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Ulcerative Colitis: Promising New Findings for Rapid Symptom Relief

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.

15th United European Gastroenterology Week (UEGW)

Paris, France / October 27-31, 2007

The challenge to long-term control of mild to moderate ulcerative colitis (UC) is not the absence of effective therapies. Rather, it is the failure of patients to remain compliant with treatment once symptoms resolve. The price of poor compliance is flare, with the potential for new complications during the period of relapse and poor control. There are a variety of data in a spectrum of diseases, such as hypertension, that demonstrate that q.d. therapies improve adherence in the absence of symptoms when compared to b.i.d. therapies. New data from the phase III studies establishing the efficacy of a long-action formulation of 5-ASA now show that there is rapid resolution of symptoms, providing critical reinforcement of the benefits of therapy right from the initial induction regimen.

Once-daily vs. Twice-daily Regimens

Dr. Stefan Schreiber, Christian Albrechts University, Kiel, Germany, reported, “The once-daily therapy achieves a time to initial symptom resolution that appears to be comparable to that of twice-daily and is, of course, superior to placebo.” According to pooled data from the two pivotal trials of the q.d. formulation of mesalamine, the time to normalization of major symptoms, including stool frequency and rectal bleeding, was indistinguishable between those randomized to a 1.2-g dose administered b.i.d., a 2.4-g dose administered q.d. or 4.8 g administered q.d. All were significantly superior to placebo.

“When starting 5-ASA, the most important immediate end point for physicians and patients is the time between initiation of therapy and symptom control,” Dr. Schreiber told delegates. The formulation evaluated in these studies was an extended-release formulation using a multi-matrix (MMX) system to transport drug to the colon and then to gradually diffuse the 5-ASA as the tablet core descends the colonic lumen. In patients with active, mild-to-moderate UC, these data “suggest that MMX mesalamine offers resolution within weeks of starting the medication.”

This new analysis included a total of 517 patients from the two multicentre, placebo-controlled and randomized phase III trials. Of these, 172 patients received 2.4 g/day of MMX mesalamine either in q.d. or b.i.d. regimens, 174 patients received 4.8 g/day q.d. of MMX mesalamine and 171 patients received placebo. Due to the nearly identical response for q.d. and b.i.d. regimens among those receiving 2.4 g/day, these groups were combined so that the comparison was between 2.4 g/day, 4.8 g/day and placebo.

“The aim of this pooled analysis was to investigate the time to initial resolution of rectal bleeding and normalization of stool frequency in patients with mild-to-moderate UC who received this 5-ASA,” Dr. Schreiber reported. “Specifically, we evaluated time to initial resolution of rectal bleeding, normalization of stool frequency, or both combined as assessed in the modified UC-DAI [Ulcerative Colitis-Disease Activity Index]. Time to resolution was defined for both as the interval between the first dose of study medication and symptom resolution [subscore of 0 for both symptoms].”

For the normalization of stool frequency, all active 5-ASA regimens demonstrated a rapid onset of action. While symptom improvement was observed within the first few days of treatment, the median time to normalization was approximately 20 days active treatment in all three cohorts. This compares well with previous studies of 5-ASA. In the placebo group, the median time to resolution was 34 days (P=0.0001). For rectal bleeding, median healing time, achieved in approximately eight days on 2.4 g/day or 4.8 g/day for the active agent, was more rapid. In the placebo group, the median time to resolution for this symptom was 16 days (P<0.0001).

The new analysis of the pooled data follows publication of both of the multicentre studies. Similarly designed, the North American study, known as 301, was led by Lichtenstein et al. (Clin Gastroenterol Hepatol 2007;5:92-102), while a trial conducted outside of North America, known as the 302 study, was led by Kamm et al. (Gastroenterology 2007;132:66-75). Both studies demonstrated comparable mucosal healing for the q.d. and b.i.d. regimens, according to a pooled data analysis (Sandborn et al. Aliment Pharmacol Ther 2007;26:205-25). Overall, mucosal healing was achieved in more than twice as many individuals receiving any regimen of mesalamine, including a q.d. regimen, when compared to placebo (approximately 36% vs. 17.5%; P<0.001).

The 303 Extension Study

An extension 303 study that entered 450 patients from both the 301 and 302 studies previously demonstrated that more than 60% of patients remained in remission at 12 months whether maintained on q.d. or b.i.d. therapy, but new 303 analyses have provided new insights about the relationship of early response to late response and the influence of previous relapse history on likelihood of remaining in remission. The study of early response to late response was made possible by an extension analysis that was included in the protocol of the 301 and 302 studies. In the extension, patients who had not achieved remission in the first eight weeks were permitted to move to a high-dose regimen of 2.4 g b.i.d. for an additional eight weeks. Those who achieved remission on the extension were then permitted to enter the 12-month 2.4 g/day mesalamine maintenance study.

“Results demonstrated that the majority of patients who achieved a remission on MMX mesalamine will remain in that remission over 12 months of mesalamine maintenance. However, the relapse rates were greater among those who took longer to achieve initial remission,” reported Dr. Michael A. Kamm, Saint Mark’s Hospital, London, UK. While relapse was only 26.6% among those who achieved remission within eight weeks on induction therapy, it rose to 49.1% in those who required 16 weeks.

In another post-hoc analysis of the 303 study data, relapse history appeared to have less of an impact on likelihood of staying in remission than delay in achieving remission on induction therapy. When patients were stratified by those who had experienced three relapses or more in the past two years or those who experienced less than three relapses, the sustained remission rates at 12 months were 59.8% in the former and 70% in the latter.

“This study shows that a low relapse history may have a positive impact on long-term remission rates. However, a majority of patients who suffered a number of relapses before starting MMX mesalamine treatment still achieved a long-term remission with the treatment,” reported Dr. Anthony Ellis, Royal Liverpool and Broadgreen Hospital, UK.

Commenting on the results of a study led by Prof. Jean-Frédéric Colombel, Claude Huriez Hospital, Lille, France, Dr. Ellis indicated that the 303 data, while substantiating the long-term benefits of 5-ASA, have been a rich source of new data about prognostic factors for sustained response.

Summary

New data from the pivotal trials with MMX mesalamine have expanded the data indicating that the recently developed q.d. formulation is at least as effective as b.i.d. therapy, including rapid relief of the most troubling UC symptoms and high rates of sustained remission, despite offering a less demanding dosing schedule. Although the advantage in acute symptomatic disease is likely to be one of convenience, the potential advantage in providing sustained remissions is an easier-to-remember once-daily dosing that will permit patients to remain on active drug, even when symptoms are no longer reminding them to take medication. This is a major advantage in a chronic disease that requires sustained compliance to prevent relapse.

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