Inflammatory bowel disease
`
`Randomised trial of once- or twice-daily MMX
`mesalazine for maintenance of remission in
`ulcerative colitis
`
`M A Kamm,1 G R Lichtenstein,2 W J Sandborn,3 S Schreiber,4 K Lees,5 K Barrett,6
`R Joseph5
`
`ABSTRACT
`Aim: Maintenance treatment in ulcerative colitis should
`be as convenient as possible, to increase the chance of
`compliance. MMX mesalazine is a once-daily, high-
`strength (1.2 g/tablet) formulation of 5-aminosalicylic
`acid. This study evaluated the safety and efficacy of MMX
`mesalazine dosed once or twice daily as maintenance
`therapy in patients with ulcerative colitis.
`Methods: This multicentre, randomised, open-label trial
`enrolled patients with strictly defined clinical and
`endoscopic remission, immediately following an episode
`of mild to moderate ulcerative colitis. Patients were
`randomised to MMX mesalazine 2.4 g/day as a single
`(261.2 g tablet) or divided dose (161.2 g tablet twice
`daily) for 12 months.
`Results: 174 patients (37.9%; safety population n = 459)
`experienced 384 adverse events, the majority of which
`were mild or moderate in intensity. Eighteen patients
`(3.9%), nine in each group, experienced a total of 22
`serious adverse events (10 in the once-daily and 12 in the
`twice-daily group). Most serious adverse events were
`gastrointestinal, experienced by 5 patients in the once-
`daily and 4 in the twice-daily group. At month 12, 64.4%
`(efficacy population, n = 451) of patients in the once-daily
`and 68.5% of patients in the twice-daily group were in
`clinical and endoscopic remission (p = 0.351). At month
`12, 88.9% and 93.2% in each group, respectively, had
`maintained clinical remission (were relapse free).
`Conclusions: MMX mesalazine 2.4 g/day administered
`as a single or divided dose demonstrated a good safety
`profile, was well tolerated and was effective as
`maintenance treatment. High clinical and endoscopic
`remission rates can be achieved with once-daily dosing.
`Trial registration number: NCT00151944.
`
`Mesalazine (5-aminosalicylic acid; 5-ASA), is the
`standard therapy for maintaining remission in
`ulcerative colitis (UC).1 2 Although currently avail-
`able mesalazine preparations have been shown to
`maintain remission, many patients are poorly
`compliant.3–7 Patients with quiescent UC who are
`non-compliant with maintenance 5-ASA therapy
`have been shown to have a fivefold greater risk of
`patients.3
`disease
`flare-ups
`than
`compliant
`Increased disease activity impacts on patient health
`and quality of life, may have economic conse-
`quences through loss of productivity or earnings,
`and results in increased hospitalisations, doctors
`visits and drug costs.8–13 In addition, regular 5-ASA
`use may reduce the risk of developing colorectal
`cancer,14 either through decreased disease activ-
`ity15 16 or through a direct anticarcinogenic effect.17
`
`As compliance is such a major factor in disease
`control,4 6 7 18 it is important to understand what
`drives non-adherence and what patients want from
`their medication. In a recently published internet-
`based survey of 1595 patients with UC receiving 5-
`ASA therapy, reasons for poor compliance included
`forgetting to take medication (stated by .90% of
`patients), ‘‘too many pills’’, ‘‘dosing required too
`many times each day’’,
`‘‘medication too incon-
`venient’’ and ‘‘no symptoms present’’,19 confirming
`the results of previous studies.3 6 20 21 In the internet
`survey, patients also expressed a wish for con-
`venient, simple dosing regimens.19 Nearly a quarter
`(23%) of the patients surveyed considered fewer
`pills and less frequent dosing as ‘‘very important’’
`attributes when selecting a treatment for their
`disease, and more than one-third (34%) considered
`convenience to be very important. A mesalazine
`preparation that involves the ingestion of fewer
`tablets, less often, might therefore be considered
`likely to impact favourably on compliance with
`maintenance therapy.
`In early 2007, mesalazine with MMX Multi
`Matrix System (MMX) technology (Lialda (Shire
`Pharmaceuticals Inc., Wayne, Pennsylvania, USA),
`hereafter referred to as MMX mesalazine) was
`approved in the USA for the induction of remission
`of mild to moderate UC in a once-daily oral dose.
`In Europe, MMX mesalazine (Mezavant XL in the
`UK; Mezavant elsewhere in the EU) has been
`approved for the induction and maintenance of
`clinical and endoscopic remission in patients with
`active, mild to moderate UC. This high-strength
`formulation of 5-ASA (1.2 g tablet) utilises MMX
`technology comprising lipophilic and hydrophilic
`excipients enclosed within a gastro-resistant, pH-
`dependent coating.22 23 The gastro-resistant film,
`covering the tablet core, delays the initial release of
`5-ASA until the tablet is exposed to pH 7 or higher,
`normally in the terminal
`ileum. As the gastro-
`resistant coating disintegrates, it is thought that
`intestinal
`fluids interact with the hydrophilic
`excipient causing the tablet to swell (much like a
`sponge in water) and form an outer viscous gel
`mass. The viscous gel mass is believed to slow
`diffusion of the 5-ASA from the tablet core into the
`colonic lumen. As the tablet core and its surround-
`ing gel mass progress through the colon,
`it is
`thought that pieces of the gel mass gradually break
`away from the core, releasing 5-ASA. It is supposed
`that the lipophilic excipient slows the penetration
`of aqueous fluids into the tablet core, reducing the
`rate of dissolution and thus prolonging therapeutic
`
`1 Department of Medicine, St
`Vincent’s Hospital, Melbourne,
`Australia; 2 Division of
`Gastroenterology, University of
`Pennsylvania, Philadelphia, USA;
`3 Inflammatory Bowel Disease
`Clinic, Mayo Clinic, Rochester,
`Minnesota, USA; 4 First
`Department of Medicine,
`Christian-Albrechts-Universita¨t,
`Kiel, Germany; 5 Shire
`Pharmaceuticals Inc., Wayne,
`Philadelphia, USA; 6 Shire
`Pharmaceuticals Inc.,
`Basingstoke, Hampshire, UK
`
`Correspondence to:
`Professor M A Kamm, St
`Vincent’s Hospital, University
`Department of Medicine,
`Victoria Parade, Fitzroy 3065,
`Melbourne, Australia; Kamm@
`ic.ac.uk
`
`Revised 28 January 2008
`Accepted 28 January 2008
`Published Online First
`13 February 2008
`
`This paper is freely available
`online under the BMJ Journals
`unlocked scheme, see http://
`gut.bmj.com/info/unlocked.dtl
`
`Gut 2008;57:893–902. doi:10.1136/gut.2007.138248
`
`893
`
`GeneriCo, Flat Line Capital
`Exhibit 1063 Page 1
`
`

`
`Inflammatory bowel disease
`
`activity. The combination of the high dose of 5-ASA per tablet
`coupled with the MMX drug delivery technology allows an
`effective dose of 5-ASA to be delivered throughout the colon in a
`single daily dose.
`In two previous phase III, randomised, placebo-controlled
`studies, by Lichtenstein et al24 (SPD476-301) and Kamm et al25
`(SPD476-302), MMX mesalazine given as 2.4 g once daily, 1.2 g
`twice daily or 4.8 g once daily was shown to be effective for the
`induction of clinical and endoscopic remission in patients with
`active, mild to moderate UC. To date, no data regarding the
`long-term safety or efficacy of MMX mesalazine, or any other
`oral 5-ASA, given once daily, have been published as a full
`article. This
`study (SPD476-303
`(clinical
`trial
`registry
`web address as of 21 July 2007: http://www.clinicaltrial.gov/
`ct/show/NCT00151944?order = 1))
`aimed
`to
`investigate
`and compare the long-term safety and efficacy of mainte-
`nance MMX mesalazine 2.4 g/day, given either as a once-daily or
`a twice-daily divided dose in patients with UC in remission.
`
`METHODS
`Patients
`Male and female patients were entered into this maintenance
`study following the induction of remission after an acute flare
`of mild to moderate UC. Patients were enrolled directly
`following up to 8 weeks’ treatment for acute disease, in the
`studies reported by Lichtenstein et al and Kamm et al,24 25
`hereafter referred to as the ‘‘parent studies’’, or following a
`further 8-week extension, study 303. Patients who achieved
`clinical and endoscopic remission (defined as a modified UC
`Disease Activity Index (UC-DAI) score of (1, with rectal
`bleeding and stool
`frequency scores of 0; a combined
`Physician’s Global Assessment (PGA) and sigmoidoscopy score
`of (1, no mucosal friability and an additional requirement
`for a >1-point reduction from baseline in sigmoidoscopy
`score) during the parent studies could directly enter into the
`12-month,
`randomised maintenance phase of
`this study.
`Patients not in remission by the end of the parent studies,
`and those who withdrew early after week 2, could enter an
`8-week extension phase of study 303 and receive open-label
`MMX mesalazine 4.8 g/day (2.4 g given twice daily)
`for
`8 weeks. Patients in remission at the end of this 8-week
`extension phase were then eligible to enter the randomised
`maintenance phase.
`Although not defined in the protocol, some additional
`patients who were not in strictly defined remission (as above),
`but deemed by their doctor to be well enough at the end of the
`parent studies or the 8-week extension phase, could enter the
`randomised maintenance phase of study 303.
`All patients were required to have a satisfactory medical
`assessment, with no clinically relevant abnormality other than
`UC. Patients withdrawn from the parent studies, because of a
`severe or serious adverse event (SAE), were not eligible. Co-
`administration of corticosteroids (systemic or rectal), other
`formulations containing 5-ASA, or immunosuppressants were
`not permitted.
`The study was conducted in accordance with current applicable
`regulations and Good Clinical Practice (GCP) guidelines, and
`complied with the principles of the amended Declaration of
`Helsinki. The institutional review board or ethics committee at
`each site approved the protocol and subsequent amendments. All
`patients gave written, informed consent.
`Here we describe the study design and results for the
`12-month, randomised maintenance phase.
`
`Study design
`Patients entering this 12-month maintenance study were
`randomised via an interactive voice recognition system to
`unblinded therapy with either MMX mesalazine 2.4 g/day
`(given once daily) or MMX mesalazine 2.4 g/day (1.2 g given
`twice daily). Patients entered through the two parent studies,
`which recruited patients from 101 centres across 19 countries
`(Australia (n = 3),
`the Czech Republic
`(n = 16), Estonia
`(n = 10), France (n = 3), Germany (n = 10), Hungary (n = 31),
`India (n = 71), Israel (n = 14), Latvia (n = 9), Lithuania (n = 14),
`Mexico, including Costa Rica (n = 18), New Zealand (n = 12),
`Poland (n = 132), Romania (n = 11), Russia (n = 113), Spain
`(n = 7), the Ukraine (n = 78) and the USA (n = 71)). The
`enrolment and treatment of patients during the current study
`are summarised in fig 1.
`Patients visited the clinic at month 0 (this visit was the same
`as the end-of-study visit of the parent studies, or the end-of-
`study visit of the 8-week extension phase of study 303), and
`then at months 1, 3, 6, 9 and 12. At month 0, patients had: a
`physical examination; haematology, biochemistry and urine
`evaluation; sigmoidoscopy, symptoms assessment, PGA, drug
`compliance check (by pill count), adverse event (AE) review and
`concomitant medication review. Vital signs were also recorded
`and, if applicable, a pregnancy test was performed. Patients
`reported rectal bleeding and stool frequency symptoms (as
`outlined by the modified UC-DAI) for the last available 3 days
`prior to the visit. Data older than 5 days were not used.
`Sigmoidoscopy was performed and inflammation scored in the
`worst inflamed area in the rectum, or in the sigmoid colon if the
`rectum was not inflamed.
`During the clinic visits at months 1, 3, 6, 9 and 12 (or at the
`early withdrawal visit), all of the above assessments were
`carried out, excluding sigmoidoscopy and PGA, which were only
`performed at the final study visit.
`
`Primary objectives and outcomes
`Given the lack of previous safety data for once-daily main-
`tenance mesalazine therapy, including MMX mesalazine, the
`pre-defined primary objective of this study was to assess the
`safety and tolerability of the two dosage regimens over
`12 months,
`including AEs, treatment exposure and time to
`withdrawal.
`All AEs were considered to be ‘‘treatment-emergent’’, as all
`patients were being actively treated in the study. AEs were
`defined as any untoward medical occurrence in a clinical
`investigation subject who was administered a pharmaceutical
`product and which did not necessarily have a causal
`relationship with this treatment. It could, therefore, be any
`unfavourable and unintended sign (including an abnormal
`laboratory finding), symptom, disease or exacerbation of the
`pre-existing condition temporally associated with the use of
`the medication.
`In addition, AEs could be defined as ‘‘treatment-related’’ and
`were defined as either (1) possibly related to study drug (ie,
`there may have been some temporal relationship between the
`event and the administration of the investigational product but
`there remained some ambiguity as to the cause) or (2) probably
`related to study drug (ie, the temporal relationship between
`the event and the administration of the investigational product
`was compelling, and/or
`followed a known or suspected
`response pattern to that product, and the event could not be
`explained by the subject’s medical condition, other therapies or
`accident).
`
`894
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`Gut 2008;57:893–902. doi:10.1136/gut.2007.138248
`
`GeneriCo, Flat Line Capital
`Exhibit 1063 Page 2
`
`

`
`Inflammatory bowel disease
`
`Figure 1
`(A) Overall study design
`(safety population) and (B) patient flow in
`the 12-month, randomised, maintenance
`phase of study SPD-476-303. *Patients
`excluded from the efficacy population
`because of study centre Good Clinical
`Practice non-compliance. {The ‘‘per-
`protocol’’ population included only those
`patients in the efficacy population who
`met the strict protocol-defined criteria for
`remission. AEs, adverse events;
`SAEs, serious adverse events.
`
`All AEs were also classified according to severity:
`c Mild: the AE was easily tolerated and did not interfere with
`usual activity
`c Moderate: the AE interfered with daily activity but the
`subject was still able to function
`c Severe: the AE was incapacitating and the subject was
`unable to work or complete usual activity.
`SAEs were defined as any untoward medical occurrence
`(whether considered to be related to the investigational product
`or not) that at any dose: resulted in death; was life-threatening
`(the subject was at risk of death at the time of the event);
`
`required inpatient hospitalisation or prolongation of existing
`hospitalisation; resulted in persistent or significant disability/
`incapacity; or resulted in a congenital abnormality/birth defect.
`
`Secondary objectives and outcomes
`Predefined secondary outcome measures included comparisons
`between the two treatment groups for: the proportion of
`patients in remission (as defined in the parent studies (above))
`at 12 months, and the components of the modified UC-DAI
`score (eg, sigmoidoscopy score).
`
`Gut 2008;57:893–902. doi:10.1136/gut.2007.138248
`
`895
`
`GeneriCo, Flat Line Capital
`Exhibit 1063 Page 3
`
`

`
`Inflammatory bowel disease
`
`Assessment of compliance was a predefined analysis whereby
`patients taking >80% of their prescribed study medication were
`considered compliant. Compliance with study medication was
`calculated by pill count.
`The UC-DAI (which comprises rectal bleeding, stool frequency,
`sigmoidoscopy and PGA scores, each assessed on a scale of 0–3 and
`summed to give a total score of 0–12, as defined by Sutherland et
`al 26) was modified in the parent studies and in this study, so that
`patients who presented with mucosal friability were given a score
`of 2 rather than 1. Using this amended scale, mucosal appearance
`was graded according to the modified UC-DAI, where a score of
`0 = normal; 1 (mild) = erythema, decreased vascular pattern
`and minimal granularity; 2 (moderate) = marked erythema,
`friability, granularity, absent vascular pattern, bleeding with
`minimal trauma and no ulcerations; 3 (severe) = ulceration and
`spontaneous bleeding. Thus, patients with any mucosal friability
`were deemed not to be in remission. The PGA is a doctor-based
`evaluation that considers the scores for rectal bleeding, stool
`frequency and sigmoidoscopy together with the patient’s general
`well-being and abdominal discomfort.
`
`Study populations
`The safety population was defined as all patients who received
`at least one dose of study medication. The efficacy population
`(‘‘intention-to-treat’’) consisted of all patients who received at
`least one dose of study medication, other than those patients
`coming from three study sites who, as previously described,24
`were excluded due to GCP non-compliance.
`A retrospectively defined population, hereafter referred to as
`the ‘‘per-protocol’’ population,
`included all patients in the
`efficacy population who met the strict protocol-defined criteria
`for remission (ie, excluded those patients who were not in
`remission as defined by the protocol, but were enrolled in the
`maintenance phase as they were deemed by their doctor to be
`well enough to receive maintenance treatment).
`
`Statistical analyses
`This study was not designed as a clinical non-inferiority study
`with minimally acceptable differences between the two treat-
`ment regimens. The sample size was dependent on the number
`of patients in clinical and endoscopic remission (defined above)
`at the end of the parent studies, or at the end of the 8 weeks of
`additional therapy with MMX mesalazine 4.8 g/day. As a result
`of this design, no sample size calculation was performed.
`Categorical values were summarised using frequencies and
`percentages, and all statistical comparisons were considered
`exploratory.
`Relapse was defined as a requirement for alternative treat-
`ment for UC, including surgery or an increase in the dose of
`MMX mesalazine above 2.4 g/day. The proportion of patients
`who were in remission at month 12 was compared between the
`two treatment groups using the x2 test. All safety summaries
`were presented for the safety population. Adverse events were
`coded using the Medical Dictionary for Regulatory Activities
`(MeDRA) version 5.1. Time to withdrawal was analysed by
`Kaplan–Meier methodology and measured from the date of the
`first dose of study medication to the withdrawal date.
`Treatment differences were analysed using a log-rank test.
`
`parent studies and 213 patients who received an additional
`8 weeks of treatment with MMX mesalazine 4.8 g/day) were
`enrolled and randomised (fig 1A).
`All patients were evaluable for safety. Eight patients (6 from
`the once-daily group and 2 from the twice-daily group) were
`excluded from the efficacy population because of non-compli-
`ance and GCP issues. A further 89 patients were excluded from
`the ‘‘per-protocol’’ population because they did not meet the
`strict protocol-defined criteria for remission. Three hundred and
`sixty-two patients were included in the ‘‘per-protocol’’ popula-
`tion, 171 in the MMX mesalazine once-daily group and 191 in
`the MMX mesalazine divided-dose group (fig 1B).
`Overall, 182 (80.9%) patients in the once-daily group and 195
`(83.3%) in the twice-daily group completed the study. The most
`common reason for discontinuation in both dose groups was
`lack of efficacy/relapse.
`
`Patient demographics
`Baseline demographic characteristics and UC history data were
`similar for patients in both dose groups (table 1). There were no
`clinically relevant differences between the two groups with
`regard to the frequency and type of concomitant medication
`taken during the study.
`
`Safety
`Extent of exposure
`There was no difference between the two treatment groups
`with regard to the mean (SD) duration of exposure to study
`treatment (47.6 (11.1) weeks in the once-daily group and 47.6
`(11.4) weeks in the twice-daily group). Although there was a
`slight gradual decrease in retention (related to the clinical
`relapse rate) over the 12-month treatment period, the retention
`rate was in excess of 90% for the first 6 months and was almost
`80% for the remainder of the study. The mean (SD) duration of
`exposure to study treatment was also similar in patients
`entering directly from the parent studies versus those entering
`from the 8-week extension phase (48.4 (9.2) weeks vs 46.6
`(13.2) weeks, respectively).
`
`Treatment-emergent AEs
`Overall, 174 patients (37.9%) experienced a total of 384 AEs, the
`majority of which were mild or moderate in intensity. There
`were no notable differences between treatment groups with
`regard to the number and types of AE experienced (table 2). The
`most frequent AEs were gastrointestinal disorders. Twelve
`patients (2.6%) had 14 severe AEs. Most severe AEs were
`gastrointestinal disorders (7 patients (1.5%)), which occurred to
`a greater extent in the once-daily group (6 patients (2.7%)) than
`the twice-daily group (1 patient (0.4%)). Only one SAE was
`considered to be possibly or probably related to study treatment
`(see below).
`
`Treatment-related AEs
`Forty-seven patients (10.2%) experienced 76 treatment-related
`AEs. There were no notable differences between treatment
`groups with regard to the number and type of treatment-related
`AEs (table 2). The most frequent treatment-related AEs were
`gastrointestinal disorders.
`
`RESULTS
`Patient flow
`The study was conducted between 26 November 2003 and
`13 March 2006. A total of 459 patients (246 directly from the
`
`SAEs
`Eighteen patients (3.9%), nine in each group, experienced a total
`of 22 SAEs (10 in the once-daily group and 12 in the twice-daily
`group) (table 2). Most SAEs were gastrointestinal disorders,
`
`896
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`Gut 2008;57:893–902. doi:10.1136/gut.2007.138248
`
`GeneriCo, Flat Line Capital
`Exhibit 1063 Page 4
`
`

`
`Table 1 Demographics and baseline characteristics on entry into the parent studies (safety population)
`
`MMX mesalazine 2.4 g/day
`(given once daily) (n = 225)
`
`MMX mesalazine 2.4 g/day (1.2 g
`given twice daily) (n = 234)
`
`Inflammatory bowel disease
`
`Male n (%)
`Mean (SD) age, years
`Non-/previous smoker, n (%)
`Caucasian, n (%)
`Diagnosis, n (%)
`Newly diagnosed
`History of UC
`Mean (SD) time since diagnosis, weeks
`Relapses in last 2 years, n (%)
`0–2
`3–6
`>7
`Missing
`Classification of disease*, n (%)
`Left-sided
`Upper limit in transverse colon
`Pancolitis
`Baseline modified UC-DAI score (at parent study entry),
`mean (SD)
`Treatment received in parent studies, n (%)
`Placebo
`MMX mesalazine 2.4 g/day
`MMX mesalazine 4.8 g/day
`Asacol
`
`106 (47.1)
`42.4 (12.1)
`213 (94.7)
`193 (85.8)
`
`32 (14.2)
`193 (85.8)
`244.5 (314.1)
`
`135 (60.0)
`76 (33.8)
`4 (1.8)
`10 (4.4)
`
`175 (77.8)
`14 (6.2)
`36 (16.0)
`6.3 (1.5)
`
`57 (25.3)
`68 (30.2)
`72 (32.0)
`28 (12.4)
`
`*Based on patient disease history.
`UC, ulcerative colitis; UC-DAI, UC Disease Activity Index.
`
`114 (48.7)
`42.6 (13.2)
`215 (91.9)
`202 (86.3)
`
`34 (14.5)
`200 (85.5)
`288.4 (338.8)
`
`144 (61.5)
`82 (35.0)
`5 (2.1)
`3 (1.3)
`
`179 (76.5)
`14 (6.0)
`40 (17.1)
`6.5 (1.4)
`
`61 (26.1)
`67 (28.6)
`70 (29.9)
`36 (15.4)
`
`which were experienced by 5 (2.2%) patients in the once-daily
`group and 4 (1.7%)
`in the twice-daily group. One SAE
`(abnormal liver function tests) in the once-daily group was
`assessed as possibly related to treatment, leading to the patient
`being withdrawn from the study at the month 1 visit. This
`patient was noted to have elevated alkaline phosphatase (ALP;
`138 U/l; normal range 31–121 U/l), aspartate transaminase
`(AST; 561 U/l; normal range 1–32 U/l) and alanine amino-
`transferase (ALT; 1058 U/l) values at month 1. Viral screening
`revealed a positive latex test for infectious mononucleosis.
`
`Discontinuations due to AEs
`Twenty-one patients (4.6%) experienced 23 AEs that led to
`withdrawal (11 patients (4.9%) in the once-daily group and 10
`patients (4.3%) in the twice-daily group). Most AEs that led to
`withdrawal were gastrointestinal disorders (9 (4.0%) patients in
`the once-daily group and 6 (2.6%) in the twice-daily group).
`Eleven patients were withdrawn due to SAEs (5 patients in the
`once-daily group and 6 in the twice-daily group). One patient
`died due to electric shock.
`
`Time to withdrawal
`There was no significant difference (p = 0.62) between the two
`groups in relation to the time to withdrawal, with a small and
`gradual decrease in retention rate being observed over the 12-
`month treatment period. The retention rate was in excess of
`90% for the first 6 months of the maintenance phase and was in
`excess of 80% for the remainder of the study.
`
`Other safety parameters
`There were no remarkable changes in vital signs or clinical
`laboratory parameters in either treatment group.
`
`Remission
`Overall remission
`In the efficacy population, 78.1% of patients in the once-daily
`group and 82.3% of patients in the divided-dose group were in
`clinical and endoscopic remission at entry (month 0) according
`to the strict criteria employed in this study (fig 2). At month 12,
`64.4% of patients in the once-daily group and 68.5% of patients
`in the divided-dose group were in strictly defined clinical and
`endoscopic remission (fig 2). There was no significant difference
`between the two treatment groups (p = 0.351, odds ratio (OR)
`0.83 (95% CI 0.56 to 1.23)).
`In the ‘‘per-protocol’’ population in which, by definition,
`100% of patients in both groups met the strict remission criteria
`at month 0, endoscopic and clinical remission were maintained
`at month 12 in 67.8% of patients in the once-daily group and
`72.3% of patients in the divided-dose group (p = 0.359, OR 0.81
`(95% CI 0.52 to 1.27)).
`
`Remission by entry route and previous treatment in the parent
`studies
`In the efficacy population, of those patients who entered the
`maintenance phase directly via the parent studies, 75.8% were
`in remission at month 12 compared with 55.9% of patients who
`entered via the 8-week extension phase (p,0.0001). Similar
`results were seen in the ‘‘per-protocol’’ population (80.7% vs
`59.7%, respectively; p,0.0001).
`In the efficacy population, remission rates for both dosing
`regimens were similar for patients entering via the parent
`studies (74.6% once daily vs 77.0% twice daily, p = 0.655, OR
`0.87 (95% CI 0.48 to 1.58)) or via the 8-week extension study,
`(52.5% once daily vs 59.1% twice daily, p = 0.334, fig 3).
`Similarly, in the ‘‘per-protocol’’ population, remission rates for
`both dosing regimens were similar for patients entering via the
`
`Gut 2008;57:893–902. doi:10.1136/gut.2007.138248
`
`897
`
`GeneriCo, Flat Line Capital
`Exhibit 1063 Page 5
`
`

`
`Inflammatory bowel disease
`
`Table 2 Summary of treatment-emergent and treatment-related adverse events occurring in >2 and >1% of
`patients, respectively, in any treatment group in the safety population
`
`Number (%) of patients
`
`MMX mesalazine 2.4 g/day (given
`once daily) (n = 225)
`
`MMX mesalazine 2.4 g/day (1.2 g
`given twice daily) (n = 234)
`
`Any AE
`Aggravated UC
`Abdominal pain (NOS)
`Abdominal pain upper
`Nasopharyngitis
`Pharyngitis
`Headache
`Any mild AE
`Any moderate AE
`Any severe AE
`Any SAE
`Any AE leading to withdrawal
`Any AE leading to death
`Any treatment-related AE
`Abdominal pain (NOS)
`Colitis ulcerative aggravated
`Diarrhoea (NOS)
`Abdominal pain upper
`Summary of SAEs
`Angina pectoris
`Pulmonary oedema
`UC
`Chronic hepatitis
`Lung abscess
`Pneumonia
`Electric shock
`Abnormal liver function test
`Cerebral infarction
`Aggravated depression
`Menometrorrhagia
`Ovarian cyst
`COPD exacerbation
`
`88 (39.1)
`24 (10.7)
`5 (2.2)
`1 (0.4)
`3 (1.3)
`5 (2.2)
`2 (0.9)
`62 (27.6)
`44 (19.6)
`7 (3.1)
`9 (4.0)
`11 (4.9)
`0 (0.0)
`25 (11.1)
`3 (1.3)
`4 (1.8)
`3 (1.3)
`1 (0.4)
`
`0
`0
`5
`1
`0
`0
`0
`1
`1
`0
`1
`1
`0
`
`86 (36.8)
`18 (7.7)
`4 (1.7)
`5 (2.1)
`5 (2.1)
`2 (0.9)
`5 (2.1)
`63 (26.9)
`38 (16.2)
`5 (2.1)
`9 (3.8)
`10 (4.3)
`1 (0.4)
`22 (9.4)
`2 (0.9)
`1 (0.4)
`2 (0.9)
`3 (1.3)
`
`1
`1
`4
`0
`1
`2
`1
`0
`0
`1
`0
`0
`1
`
`AE, adverse event; COPD, chronic obstructive pulmonary disease; NOS, not otherwise specified; SAE, serious adverse event;
`UC, ulcerative colitis.
`
`Figure 2 Remission rates at month 0 and month 12 in the efficacy and
`‘‘per-protocol’’ populations following treatment with MMX mesalazine
`2.4 g/day given once daily or twice daily.
`
`Figure 3 Remission rates at month 0 and month 12 by study entry
`route (8-week extension phase of study 303 or parent studies) in the
`efficacy population following treatment with MMX mesalazine 2.4 g/day
`given once daily or twice daily.
`
`898
`
`Gut 2008;57:893–902. doi:10.1136/gut.2007.138248
`
`GeneriCo, Flat Line Capital
`Exhibit 1063 Page 6
`
`

`
`Inflammatory bowel disease
`
`Table 3 Summary of patients in remission at month 12 stratified by previous treatment and entry route (efficacy population; n = 451)
`
`Patients in remission at the end of 12 months, n (%)
`
`MMX mesalazine 2.4 g/day
`
`Treatment in parent studies
`
`Entry route into maintenance phase
`
`2.4 g given once daily (n = 225) 1.2 g given twice daily (n = 234)
`
`Total
`
`Placebo
`
`MMX mesalazine 2.4 g/day*
`
`MMX mesalamine 4.8 g/day
`
`Asacol 2.4 g/day{
`
`Direct
`Via 8-week extension
`Direct
`Via 8-week extension
`Direct
`Via 8-week extension
`Direct
`Via 8-week extension
`
`18/22 (81.8)
`19/34 (55.9)
`25/37 (67.6)
`14/29 (48.3)
`30/42 (71.4)
`15/27 (55.6)
`15/17 (88.2)
`5/11 (45.5)
`
`16/20 (80.0)
`25/41 (61.0)
`33/42 (78.6)
`13/24 (54.2)
`32/41 (78.0)
`17/28 (60.7)
`13/19 (68.4)
`10/17 (58.8)
`
`34/42 (81.0)
`44/75 (58.7)
`58/79 (73.4)
`27/53 (50.9)
`62/83 (74.7)
`32/55 (58.2)
`28/36 (77.8)
`15/28 (53.6)
`
`*Patients received MMX mesalazine 2.4 g/day given once daily in the Kamm study,25 and as 1.2 g twice daily in the Lichtenstein study.24 {Patients received Asacol 2.4 g/day (given
`as 0.8 g three times daily) as a reference arm in study 302 only.
`
`(81.2% once daily vs 80.2% twice daily;
`studies
`parent
`p = 0.869) or via the 8-week extension phase (54.7% once daily
`vs 64.2% twice daily; p = 0.190).
`Patients’ remission rates, stratified by the treatment received
`in the parent studies, are shown in table 3.
`
`Remission rates for patients who did not meet strict entry criteria at
`baseline (n = 89)
`Eighty-nine patients entered the maintenance phase of this
`study who were not in strictly defined clinical and endoscopic
`remission at baseline, but who were considered to be well
`enough by their treating doctor. Their remission rates were less
`than those achieved by the intention-to-treat population as a
`whole. Of these 89 patients, remission rates at 12 months were
`similar between patients dosed once daily (52.1% (25/48
`patients)) or twice daily (51.2% (21/41 patients) p = 0.935).
`Of these patients, those who entered the maintenance phase
`through the 8-week extension phase, there was no significant
`difference between the two treatment groups in relation to
`endoscopic and clinical
`remission (40% once daily (6/15
`patients) vs 26.7% twice daily (4/15 patients) p = 0.44).
`Similar numbers of patients who entered the maintenance
`phase directly from the parent study were in remission at
`12 months irrespective of maintenance therapy dose regimen
`(57.6% once daily (19/33 patients) vs 65.4% twice daily (17/26
`patients) p = 0.541).
`
`Relapse rates
`At 12 months, the proportion of patients in the efficacy
`population who had not relapsed was 88.9% in the once-daily
`group and 93.2% in the twice-daily group. Similarly, in the ‘‘per-
`protocol’’ population, the proportion of patients who had not
`relapsed at 12 months was 88.7% in the once-daily group and
`92.5% in the twice-daily group.
`
`Mucosal appearance
`The degree of mucosal inflammation at parent study baseline,
`upon entry to the maintenance phase and at 12 months is
`shown in table 4 for the efficacy and ‘‘per-protocol’’ popula-
`tions. In both populations, the majority of patients in both
`treatment groups had a moderately inflamed mucosal appear-
`ance (median sigmoidoscopy score of 2) at parent study
`baseline. At entry to the maintenance study, the majority of
`patients in both groups had a normal mucosal appearance
`(sigmoidoscopy score of 0), with the remainder having a
`sigmoidoscopy score of 1. At month 12, these sigmoidoscopy
`scores had largely been maintained; in the efficacy population,
`
`approximately 78% of patients had a sigmoidoscopy score of 0
`or 1, while in the ‘‘per-protocol’’ population, approximately
`81% of patients had a sigmoidoscopy score of 0 or 1. For both
`the efficacy and ‘‘per-protocol’’ populations, there were no
`apparent differences between the two dosing regimens in the
`distribution of sigmoidoscopy scores after 12 months’ therapy.
`
`Compliance
`No notable differences in compliance rates were observed
`between treatment groups (safety population) at any visit.
`Overall, 442 (96.3%) patients took >80% of their prescribed
`study medication (93.3% in the once-daily group and 99.6% in
`the twice-daily group).
`
`DISCUSSION
`This study is the first to describe the safety and efficacy of
`MMX mesalazine administered once or twice daily for the
`maintenance of remission of UC, over a period of 12 months.
`To our knowledge, to date no data have been published in a full
`article regarding the long-term safety of once-daily 5-ASA use or
`long-term use of MMX technology. MMX mesalazine 2.4 g/day
`