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.

45th Annual Meeting of the Canadian Association of Gastroenterology Canadian Digestive Diseases Week 2007

Banff, Alberta / February 16-20, 2007

Here at the Canadian Digestive Diseases Week, a number of specialists reported on new studies investigating mesalamine with multimatrix (MMX) technology therapy utilizing the data from the SPD476-301 and -302 trials. This formulation of 5-ASA mesalamine is a novel, high-strength 1.2-g tablet designed for once-daily dosing, combined with a gastro-resistant film (to delay drug release until pH>7, normally found in the terminal ileum). Upon exposure to intestinal fluid, the hydrophilic matrix within the core swells into a gel mass. Pieces of the gel mass break off in the colon and release the medication. A second matrix interspersed with the 5-ASA, the lipophilic matrix, further slows the dissolution of the agent.

Inducing Complete Mucosal Healing

Incomplete mucosal healing in patients with symptomatic remission has been linked with higher ulcerative colitis (UC) relapse rates relative to patients who have complete mucosal healing.

According to Dr. William Sandborn, Professor of Medicine, Inflammatory Bowel Disease Clinic, Mayo Clinic, Rochester, Minnesota, up to eight weeks of therapy with MMX 5-ASA effectively induces complete mucosal healing in approximately one-third of patients with active mild-to-moderate UC. It also substantially reduces the proportion of patients with moderate or severe sigmoidoscopy findings relative to placebo, he noted.

Dr. Sandborn cited an analysis of complete mucosal healing (i.e. decreased sigmoidoscopy score down to 0) during mesalamine therapy using pooled data from the SPD476-301 and -302 trials. He and co-researchers examined the data for complete mucosal healing following treatment in patients with active mild-to-moderate UC. Patients received the active treatment at 2.4 g/day given once or twice daily (1.2 g tablet), 4.8 g/day (q.d. in both studies), or placebo. The primary end point for this study was clinical and endoscopic remission at week 8. For the purposes of this analysis, mucosal healing (assessed by sigmoidoscopy) was evaluated at week 8 or early withdrawal. After up to eight weeks, higher complete mucosal healing rates were observed with 2.4 g/day (55/172 [32.0%]) and 4.8 g/day (56/174 [32.2%]) than with placebo (27/171 [15.8%]). This is an important finding, since endoscopic remission is a more accurate predictor of remission than the clinical marker.

Effect of Age on Clinical Outcome

In a second post-hoc analysis of data from the SPD476-301 and -302 trials, Dr. Sandborn and colleagues explored the effect of age on clinical outcome. They found the active therapy effectively induced clinical and endoscopic remission in patients with active mild-to-moderate UC, regardless of their age.

In this analysis, patients received MMX mesalamine 2.4 g/day given either once or twice daily (1.2 g tablet), 4.8 g/day (q.d. in both studies), or placebo. The primary end point was clinical and endoscopic remission at week 8 using stringent criteria (modified UC-disease activity index score £1, a rectal bleeding and stool frequency score of 0, no mucosal friability and ³1 point reduction in sigmoidoscopy score from baseline). In patients aged <55 years, significantly higher remission rates were observed following 2.4 g/day (51/143 [35.7%]; P<0.001) and 4.8 g/day (48/138 [34.8%]; P<0.001) than with placebo (24/138 [17.4%]). For patients aged 55 years and over, similar increases in remission rate were observed with 2.4 g/day (13/29 [44.8%]) and 4.8 g/day (13/36 [36.1%]) compared with placebo (6/33 [18.2%]), although due to the low numbers of patients in this group, only the 2.4 g/day dose demonstrated statistical significance vs. placebo (P=0.02). Logistic regression analysis confirmed there was no significant interaction between age and treatment (P=0.801), reported Dr. Sandborn.

Endoscopically Measured Mucosal Healing

The Assessing the Safety and Clinical Efficacy of a New Dose of 5-ASA (ASCEND) I and II trials were phase III, multicentre, randomized, double-blind analyses assessing the efficacy of mesalamine therapy in patients with UC. Researchers pooled 423 eligible patients who had moderate activity of UC.

Dr. Gary Lichtenstein, Director, Inflammatory Bowel Disease Program and Professor of Medicine, University of Pennsylvania, Philadelphia, and colleagues conducted an investigation on the effect of delayed-release oral mesalamine 4.8 g/day vs. 2.4 g/day on endoscopically measured mucosal healing in patients with moderately active UC, for a duration of six weeks. Mucosal healing was defined as an endoscopy subscore of 0 or 1.

Regardless of dose and as early as three weeks, treatment induced endoscopically measured mucosal healing in >50% of patients, he added. Compared to 2.4 g/day, initiating therapy with 4.8 g/day significantly improved endoscopically measured mucosal healing in patients with moderately active UC, concluded Dr. Lichtenstein.

Mucosal Healing Correlated with Response to Therapy

Dr. David Rubin, Assistant Professor of Medicine, University of Chicago, was the principal investigator in a study of the correlation between endoscopically measured mucosal healing and response to therapy with delayed-release oral mesalamine 4.8 g/day and 2.4 g/day in patients with moderately active UC.

According to Dr. Rubin, mucosal healing was defined as an endoscopy score of 0 or 1 and Patient Functional Assessment (PFA) was based on a 4-point scale from 0 to 3. As such, 391 patients with moderately active UC (baseline Physician’s Global Assessment [PGA] 2) and baseline endoscopy subscore ³2 were included in this analysis. Overall at six weeks, 67% of moderate UC patients who achieved treatment success also had mucosal healing (Kappa=0.6938). This finding was consistent regardless of daily dose. An endoscopic score of 0 alone was poorly correlated with treatment success but did improve from three weeks to six weeks (Kappa=0.1176 and 0.2252, respectively).

Successful management of moderately active UC with mesalamine is associated with improved mucosal integrity in as early as three and six weeks, reported Dr. Rubin, pointing out that there is a lack of association between endoscopic improvement and PFA. Further studies assessing endoscopic mucosal improvement are needed, he suggested.

“We really do believe that the way the mucosa appears is an important outcome for therapies and that it is likely to be demonstrated soon that mucosal healing will, in a more clearly defined way, in fact be associated with better longer-term outcomes,” Dr. Rubin told the audience. “These studies are just the beginning. They are limited in that assessment but they do provide us with some important information.”

Summary

He remarked, “Mucosal healing as a concept hasn’t reached clinical practice yet. In order for it to reach clinical practice, we do need more evidence that it is associated with longer-term beneficial outcomes and we need a less invasive way to assess mucosal improvement or mucosal healing. We need surrogate markers that correlate to mucosal healing that will enable physicians, in a non-invasive or minimally invasive way, to assess this outcome. We’ve become interested in the concept of mucosal healing or mucosal improvement as a marker of what, at first glance, is intuitive. If you are able to document that the control of the underlying inflammatory disease is successful enough to achieve healing of the injured bowel, it will correlate to improved symptoms. What we expect is that it will correlate to longer-term stable outcomes.”

Note: At the time of printing, the 5-ASA MMX formulation is not available in Canada.