Reports

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PRIORITY PRESS - 111th Annual Digestive Disease Week (DDW)

New Orleans, Louisiana / May 1-5, 2010

New data generated from the large multinational PODIUM (Pentasa Once Daily in Ulcerative Colitis for Maintenance of Remission) trial published last year (Dignass et al. Clin Gastroenterol Hepatol 2009;7:762-9) demonstrates that once-daily sachets of extended-release mesalamine are highly effective for sustained healing as well as remission in patients with ulcerative colitis (UC).

Mucosal Healing

While remission was the primary end point of the published study, which randomized patients to mesalamine 2 g once daily or 1 g twice daily (b.i.d.), the newly released data were based on healing. “On the basis of the mucosal appearance, the two study groups did not differ significantly, but there was a tendency towards a higher percentage of patients with completely normal appearing mucosa in the once-daily group,” reported Dr. Axel Dignass, Department of Gastroenterology, Markus Hospital, Frankfurt, Germany. “These results are in line with the superiority of the once-daily compared to the b.i.d. regimen previously shown for the remission end point.” Although both regimens were effective, the once-daily regimen was preferred.

The new data are drawn from PODIUM, which randomized 362 patients with quiescent UC to mesalamine extended-release sachets in once-daily or b.i.d. doses and compared them for remission at 12 months (Dignass et al. 2009). In that study, 70.9% of those on once-daily vs. 58.9% of those on b.i.d. dosing met the criterion for remission which was evaluated with the UC Disease Activity Index (UCDAI). In that study, adherence was significantly greater at most timepoints on the once-daily regimen, according to self-reports, which may have explained the advantage for the 2 g once-daily regimen.

The new analysis from the same trial was based on sigmoidoscopic evaluation at 12 months. Mucosal status was based on a 3-point UCDAI mucosal appearance assessment. In the analysis, normal mucosa produced a score of 0; erythema, reduced capillary network, mild friability or minimal granularity produced a score of 1, while more severe disease rated a score of 3. At baseline, essentially all patients (>99%) had a score of 0 or 1 of which slightly more (~55%) had a score of 0.

At the end of 12 months, a mucosal healing score of 0 or 1 was retained in 85.1% and 81.4% of those randomized to 2 g once-daily and 1 g b.i.d., respectively. In the once-daily group, 49.3% had a score of 0, signalling complete healing which was numerically but not significantly higher than the 46.2% in the b.i.d. group. Dr. Dignass noted the high rates of mucosal healing are potentially important because of a growing but incomplete body of evidence suggesting that healing is prognostic for quiescent disease.

Left-sided Colitis

In another analysis from the PODIUM study, very similar findings were generated for the subgroup of patients with left-sided colitis. Again, both 2 g once-daily and 1 g b.i.d. doses were effective and well tolerated, but the once-daily dose tended to offer better efficacy. In PODIUM, among the 261 patients (72%) with left-sided colitis, remission rates at 12 months were 71% on once-daily and 59% on b.i.d. dosing (P=0.024). In agreement with Dr. Dignass, the lead author of this substudy, Dr. Séverine Vermeire, University Hospital, Leuven, Belgium, characterized the 2 g dose as “preferred” based on the efficacy, which is likely to have been at least partially due to better compliance. According to Dr. Vermeire, the ability of once-daily dosing to facilitate compliance should not be overlooked as a potential factor to favourably influence quality of life in a population with a chronic disease who may require life-long treatment.

Sustaining Remission After Crohn’s Disease Surgery

One reason that mesalamine and other 5-aminosalicylates (5-ASA) are considered first-line therapy in most of the current treatment guidelines is that these therapies are not only effective but also better tolerated than alternative UC agents. However, the tolerability is not a trade-off for potency. These agents are capable of sustaining remission even in Crohn’s disease (CD), which is often more aggressive, according to a newly completed meta-analysis of eight placebo-controlled trials. In this meta-analysis which included 1242 patients, the risk of a relapse after surgically-induced remission was reduced 32% (OR 0.68; 95% CI, 0.52-0.90; P=0.007) by 5-ASA relative to placebo. “There was no statistically significant heterogeneity among the eight trials comparing 5-ASA with placebo,” reported Dr. Morris Gordon, Department of Pediatric Gastroenterology, Royal Manchester Children’s Hospital, UK.

He reported that efforts to compare 5-ASA to azathioprine failed because of a lack of data, but he indicated that they do support a role for 5-ASA. He noted that the one strength of 5-ASA in CD as well as UC maintenance is safety. In the meta-analysis, the incidence of adverse events was not significantly different in patients receiving 5-ASA than in those receiving placebo.

Maximizing Therapy and Time to Remission

The stepped-up therapy approach in UC calls for immunosuppressive agents such as azathioprine in patients who fail 5-ASA agents such as mesalamine, but there is substantial concern that many clinicians are not sufficiently diligent in maximizing the potential of first-line therapy before moving to agents less well tolerated. A few years ago a multinational study called PINCE demonstrated that remission rates after eight weeks of extended-release mesalamine sachets could be substantially increased with concomitant mesalamine enemas (Marteau et al. Gut 2005;54:960-5). In new data from the same trial, it was shown that the addition of the enemas not only increased remission rates but also greatly accelerated the time to remission with twice the proportion of patients symptom-free at two weeks (60% vs. 30%).

“These data demonstrating a very rapid effect of therapy have important implications for patient satisfaction and commitment to treatment, leading to improved outcomes,” reported Dr. Philippe Marteau, Gastroenterology Department, Lariboisière Hospital, Paris, France. Citing the abundant data associating poor adherence with an increased risk of relapse, Dr. Marteau indicated that such factors as rapid relief and simple dosing regimens might determine success independent of the efficacy of the therapeutic agent.

Colorectal Cancer Risk Reduction

While the focus of both clinicians and patients is generally on sustained remission of UC, the ability of mesalamine and other 5-ASA preparations to reduce the risk of colorectal cancer (CRC) is an important additional reason to maintain as many UC patients as possible on this first-line therapy.

In new data from the CESAME (Cancers et Sur-risque Associé aux Maladies Inflammatoires Chroniques de l’Intestin en France) cohort of almost 20,000 inflammatory bowel disease patients in France, there was a 48% reduction (P=0.03) in CRC for those exposed to 5-ASA with even greater statistically significant reductions in those with longstanding UC or with risk factors for CRC, according to Dr. Laurent Beaugerie, Department of Gastroenterology, Hôpital Saint-Antoine, Paris. “These results are consistent with a variety of other data that the chemopreventive effect of 5-ASA on CRC is real,” he told delegates, citing a previous meta-analysis which also found the cancer risk reduction on 5-ASA to be approximately 50%. Although the CESAME data also associated thiopurines with a cancer risk reduction, it did not reach statistical significance, suggesting that the preventive effect of 5-ASA is achieved by a mechanism additional to disease control.

Summary

The 5-ASA agents, such as extended-release mesalamine sachets, are recognized as well-tolerated first-line agents for mild to moderate UC, but their potency is wholly dependent on compliance. Compliance has repeatedly been demonstrated as a variable for treatment success in such studies as PODIUM, which has now demonstrated that remission at 12 months includes healing in the vast majority of patients. The simplicity of once-daily dosing appears to be a factor in maximizing compliance but patient education that addresses the potential for an improved prognosis, including cancer prevention, is also appropriate.