Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

71st Annual Scientific Meeting of the American College of Gastroenterology

Las Vegas, Nevada / October 21-25, 2006

Optimizing therapy for inflammatory bowel disease (IBD) represents a challenge to clinicians for a number of reasons, particularly patient adherence to medication and the wide array of conventional agents from which to choose, each with its own risks and benefits.

Oral 5-aminosalicylic acid (5-ASA), such as mesalamine, is regarded as a first-line therapy for the induction and maintenance of remission of mild to moderate ulcerative colitis (UC), but one major problem with 5-ASA has been patient adherence. Dosing regimens are complex, which may lead to poor compliance and reduced efficacy. Two formulations of 5-ASA are in use currently: a delayed-release and a controlled-release tablet. Eight to 16 pills per day in three to four divided doses is necessary for induction of response or remission. Patients on maintenance therapy must take at least one pill given t.i.d. for the rest of their lives.

According to Dr. Gary Lichtenstein, Division of Gastroenterology, University of Pennsylvania, Philadelphia, “We know that 60% of patients on mesalamine in remission don’t take medication after six months of treatment.” Patients who are nonadherent to their maintenance 5-ASA regimen have more than a fivefold increased risk of recurrence compared with individuals who take at least 80% of their prescribed dose. “If you have a patient with mild to moderate active UC, you want to treat that patient with an agent that he or she is going to take and that is effective,” noted Dr. Lichtenstein.

One possible solution to the adherence problem may lie in a once-daily formulation of 5-ASA that relies on multi-matrix (MMX) technology, Dr. Lichtenstein told the audience. This high-strength formulation (1.2 g of mesalamine per tablet) is designed to provide continuous and prolonged exposure of the colonic mucosa to 5-ASA by using hydrophilic and lipophilic matrices enclosed within a gastro-resistant, pH-dependent coating. The gastro-resistant polymer delays the release of the active drug until it reaches the terminal ileum.This drug delivery technology is believed to extend delivery of 5-ASA consistently throughout the entire colon.

Treatment Options

As reported by Dr. Stephen Hanauer, Section of Gastroenterology and Nutrition, IBD Research Center, Chicago, Illinois, “Oral 5-ASA is effective in left-sided UC, which affects nearly 80% of patients who are diagnosed with UC. Topical 5-ASA is most effective in distal disease and as an adjunct in extensive UC.” He further indicated that in extensive mild to moderate UC, oral mesalamine 4 g/day in divided doses plus mesalamine enema was superior to oral therapy plus placebo enema in inducing remission and achieving improvement at eight weeks.

When using oral 5-ASA for UC, “remember that there is a dose response,” cautioned Dr. Hanauer. The percentage of patients who achieve remission or experience improvement ranges from a low of 27% with 1.6 g/day of mesalamine to 74% with 4.8 g/day. If the response to oral 5-ASA is inadequate, consider that the patient may have moderate as opposed to mild disease, and adjust the dosage accordingly, he suggested. Response rates are not different between 2.4 g/day and 4.8 g/day when the disease is mild, but moderate disease is more likely to respond to a daily 5-ASA dose of 4.8 g/day.

The ASCEND II (Assessing the Safety and Clinical Efficacy of a New Dose of 5-ASA) study was undertaken in 268 patients with moderately active UC who were randomly assigned to either 2.4 g/day of mesalamine using a 400-mg dosage form or 4.8 g/day using an 800-mg dosage form. Treatment duration was six weeks, at which time treatment success (response or remission) was achieved in 72% of the patients assigned to 4.8 g/day compared with 59% of those assigned to 2.4 g/day (P=0.0357). “Consider 4 to 5 g/day of 5-ASA for failures at lower doses,” recommended Dr. Hanauer.

The need for corticosteroids reflects a more complicated disease course, with rapid progression of the disease likely. “Once they need steroids, the course is different,” he remarked. In the community, 85% of UC patients show a complete or partial response to steroids at one month, but less than half have a prolonged response (one year), 22% become steroid-dependent, and about 30% require surgery within that first year. These data were obtained before the era of biologics,” noted Dr. Hanauer.

The biologic agent infliximab is effective in moderate to severe refractory UC, with clinical remission rates at 30 weeks of about 37% in this patient group treated with 10 mg/kg of infliximab. However, “Cyclosporine produces more robust and consistent responses in severe fulminant hospitalized patients,” he explained, “and 80% of patients with severe corticosteroid-refractory UC have a response to intravenous cyclosporine,” whereas response to placebo is 0%. In severe steroid-refractory UC, the response to infliximab is about 50%.

Corroborative Findings

Findings presented here and at previous scientific sessions show that the MMX formulation of mesalamine is equally effective as currently available formulations, and the added benefit of once-daily dosing is hoped to improve adherence and thus patient outcome.

Dr. Hanauer discussed two pivotal phase III studies (301 and 302) that were presented at Digestive Disease Week 2006 in Los Angeles. The results indicated that MMX mesalamine induced remission of active mild to moderate UC in patients who were either switched from other oral 5-ASA therapies or who were 5-ASA-naïve. Both once-daily and twice-daily MMX induced remission in patients with left-sided or extensive UC. Studies 301 and 302 were prospective, randomized, multicentre, double-blind, placebo-controlled, eight-week studies examining the efficacy and tolerability of the novel formulation in once-daily and twice-daily dosing. The data for both studies combined 517 patients receiving MMX mesalamine 2.4 g/day (given once or twice daily, n=172); MMX mesalamine 4.8 g/day (given once daily; n=174) or placebo (n=171). Some 37.2% of patients assigned to 2.4 g/day achieved remission compared with 17.5% assigned to placebo (P<0.001). Significantly more patients randomized to 4.8 g/day achieved remission compared with patients randomized to placebo (35.1% vs. 17.5% P<0.001). In patients with left-sided UC, either 2.4 g/day or 4.8 g/day was associated with significantly greater remission compared with placebo (P<0.001 for 2.4 g/day vs. placebo; P=0.006 for 4.8 g/day vs. placebo) (Figure 1).

Figure 1. Treatment Efficacy

Dr. Hanauer noted that the higher dosage was more effective than the lower dosage in patients with prior 5-ASA use. Among the 5-ASA-naïve patients, greater proportions of patients in both MMX groups achieved remission compared with placebo.

Updated Results

As presented here, induction of remission was measured in study 302, which was used to calculate the number needed to treat to induce one remission after eight weeks of therapy. “In an effort to enhance compliance, this study was designed to specifically look at whether we can lessen the pill burden to increase the likelihood that people will take the medication, and in addition, make it just once a day,” reported Dr. Lichtenstein. In this study, 341 patients with active mild to moderate UC were randomized to MMX mesalamine 2.4 g q.d. MMX mesalamine 4.8 g q.d., mesalamine 2.4 g t.i.d, or placebo.

Remission in these studies was defined as a modified UC disease activity index (UC-DAI) of £1, with a rectal bleeding and stool frequency score of 0, no mucosal friability, and ³1-point reduction in sigmoidoscopy score from baseline. The standard UC-DAI allows patients with mild friability to be given a sigmoidoscopy score of 1. In the modified UC-DAI, however, patients with any mucosal friability were given a score ³2 and were not, therefore, considered to be in remission. “These were very stringent criteria to meet the definition of remission,” noted Dr. Lichtenstein.

Remission rates were significantly greater with either active dosage compared with placebo (P£0.01). In contrast, mesalamine 2.4 g/day given in t.i.d. doses was not significantly superior to placebo in inducing remission (Figure 2). The number needed to treat for inducing remission with the MMX formulation was 6 vs.10 for the thrice-daily
re 2. Remission Rates

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In a pooled analysis of studies 301 and 302, remission rates were analyzed separately for men and women. A significantly greater proportion of both men and women receiving MMX mesalamine 2.4 or 4.8 g/day achieved remission at week 8 compared with placebo. A higher percentage of women than men achieved remission in all three active treatment groups. Relative to placebo, the most recent formulation of mesalamine increased the odds of achieving remission by approximately 2.6-fold for men and threefold for women, which suggests that there was no difference in the magnitude of MMX mesalamine efficacy between genders, commented Dr. Lichtenstein.

Although gender specificity did affect remission rates, logistic regression analysis of treatment by gender interaction demonstrated that the efficacy of MMX mesalamine was not dependent on gender, nor was there a difference in remission rates between the two MMX formulations. For both men and women, a significantly greater reduction in overall modified UC-DAI score was observed in the two MMX groups compared with the placebo group (P£0.001 for all comparisons).

Tolerability Profile

An interim safety analysis of an open-label extension study of MMX mesalamine for maintaining remission in patients with mild to moderate UC demonstrated good tolerability, with a safety profile similar to that of previous 5-ASA preparations for maintenance UC therapy. This analysis included 458 patients who were in clinical and endoscopic remission after induction therapy with MMX mesalamine. All received 2.4 g/day, either given once daily or as 1.2 g twice daily. Also included in the safety analysis were 313 patients in an acute-phase study. More than 77.5% of patients were exposed to 2.4 g/day in the maintenance phase for at least 36 weeks. During the maintenance phase, the proportion of patients who experienced adverse events, treatment-related adverse events, and serious adverse events was similar in both treatment arms. However, the number of serious adverse events was greater in the group receiving twice-daily therapy. More than 90% of the adverse events overall were mild to moderate in severity. The most commonly reported adverse events were UC flare, nasopharyngitis, and headache. Gastrointestinal (GI) disorders were the most common treatment-related adverse events in both phases of the study, reported by 14 of patients (4.5%)in the acute phase, eight patients (3.5%) in the once-daily maintenance group, and six patients (2.6%) in the twice-daily maintenance group.

In the maintenance phase, most withdrawals due to adverse events resulted from GI disorders: seven patients (3.1%) in the 2.4-g once-daily group and four patients (1.7%) in the 1.2-g twice-daily group.

The most frequently reported serious adverse events in both phases of the study were GI disorders. Only two serious adverse events were considered possibly related to study medication. These were pancreatitis (acute phase) that resolved within 28 days after study medication withdrawal, and elevated liver enzymes (one patient in both the acute and maintenance phases), possibly due to infectious mononucleosis.

Summary

The induction of an effective and long-lasting clinical remission is critical to avoid relapse in UC. Maintenance therapy should begin only after achieving a favourable clinical response to induction therapy. As such, a higher dosage formulation has demonstrated to be more effective than lower dosage and this allows for reduction in the number of pills that will hopefully address long-term treatment adherence in UC patients. The novel once-daily, high-strength, controlled and sustained MMX mesalamine formulation has proven efficacious in inducing clinical remission in mild-to-moderate UC patients. Furthermore, this 5-ASA has a safety profile which is similar to other mesalamine preparations in maintenance therapy.

Note: At the time of printing, MMX mesalamine is not available in Canada.