Reports

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PRIORITY PRESS - Canadian Digestive Diseases Week

Toronto, Ontario / February 27- March 2, 2010

Inflammatory bowel disease (IBD) includes ulcerative colitis (UC) and Crohn’s disease (CD). Both are chronic conditions with an unpredictable course of intermittent flares and remission. The immediate treatment goals for acute episodes of either form of IBD are to quickly control symptoms to improve quality of life, and to induce and maintain long-term remission.

Mesalamine (also called 5-aminosalicylic acid or 5-ASA) continues to be the first-line mainstay therapy for mild to moderate UC. Unmodified mesalamine is rapidly absorbed from the proximal gastrointestinal (GI) tract, limiting its availability to the colonic mucosa. Sulfasalazine was developed so that the active ingredient would be linked to a sulfapyridine carrier molecule, protecting it from degradation. However, dose-related toxicity associated with the sulfapyridine moiety was common and divided dosing was necessary. Newer formulations of oral mesalamine have since been developed to exclude sulfapyridine and instead, use technology like delayed-release Eudragit coatings to target delivery to different areas of the GI tract. However, divided dosing administration was well-accepted and persisted both in clinical trials and in practice.

Recently, there has been growing interest in studying the use of once-daily dosing with different oral mesalamine formulations. One such trial examined two doses of multi-matrix (MMX) mesalamine given once or twice daily in active, mild to moderate UC patients, and found both to be effective in inducing remission (Clin Gastroenterol Hepatol 2007;5(1):95-102). The question remains as to whether this dosing can be done with other oral 5-ASAs. In a study looking at plasma pharmacokinetic parameters, investigators found no apparent difference in release profile following dosing with mesalamine administered once-daily as an MMX formulation or a Eudragit-S formulation. The next step was to evaluate the efficacy of this formulation dosed once-daily in a well-designed clinical trial.

QDIEM Findings

The QDIEM (QD Dosing Investigation for Efficacy in UC Maintenance) study is the largest prospective IBD trial ever conducted. It was recently published in Gastroenterology and was presented in Toronto during the 2010 Canadian Digestive Diseases Week (CDDW).

The goal of QDIEM was to examine the efficacy and safety of once-daily dosing of delayed-release mesalamine (Eudragit-S formulation) compared with twice-daily dosing for maintaining remission in UC patients. The primary efficacy analysis was designed to assess whether the once-daily dosing regimen was noninferior to twice-daily dosing for maintenance of clinical remission at month 6. Patients randomized and dosed (n=1023) had mild to moderate UC maintained in clinical remission for at least 3 months, and were on a stable dose of mesalamine ranging from 1.6 to 2.4 g/day.

At month 6, 90.5% of the once-daily dosing group had maintained clinical remission compared with 91.8% in the twice-daily dosing group (P=0.50). At month 12, 85.4% of patients were still in clinical remission in both treatment arms (P=0.98). No differences in time-to-relapse or patient-defined remission were reported at any time point. As assessed by the medication adherence report scale (MARS) questionnaire, adherence to the medication was high in both groups, but patients indicated they preferred taking medication fewer times a day.

The incidence of withdrawals as a result of adverse events (AEs) was low for both dosing regimens. The incidence of serious AEs was 3.5% in the once-daily group and 1.8% in the twice-daily group (but this was not significant). All serious AEs were judged by investigators to be “doubtfully related” to the study drug with the exception of one patient in the twice-daily group.

The QDIEM study reinforces other evidence that once-daily administration of delayed-release mesalamine is effective for the maintenance of remission in mild to moderate UC. This may be relevant for some patients where dosing frequency is a factor in adherence. However, since adherence is multifactorial, poor adherence is not necessarily resolved by addressing dosing frequency alone. In fact, some studies have shown that once-daily and twice-daily dosing lead to comparable adherence and patient satisfaction rates (Clin Gastroenterol Hepatol 2003;1:170-3, Clin Therapeutics 1984;6(5):592-9). Since poor adherence in UC patients is linked to an increased risk of relapse (Am J Med 2003;114:39-43), a greater need for surgery and a higher risk of colon cancer, it is important to discuss with the patient all the relevant factors and develop an individualized solution.

The Biologic Era

The acute treatment goals of symptom control and improvement in quality of life do not change in more severe forms of IBD, nor does the need to induce and maintain remission. As immunomodulators or biologics become necessary to achieve this, rapid remission induction and maintenance without steroid dependence with minimal side effects remain the key objectives. Here at the CDDW, particular emphasis was placed on the long-term efficacy of some of the newer tumour necrosis factor (TNF) alpha inhibitors.

The ADHERE study was an open-label extension of CHARM, the registration study with adalimumab for CD.

In ADHERE, continued adalimumab therapy was associated with sustained maintenance of remission. Of those in remission after the first year of CHARM, 83% remained in remission for an additional two years. The authors further reported “clinically meaningful” rates of steroid-free remission among those patients who were receiving steroids when they entered CHARM.

In moderate to severe CD, biologics have proven to be an important addition in the induction and maintenance of steroid-free remission. However, loss of response or antibody development over time remains an issue. Switching to another biologic may help reinstate remission. To that end, Fedorak et al. of the WELCOME study assessed the efficacy of certolizumab pegol in patients with moderate to severe CD who had either lost their response to infliximab or who had developed a hypersensitivity reaction to the drug. In WELCOME, 38.3% of the cohort had achieved a clinical response at week 26, and response rates were not different between patients who received the agent every two weeks or those who received it every four weeks. The presence of antibodies at baseline did not affect early response rates. Although some have claimed that certolizumab and adalimumab do not cross react with antibodies to infliximab, there has been some inconsistency in the literature. Appropriate strategies for ordering anti-TNF agents in the event of a first-line failure are still being evaluated.

Controversy of Moderate Disease

One of the most difficult areas of clinical practice is what to do with patients with IBD who do not have a clear indication for top-down therapy with a biologic agent, but fail first-line therapies. Time-dependent treatment algorithms in moderate CD and UC were proposed by Panaccione et al. (Aliment Pharmacol Ther 2008;28:674-88) where the key to modifying therapy is time to response in the context of disease severity. In this respect, 5-ASA is the first-line option for mild to moderate UC while budesonide or antibiotics can be considered for mild to moderate CD, with the option of more aggressive therapy if adequate control is not achieved or recurrences are frequent. For moderate to severe disease, biologics should be considered as first-line therapy after a time-limited trial of systemic steroids and immunomodulators.

Due to the variability in disease expression, strict indicators for stepping up treatment remain difficult to define, but the goals of rapid mucosal healing, sustained remission and avoidance of steroid dependency are common goals to all treatments.

Summary

The development of delayed-release formulations of 5-ASA has been an important step forward for remission and control of mild to moderate UC. New data suggest that patients who respond to these formulations can maintain disease control with once-daily dosing for up to two or more years. As the severity of UC and CD increases, more aggressive therapies are needed, but the goals remain the same—rapid control of symptoms followed by long periods of disease quiescence. The frequent need for steroids to control acute attacks is a signal that patients require more aggressive therapy but with the expanded therapeutic armamentarium for IBD today, physicians should be able to induce and maintain remission for the great majority of patients.