMXmesalamine was evaluated in 52 healthy subjects following singleor repeated oral administration of MMX mesalamine at clinicallyrecommended doses (2.4 or 4.8 g/day) in the fed state [59]. Anal-ysis of the area under the plasma concentration–time curve(AUC) for 5-ASA revealed two absorption peaks after singleand repeated dosing, one at approximately 8 h postdose and thesecond at 22 h or later. The total absorption of 5-ASA onrepeated dosing was found to be dose independent andaccounted for approximately 21–22% of the administered

dose. The maximum plasma concentration (Cmax) was achievedafter about 8 h at both doses following single or repeated dos-ing, and steady-state concentrations of 5-ASA were achievedafter 48 h of repeated dosing. Similarly to total absorption, themean observed accumulation was also dose independent andranged between 1.7- and 2.4-fold after 14 days. The terminalhalf-life of MMX mesalamine was variable (range: 0.6–20.8 h),and renal elimination of unchanged 5-ASA was less than 8% ofthe administered dose. The major metabolite of 5-ASA,N-acetyl-5-ASA (N-Ac-5-ASA; the formation of which resultsfrom N-acetyltransferase activity in the liver and intestinalmucosa [49]), showed a similar PK profile to 5-ASA.

In a separate single-dose study, MMX mesalamine (at dosesof 1.2, 2.4 and 4.8 g) was administered in the fasted state to47 healthy subjects [60]. In addition, volunteers also received asingle dose of 4.8 g following a high-fat meal. In the fastedstate, plasma concentrations of 5-ASA were detectable 2 h post-dose and reached a maximum by 9–12 h. As in the previousstudy, the PK parameters were variable, including the terminalhalf-life, which ranged from 0.7 to 44.6 h. 5-ASA systemicexposure (AUC) increased in a dose-proportional mannerbetween doses of 1.2 and 4.8 g, and the disposition of N-Ac-5-ASA was shown to be similar to that of the parent drug. Inthe second phase of the study, administration of a single 4.8-gdose with a high-fat meal resulted in further delay in absorptionwith an increased lag time. This delay is in accordance withprevious findings demonstrating delayed gastric emptying withenteric coated tablets following food intake [35]. Importantly,the PK profiles of 5-ASA and N-Ac-5-ASA in both of thesestudies are consistent with a delayed- and prolonged-releaseoral 5-ASA formulation, and are also similar to profilesreported for other oral 5-ASA formulations [61].

PharmacodynamicsThe pharmacodynamics of MMX mesalamine have been investi-gated using two different, but complementary, methods:γ scintigraphy and a simulated GI tract model. In theγ scintigraphy study, the colonic distribution of 5-ASA followingrelease from MMX mesalamine was studied in 12 healthy malevolunteers [62]. All subjects received a single MMX mesalaminetablet (containing 1200 mg of 5-ASA) tagged with a radioactivetracer molecule (152Sm2O3). On imaging, distribution of thetracer molecule was observed throughout the ascending or trans-verse colon approximately 7 h following ingestion of the tablet.The radioactivity then spread homogeneously throughout theentire colon, indicating sustained release. Subsequently, the tracermolecule entered the sigmoid colon after 13 h, and was stilldetectable 24 h postingestion. Based on experience of previousstudies of this nature, it is believed that the release and distribu-tion of the radio-isotope tracer parallels that of the release anddistribution of the active drug from the tablet core. This suggeststhat 5-ASA is released from the MMX mesalamine tablet in adelayed and sustained fashion. The results of concurrent PKexperiments, conducted to verify 5-ASA release, suggest that

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comparatively small amounts of 5-ASA are absorbed duringtransit through the small intestine and ileum, and approximately80% of 5-ASA is absorbed in the colon [62].

Similar findings were obtained in an artificial environmentwhere the release kinetics of 5-ASA from MMX mesalaminewere assessed using a dynamic in vitro GI tract system (TNOGastroIntestinal Model; TIM-1 and -2) that simulates thephysiologic conditions in the adult human GI tract [58]. Thiscomputer-controlled, multicompartmental system, was usedto explore the GI transit of a single MMX mesalamine1200 mg tablet over a 24-h period. The system incorporatesremoval of released drug via dialysis and automated samplingtaken at various sections of the system (i.e., the simulated

stomach, duodenum, jejunum, ileum and colon). The resultsof the study showed that the vast majority of 5-ASA withineach MMX mesalamine tablet was released and bioaccessiblein the simulated colon (69–78%), and less than 1% wasreleased in the simulated stomach or small intestine. Further-more, it was also shown that food had a minimal effect on thebioaccessibility of 5-ASA, and that the release of 5-ASA wasprolonged throughout the simulated colon. The differences inintestinal absorption of 5-ASA reported in this and theγ scintigraphy study [62] probably reflect the distinct methodsused, and their intrinsic limitations. Nevertheless, both stud-ies support the proposed ‘prolonged-release’ mode of action ofMMX mesalamine (FIGURE 1) [58].

Figure 1. Proposed mechanism of action of MMX™ mesalamine.Reproduced with permission from [58].

5-ASA released from hydrophilic matrix

A B

C D

MMX Multi Matrix System™ core

Gastroresistant pH-dependent coating

Hydrophilic matrix

Lipophilic matrix

5-ASA

Mucosal wall Gel fragmentHydrophilic matrix swells forming viscous gel mass

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Clinical efficacyPhase II studiesThe preliminary efficacy of MMX mesalamine was investi-gated in two pilot Phase II studies involving patients withmild-to-moderately active UC. The first study, conducted inItaly, was an 8-week, randomized, double-blind, multicentertrial exploring the relative efficacy of MMX mesalamine3.6 g/day (given as 1.2 g three-times daily) versus a 4-gmesalamine enema (pH-dependent, delayed-release mesala-mine; administered once-daily) in 79 patients with left-sidedcolitis [57]. After 8 weeks of treatment, similar rates of clinicalremission (primary end point; defined as a RachmilewitzClinical Activity Index [63] score of ≤ 4) were reported withMMX mesalamine 3.6 g/day (60.0%) and the rectal 5-ASAenema (50.0%). Likewise, similar endoscopic remission(defined as a Rachmilewitz Endoscopic Activity Index [63]

score of ≤ 2) rates were reported in the two groups at the endof the study (45.0 vs 36.8%, respectively).

The second study was an 8-week, randomized, multicenter,double-blind, parallel-group, dose-ranging trial that com-pared the safety and efficacy of three different doses of MMXmesalamine (1.2 vs 2.4 vs 4.8 g once-daily) in 38 patientswith newly diagnosed or relapsing UC [64]. The results of thestudy demonstrated the clinical effectiveness of the 2.4 and4.8 g/day doses, while the 1.2 g dose was not seen to conferany clinical benefit. At the end of the study, higher remissionrates (primary end point; defined as the percentage of patientsachieving an UC Disease Activity Index [DAI] score [65] of≤ 1, a score of 0 for rectal bleeding and stool frequency, and≥ 1-point reduction in sigmoidoscopy score from baseline)were reported in the 2.4 and 4.8 g/day dose groups (31 and18%, respectively) than in the 1.2 g/day group (0%). How-ever, the differences were not statistically significant due tothe small sample size. As with the remission rates, the 2.4 and4.8 g/day doses also provided a greater improvement frombaseline in the total and component UC-DAI scores com-pared with the 1.2 g/day dose. These data supported the priordecision to select the 2.4 and 4.8 g/day doses for further studyin Phase III trials.

Phase III studiesInduction of remission trialsThe registration of MMX mesalamine in the USA, Canada,and Europe was based primarily on data from three pivotalPhase III studies (FIGURE 3). The first two studies were 8-week,international, multicenter, randomized, double-blind trialsby Lichtenstein et al. (SPD476-301) and Kamm et al.(SPD476-302) comparing the efficacy of MMX mesalaminewith placebo for the induction of remission in patients withactive, mild-to-moderate UC [66,67]. The two trials had a verysimilar design in that both studies recruited male and femalepatients aged 18 years or over, with either newly diagnosed ornewly relapsed UC that was mild-to-moderately active, with

compatible histology. With regard to treatment, in the studyreported by Lichtenstein et al. [67], 280 patients receivedMMX mesalamine 2.4 g/day (1.2 g administered twicedaily), MMX mesalamine 4.8 g/day (once-daily) or placebo.In the study reported by Kamm et al. [66], 343 patientsreceived MMX mesalamine 2.4 g/day (once-daily), MMXmesalamine 4.8 g/day (once-daily), placebo, or the US for-mulation of pH-dependent, delayed-release mesalamine2.4 g/day (0.8 g three-times daily as an active internal refer-ence arm). The primary end point of both studies was thepercentage of patients in remission at week 8. However, incontrast to the previous Phase II studies, a more stringentdefinition of remission was employed. Indeed, throughoutthe Phase III program, remission was defined as a UC-DAIscore of 1 or less, calculated as scores of 0 for rectal bleedingand stool frequency, a combined PGA and sigmoidoscopy scoreof 1 or less, no mucosal friability, and a sigmoidoscopy scorereduction of 1 or more from baseline. While this appears to bethe same as that used in the D’Haens trial [64], the UC-DAIscoring system [65] was in fact modified for the Phase III pro-gram such that patients with mucosal friability (i.e., micro-ulceration) could only be assigned a sigmoidoscopy score of 2or more. Therefore, patients with mucosal friability were notconsidered to be in endoscopic remission.

In terms of efficacy, a significant improvement in strictlydefined clinical and endoscopic remission rates were observedwith MMX mesalamine versus placebo at week 8, both in theindividual studies (TABLE 3) [66,67] and in a pooled analysis of datafrom both trials (TABLE 3) [68]. By contrast, pH-dependent,delayed-release mesalamine 2.4 g/day did not significantlyimprove the 8-week remission rate versus placebo in the studyreported by Kamm et al. [66]. Although both doses of MMXmesalamine were more effective at inducing remission than pla-cebo, there were no statistical differences between the two dosegroups. This was a little suprising, as earlier Phase II data hadshown that the 4.8 g/day dose was associated with a sevenfoldhigher mean colonic mucosal 5-ASA concentration than the2.4 g/day dose [64].

Analysis of secondary endpoints showed that MMX mesala-mine was also superior to placebo with regard to inducing clin-ical improvement, reducing treatment failures, decreasing the

Figure 2. Mesalamine.

COOH

OH

NH2

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total modified UC-DAI score, reducing symptoms, andimproving mucosal appearance (TABLE 4) [66–69]. In addition,there was a slight trend for improved total UC-DAI, sigmoido-scopy, and PGA scores, with the higher dose of MMX mesala-mine (TABLE 4) [66–68]. Notably, complete mucosal healing (sig-moidoscopy score of 0) was seen in approximately a third ofpatients treated with MMX mesalamine. This may be impor-tant, as induction of mucosal healing appears to be a better pre-dictor of long-term remission than the induction of clinicalremission alone (i.e., remission of symptoms only) [70,71].Median time to resolution of symptoms (overall, rectal bleedingand stool frequency normalization) was also found to be signif-icantly shorter in the two MMX mesalamine groups comparedwith the placebo group in a combined analysis of data from thetwo studies (TABLE 4) [69].

Further analyses of the Phase III data (both planned andpost hoc) have since demonstrated the superiority of MMXmesalamine (2.4 or 4.8 g/day) over placebo at inducing clini-cal and endoscopic remission in subgroups of patients strati-fied according to gender [72], disease extent (left-sided vsextensive; [73]), and disease severity (mild vs moderate; [74]),with the 2.4 and 4.8 g/day doses providing similar levels ofbenefit. An additional post hoc analysis also evaluated the effi-cacy of MMX mesalamine in patients who had switcheddirectly from prior low-dose oral 5-ASA therapy (taking oral5-ASA therapy [≤2 g/day] during the 5 days prior to baseline)and 5-ASA-naive or discontinued patients (no oral 5-ASA in the6-week period prior to baseline or had discontinued oral 5-ASAtherapy [≤2 g/day] > 5 days prior to baseline) [75]. Both doses ofMMX mesalamine were shown to be superior to placebo at

Figure 3. Design and patient flow for the three Phase III studies and open-label extension study of MMX™ mesalamine in patients with ulcerative colitis.*Remission was defined as an Ulcerative Colitis Disease Activity Index score of ≤ 1, calculated as scores of 0 for rectal bleeding and stool frequency, a combined Physician’s Global Assessment and sigmoidoscopy score of ≤ 1, no mucosal friability, and a sigmoidoscopy score reduction of ≥ 1 from baseline.b.i.d.: Twice daily; q.d.: Once daily; t.i.d.: Three-times daily.Data from [65].

Induction study SPD476-301n = 280

Induction study SPD476-302n = 343

MMX 2.4 g/day (1.2 g b.i.d.)

MMX 2.4 g/day q.d.

Asacol2.4 g/day (0.8 g t.i.d.)

MMX 4.8 g/day q.d.

Patients in remission*

Patients in remission*

Patients not in remission

Patients not in remission

Maintenance study SPD476-303n = 459

MMX2.4 g/dayq.d.

MMX2.4 g/day(1.2 g b.i.d.)

MMX4.8 g/dayq.d.

Placebo Placebo

8 weeks 8 weeks

8 weeks

12 months

Open-label extension studySPD476-303n = 304MMX 4.8 g/day(2.4 g b.i.d.)

Expert Rev. Med. Devices, © Future Science Group Ltd (2008).

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inducing remission in 5-ASA-naive or discontinued patients. Inthis patient subgroup, remission rates of 42.9, 33.0 and 13.8%were reported at week 8 in the MMX mesalamine 2.4 g/day,4.8 g/day and placebo groups, respectively (p < 0.01 vs placebofor both MMX mesalamine groups). However, only MMXmesalamine 4.8 g/day was superior to placebo (p < 0.05) inthose patients who had switched from prior low-dose 5-ASA(week 8 remission rates were 31.8, 37.5 and 20.9%, respec-tively). This suggests that patients with active UC, despitetreatment with low-dose 5-ASA, might benefit from switchingto a high dose of MMX mesalamine.

Induction & long-term safety trialThe third trial (SPD476-303; [76]) in the Phase III programwas designed to evaluate MMX mesalamine safety during themaintenance of remission of UC, and employed the samestrict criteria to define remission as used in the inductionstudies (FIGURE 3) [77]. This study enrolled patients directly fromthe two previous induction trials. Those patients who hadachieved remission in the induction trials could opt to be ran-domized to 12 months of maintenance treatment with MMXmesalamine 2.4 g/day once-daily or as 1.2 g, twice-daily (the303 long-term extension study, [76]). However, those patientswho did not achieve remission in the induction trials couldopt to receive 8 weeks of additional induction therapy withopen-label MMX mesalamine 4.8 g/day given as 2.4 g, twice-daily (the 303 acute extension study [78]). Patients whoachieved remission in this extension phase could then opt toenter the 303 long-term extension study.

8-week acute extension phase

Of the 304 patients who entered the 303 acute extension phase,nearly 60% had achieved clinical and endoscopic remission byweek 8 [78]. This was accompanied by improvements from base-line in the total modified UC-DAI and component symptomscores. These results suggest that in order to achieve remission,some patients may require longer (up to 16 weeks) or high-dose

(4.8 g/day, given as 2.4 g, twice-daily) therapy with MMXmesalamine, either as dose escalation (in patients initiallytreated with low-dose 5-ASA [MMX mesalamine or pH-dependent, delayed-release mesalamine]), or as a continuedhigh dose (in patients initially treated with MMX mesalamine4.8 g/day). Although a dose–response effect for 5-ASA between2.4 and 4.8 g/day in mild-to-moderate UC has yet to be proven,most studies investigating dose-response have been conductedover 6–8 weeks [50,79] and it is possible that more patientsenrolled in these studies may have achieved remission followingprolonged 5-ASA therapy at a dose of 2.4 g/day.

12-month maintenance phase

Of the 362 patients in strictly defined remission who enteredthe 303 long-term extension, 68% in the once-daily groupand 72% in the twice-daily group were in clinical and endo-scopic remission at month 12 [77]. Additionally, the propor-tion of patients who had not relapsed (defined as a require-ment for alternative treatment for UC, including surgery, oran increase in the dose of MMX mesalamine above2.4 g/day) at 12 months was 89% in the once-daily groupand 93% in the twice-daily group. These results suggest thatMMX mesalamine can effectively maintain remission inpatients with UC. Further subgroup analyses have shownthat MMX mesalamine is similarly effective at maintainingremission in patients with mild or moderate disease [80], andin patients with extensive or left-sided UC [81]. By contrast,MMX mesalamine 2.4 g/day appears to be less effective atmaintaining remission in patients initially treated with a2.4 g/day dose who had required a dose escalation to4.8 g/day (in the 303 acute extension phase) in order toachieve remission compared with those who had achievedremission, on a dose of 2.4 g/day (in the Phase III studies)without dose escalation [82]. These patients may represent adifficult to treat subpopulation who might require a highermaintenance dose of MMX mesalamine. Other analyses haveshown that relapse history has little influence on the ability

Table 3. Stringently defined clinical and endoscopic remission rates at week 8 (primary end point) in the two Phase III induction-of-remission studies.

Study Percentage of patients in remission (p-value vs placebo) Ref.

MMX mesalamine 2.4 g/day

MMX mesalamine 4.8 g/day

Placebo pH-dependent, delayed-release mesalamine* 2.4 g/day

Lichtenstein et al. (2007) 34.1‡ 29.2§ 12.9 [67]

Kamm et al. (2007) 40.5§ 41.2§ 22.1 32.6¶ [66]

Pooled analysis

Patients in remission (%) 37.2# 35.1# 17.5 32.6 [68]

*pH-dependent, delayed-release mesalamine (Asacol®) present as a reference arm in the Kamm study only.‡p ≤ 0.001.§p ≤ 0.01 vs placebo.¶Not significant vs placebo.#p < 0.001 vs placebo.

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of MMX mesalamine to maintain remission [83], and thatMMX mesalamine is an effective maintenance therapy, irre-spective of whether MMX mesalamine or pH-dependent,delayed-release mesalamine is used to achieve remission [84].

Safety & tolerabilityThe results of all clinical studies conducted so far indicatethat MMX mesalamine is generally very well tolerated, with asafety profile that is broadly similar to other oral nonsulfa5-ASA therapies [9,10,66,68]. A recent analysis of combined datafrom the two pivotal, Phase III, induction-of-remission stud-ies showed that the frequency of AE reporting with MMXmesalamine was almost identical to that seen with placebo(TABLE 5) [68]. There was also no evidence of a dose–responserelationship for any safety parameter, and most AEs were mildor moderate in intensity. Additionally, patients who receivedMMX mesalamine were less likely to withdraw early from thestudies (for any reason or owing to adverse events) than thosewho received placebo [66–68]. GI disorders (including abdomi-nal pain, worsening UC, diarrhea, flatulence and nausea) werethe most common AEs, occurring in 18.1, 11.7 and 24.0% ofpatients in the MMX mesalamine 2.4, 4.8 g/day and placebogroup, respectively [68].

During the Phase III program, three cases of pancreatitiswere reported with MMX mesalamine (two cases in one ofthe Phase III induction studies [67] and one case in the 303acute extension study [85]. However, all three cases of pancre-atitis, a well-known side effect of mesalamine [86–89], resolved

quickly without complications following treatment with-drawal. Treatment discontinuation is therefore advised ifpatients experience this side effect.

As in the induction-of-remission studies, MMX mesala-mine was similarly well tolerated in the 12-month long-termsafety study [90]. Significantly, no new or unexpected safetyfindings were reported with MMX mesalamine during the12-month treatment period.

Regulatory affairsThe approved indications for MMX mesalamine are detailedin TABLE 6.

ConclusionLarge-scale clinical studies show that the new oral 5-ASA for-mulation MMX mesalamine (taken as a once-daily dose of2.4 or 4.8 g) is an effective treatment for inducing clinicalremission and mucosal healing in patients with active, mild-to-moderate UC. Furthermore, an additional 8 weeks ofMMX mesalamine 4.8 g/day can induce remission in themajority of patients who fail to respond to an initial 8 weeksof therapy. While a timely response to treatment is important,this approach should, for many patients, prevent the require-ment for therapeutic escalation to steroids or other immuno-suppressants. Furthermore, once remission is achieved, MMXmesalamine has been shown to effectively maintain periods ofremission in the vast majority of patients for at least

Table 4. Summary of the clinical efficacy of MMX mesalamine in a pooled analysis of data from two Phase III induction-of-remission studies.

End point* MMX mesalamine 2.4 g/day (n = 172)

MMX mesalamine 4.8 g/day (n = 174)

Placebo (n = 171)

Patients in clinical and endoscopic remission (%) 37.2‡ 35.1‡ 17.5

Patients with clinical improvement (%) 58.1‡ 62.1‡ 32.7

Treatment failures (%) 25.0‡ 22.4‡ 50.9

Mean improvement in total modified UC-DAI score (%) 52‡ 57‡ 25

Patients with improved sigmoidoscopy score (%) 67.4 74.1 39.2

Patients with improved PGA score (%) 66.3 70.7 42.1

Patients with complete mucosal healing (%) 32.0 32.2 15.8

Median time to symptom resolution (days) 25§ 26§ 44

Median time to resolution of rectal bleeding (days) 7§ 8§ 16

Median time to stool frequency normalization (days) 19§ 20§ 34

*Assessments performed at the end of the study (week 8 or study end point [week 8 data combined with last observation carried forward data for patients who had discontinued prematurely]). Improvements are expressed relative to baseline.‡p ≤ 0.001 vs placebo.§p ≤ 0.0001 vs placebo.PGA: Physician’s Global Assessment; UC-DAI: Ulcerative Colitis Disease Activity Index.Data from [68,69].

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12 months, whilst being well tolerated. As well as inducingand maintaining remission, patients with mild-to-moderateUC, particularly those who report difficulties with multipledaily 5-ASA formulations, may benefit from the simplifieddosing regimen of MMX mesalamine.

Expert commentaryWith their simplified dosing regimens, and ability to induceand maintain clinical remission and mucosal healing, modern5-ASA formulations have the potential to maximize therapeuticefficacy and patient acceptance. MMX mesalamine thereforerepresents an important addition to the range of treatmentsavailable to treat active UC and maintain remission. In thefuture, head-to-head comparative trials are required to establishwhether the pharmacological benefits associated with the noveldelivery characteristics of MMX mesalamine will translate intoimproved efficacy over other 5-ASA therapies. A model for suchtrials could be the Phase III study of MMX mesalamine, inwhich pH-dependent, delayed-release mesalamine was includedas an internal reference arm (to validate the study design) [66].While the study was not designed to compare active treatments,studies to confirm the 8% difference in remission rates seen in

the Kamm study would require approximately 850 patients tobe adequately powered. This nominal difference in efficacybetween MMX mesalamine (at either the 2.4 or 4.8 g/day dose)and pH-dependent, delayed-release mesalamine (2.4 g/day) didnot reach statistical significance in this underpowered studywith 343 patients [66]. A large Phase III trial is now planned tocompare the efficacy and safety of MMX mesalamine 2.4 g/day(once-daily) with pH-dependent, delayed-release mesalamine1.6 g/day (0.8 g, twice-daily) for the maintenance of remissionin over 800 patients with quiescent UC. It is anticipated thatthe study will be completed in early 2010.

As discussed previously, pill burden and multiple-daily dosingare well-established reasons for patients not adhering to their pre-scribed medication [36]. Low-frequency dosing and a low pill bur-den have the potential to result in better patient adherence and,consequently, better clinical outcomes. Compliance to studymedication in the induction of remission trial reported by Kammet al. found that compliance rates with MMX mesalamine(95.3%) and pH-dependent, delayed-release mesalamine(97.7%) were similar [66]. However, since this study was designedto distribute medication in a double-dummy fashion, all patientswere dosed three-times daily and this finding most likely repre-sents the enhanced compliance frequency seen in clinical trials.

Table 5. Summary of treatment-emergent adverse events reported with MMX mesalamine in a pooled analysis of data from two Phase III induction-of-remission studies.

Patients with MMX mesalamine 2.4 g/day (n = 177)

MMX mesalamine 4.8 g/day (n = 179)

Placebo(n = 179)

Adverse event (%) 36.2 32.4 34.6

– Mild 28.2 24.0 17.3

– Moderate 13.0 11.7 17.9

– Severe 1.1 2.2 6.1

Adverse events occurring in ≥5% of patients (%)

– UC 4.0 0.6 6.1

– Headache 5.6 3.4 0.6

Treatment-related adverse event (%) 14.1 14.5 14.0

Serious adverse event (%) 1.7 1.1 2.8

– Worsening UC 0.6 0.0 2.8*

– Pancreatitis 0.6 0.6 0.0

– Colonic hemorrhage 0.0 0.0 0.6

– Perianal abscess 0.6 0.0 0.0

– Urinary retention 0.6 0.0 0.0

– Gastroenteritis viral 0.0 0.6 0.0

Adverse event leading to withdrawal (%) 3.4 1.1 7.3

*One patient experienced two events. The second event occurred 22 days after withdrawal due to a separate case of aggravated UC.UC: Ulcerative colitis.Data from [68].

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Compliance rates in clinical trials are not representative of thosein a population setting. Therefore, prospective, community-based studies are now required to investigate adherence to MMXmesalamine and other 5-ASA therapies, and its association withtreatment acceptance and success.

Five-year viewThe protection of intellectual property in the 5-ASA market is notdriven by substance patents, as 5-ASA is a chemical entity that isfree of rights for use in the treatment of inflammatory bowel dis-ease. In this market, intellectual property is generated through theinvention of galenics that regulate 5-ASA release during boweltransit, and allow an oral ‘topical’ treatment of the inflamed ileumand large intestine, rather than systemic absorption. Over the nextfew years, we will see an interesting transformation of the market,as many pharmaceutical companies lose the patent protection ontheir 5-ASA tablet galenics. Given this factor, and the continuingdesire to improve treatment, substantial efforts have been made bythe affected companies to develop alternative galenics. The result-ing ‘micropellet sachet’ formulations may allow a reduced dosingfrequency compared with their tablet counterparts, but areunlikely to be readily accepted by all patients, as many patientsprefer tablets. The MMX formulation, a tablet-based, once-daily5-ASA treatment with an unprecedented high concentration ofactive drug per tablet, has the potential to occupy a large share ofthe tablet market. Ultimately, the size of the market share willdepend on pricing. This will be a particular issue in government-regulated markets, where the low cost of generic drugs can oftennegate innovative improvements in galenic formulations. Theoutcome of comparative trials is likely to set the pace for pricingin most European markets. If a novel formulation like MMXmesalamine could be singled out as being more effective thanother 5-ASA drugs, innovative branded products would stand outagainst the background of 5-ASA generics. Such a scenario wouldstrongly support an argument for differential pricing.

As oral 5-ASA therapies will remain the mainstay of treatmentfor mild-to-moderate UC for the foreseeable future, we now alsoneed to concentrate our research efforts on optimizing the use ofthese drugs. This will help to contain the overall costs of UCmanagement. The key to optimizing 5-ASA therapy is improvingpatient adherence, a factor intrinsically linked with both short-and long-term prognosis. Use of new convenient, high-strength

therapies should help to improve adherence. Community-basedobservational studies are required to monitor this. However,improving patient adherence will also require better educationand improved patient–doctor relationships, which will involveregular consultations to review treatment and overall diseasemanagement. In order to further optimize outcomes, we alsoneed to standardize the assessment of therapies in clinical studies.Indirect retrospective comparisons of different treatments (e.g.,by meta-analysis) are currently almost impossible to make due tothe diversity of end points used in UC trials. For all new studies,remission must be clearly defined, and should include cessationof bleeding and mucosal healing, as these appear to be objectiveand reliable measures of treatment success and long-term clinicaloutcome. By standardizing the assessment of therapies, we will beable to compare different treatments in different situations,which in turn will facilitate decision making. Finally, we mayhave to rethink treatment schedules and clinical trial design,given the new evidence showing that extended treatment withhigh-dose 5-ASA benefits many patients who would previouslyhave been classed as 5-ASA-refractory. Clearly, any advances intreatment and assessment need to be reflected in new clinicalpractice guidelines.

Information resources

• Additional information on MMX mesalamine (includingUS prescribing information) can be found by visiting:www.lialda.com/professional/

Financial & competing interests disclosure

Stefan Schreiber has served as a consultant for, and has participated incontinuing medical education events indirectly sponsored by, ShirePharmaceuticals Inc. He has received honoraria for lectures from the Falk-Foundation and has given consultancy advice to Proctor & Gamble Inc.The authors have no other relevant affiliations or financial involvementwith any organization or entity with a financial interest in or financialconflict with the subject matter or materials discussed in the manuscriptapart from those disclosed.

Writing assistance was utilized in the production of this manuscript.The authors acknowledge the contribution of Duncan Campbell(GeoMed) and Mark Richardson (contract writer) for medical writingsupport, Sarah Wright (GeoMed) for editorial assistance and ShirePharmaceuticals Group plc for financial support.

Table 6. Approved indications for MMX mesalamine.

Country/region Therapeutic indication Recommended dosing regimen

USA Induction of remission of active, mild-to-moderate ulcerative colitis 2.4 or 4.8 g/day q.d.

Canada Induction of clinical and endoscopic remission in patients with mild-to-moderate ulcerative colitis

2.4 or 4.8 g/day q.d.

Europe Induction of clinical and endoscopic remission in patients with mild-to-moderate, active ulcerative colitis; and the maintenance of remission

2.4 or 4.8 g/day q.d. (induction) 2.4 g/day q.d. (maintenance)

q.d.: Once daily.

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Key issues

• Ulcerative colitis (UC) is a chronic, idiopathic, inflammatory disease of the colon characterized by an unpredictable relapsing–remitting course.

• The recommended first-line therapy for the treatment of symptoms in patients with active, mild-to-moderate UC, and for maintenance of remission, is 5-aminosalicylic acid (ASA), of which there are a variety of oral and rectal formulations.

• Oral 5-ASA therapies include pH-dependent release, time-dependent controlled-release and diazo-bonded formulations. Although largely effective, the efficacy of many of these therapies can be compromised by poor patient adherence.

• The reasons for poor adherence are multifactorial, but include the number of pills and frequency of dosing. This is important as many conventional oral 5-ASA therapies require multiple daily dosing (three- or four-times daily) and consumption of a large number of tablets or capsules (up to 12 per day).

• Owing to adherence issues, several new oral 5-ASA formulations have been developed with the aim of reducing pill burden, lowering dosing frequency, and/or improving ease and convenience of administration.

• One of these new therapies is mesalamine with MMX Multi Matrix System® (MMX™; hereafter referred to as MMX mesalamine), a new, oral, high-strength (1.2 g/tablet) formulation of 5-ASA designed for once-daily administration. MMX mesalamine utilizes MMX technology designed to provide delayed and prolonged release of 5-ASA throughout the colon.

• The results of pharmacokinetic and pharmacodynamic studies with MMX mesalamine are consistent with a delayed- and prolonged-release 5-ASA formulation.

• Following demonstration of preliminary efficacy in Phase II studies, two large, 8-week, double-blind, placebo-controlled, Phase III clinical trials showed that MMX mesalamine (taken as a once-daily dose of 2.4 or 4.8 g) is an effective treatment for inducing clinical remission and mucosal healing in patients with active, mild-to-moderate UC.

• MMX mesalamine 4.8 g/day was shown to induce remission in the majority of patients who failed to respond to the initial 8 weeks of therapy.

• Extended therapy with MMX mesalamine beyond the recommended 8 weeks in patients who do not respond to initial 5-ASA therapy may prevent escalation to steroids or biologics.

• MMX mesalamine was shown to effectively maintain periods of remission in the vast majority of patients for at least 12 months.

• All oral 5-ASA therapies, including MMX mesalamine, are very well tolerated.

ReferencesPapers of special note have been highlighted as:• of interest•• of considerable interest

1 Neuman MG. Immune dysfunction in inflammatory bowel disease. Transl. Res. 149, 173–186 (2007).

2 Carter MJ, Lobo AJ, Travis SP. Guidelines for the management of inflammatory bowel disease in adults. Gut 53, V1–V16 (2004).

•• Describes current UK guidelines for ulcerative colitis (UC) and recommended treatment strategies.

3 Ghosh S, Shand A, Ferguson A. Ulcerative colitis. Br. Med. J. 320, 1119–1123 (2000).

4 Bitton A. Medical management of ulcerative proctitis, proctosigmoiditis, and left-sided colitis. Semin. Gastrointest. Dis. 12, 263–274 (2001).

5 Ullman TA. Preventing neoplastic progression in ulcerative colitis. J. Clin. Gastroenterol. 39, S66–S69 (2005).

6 Lakatos PL. Recent trends in the epidemiology of inflammatory bowel diseases: up or down? World J. Gastroenterol. 12, 6102–6108 (2006).

7 Loftus EV Jr. Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences. Gastroenterology 126, 1504–1517 (2004).

8 Kornbluth A, Sachar DB. Ulcerative colitis practice guidelines in adults (update): American College of Gastroenterology, practice parameters committee. Am. J. Gastroenterol. 99, 1371–1385 (2004).

•• Describes current US guidelines for UC and recommended treatment strategies.

9 Sutherland L, MacDonald JK. Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis. Cochrane Database Syst. Rev. 2, CD000544 (2006).

10 Sutherland L, MacDonald JK. Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis. Cochrane Database Syst. Rev. CD000543 (2006).

11 Velayos FS, Terdiman JP, Walsh JM. Effect of 5-aminosalicylate use on colorectal cancer and dysplasia risk: a systematic review and metaanalysis of observational studies. Am. J. Gastroenterol. 100, 1345–1353 (2005).

• Supports a protective association between 5-aminosalicylic acid (ASA) and the risk of colorectal cancer (CRC).

12 Qureshi AI, Cohen RD. Mesalamine delivery systems: do they really make much difference? Adv. Drug Deliv. Rev. 57, 281–302 (2005).

13 Stenson WF, Lobos E. Sulfasalazine inhibits the synthesis of chemotactic lipids by neutrophils. J. Clin. Invest. 69, 494–497 (1982).

14 Mahida YR, Lamming CE, Gallagher A, Hawthorne AB, Hawkey CJ. 5-aminosalicylic acid is a potent inhibitor of interleukin 1β production in organ culture of colonic biopsy specimens from patients with inflammatory bowel disease. Gut 32, 50–54 (1991).

15 Rachmilewitz D, Karmeli F, Schwartz LW, Simon PL. Effect of aminophenols (5-ASA and 4-ASA) on colonic interleukin-1 generation. Gut 33, 929–932 (1992).

16 Kaiser GC, Yan F, Polk DB. Mesalamine blocks tumor necrosis factor growth inhibition and nuclear factor κB activation in mouse colonocytes. Gastroenterology 116, 602–609 (1999).

17 Egan LJ, Mays DC, Huntoon CJ et al. Inhibition of interleukin-1-stimulated NF-κB RelA/p65 phosphorylation by mesalamine is accompanied by decreased transcriptional activity. J. Biol. Chem. 274, 26448–26453 (1999).

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18 Ahnfelt-Ronne I, Nielsen OH, Christensen A, Langholz E, Binder V, Riis P. Clinical evidence supporting the radical scavenger mechanism of 5-aminosalicylic acid. Gastroenterology 98, 1162–1169 (1990).

19 Rousseaux C, Lefebvre B, Dubuquoy L et al. Intestinal antiinflammatory effect of 5-aminosalicylic acid is dependent on peroxisome proliferator-activated receptor-γ. J. Exp. Med. 201, 1205–1215 (2005).

20 Lewis JD, Lichtenstein GR, Deren JJ et al. A randomized, placebo-controlled trial of the PPAR-γ ligand rosiglitazone for active ulcerative colitis. Gastroenterology 13(24 Suppl. 1), (2007) (Abstract 639A).

21 Marteau P, Probert CS, Lindgren S et al. Combined oral and enema treatment with Pentasa (mesalazine) is superior to oral therapy alone in patients with extensive mild/moderate active ulcerative colitis: a randomised, double blind, placebo controlled study. Gut 54, 960–965 (2005).

22 Blonski W, Lichtenstein GR. Complications of biological therapy for inflammatory bowel diseases. Curr. Opin Gastroenterol. 22, 30–43 (2006).

23 Katz JA. Treatment of inflammatory bowel disease with corticosteroids. Gastroenterol. Clin. North Am. 33, 171–189vii (2004).

24 Siegel CA, Sands BE. Review article: practical management of inflammatory bowel disease patients taking immunomodulators. Aliment. Pharmacol. Ther. 22, 1–16 (2005).

25 Cohen RD. Review article: evolutionary advances in the delivery of aminosalicylates for the treatment of ulcerative colitis. Aliment. Pharmacol. Ther. 24, 465–474 (2006).

• Review exploring the limitations of current 5-ASA therapies and the evolution of novel oral formulations.

26 Moshkovska T, Mayberry JF. Duration of treatment with 5-aminosalicylic acid compounds. World J. Gastroenterol. 13, 4310–4315 (2007).

27 Azad Khan AK, Piris J, Truelove SC. An experiment to determine the active therapeutic moiety of sulphasalazine. Lancet 2, 892–895 (1977).

28 Hanauer SB. Review article: aminosalicylates in inflammatory bowel disease. Aliment. Pharmacol. Ther. 20(Suppl. 4), 60–65 (2004).

29 Lim WC, Hanauer SB. Controversies with aminosalicylates in inflammatory bowel disease. Rev. Gastroenterol. Disord. 4, 104–117 (2004).

30 Courtney MG, Nunes DP, Bergin CF et al. Randomised comparison of olsalazine and mesalazine in prevention of relapses in ulcerative colitis. Lancet 339, 1279–1281 (1992).

31 Green JR, Gibson JA, Kerr GD et al. Maintenance of remission of ulcerative colitis: a comparison between balsalazide 3 g daily and mesalazine 1.2 g daily over 12 months. ABACUS Investigator group. Aliment. Pharmacol. Ther. 12, 1207–1216 (1998).

32 Levine DS, Riff DS, Pruitt R et al. A randomized, double-blind, dose-response comparison of balsalazide (6.75 g), balsalazide (2.25 g), and mesalamine (2.4 g) in the treatment of active, mild-to-moderate ulcerative coltis. Am. J. Gastroenterol. 97, 1398–1407 (2002).

33 Pruitt RE, Hanson J, Safdi M et al. Balsalazide is superior to mesalamine in the time to improvment in signs and symptoms of acute mild-to-moderate ulcerative colitis. Am. J. Gastroenterol. 97, 3078–3086 (2002).

34 De Vos M, Verdievel H, Schoonjans R, Praet M, Bogaert M, Barbier F. Concentrations of 5-ASA and Ac-5-ASA in human ileocolonic biopsy homogenates after oral 5-ASA preparations. Gut 33, 1338–1342 (1992).

35 Ewe K, Press AG, Oestreicher M. The effect of food intake on the gastric emptying of gastric juice-resistant tablets and capsules. Dtsch. Med. Wochenschr. 117, 287–290 (1992).

36 Kane SV. Systematic review: adherence issues in the treatment of ulcerative colitis. Aliment. Pharmacol. Ther. 23, 577–585 (2006).

• Discusses the reasons for, and consequences of, nonadherence to prescribed UC medication.

37 Nugent SG, Kumar D, Rampton DS, Evans DF. Intestinal luminal pH in inflammatory bowel disease: possible determinants and implications for therapy with aminosalicylates and other drugs. Gut 48, 571–577 (2001).

38 Rochester J, Abreu MT. Ulcerative colitis therapy: importance of delivery mechanisms. Rev. Gastroenterol. Disord. 5, 215–222 (2005).

39 Kane SV, Cohen RD, Aikens JE, Hanauer SB. Prevalence of nonadherence with maintenance mesalamine in quiescent ulcerative colitis. Am. J. Gastroenterol. 96, 2929–2933 (2001).

40 Kane S, Huo D, Aikens J, Hanauer S. Medication nonadherence and the outcomes of patients with quiescent ulcerative colitis. Am. J. Med. 114, 39–43 (2003).

• Explores the effects of nonadherence to prescribed UC medication.

41 Shale MJ, Riley SA. Studies of compliance with delayed-release mesalazine therapy in patients with inflammatory bowel disease. Aliment. Pharmacol. Ther. 18, 191–198 (2003).

42 van Hees PA, van Tongeren JH. Compliance to therapy in patients on a maintenance dose of sulfasalazine. J. Clin. Gastroenterol. 4, 333–336 (1982).

43 Levy RL, Feld AD. Increasing patient adherence to gastroenterology treatment and prevention regimens. Am. J. Gastroenterol. 94, 1733–1742 (1999).

44 Loftus EV Jr. A practical perspective on ulcerative colitis: patients’ needs from aminosalicylate therapies. Inflamm. Bowel. Dis. 12, 1107–1113 (2006).

45 Bernklev T, Jahnsen J, Aadland E et al. Health-related quality of life in patients with inflammatory bowel disease five years after the initial diagnosis. Scand. J. Gastroenterol. 39, 365–373 (2004).

46 Casellas F, Arenas JI, Baudet JS et al. Impairment of health-related quality of life in patients with inflammatory bowel disease: a Spanish multicenter study. Inflamm. Bowel Dis. 11, 488–496 (2005).

47 Han SW, McColl E, Barton JR, James P, Steen IN, Welfare MR. Predictors of quality of life in ulcerative colitis: the importance of symptoms and illness representations. Inflamm. Bowel Dis. 11, 24–34 (2005).

48 Janke KH, Klump B, Gregor M, Meisner C, Haeuser W. Determinants of life satisfaction in inflammatory bowel disease. Inflamm. Bowel Dis. 11, 272–286 (2005).

49 Lialda™ (mesalamine) delayed release tablets, prescribing information. Shire US Inc., Wayne PA USA (2007).

50 Hanauer S, Sandborn W, Kornbluth A et al. Delayed-release oral mesalamine at 4.8 g/day (800 mg tablet) for the treatment of moderately active ulcerative colitis: the ASCEND II trial. Am. J. Gastroenterol. 100, 2478–2485 (2005).

51 Hanauer SB, Sandborn WJ, Dallaire C et al. Delayed-release oral mesalamine 4.8 g/day (800 mg tablets) compared to 2.4 g/day (400 mg tablets) for the treatment of mildly to moderately active ulcerative colitis: The ASCEND I trial. Can. J. Gastroenterol. 21, 827–834 (2007).

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www.expert-reviews.com 313

52 Hanauer S, Schwartz J, Robinson M et al.; Pentasa Study Group. Mesalamine capsules for treatment of active ulcerative colitis: results of a controlled trial. Am. J. Gastroenterol. 88, 1188–1197 (1993).

53 Brunner M, Greinwald R, Kletter K, Kvaternik H, Corrado M, Eichler HMM. Gastrointestinal transit and release of 5-aminosalicylic acid from 153Sm-labelled mesalazine pellets vs. tablets in male healthy volunteers. Aliment. Pharmacol. Ther. 17, 1163–1169 (2003).

54 Wilding I, Behrens C, Tardif S, Wray H, Bias P, Albrecht W. Combined scintigraphic and pharmacokinetic investigation of enteric-coated mesalazine micropellets in healthy subjects. Aliment. Pharmacol. Ther. 17, 1153–1162 (2003).

55 Farup P, Hinterleitner T, Lukas M et al. Mesalazine 4 g daily given as prolonged-release granules twice daily and four times daily is at least as effective as prolonged-release tablets four times daily in patients with ulcerative colitis. Inflamm. Bowel Dis. 7, 237–242 (2001).

• Demonstrates that granules given two- or four-times daily are at least as effective as tablets given four-times daily.

56 Raedler A, Behrens C, Bias P. Mesalazine (5-aminosalicylic acid) micropellets show similar efficacy and tolerability to mesalazine tablets in patients with ulcerative colitis – results from a randomized-controlled trial. Aliment. Pharmacol. Ther. 20, 1353–1363 (2004).

57 Prantera C, Viscido A, Biancone L, Francavilla A, Giglio L, Campieri M. A new oral delivery system for 5-ASA: preliminary clinical findings for MMx. Inflamm. Bowel Dis. 11, 421–427 (2005).

• Preliminary studies indicating comparable results with MMX mesalamine tablets and mesalamine enema.

58 Tenjarla S, Romasanta V, Zeijdner E, Villa R, Moro L. Release of 5-aminosalicylate from the MMX™ mesalamine tablet during transit through a simulated gastrointestinal tract system. Adv. Ther. 24, 826–840 (2007).

•• Investigates the mechanism of action of mesalamine with MMX technology using a simulated GI tract.

59 Pierce D, Martin P, Kern M, Lees K. MMX™ mesalazine: a pharmacokinetic profile following single and multiple doses. Gut 56, (2007) (Abstract MON-G-348).

60 Pierce D, Martin P, Kern M, Lees K. MMX™ mesalazine: a pharmacokinetic evaluation of dose proportionality and the effect of food. Gut 56, (2007) (Abstract MON-G-349).

61 Sandborn WJ, Hanauer SB. Systematic review: the pharmacokinetic profiles of oral mesalazine formulations and mesalazine pro-drugs used in the management of ulcerative colitis. Aliment. Pharmacol. Ther. 17, 29–42 (2003).

62 Brunner M, Assandri R, Kletter K et al. Gastrointestinal transit and 5-ASA release from a new mesalazine extended-release formulation. Aliment. Pharmacol. Ther. 17, 395–402 (2003).

•• Uses γ-scintigraphy to demonstrate continuous release of 5-ASA throughout the colon from 153Sm-labeled MMX mesalamine tablets.

63 Rachmilewitz D. Coated mesalazine (5-aminosalicylic acid) versus sulphasalazine in the treatment of active ulcerative colitis: a randomised trial. BMJ 298, 82–86 (1989).

64 D’Haens G, Hommes D, Engels L et al. Once daily MMX mesalazine for the treatment of mild-to-moderate ulcerative colitis: a Phase II, dose-ranging study. Aliment. Pharmacol. Ther. 24, 1087–1097 (2006).

• Phase II dose-ranging studies for MMX mesalamine.

65 Sutherland LR, Martin F, Greer S et al. 5-Aminosalicylic acid enema in the treatment of distal ulcerative colitis, proctosigmoiditis, and proctitis. Gastroenterology 92, 1894–1898 (1987).

66 Kamm MA, Sandborn WJ, Gassull M et al. Once-daily high concentration MMX mesalamine in active ulcerative colitis. Gastroenterology 132, 66–75 (2007).

•• Pivotal MMX mesalamine Phase III trial data (SPD476-302).

67 Lichtenstein GR, Kamm MA, Boddu P et al. Effect of once- or twice-daily MMX mesalamine (SPD476) for the induction of remission of mild to moderately active ulcerative colitis. Clin. Gastroenterol. Hepatol. 5, 95–102 (2007).

•• Pivotal MMX mesalamine Phase III trial data (SPD476-301).

68 Sandborn WJ, Kamm MA, Lichtenstein GR, Lyne A, Butler T, Joseph RE. Multi Matrix System (MMX®) mesalazine for the induction of remission in patients with mild-to-moderate

ulcerative colitis: a combined analysis of two randomized, double-blind, placebo-controlled trials. Aliment. Pharmacol. Ther. 26, 205–215 (2007).

•• Pooled analysis of data from MMX mesalamine trials 301 and 302 [66,67].

69 Sandborn WJ, Karlstadt RG, Barrett K, Joseph RE. Time to intial symptom resolution withh MMX™ mesalamine therapy for active, mild-to-moderate ulcerative colitis. Am. J. Gastroenterol. 102, (2007) (Abstract 619).

70 Froslie KF, Jahnsen J, Moum BA, Vatn MH. Mucosal healing in inflammatory bowel disease: results from a Norwegian population-based cohort. Gastroenterology 133, 412–422 (2007).

71 Meucci G, Fasoli R, Saibeni S et al. Prognostic significance of endoscopy remission in patients with active ulcerative colitis treated with oral and topical mesalazine: preliminary results of a prospective, multicenter study. Gastroenterology 130, A-197 (2006) (Abstract S1302).

72 Gassull M, Lichtenstein G, Sandborn W, Kamm M, Barrett K, Joseph R. MMX Mesalazine is an effective treatment for men and women with mild-to-moderate, active ulcerative colitis. J. Crohn’s Colitis Suppl. 1(18), P057 (2007).

73 Kamm MA, Lichtenstein GR, Sandborn WJ et al. SPD476, a novel formulation of 5-ASA given once or twice daily, is effective for the induction of remission of left-sided and extensive ulcerative colitis: an analysis of combined data from two pivotal, randomized, placebo-controlled Phase III studies. Gastroenterology 130(4 Suppl. 2), A484 (2006) (Abstract T1148).

74 Lichtenstein GR, Kamm MA, Sandborn WJ et al. Once- and twice-daily SPD476, a novel, high-strength formulation of 5-ASA, induces remission of both mild and moderate ulcerative colitis: a prespecified analysis of combined data from two pivotal, randomized, placebo-controlled, Phase III studies. Gastroenterology 130(4 Suppl. 2), A-484 (2006) (Abstract T1147).

75 Sandborn WJ, Kamm MA, Lichtenstein GR et al. SPD476, a novel, high-strength 5-ASA formulation induces remission of active, mild-to-moderate ulcerative colitis in subjects that are switched from low-dose oral 5-ASA therapy or are 5-ASA naive: an analysis of pooled data from two Phase III studies. Gastroenterology 130(4 Suppl. 2), A482 (2006) (Abstract T1139).

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• Indicates that MMX mesalamine is effective in 5-ASA naive patients, and those switching from previous 5-ASA therapies, and may improve compliance.

76 Kamm MA, Lichtenstein GR, Sandborn WJ et al. Randomized trial of once- or twice-daily MMX™ mesalamine for maintenance of remission in ulcerative colitis. Gut (2008) (In Press).

77 Kamm MA, Colombel J.-F, Kornbluth A et al. A randomized comparison of once- versus twice-daily MMX mesalamine for the maintenance of remission in mild-to-moderate ulceratice colitis. Gastroenterology 132, A510 (2007) (Abstract T1296).

78 Lichtenstein GR, Kamm MA, Panaccione R, Barrett K, Lees K, Joseph R. The effect of prolonged therapy with MMX™ mesalamine in patients with acute, mild-to-moderate ulcerative colitis. Am. J. Gastroenterol. 102, S2 (2007) (Abstract 953).

79 Kruis W, Bar-Meir S, Feher J et al. The optimal dose of 5-aminosalicylic acid in active ulcerative colitis: a dose-finding study with newly developed mesalamine. Clin. Gastroenterol. Hepatol. 1, 36–43 (2003).

80 Panaccione R, Kamm M, Karlstadt RG, Diebold R, Barrett K, Joseph RE. Once- or twice-daily MMX™ mesalamine for the maintenance of remission of mild or moderate ulcerative colitis. Am. J. Gastroenterol. 102, (2007) (Abstract 950).

81 Lichtenstein G, Kamm MA, Karlstadt RG, Diebold R, Barrett K, Joseph R. MMX™ mesalamine is effective for the maintenance of ulcerative colitis remission in both left sided and extensive disease. Am. J. Gastroenterol. 102(Suppl. 2), 1049–1058 (2007) (Abstract 949).

82 Hanauer SB, Kamm MA, Diebold R, Barrett K, Joseph RE. Long-term remission rates in patients with mild-to-moderate ulcerative colitis who require an MMX™ mesalamine dose increase to induce initial remission. Am. J. Gastroenterol. 102, (2007) (Abstract 614).

83 Sandborn WJ, Karlstadt RG, Barrett K, Joseph RE. MMX™ mesalamine is effective for the maintenance of remission of mild-to-moderate ulcerative colitis

irrespective of patients’ previous relapse history. Am. J. Gastroenterol. 102, (2007) (Abstract 283).

84 Lichtenstein GR, Diebold R, Karlstadt RG, Barrett K, Joseph RE. Patients with quiescent mild-to-moderate ulcerative colitis receiving a multiple-daily dose 5-aminosalicylic acid formulation can maintain remission with once- or twice-daily MMX® mesalamine. Gastroenterology 132, A-510 (2007) (Abstract T1295).

85 Lichtenstein G, Katz S, Christenson A, Lees K, Barrett K, Joseph R. Safety of MMX mesalamine, a novel, once-daily 5-aminosalicylic acid (5-ASA) formulation for the treatment of ulcerative colitis, following 8 weeks’ treatment: data from three Phase III studies. J. Am. Pharm. Assoc. 47, 210–211 (2007).

86 Adachi E, Okazaki K, Matsushima Y et al. Acute pancreatitis secondary to 5-aminosalicylic acid therapy in a patient with ulcerative colitis. Int. J. Pancreatol. 25, 217–221 (1999).

87 Decocq G, Gras-Champel V, Vrolant-Mille C et al. Acute pancreatitis induced by drugs derived from 5-aminosalicylic acid: case report and review of the literature. Therapie 54, 41–48 (1999).

88 Lankisch PG, Droge M, Gottesleben F. Drug induced acute pancreatitis: incidence and severity. Gut 37, 565–567 (1995).

89 Marteau P, Nelet F, Le Lu M, Devaux C. Adverse events in patients treated with 5-aminosalicyclic acid: 1993–1994 pharmacovigilance report for Pentasa in France. Aliment. Pharmacol. Ther. 10, 949–956 (1996).

90 Kamm MA, Lichtenstein GR, Sandborn WJ, Barrett K, Joseph R. MMX™ mesalazine is well tolerated during 12 months’ maintenance treatment of mild-to-moderate ulcerative colitis. Gut 56, A113 (2007).

Websites

101 Crohn’s and Colitis Foundation of America (CCFA). What is IBD? Possible complications.www.ccfa.org/info/about/complications

102 Sandborn WJ. New advances in 5-ASA therapy for ulcerative colitis. Advances in Inflammatory Bowel disease (Volume 4).www.medscape.com/viewarticle/553568

103 Pentasa® Sachet 1g prolonged release granules. UK summary of product characteristics.www.ferring.co.uk/index.php?option=com_docman&task=doc_download&gid=24&Itemid=52

104 Answers to your questions about Asacol 800®.www.pharmacygateway.ca/pdfs/2007/05/pg_qa_asacol_en_may07.pdf

105 Merckle Recordati GmbH. Calversal micropellets 1.5 g.www.merckle-recordati.de/

106 Onmeda, Medikament. Salofalk 500–1000 mg Granu-Stix.http://medikamente.onmeda.de/Medikament/Salofalk+500+mg%7C-1000+mg+Granu-Stix+.htm

Affiliations

• Stefan SchreiberProfessor of Medicine & Gastroenterology, Institute for Clinical Molecular Biology, Center for Conservative Medicine, Schittenhelmstr. 12, 24105, Kiel, GermanyTel.: +49 431 597 2350Fax: +49 431 597 [email protected]

• Michael A KammProfessor of Gastroenterology, St Vincent’s Hospital, Melbourne, Australia;and, Imperial College London, London, UKTel.:+ 61 392 882 574Fax: +61 392 882 [email protected]

• Gary R LichtensteinProfessor of Medicine, Division of Gastroenterology, Department of Medicine, University of Pennsylvania School of Medicine, 3400 Spruce Street, 3rd Floor Ravdin Building, Philadelphia, PA 19104-4283, USATel.: +1 215 349 8222Fax: +1 215 349 [email protected]