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Canadian Digestive Diseases Week 2008

Montreal, Quebec / February 29-March 3, 2008

Reviewed and endorsed by the Canadian Gastroenterology Association

Mucosal healing appears to predict a greater likelihood of an extended remission than the absence of healing in ulcerative colitis (UC). This has placed an emphasis on achieving healing with first-line therapy. While there has been debate about the risk:benefit ratio of potent but less well-tolerated therapies in early treatment of mild-to-moderate UC, two large studies have demonstrated that high doses of an extended-release 5-aminosalicylic acid (5-ASA) are capable of achieving very favourable rates of early and extended remission. In the two trials, both delivering 2.4 to 4.8 g/day of mesalazine within a system designed to diffuse active drug through the colon, 56.6% of patients achieved remission and remained relapse-free for one year.

Studies on Remission

By including “patients who achieved remission and subsequently withdrew from any of the studies, this approach allowed a more realistic view of remission rates in clinical practice, where patients may choose to stop therapy at any point,” stated Dr. Remo Panaccione, Division of Gastroenterology, University of Calgary, Alberta. Collating data from the two similarly designed trials, Dr. Panaccione reported that early clinical and endoscopic remission using very rigorous definitions for both was achieved in 63% of patients, a rate that continues to support 5-ASA as a first-line therapy if administered in the protocol used in these studies.

The acute remission rates of both studies have been published previously, but Dr. Panaccione prepared a summary of the combined data on long-term remission for a presentation here at the CDDW. One trial, primarily conducted in North America, contributed 241 of the 280 patients initially randomized for an acute remission end point (Lichtenstein et al. Clin Gastroenterol Hepatol 2007;5:95-102) to an extension study of long-term remission. The other trial, primarily conducted in Europe (Kamm et al. Gastroenterology 2007;132:66-75), contributed 317 of the 343 initially randomized patients. In both acute-remission studies, the initial goal was to compare remission rates at the end of eight weeks in patients randomized to the Multi Matrix System (MMX) formulation of mesalazine given in doses of 2.4 to 4.8 g daily, or placebo. Of those who entered the extension study, the 346 patients initially treated with MMX mesalazine were evaluated for long-term outcomes.

Study Findings

Of the patients in this combined analysis, 36% achieved clinical and endoscopic remission on the first eight-week course of MMX mesalazine and went directly to the long-term maintenance phase. In those who received a second eight-week course of MMX mesalazine 4.8 g/day, 61% achieved both clinical and endoscopic remission. The predefined criteria for clinical and endoscopic remission were rigorous. Specifically, a modified Ulcerative Colitis Disease Activity Index (UCDAI) total score of £1 was required as calculated by four factors: a score of 0 for rectal bleeding and for stool frequency; a combined Physician’s Global Assessment (PGA) and sigmoidoscopy score of £1; a reduction in sigmoidoscopy score of ³1 from baseline; and no mucosal friability.

While the definition of remission was strict, the definition of relapse was less so, creating a difficult standard for remaining free of disease at the end of the induction phase and the one-year follow-up. “Relapse was defined as a requirement for alternative treatment for UC exacerbation, including any medication other than MMX mesalazine or surgery or the need for a dose increase of MMX mesalazine,” Dr. Panaccione noted.

Using these criteria, 196 (56.6%) of the 346 patients who were initially randomized to MMX mesalazine therapy in the North American and European studies remained relapse-free for 12 months after achieving clinical and endoscopic remission. This figure is reached even though all dropouts for any reason were counted. When limited to the patients who were in remission on MMX mesalazine at the time that they initiated the maintenance regimen, the proportion of patients who remained in remission at the end of 12 months approached 70% whether treated with 2.4 g/day or 1.2 g b.i.d. Both doses were well tolerated with few dropouts for treatment-related side effects.

Extended Therapy

One of the most important aspects of this analysis, addressed in more detail in a separate presentation for which Dr. William Sandborn, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, served as the first author, is the large boost in remissions achieved with a second eight-week course of MMX mesalazine. While more than one-third of patients were able to achieve clinical and endoscopic remission on a single eight-week course of MMX mesalazine, the second course was even more effective when evaluated as a per cent response. By producing a 61% response rate among those not yet in clinical and endoscopic remission after the first course, the second course almost doubled the total proportion of MMX mesalazine patients who could be evaluated for long-term disease-free status.

“An additional eight weeks of MMX mesalazine therapy was able to induce stringently defined remission in a large proportion of patients taking an initial eight weeks of 5-ASA therapy,” reported the team of investigators. Although the lead author Dr. Sandborn did not attend the CDDW this year, he emphasized in his written summary that this result is important because “it is possible that in some patients, therapeutic transition to steroids or other immunosuppressive agents may be avoided by continuing 5-ASA treatment beyond eight weeks,” he explained.

Avoiding steroids, which are poorly accepted by patients and create a risk for steroid dependence, is an important clinical outcome. Although clinicians often feel compelled to offer an alternative therapy in patients with persistent symptoms after eight weeks of treatment, the evidence that more than 61% of patients can achieve endoscopic remission with a second eight-week course should be reassuring to those trying to avoid less well-tolerated therapy. A substantial proportion of patients well informed about the benefit-to-risk advantages of a second course of 5-ASA are expected to select this option based on these results.

The Importance of Mucosal Healing

Whether remission was achieved after an initial eight-week course or a second eight-week course, the majority of patients remained in remission at one year. This finding is consistent with the growing body of evidence that strictly defined mucosal healing predicts sustained protection against relapse. It also demonstrates that this is true regardless of the therapy that achieved mucosal healing, including 5-ASA. Although there are limited data comparing 5-ASA and immunosuppressive therapies in mild-to-moderate UC, quiescent disease predicts quiescence no matter how healing was achieved.

The relative efficacy of other 5-ASA formulations in repeating the results observed in this study is unknown. These formulations differ in a variety of ways, including their strength and their delivery system. The MMX system, which facilitates once-daily dosing, a potential advantage for compliance, prevents release of active drug until it is exposed to a pH of 7.0, which usually occurs in the terminal ileum. Once the pill begins to degrade, it employs a hydrophilic property of the pill construction to produce changes in an interior gel mass that controls diffusion of the drug as it descends the colon. Recognizing its efficacy for mucosal healing, Canada has approved MMX mesalazine for the induction of clinical and endoscopic remission in mild-to-moderate UC. The new data provide objective data with which to inform patients about efficacy.

“When starting a patient with active, mild-to-moderate UC on a 5-ASA therapy, it is important for physicians to be aware of the probability of that patient achieving remission in a given time [and] the probability of a patient not relapsing once remission has been achieved,” stated Dr. Panaccione, indicating the rationale for this study. He noted that on the basis of these results, “almost two-thirds of patients achieved clinical and endoscopic remission with eight to 16 weeks therapy with MMX mesalazine.”

Summary

Consistent with other data, effective mucosal healing in patients with UC predicts a long-term remission. In collated data from two studies evaluating MMX mesalazine, acute endoscopic and clinical remission was achieved in about one-third of patients receiving eight weeks of treatment but rose to almost two-thirds when those who did not heal on the first eight weeks received a second eight-week course. The majority of patients who achieved endoscopic and clinical remission after the acute course remained in remission at one year without the need for immunosuppressive therapies.