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.

Digestive Disease Week 2007

Washington, DC / May 20-23, 2007

Ulcerative colitis (UC) is a disease characterized by unpredictable and often debilitating flares of mucosal inflammation. Control of acute flares is often achieved with intensification of treatment, but avoiding flares with effective maintenance therapy is critical to preventing disruptions in daily routine and maintaining an acceptable quality of life. In chronic disease, strategies for maintenance require efficacy to be balanced against tolerability, safety and convenience, all of which may influence compliance.

Recent Findings

Two extension studies of pivotal phase III trials with newer therapies demonstrate long-term disease control, a critical advance for UC treatment. Of these, the most significant is one conducted with a novel high-strength formulation of mesalamine that can be administered once daily. Drugs in the 5-aminosalicylic acid (ASA) therapeutic class, such as mesalamine, are already established as first-line strategies. The new study provided 12-month data.

Dr. Michael Kamm, Division of Gastroenterology, St. Mark’s Hospital, London, UK, reported, “Less than 15% of patients experienced a clinical relapse over long-term evaluation. Moreover, more than two-thirds of patients remained in remission using the most stringent clinical and endoscopic criteria.”

The mesalamine trial was conducted with a new multi-matrix system (MMX) recently approved for induction of UC remission based on two multicentre, randomized phase III studies. The matrix of lipophilic and hydrophilic excipients is designed to delay release until the mesalamine reaches the colon and then, through gradual dissolution of the matrix coating, provide better drug exposure as the agent reaches the diseased tissue. In previous preparations of 5-ASA, including those that are delayed-release, several pills taken in multiple doses were required to deliver sufficient drug to the area of inflammation. In most patients, the MMX technology permits once-daily dosing.

In the extension trial, 362 patients who had participated in either one of the phase III placebo-controlled trials and achieved both clinical and endoscopic remission were maintained on 2.4 g of the MMX mesalamine for 12 months. About half received the agent once-daily and the other half were placed on a twice-daily regimen. Patients were followed for both clinical and endoscopic relapse. Both doses performed well with no significant difference between them. At the end of 12 months, 88.7% of patients on the q.d. regimen and 92.5% of those on the b.i.d. regimen were in clinical remission. Strict endoscopic remission, defined as sigmoidoscopy score of 1.0 or less and absence of mucosal friability, was achieved in 67.8% and 72.3%, respectively.

Dr. Kamm explained, “This study was not powered to compare the two regimens, but exploratory analyses have revealed no significant differences between the q.d. and b.i.d. dosing in terms of remission rates or relapse rates.” Although he acknowledged that compliance in a clinical trial might not be reflective of compliance in an uncontrolled setting, “a low pill burden and less frequent dosing have been repeatedly shown to be better accepted by patients in a variety of disease states,” he stressed.

Differentiating Formulations

The two phase III studies with the MMX mesalamine formulation featured different designs. In one, 280 UC patients were randomized to 2.4 g/day (1.2 g b.i.d.), 4.8 g/day (q.d.) or placebo and then followed over eight weeks (Lichtenstein et al. Clin Gastroenterol Hepatol 2007;5:95-102). Clinical and endoscopic remission at the end of the trial was more than doubled with active treatment vs. placebo (34.1% and 29.2% vs. 12.9%). In the other, 343 UC patients were randomized to 2.4 g MMX mesalamine q.d., 4.8 g MMX mesalamine q.d., 800 mg of delayed-release (DR) mesalamine t.i.d. (total dose 2.4 g/day); or placebo (Kamm et al. Gastroenterology 2007;132:66-75). Both of the active formulations achieved a clinical and endoscopic remission rate of 41% vs. 22.1% for placebo.

Remission Rates

“As demonstrated previously, mesalamine is efficacious and well-tolerated for the induction of clinical and endoscopic remission. However, the once-daily formulation was no less effective than one requiring multiple doses, which has implications for treatment compliance,” indicated Dr. Kamm. Moreover, he provided data from an initial extension trial that pooled 156 patients who did not achieve remission in either of the eight-week phase III studies and placed them on a regimen of 4.8 g/day for an additional eight weeks. The remission rate was 60.9%. Those in remission were then entered into the long-term maintenance trial, receiving the 2.4 g/day q.d. of MMX mesalamine.

“Of the active mild-to-moderate UC patients initially randomized [to MMX mesalamine], 56.6% achieved clinical and endoscopic remission within 16 weeks and remained relapse-free for an additional 12 months,” Dr. Kamm told delegates.

There was also a subgroup of 47 patients who achieved clinical and endoscopic remission on the DR multiple-dose mesalamine by 16 weeks and were then maintained on MMX mesalamine 2.4 g/day for the 12-month extension study. Of these, 77.8% remained in remission at the end of 12 months, which was similar to the proportion of patients who started on MMX mesalamine.

According to Dr. Gary R. Lichtenstein, Division of Gastroenterology, University of Pennsylvania, Philadelphia, and senior author of this analysis, “The once-daily formulation of mesalamine is an efficacious long-term maintenance therapy for patients with mild-to-moderate UC, irrespective of the prior 5-ASA therapy that was used to achieve remission.”

These results confirm an important long-term benefit from a once-daily therapy in patients with mild-to-moderate UC, but there were also encouraging data from an extension trial in patients with severe disease typically refractory to 5-ASA. In new data generated from patients who participated in the phase III registration trials for infliximab in UC, high rates of control were observed over two years. Presented by Dr. Walter Reinisch, Professor of Medicine, University of Vienna, Austria, the extension trial included 291 patients who participated in either of the Active Ulcerative Colitis trials (ACT I and II). Patients in remission continued to receive their assigned treatments which were 5 mg/kg or 10 mg/kg infliximab. Data are now available on 215 patients followed for one year and 92 patients followed for two years.

“Relapses were infrequent, and health-related quality- of-life scores improved over time. In those who remained on therapy over two years, 98% were completely off corticosteroids,” reported Dr. Reinisch. He noted that although serious side effects with infliximab were reported in ACT (Rutgeerts et al. N Engl J Med 2005;353:2462-76), there were few serious side effects encountered during the extension, with the exception of a single case of sarcoidosis. Nevertheless, in patients with severe UC, the extension data suggest “infliximab is effective long-term” and that includes improvements in quality of life.

“Further studies are required to determine if higher doses of mesalamine maintenance therapy may be required in patients who have severe endoscopic findings at baseline,” Dr. Lichtenstein reported. But “the development of more straightforward maintenance therapies has substantial potential advantages in the treatment of UC.”

Summary

New data from UC extension trials suggest that options are improving for preventing relapse in both mild-to-moderate and refractory disease. A new once-daily formulation of mesalamine and a biologic were both associated with sustained remissions when administered long-term in those patients with active UC whose disease was initially controlled with an induction regimen of the same agent.The extension data are also encouraging because UC is a chronic condition that imposes a high clinical burden. There is no known cure for UC, making each incremental improvement in treatment critical for patients with life-long disease. Simplifying dosing regimens to improve compliance may provide a substantial advantage in long-term control.

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