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PRIORITY PRESS - 5th Congress of the European Crohn’s and Colitis Organisation (ECCO)

Prague, Czech Republic / February 25-27, 2010

It is estimated that around 50% of patients with ulcerative colitis (UC) or Crohn’s disease are treated with 5-aminosalicylic acid (5-ASA). Its anti-inflammatory properties—exerted through inhibition of the NK-?B pathway, cyclooxygenase activation and prostaglandin expression and enhanced PPAR? expression/activation—are responsible for its efficacy in those patients. In addition to its anti-inflammatory properties, 5-ASA is also known to exercise an anti-neoplastic effect, an important consideration as UC is associated with an increased risk of colorectal cancer. More recently, an analgesic effect has also been described for this compound.

When 5-ASAs first started to be used, they were often given four times daily. Further developments in formulation reduced that frequency to twice-daily and, more recently, once-daily dosing has been shown to be as effective as b.i.d. dosing.

The Importance of Adherence

The PODIUM (Pentasa Once Daily in Ulcerative Colitis for Maintenance of Remission) trial demonstrated higher remission rates at 12 months with the controlled-release formulation of 5-ASA 2 g sachets once daily vs. the 1 g sachets b.i.d. formulation (Clin Gastroenterol Hepatol 2009;7(7):762-9). According to Dr. Axel U. Dignass, Markus Hospital, Frankfurt, Germany, the study was designed to show non-inferiority but the higher once-daily dosing remission rate difference of 11.9% was significant (P=0.024).

Along with high remission rates in PODIUM, adherence, as measured on a visual analogue scale, was also significantly better in the once-daily dosing arm. Although a pharmacological effect could not be ruled out, it appeared to investigators that improved adherence explained at least some of the superiority observed in this trial.

According to Dr. Dignass, “Non-adherence is a major problem in patients with quiescent UC where non-adherence may be as high as 90%.” The greatest problem lies with quiescent patients, as the perceived benefit may not be as great as during a flare. It is important to try to ensure adherence as outcomes are likely to be better in adherent patients, as illustrated by a prospective study of 99 patients with UC in remission, in which two groups—adherent and non-adherent—were established (Am J Med 2003 Jan;114(1):39-43). At six months, all recurrences occurred in patients who were non-adherent.

A vital aspect of adherence is patient education. Physicians need to take time to explain to patients why they are taking the medication and the benefits in terms of maintaining remission. This personalized approach recognizes that different patients have different concerns and needs. Taking these into account can help ensure that patients take their maintenance medication, and so remain in remission.

PODIUM and Mucosal Healing

While mucosal healing is becoming an important end point in clinical trials, its prognostic value is still controversial as many clinical trials use different definitions for this parameter. In an analysis of PODIUM, Dr. Dignass evaluated the effects of once- and twice-daily dosing on mucosal appearance in those patients in remission.

Mucosal appearance at baseline was normal (0 score) in 54.3% of the once-daily and 58.6% of the b.i.d. treatment groups; 99.4% and 99.5%, respectively, had a score of 0 or 1. At 12 months, normal mucosal appearance (0 score) was observed in 49.3% of the once-daily and in 46.2% of the b.i.d. treatment groups, while 85.4% and 81.4%, respectively, had a score of 0 or 1. In the per-protocol-treated patients at study end, there was a non-significant difference of the mean mucosa score (0 to 3) of 0.70 for the once-daily-treated group and 0.75 for the b.i.d. group.

According to Dr. Dignass, this analysis showed that a high number of patients will maintain mucosal healing with either a once-daily or b.i.d. dosing strategy and noted that mucosal healing was “an increasingly important end point in clinical trials. Together with improvement of symptoms, it reflects the success of the treatment on each individual patient."

Left-sided Colitis

Activity of 5-ASA throughout the whole gastrointestinal tract is often believed to be limited. A poster presented by Prof. Severine Vermeire, Katholieke Universiteit, Leuven, Belgium, and colleagues revealed the findings of a subanalysis of the PODIUM study aimed at investigating the efficacy of once-daily maintenance dosing with 5-ASA in patients with left-sided colitis. In total, 259 patients were included in the analysis (72% of the original cohort). At one year, remission rates were 69% for once-daily dosing vs. 61% for twice-daily dosing—similar to the overall cohort although in this case the difference was not significant. The authors concluded that the once-daily formulation tended toward better efficacy than twice-daily dosing in patients with left-sided colitis. These results further confirm the place of once-daily treatment as maintenance therapy in patients with left-sided colitis and support the availability of sufficient medication in the distal colon.

Rationale for Maintaining 5-ASA in Patients on Immunomodulators

For maintenance therapy, ECCO guidelines recommend oral 5-ASA-containing compounds as first-line maintenance in patients responding to 5-ASA- or steroid-induction therapy and that a combination of oral and topical 5-ASA can be used as a second-line maintenance therapy. “This is interesting,” commented Dr. Simon Travis, John Radcliffe Hospital, Oxford, UK. “If you are thinking of starting someone on an immunomodulator, maybe just starting them on topical 5-ASA might provide an answer.”

A common point of discussion in clinical practice is whether to discontinue 5-ASA treatment when azathioprine is indicated in a patient for maintenance therapy. According to data presented by Dr. Travis, “Eighty per cent of patients with UC are also on 5-ASA.” He added, “This is mainly to do with the antineoplastic properties [of 5-ASA]; [it] has been shown to halve the risk of colorectal cancer.”

Increasing Early Response

In the PINCE trial, 127 patients with active mild or moderate UC were randomized to receive oral 5-ASA and a 5-ASA enema or oral 5-ASA and a placebo enema. The end point was clinical remission (UC-disease activity index [DAI] <2) or improvement (UC-DAI decrease =2) after 2, 4 and 8 weeks of therapy. At week 8, “Remission was 64% in those given combination therapy and 43% in those receiving placebo enema so there was a therapeutic benefit of about 20%,” stated Dr. Travis.

A post-hoc analysis presented here at ECCO assessed early response after two weeks of therapy. Findings showed a significantly higher improvement rate with the combination 5-ASA enema and oral regimen according to UC-DAI vs. oral and placebo enema (P=0.0032).

A recent quality-of-life and pharmacoeconomics study based on the primary PINCE data (Digestion 2009;80(4): 241-6) found a significantly higher health-related quality of life in patients receiving active enema vs. those on placebo enema. “The cost of therapy was of course higher over a 60-week period, about £500 [$800 CAD], but when you looked at the improved quality of life and the overall cost of therapy, there was in fact a savings over the study period,” explained Dr. Travis.

Optimizing 5-ASA Therapy

Prof. Pierre Desreumaux, University of Lille, France, explained, “There are three main possibilities for optimizing 5-ASA: the first is to modify the formulation; the second is to modify the metabolism; and the third is to modify the structure.” In the case of structural modifications, Prof. Desreumaux described an experimental compound known as GED0507, which has the advantage—unlike unmodified 5-ASA—that its principal metabolite is also active. GED0507 will soon be entering phase I clinical trials. The metabolism of 5-ASA, in particular N-acyl conjugation, could be inhibited by co-administration with flavonoids, although this option has yet to be tested in a clinical setting.

Summary

The mainstay of mild to moderate UC treatment is still 5-ASA and the development of once-daily dosing has improved adherence and efficacy. PODIUM has demonstrated that enough 5-ASA remains available and active to provide high remission rates in left-sided colitis. Adherence remains a difficult variable to control but more trials report on better adherence with simplified dosage and earlier treatment efficacy. This, in combination with more personalized care, should help improve outcomes in patients with mild-to-moderate UC.