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United European Gastroenterology Week (UEGW)

Vienna, Austria / October 18-22, 2008

Numerous guidelines identify 5-aminosalicylates (5-ASA) as the first-line treatment for mild-to-moderate ulcerative colitis (UC) because these agents are safe and well tolerated. They have also been associated with significant protection against colon cancer, for which the risk is substantially increased in UC patients. Despite the first-line designation, a substantial proportion of patients are rapidly switched to less well tolerated therapies due to inadequate control on the initial 5-ASA regimen. New data suggest this proportion can be reduced markedly if managed with an optimal current formulation.

“The question becomes whether all 5-ASA formulations are born equal,” observed Dr. Michael Kamm, St. Vincent’s Hospital, University of Melbourne, Australia. “Frankly, the answer is no. Those of us who are interested in this field think that the different preparations, which have very different release profiles, do affect the pharmacokinetics of these drugs and do alter the rate of response.”

There are direct comparisons even among controlled-release 5-ASA formulations that support a difference. In a study published by Dr. Kamm and colleagues last year (Gastroenterology 2007;132:66-75), a mesalamine using a multi matrix system (MMX) release and a mesalamine using another delayed-release technology (AsacolTM) were both compared to placebo for mucosal healing. The clinical and mucosal healing rates were approximately 41% for MMX mesalamine (either of the 2.4 or 4.8 g/day dosages evaluated), 33% for the delayed-release mesalamine (2.4 g in three divided doses) and 22% for placebo. The advantage for the delayed-release formulation over placebo did not reach statistical significance (P=0.124), while both formulations of MMX mesalamine did (P=0.007 for the higher dose).

The 40% remission rate on the MMX mesalamine was among the highest so far reported, but a more recent study with the same agent has demonstrated that even higher rates of success can be achieved if patients are allowed to stay on the drug for a longer period. In a study that may change the paradigm for initial management, 304 patients who participated in one of two phase III studies with MMX mesalamine but did not heal (40% of patients in both trials did achieve strictly defined mucosal healing on the initial course) were entered into a second eight weeks of therapy. At the end of this period, 59.5% achieved mucosal healing (Kamm et al. Inflamm Bowel Dis 2008; Epub ahead of print).

“Our traditional approach has been to treat patients for eight weeks and if they are not in remission, to give them something else,” Dr. Kamm observed. “This study demonstrates that you can achieve remission on 5-ASA in two-thirds of patients if you give them a high enough dose for a long enough period. It suggests that we need to be more flexible with these drugs if we want to keep our patients on this first-line therapy.”

The evidence that some patients improve gradually and may still achieve endoscopic healing with a longer course of therapy is new information. According to Dr. Kamm, who identified endoscopic healing as a critical end point for acute therapy because of evidence that patients have a reduced risk of relapse and a better prognosis, the specific 5-ASA formulation is likely to be important. Although once-daily formulations were initially developed to improve compliance, it now appears that the pharmacodynamics of some q.d. preparations provide an advantage over multiple doses even when the total daily dose is similar.

“It is probably more effective to give a single daily dose of 5-ASA in terms of the concentration being achieved in the inflamed mucosa,” Dr. Kamm speculated. Noting that 5-ASA oral formulations have increased in dose from about 500 mg per pill to the 1.2 g now available in a single MMX mesalamine pill, he believes that high-dose q.d. formulations exert an important downregulation of inflammatory signals in active disease.

The same principle may be important in maintenance treatment, which Dr. Kamm also believes is dose-dependent. He said that although there has been a great deal of controversy about the optimal maintenance dose, “I think I can summarize the current thinking by saying that about 2 g/day regardless of preparation is probably reasonable in most patients.”

At this dose, the vast majority of patients can expect to remain in remission for extended periods. According to recently published data with MMX mesalamine, which evaluated 2.4 g/day either in a q.d. regimen or as 1.2 g b.i.d., the strictly-defined, relapse-free remission on endoscopic control was approximately 70% at the end of one year (Kamm et al. Gut 2008;57:893-902). The clinical remission rate at the end of one year was 90%. Both are impressive numbers relative to many previous studies with 5-ASA therapies.

Over the past several years, 5-ASA has been overshadowed in the treatment of inflammatory bowel diseases (IBD) by the development of biologics. Although these are providing very encouraging rates of disease control at the severe end of the disease spectrum, the progress with new formulations and delivery systems of 5-ASA may permit a greater proportion of patients to achieve initial disease quiescence that keeps them from progressing to advanced disease stages. Trying to draw attention back to 5-ASA, Dr. Kamm characterized 5-ASA as “a real winner” in the newer higher dose formulations. He asked rhetorically how often one sees an effective drug that is so safe in such a difficult disease as UC.

The protection offered by 5-ASA against cancer is not the least of its attributes. Numerous studies suggest the reduction in cancer risk may be as high as 80% with regular use. Of the studies, the most compelling may be an evaluation of healthcare data collected in the UK, according to Dr. Kamm. In a database with 5 million patients overall and 18,969 with a diagnosis of UC, there was a strong correlation with increasing 5-ASA compliance and increasing reductions in cancer risk (van Staa et al. Gut 2005;54:1573-78). The data for cancer protection have been sufficiently consistent, that Dr. Kamm reported he now maintains patients on 5-ASA for chemoprevention even after they have progressed to azathioprine.

The progress with newer 5-ASA therapies has immediate relevance to daily clinical choices, according to Dr. Kamm. He reported that he not only initiates new patients on the q.d. high-dose formulations but he has also switched most patients previously prescribed earlier-generation 5-ASA agents. He emphasized that patients should not only be switched to q.d. regimens for convenience but also for greater efficacy.

Summary

A far larger number of UC patients with mild to moderate disease can expect to be healed and effectively maintained on newer 5-ASA formulations than those available previously. The evidence that larger doses and q.d. regimens increase rates of clinical and mucosal healing has been confirmed in controlled studies. According to studies conducted with MMX mesalamine, which provides the highest dose of 5-ASA in a single controlled-release pill, up to 60% of patients can achieve mucosal healing, a critical predictor of sustained remission. Once in remission and on a maintenance regimen, trials suggest clinical remission rates at one year reach 90%. The efficacy of current agents means the majority of patients with mild to moderate UC can avoid less well-tolerated second-line regimens.