Mezavant
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Mezavant - Scientific Information

Manufacture: Shire, Inc.
Country: Canada
Condition: Crohn's Disease, Maintenance, Crohn's Disease, Inflammatory Bowel Disease, Ulcerative Colitis, Ulcerative Colitis, Active, Ulcerative Colitis, Maintenance, Ulcerative Proctitis
Class: 5-aminosalicylates
Form: Tablets
Ingredients: mesalamine, carnauba wax, magnesium stearate, methacrylic acid – methyl methacrylate copolymer (1:1), methacrylic acid – methyl methacrylate copolymer (1:2), red ferric oxide (E172), polyethylene glycol (macrogol) 6000, silica (colloidal hydrated), sodium carboxymethylcellulose, sodium starch glycolate (type A), stearic acid, talc, titanium dioxide (E171) and triethylcitrate

Pharmaceutical Information

Drug Substance

Proper name: mesalamine
Chemical name: 5-amino-2-hydroxybenzoic acid
Molecular formula and molecular mass: C7H7NO3 153.14
Structural formula:


Physicochemical properties: Mesalamine is an almost white to light pink/gray/brown powder or crystals that decomposes at 280°C and is very slightly soluble in water.
The pH of 2.5% aqueous suspension is 3.5-4.5.
pKa value: 5.8

Clinical Trials

Active, Mild to Moderate Ulcerative Colitis

Two similarly designed, randomized, double -blind, placebo-controlled trials were conducted in adult patients with active, mild to moderate ulcerative colitis. Study SPD476-301 assessed the efficacy and safety of MEZAVANT 2.4g/day (1.2g given twice daily) and 4.8g/day (given once daily) against placebo in 280 patients. Study SPD476-302 assessed the safety and efficacy of MEZAVANT 2.4g/day and 4.8g/day (both given once daily) against placebo in 341 patients. A pH-dependent delayed-release mesalamine 2.4g/day (administered as two 400mg tablets given three times daily) was included in this study as a reference arm; the study was not designed to demonstrate non-inferiority of MEZAVANT against pH-dependent delayed-release mesalamine.

Maintenance of Remission

A multicenter, randomized, double-blind, double-dummy, parallel-group, non-inferiority, active comparator study (SPD476-304) was designed to assess the number of subjects who remained in endoscopic remission (maintenance of mucosal healing) following 6 months of study treatment. Subjects were randomized in a 1:1 ratio to receive either MEZAVANT 2.4g/day administered once daily (QD) or pH-dependent delayed-release mesalamine 1.6g/day administered as two 400mg tablets given twice daily (BID).

Study Demographics and Trial Design

Table 1: Summary of Baseline Demographic Characteristics for Patients with Ulcerative Colitis
Study # Trial design Dosage, route of
administration and
duration
Study subjects
(n=number)
Mean age
(Range)
Gender
SPD476-301 Randomized, doubleblind, placebo-controlled trial conducted in subjects with active, mild to moderate UC to assess the efficacy and safety of MEZAVANT. 2.4g/day administered as 1.2g twice daily and 4.8g/day administered once daily

Oral

8 weeks
262a 41.5
(18-76)
M=51.5%
F=48.5%
SPD476-302 Randomized, double-blind, placebo-controlled trial conducted in subjects with active, mild to moderate UC to assess the safety and efficacy of MEZAVANT. This study included a comparator, pH-dependent delayed release mesalamine, as an internal reference arm. 2.4g/day and 4.8g/day administered once daily

pH-dependent delayed-release mesalamine 2.4g/day, administered as 2x400mg three times daily
341a 43.2
(18-78)
M=47.5%
F=52.5%
SPD476-304 Randomized, double-blind, doubledummy, parallel-group, non-inferiority, active comparator study conducted in subjects with mild to moderate UC to assess the number of subjects who remained in endoscopic remission following six (6) months of study treatment. 2.4g/day administered once daily

pH-dependent delayed-release mesalamine 1.6g/day in divided dose, administered as 0.8g twice daily (BID)
679b 45.4
(18-85)
M=50.8%
F=49.2%

a Based on ITT population
b Based on Per Protocol population

Study Results

Induction of remission, including clinical remission and mucosal healing

The primary efficacy endpoint in studies SPD476-301 and SPD476-302 was to compare the percentage of patients in remission, a composite endpoint indicative of clinical remission and mucosal healing, after 8 weeks of treatment for the MEZAVANT treatment groups vs. placebo. Remission was defined as an Ulcerative Colitis Disease Activity Index (UC-DAI) score of 1. To be considered in remission, a subject was required to have no blood in stools and normal stool frequency. Also, they could have either a Physician Global Assessment of 1 (mild disease) or improvement of the mucosal appearance that lead to a maximum sigmoidoscopy score of 1 (mild erythema, decreased vascularity, minimal granularity) as long as there had been at least a 1-point drop from baseline in the sigmoidoscopy score. The scoring system used for sigmoidoscopy was modified to be more stringent than the standard UC-DAI system, which allows patients with mild friability to be given a sigmoidoscopy score of 1. Results for the primary variable of remission in study SPD476-301 are shown in Table 2. Both MEZAVANT 2.4g/day (1.2g given twice daily) and 4.8g/day (given once daily) demonstrated superiority over placebo. Results for study SPD476-302 are also shown in Table 2. Both MEZAVANT 2.4g/day and 4.8g/day (both given once daily) demonstrated superiority over placebo.

Table 2: Summary of Primary Efficacy Results for Studies SPD476-301 and SPD476-302 in Mild to Moderate, Active Ulcerative Colitis – ITT Population
SPD476-301 SPD476-302
Placebo
n=85
MEZAVANT
2.4g/day BID
n=88
MEZAVANT
4.8g/day QD
n=89
Placebo
n=86
MEZAVANT
2.4g/day QD
n=84
MEZAVANT
4.8g/day QD
n=85
pH-dependent
delayed-release
mesalaminea
2.4g/day
(0.8g given
TID)
n=86
Number of subjects in remission*
n (%) 11 (12.9) 30 (34.1) 26 (29.2) 19 (22.1) 34 (40.5) 35 (41.2) 28 (32.6)
Comparison of active vs. placebo
Odds ratio 3.48 2.78 2.40 2.47 1.70
CI 1.44, 8.41 1.27, 6.06 1.23, 4.69 1.15, 5.30 0.86, 3.36
p-value 0.001 0.009 0.010 0.007 0.124

a pH-dependent delayed-release mesalamine was included in this study as a reference arm; the study was not designed to demonstrate non-inferiority of MEZAVANT against pH-dependent delayed-release mesalamine.
* Remission was defined as an Ulcerative Colitis Disease Activity Index (UC-DAI) score of 1. To be considered in remission, a subject was required to have no blood in stools and normal stool frequency. Also, they could have either a Physician Global Assessment of 1 (mild disease) or improvement of the mucosal appearance that lead to a maximum sigmoidoscopy score of 1 (mild erythema, decreased vascularity, minimal granularity) as long as there had been at least a 1-point drop from baseline in the sigmoidoscopy score. The scoring system used for sigmoidoscopy was modified to be more stringent than the standard UC-DAI system, which allows patients with mild friability to be given a sigmoidoscopy score of 1.
Values from the chi-squared test.
Study-wise false-positive error rate was controlled using the Bonferroni-Holm method. The treatment comparison with the smaller p-value was evaluated at the 0.025 significance level. If this was significant, the treatment comparison with the larger p-value was evaluated at the 0.05 significance level. Confidence Intervals (CI) presented are analogous to the significance level, i.e., 97.5% and 95%.

The studies were not powered to look at differences between MEZAVANT doses. There was no statistically significant difference in remission rates between MEZAVANT 2.4g/day twice daily and MEZAVANT 4.8g/day once daily or between MEZAVANT 2.4g/day once daily and MEZAVANT 4.8g/day once daily. The secondary efficacy parameters, including clinical improvement and change in UC-DAI score and its components (including assessment of treatment failure, clinical remission and sigmoidoscopy) supported the primary findings by demonstrating statistical significance over placebo (results are shown in Table 3 and Table 4). There was no statistically significant difference between MEZAVANT 2.4g/day and 4.8g/day dose groups in clinical improvement, clinical remission and sigmoidoscopic improvement; however, MEZAVANT 4.8g/day showed trends for improved efficacy over MEZAVANT 2.4g/day after 8 weeks of treatment in terms of sigmoidoscopic outcome (one of four components of the UC-DAI) and clinical improvement (defined as a drop in the UC-DAI score of at least 3 points).

Table 3: Study SPD476-301: Secondary Efficacy Results (% Patients)
Secondary Efficacy Endpoints MEZAVANT
2.4g/day
(Given 1.2g BID)
n=88
MEZAVANT
4.8g/day
(Given QD)
n=89
Placebo
n=85
Clinical Improvementa
(reduction in UC-DAI score from baseline of ≥3 points)
55.7%*** 59.6%*** 25.9%
Treatment Failurea
(unchanged, worsened, or missing UC-DAI scores)
28.4%*** 24.7%*** 54.1%
Clinical Remissiona
(scores of 0 for stool frequency and rectal bleeding)
37.5%** 32.6%* 18.8%
Sigmoidoscopic Improvementa 64.8%** 71.9%*** 36.5%
Change from baseline in UC-DAI score
(least squares mean change)
-2.71*** -3.46*** -0.79

a the % data represents the proportion of subjects.
*p<0.05, **p<0.01, ***p<0.001 (each vs. placebo)
Clinical Improvement, Treatment Failure and Clinical Remission: p-value from the chi- squared test. Sigmoidoscopic Improvement: p-value from the Mantel-Haenszel chi-squared test with the alternative hypothesis of linear association.
Change from baseline in UC-DAI score: ANCOVA with change from baseline as the response variable and baseline UC-DAI score, treatment group and pooled centre as explanatory variables.

Table 4: Study SPD476-302: Secondary Efficacy Results (% Patients)
Secondary Efficacy Endpoints MEZAVANT
2.4g/day
(Given QD)
n=84
MEZAVANT
4.8g/day
(Given QD)
n=85
pH-dependent
delayed-release
mesalaminea
2.4g/day
(0.8g given
TID)
n=86
Placebo
n=86
Clinical Improvementb
(reduction in UC-DAI score from baseline of ≥3 points)
60.7%** 64.7%*** 55.8%* 39.5%
Treatment Failureb
(unchanged, worsened, or missing UC-DAI scores)
21.4%*** 20.0%*** 27.9%** 47.7%
Clinical Remissionb
(scores of 0 for stool frequency and rectal bleeding)
41.7%** 41.2%** 33.7%NS 22.1%
Sigmoidoscopic Improvementb 70.2%*** 76.5%*** 60.5%* 41.9%
Change from baseline in UC-DAI score
(least squares mean change)
-3.34** -3.58** -3.11* -1.94

a pH-dependent delayed-release mesalamine was included in this study as a reference arm and was not designed to demonstrate non-inferiority of MEZAVANT against pH-dependent delayed-release mesalamine.
b the % data represents the proportion of subjects.
*p<0.05, **p<0.01, ***p<0.001 (each vs. placebo); NS: p 0.05 (vs. placebo)

Clinical Improvement, Treatment Failure and Clinical Remission: p-value from the chi- squared test. Sigmoidoscopic Improvement: p-value from the Mantel-Haenszel chi-squared test with the alternative hypothesis of linear association.
Change from baseline in UC-DAI score: ANCOVA with change from baseline as the response variable and baseline UC-DAI score, treatment group and pooled centre as explanatory variables.

Maintenance of remission, including clinical remission and mucosal healing

The primary efficacy endpoint in study SPD476-304 was the proportion of subjects in endoscopic remission at Month 6 using the Per Protocol population. Endoscopic remission (mucosal healing) was defined by a modified UC-DAI endoscopy component score of ≤1. MEZAVANT met the primary endpoint of non- inferiority of - 10% versus pH-dependent delayed-release mesalamine in the proportion of subjects in endoscopic remission (maintenance of mucosal healing) at 6 months.

Table 5: Summary of Primary Efficacy Results for Study SPD476-304 in Mild to Moderate Ulcerative Colitis
Analysis of the Proportion of Subjects in Endoscopic Remission at Month 6
(Mucosal Healing) (Per Protocol Population)
MEZAVANT 2.4g/day (given QD)
n=343
Month 6 Subjects in endoscopic remission (n, %) 287 (83.7)

Endoscopic remission (mucosal healing) was defined by a modified UC-DAI endoscopy component score of ≤1. The scoring system used for sigmoidoscopy was modified to be more stringent than the standard UC-DAI system, which allows patients with mild friability to be given a sigmoidoscopy score of 1.

The proportion of subjects who reached remission in this study using MEZAVANT 2.4g/day QD (83.7%) was similar to that seen using the comparator (pH-dependent delayed-release mesalamine 1.6g/day [0.8g BID]; 81.5%).

Secondary endpoint analyses demonstrated that MEZAVANT achieved a similarly high proportion of subjects in endoscopic remission (mucosal healing) with no or mild symptoms, clinical remission, improved or same endoscopy scores, and improved or same Physician Global Assessment scores, as compared to pH-dependent delayed-release mesalamine as well as similar changes in modified UC-DAI scores.

A randomized, open-label extension study to studies SPD476-301 and SPD476-302 was designed to assess the long-term safety and tolerability of MEZAVANT 2.4g/day administered once daily and in 2 divided doses (1.2g BID) in the maintenance of ulcerative colitis in remission over 12 months. This study, study SPD476-303, included an 8-week Acute Extension Phase during which MEZAVANT 4.8g/day dose was administered BID, and a 12-month Maintenance Phase during which MEZAVANT 2.4g/day dose was administered either (1.2g) BID or QD. Efficacy was a secondary objective of this extension study.

The 12-month safety results from the SPD476-303 study are consistent with previously reported safety data. The efficacy endpoints were time to relapse for the Maintenance Phase; and the percentage of subjects in remission at the end of the study for the Acute and Maintenance phases.

Time to relapse was defined as the time at which a subject withdrew from the Maintenance Phase due to a requirement for alternative ulcerative colitis medication denoted by “Lack of Efficacy/Relapse.” The proportion of subjects withdrawing due to a need for alternative ulcerative colitis medication in the Maintenance Phase Efficacy population was low. Both treatment groups had similar times to relapse for the duration of the Maintenance Phase. At 12 months (360 days), the proportion of subjects who had not relapsed (i.e., relapse-free) was approximately 88% in the MEZAVANT 2.4g/day QD group and 92% in the MEZAVANT 1.2g BID (total 2.4g/day) group.

Remission was defined as modified UC-DAI score 1 with a score of 0 for rectal bleeding and stool frequency, and at least a 1-point reduction from parent study baseline in the sigmoidoscopy score. Overall 59.5% of subjects achieved remission at the end of the Acute Extension Phase (Month 2). At Month 12 of the Maintenance Phase, 64.4% of subjects in the MEZAVANT 2.4g/day QD group and 68.5% of subjects in the MEZAVANT 1.2g BID (total 2.4g/day) group met the strict remission criteria; no statistically significant differences were observed between treatment groups.

An open-label study (SPD476-404) was designed to assess clinical recurrence related to compliance with treatment with MEZAVANT 2.4g/day given once daily for the maintenance of quiescent ulcerative colitis. Subjects entered the 12-month Maintenance Phase either directly or after completion of an 8 -week acute phase. The primary analysis was the proportion of subjects with clinical recurrence at Month 6 of the Maintenance Phase. 76.5% of subjects who had sufficient data to calculate clinical recurrence at Month 6 did not have disease recurrence after 6 months of maintenance treatment with MEZAVANT.

The results of the secondary efficacy parameters (clinical recurrence at 12 months, proportion of subjects with quiescent ulcerative colitis, endoscopic remission, and time to clinical recurrence) supported the primary findings of consistently maintaining quiescence of ulcerative colitis through 12 months of maintenance treatment with MEZAVANT. Another study objective was also to assess health-related quality of life (QoL) at baseline of the Acute Phase, Week 8 Acute Phase/Baseline Maintenance Phase, 6 months, and 12 months. Non-quiescent UC subjects who received MEZAVANT treatment during the Acute Phase showed statistically and clinically significant improvement on almost all measured aspects of health-related QoL measures using the three questionnaires (Medical Outcomes Study 12 Item Short Form Health Survey, the Short Inflammatory Bowel Disease Questionnaire, and the Work Productivity and Activity Impairment Questionnaire: Specific Health Problem v2.0), particularly on physical role, disease-related QoL (such as pain, urgency, and anxiety), and work productivity loss and activity impairment.

Pharmacokinetics

In a parallel -group, two-period pharmacokinetic study of MEZAVANT 2.4g/day or 4.8g/day, where single and multiple doses were administered once daily with standard meals in 56 healthy volunteers (28 per dose group), plasma concentrations of mesalamine were detectable after 4 hours and were maximal by 8 hours after the single dose. Steady-state was achieved generally by 2 days after dosing. Accumulation was found to be between 1.7- and 2.4- fold and was independent of dose. This extent of accumulation was only modestly greater (1.1- to 1.4-fold) than predictable from single-dose pharmacokinetics. There was no evidence of steady-state systemic exposure increasing more than proportionately with dose. The principal pharmacokinetic parameters are presented in Table 6.

Table 6: Principal Pharmacokinetic Parameters of 5 -ASA following Administration of MEZAVANT in a 2.4g/day and 4.8g/day Single and Multiple Dose Study
Study/Dose tlag (h)
(mean±SD)
tmax (h)
(mean±SD)
Cmax (ng/mL)
(mean±SD)
AUC0-t
(ng.h/mL)
(mean±SD)
AUC0-∞
(ng.h/mL)
(mean±SD)
t1/2 (h)
(mean±SD)
% Dose
absorbed
2.4g single dose
n=28
5.2 ± 3.9 13.2 ± 10.0 2932 ± 2957 18573 ± 10969
(t=up to 120h)
19852 ± 11740 7.41 ± 4.65 25.2 ± 10.4
2.4g/day QD multiple dose (Day 14 data)
n=28
0.0 ± 0.0 9.07 ± 5.37 2918 ± 2164 22319 ± 13697
(t=24h)
N/A N/A 22.4 ± 9.25
4.8g single dose
n=28
4.9 ± 4.2 14.4 ± 9.68 4385 ± 3033 47785 ± 22421
(t=up to 120h)
48141 ± 25627 6.28 ± 5.31 27.0 ± 12.6
4.8/day QD multiple dose (Day 14 data)
n=28
0.21 ± 0.83 9.60 ± 3.78 5280 ± 3146 49559 ± 23780
(t=24h)
N/A N/A 20.8 ± 11.6

N/A: Not Applicable

Detailed Pharmacology

In regard to the exact mechanism of action of mesalamine, it is not clear which of the many actions of the compound is responsible for its therapeutic effects in Inflammatory Bowel Disease. For example, mesalamine has been shown to possess anti-oxidant properties in a range of systems in vitro. It also stimulates phospholipase D activity which may inhibit pro-inflammatory events. Mesalamine has also been shown to inhibit the production of the metabolites of arachidonic acid, particularly leukotriene B4 (LTB4), an important mediator in chronic inflammatory diseases.

Mesalamine has the potential to inhibit the activation of nuclear factor kappa B (NFκB) and consequently the production of key pro-inflammatory cytokines. More recently, it has been proposed that impairment of PPAR-γ nuclear receptors ( γ-form of peroxisome proliferator-activated receptors) may be implicated in ulcerative colitis. PPAR-γ receptor agonists have shown efficacy in ulcerative colitis and evidence has been accumulating that the mechanism of action of mesalamine may be mediated by PPAR-γ receptors. However it may be a combination of all such actions, which ultimately culminates in the drug’s efficacy.

The pharmacodynamic actions of mesalamine occur in the colonic/rectal mucosa local to the delivery of drug from MEZAVANT into the lumen. There is information suggesting that severity of colonic inflammation in ulcerative colitis patients treated with mesalamine is inversely correlated with mucosal concentrations of mesalamine. However, plasma concentrations representing systemically absorbed mesalamine are not believed to contribute extensively to efficacy.

No animal studies of absorption, distribution, metabolism and excretion of mesalamine following administration of MEZAVANT have been conducted. However, numerous non-clinical drug metabolism and pharmacokinetic studies as well as clinical pharmacokinetics studies on various mesalamine formulations have been reported in the literature.

Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 104-week dietary carcinogenicity study of mesalamine, CD-1 mice were treated with doses up to 2500mg/kg/day and it was not tumorigenic. This dose is 2.2 times the maximum recommended human dose (based on body surface area comparison) of MEZAVANT. Furthermore, in a 104-week dietary carcinogenicity study in Wistar rats, mesalamine up to a dose of 800mg/kg/day was not tumorigenic. This dose is 1.4 times the recommended human dose (based on body surface area comparison) of MEZAVANT.

No evidence of mutagenicity was observed in an in vitro Ames test or an in vivo mouse micronucleus test.

No effects on fertility or reproductive performance were observed in male or female rats at oral doses of mesalamine up to 296mg/kg/day.

Pregnancy – Teratogenic Effects

Reproduction studies have been performed in rats at doses up to 480mg/kg/day and have revealed no evidence of teratogenic effects or harm to the fetus due to mesalamine. Animal reproduction studies are not always predictive of human response.