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.

14th United European Gastroenterology Week (UEGW)

Berlin, Germany / October 21-25, 2006

Most treatment guidelines for ulcerative colitis (UC) advocate 5-aminosalicylic acid (5-ASA) induction and maintenance, but there has been a strong impetus to intensify efforts to keep patients on effective maintenance regimens once acute symptoms are controlled. Benefits of keeping disease quiescent accrue over time when measured across a broad array of outcomes. These not only include protection from the disruption in activities of daily living associated with relapse, but protection from repeat hospitalization as well, and a reduction in the risk of colorectal cancer. Although UC is perceived as an episodic condition, relapses are largely preventable. There are now several studies that show a direct relationship between compliance and prolonged remission.

Adherence: Key Target to Improve Outcomes

According to Dr. Stefan Schreiber, Head, Institute for Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany, “Non-compliance with 5-ASA therapy has considerable clinical implications. Patients who are non-compliant with prescribed therapy are at greater risk of symptomatic exacerbation compared with those who do comply. The immediate result is a diminished quality of life, where the degree of impaired quality of life is directly correlated with disease severity and the duration of aggravated symptoms.”

In one frequently cited study (Kane et al. Am J Med 2003;114:39-43), 89% of compliant patients vs. 39% of non-compliant patients (P=0.001) on 5-ASA therapy with mild to moderate UC remained in remission at the end of two years. In other studies, the risk of a disease flare has been calculated to be as much as five times higher in patients who are non-compliant relative to those who adhere to their regimen. While non-compliance to therapy is a prevalent issue throughout clinical medicine, it has posed a particular threat in UC. In patients in remission, the challenge of remaining adherent to complicated regimens requiring multiple doses per day often increases when the relationship between treatment and disease control becomes disassociated over time.

“Effective, currently prescribed formulations need to be given in inconvenient, multiple daily doses. Patient compliance with these regimens is known to be low, thus drug efficacy is compromised and the risk of disease flare is increased,” observed Dr. John Nicholls, St. Mark’s Hospital, London, UK. While he also pointed to evidence that poor disease control increases the risk of colorectal cancer, he cautioned that the economic consequences provide an equally compelling argument to step up compliance.

Costs Incurred by Non-Compliance

As Dr. Nicholls explained, “The burden of disease associated with UC results in time off work, loss of earnings, and potential hospitalization, which may involve step-up therapy such as expensive immunological therapies and surgery. This will have an impact on health resources and affect patient well-being and quality of life.”

In many current guidelines, including those being prepared for Europe, mesalamine is the first-line therapy for mild-to-moderate UC. In upcoming European guidelines previewed by Dr. Eduard F. Stange, Robert Bosch Krankenhaus, Stuttgart, Germany, the combination of oral mesalamine plus topical aminosalicylates for mild to moderate left-sided UC were given the highest grade (A) recommendation based on the highest level of evidence (1A). Although the current formulation requires multiple doses, new findings on a once-daily formulation appear to indicate a simplified therapy with the potential to boost compliance.

“Two phase III trials have been completed with this delayed-release formulation, and the efficacy was very encouraging,” reported Dr. Michael A. Kamm, St. Mark’s Hospital, London. Initial studies were largely focused on induction of remission. The ability of the compound to deliver relatively consistent levels of drug over each once-daily dosing period is credited with providing very high rates of response, even in patients with extensive disease. As previous experience suggests that agents effective for induction will also prevent relapse, the new formulation may well provide the convenience needed to enhance compliance.

Towards Dosing Simplification

The once-daily formulation of mesalamine employs a patented multi-matrix (MMX) system in which the pH of the terminal ileum is employed to activate slow diffusion of the drug. This technology is designed to prolong the period of therapeutic activity to provide a steady state of clinical activity and simplify dosing. In combined data from two multicentre phase III, placebo-controlled trials studies presented by Dr. Kamm, clinical improvement at eight weeks was achieved by 32.7% of placebo patients vs. 58.1% of those randomized to once-daily 2.4 g and 62.1% of those randomized to once-daily 4.8 g (P<0.001 vs. placebo for both doses).

Dr. Kamm reported, “The once-daily mesalamine formulation was effective at either dose, while the safety profile was similar to that seen with other mesalamine formulations.” The significance of these findings is that “a convenient therapy that effectively treats all forms of mild-to-moderate UC has the potential to lift the clinical and economic burden of this disease.”

The pooled data included 517 patients in an intent-to-treat analysis. Patients were randomized to mesalamine 2.4 g, 4.8 g once-daily or placebo. The relative difference between the rates of endoscopic remissions reflected the difference in clinical improvement. At the end of eight weeks, 37.2% of those receiving 2.4 g, 35.1% of those receiving 4.8 g once daily and 17.5% of those receiving placebo were in endoscopic remission (P<0.001 for either active treatment vs. placebo). The incidence of adverse events did not differ significantly with 36.2%, 32.4%, and 34.6% reported in the three groups, respectively. Withdrawal rates for an adverse event were 3.4%, 1.1%, and 7.3%, respectively.

Regarding his review of the safety data, Dr. Schreiber confirmed, “These combined data confirm that MMX mesalamine is well tolerated at doses of 2.4 g and 4.8 g daily with fewer discontinuations due to adverse events than placebo.” Due to the similarity in safety between this and other 5-ASA formulations, he also concluded that this drug “has the potential to increase compliance and enhance treatment success in UC patients.”

Subgroup analyses provided additional support for the overall conclusions. In an analysis of patients who had previously received 5-ASA therapy, findings demonstrated that the once-daily formulation still achieved significant activity, although Dr. Kamm indicated that the 4.8 g once-daily dose appeared to be more active in this group. He also reported that the MMX formulation was found to provide similar efficacy in those patients with extensive disease when compared to those with left-side disease alone.

The Future of Ulcerative Colitis Management

The once-daily formulation is not the definitive method of improving outcomes in patients with UC, but it is emblematic of the types of strategies required to take a more aggressive approach to maintaining remission once it is achieved. Although current therapies are not infallible, they are effective for a substantial proportion of patients when given in adequate doses in a rigorously maintained regimen.

While Dr. Kamm suggested that “the future of mesalamine therapy will be once-daily dosing,” he indicated that the most important change will be better patient adherence. Concurred Dr. Marc Lemann, Hôpital Saint-Louis, Paris, France, “The [current] guidelines appear to be based on an underlying acceptance of the doctrine that patients will relapse. In other chronic disease areas, such as asthma, the management strategy has switched from the treatment of exacerbations to focus on the prevention of exacerbations. Similarly, the strategy for the treatment of UC should be modifying the long-term disease burden by preventing relapse, inflammation and cancer.”

Summary

Insufficient attention has been paid to adherence as a strategy to improve quality of life and outcome in UC patients at persistent risk of disease flares. The development of once-daily 5-ASA is part of an effort to increase compliance to UC maintenance therapies. Strict adherence reduces the risk of relapse and hospitalization and is projected to reduce the risk of colorectal cancer.

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