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.

PRIORITY PRESS - Inflammatory Bowel Diseases 2011: 6th Congress of the European Crohn’s and Colitis Organisation (ECCO)

Dublin, Ireland / February 24-26, 2011

Escalation in CD

In Crohn’s disease (CD) patients who have an incomplete response, the treatment dose can be adjusted from 5 mg/kg to 10 mg/kg every 8 weeks for infliximab and from 40 mg every other week (eow) to 40 mg/week for adalimumab. The extent to which these higher doses are used in a real-world setting was previously unknown, but the results of a retrospective study presented here at ECCO showed that patients treated with infliximab have a significantly higher rate of dosage adjustment compared with patients treated with adalimumab.

Researcher Alexandra Goyette, MSc, Montreal, Quebec, described how she and investigators from the Université de Montréal used real-world data from a random sample of 290 CD patients identified from the Régie de l’assurance maladie du Québec public database. Patients started adalimumab or infliximab between February and December 2008. Adalimumab dose increase was considered when the dose received exceeded 40 mg eow over a period of at least 8 weeks. Infliximab dose increase was considered when the dose was increased, or when the interval between doses was reduced for 2 periods of 8 weeks after the third injection.

After 12 months, 14.2% of patients on adalimumab vs. 22.2% of patients on infliximab had had a dose adjustment (P<0.05). In the subgroup of adalimumab patients who were naïve to infliximab, dose escalation occurred in 13.0% compared with 17.0% of those who had previously used infliximab.

Goyette reported that adalimumab was associated with significant cost savings over infliximab in both patients with and without dose escalation. Over 12 months, the average medication costs in Canadian dollars were $12,892 for adalimumab and $18,580 for infliximab (P<0.01) for patients who had no dose increase, and $22,836 with adalimumab and $29,088 with infliximab (P<0.01) for patients who had a dose increase. “Calculating on the basis of recommended dosages gave a similar result, i.e., a 30% difference between infliximab and adalimumab,” she added, noting that per dose, infliximab is more expensive than adalimumab. “The commercial significance of savings with adalimumab over infliximab is very interesting for payers, so we expect that there would be some recommendations coming from these data,” she predicted.

Induction and Maintenance Therapy for Pediatric CD

CD in children aged under 16 years, which tends to be more severe and extensive than adult CD, is an increasing problem. Infliximab is indicated for the treatment of pediatric patients with moderately to severely active CD who have had an inadequate response to conventional therapy. Adalimumab is in a development program for pediatric CD. In a pivotal trial presented here at ECCO by Dr. Anne Griffiths, Hospital for Sick Children, Toronto, Ontario, adalimumab was seen to be efficacious for inducing and maintaining remission of CD, with a safety profile comparable to that seen in adult CD patients.

The 52-week, randomized, controlled, double-blind study (M06-806) was carried out in 192 patients aged 6 to 17 years with CD (Pediatrics Crohn’s Disease Activity Index [PCDAI] >30 for =12 weeks), despite concurrent treatment, or failure/intolerance of treatment with oral corticosteroids and/or immunosuppressants. Treatment consisted of adalimumab induction as either “high” dose (160/80 mg for body weight =40 kg or 80/40 mg for body weight <40 kg) or “low” dose (80/40 mg or 40/20 mg, respectively). At week 4, patients were randomized to adalimumab maintenance therapy for 48 weeks at high dose (40 mg eow for body weight =40 kg or 20 mg eow for body weight <40 kg) or low dose (20 mg eow or 10 mg eow, respectively). A higher proportion of high-dose patients (38.7%) than low-dose patients (28.4%) achieved clinical remission (PCDAI =10) at week 26, the primary end point of the trial. Results were similar at week 52 (33.3% vs 23.2%, respectively). The greatest efficacy was seen in infliximab-naïve patients, especially those who responded to adalimumab induction, Dr. Griffiths noted.

Expanding Treatment Options in UC

In ulcerative colitis (UC), only infliximab is currently approved for use in patients with moderate to severe UC who have had an inadequate response to conventional therapy. The results of the first study to compare infliximab-based strategies with azathioprine (AZA) monotherapy in UC patients, the UC SUCCESS trial, were presented by Dr. Remo Panaccione, University of Calgary, Alberta. Findings showed that combined treatment with infliximab plus AZA was superior to either AZA or infliximab monotherapy in inducing steroid-free remission in patients with moderate-to-severe UC who were biologic-naïve; failing corticosteroids; and were naïve to AZA or who had stopped AZA treatment at least 3 months earlier. A 22% steroid-free remission rate at 16 weeks with infliximab was augmented to 40% by combination with AZA. The results of UC SUCCESS supported the findings of the SONIC study in CD patients, Dr. Panaccione noted.

A global clinical development program is underway with adalimumab in UC. Data from 2 phase III randomized, controlled, double-blind studies in patients with moderate to severe UC presented here at the congress demonstrated the efficacy of adalimumab in inducing and maintaining clinical remission in UC patients with an inadequate response to conventional therapy. Dr. Gert Van Assche, University Hospital of Gasthuisberg, Leuven, Belgium, presented the results of M06-827, which enrolled 494 intent-to-treat (ITT) adults with UC (Mayo score 6-12 and endoscopic subscore 2-3) despite treatment with corticosteroids and/or immunosuppressants. The trial included patients who had discontinued an anti-TNF agent due to intolerance or loss of response. Patients were randomized to receive placebo or adalimumab 160 mg at week 0, 80 mg at week 2 and 40 mg at week 4. Patients demonstrating inadequate response could switch to open-label 40 mg eow at week 12. Dose escalation to 40 mg weekly was permitted for patients with inadequate response on open-label administration. A greater proportion of patients treated with active therapy achieved the co-primary end points, clinical remission at week 8 and at week 52, compared with patients on placebo. Significantly more actively treated patients also achieved clinical response and mucosal healing, and sustained clinical remission, response and mucosal healing at week 8 and 52, compared with placebo. The effect of adalimumab was greater in patients who were naïve to anti-TNF treatment. “We now know that adalimumab is another option in UC, particularly in anti-TNF-naïve patients,” Dr. Van Assche declared. Non-anti-TNFs with a different mechanism of action might offer a solution for patients previously treated with an anti-TNF agent, he suggested. He also presented data showing that significantly more adalimumab-treated patients in the trial had improvements in health-related quality of life, measured as an increase in Inflammatory Bowel Disease Questionnaire score =16 points.

Dr. Walter Reinisch, Medical University, Vienna, Austria, reported week 52 results from the open-label extension phase of M06-826, an 8-week, randomized controlled trial in 390 UC anti-TNF-naïve patients. Two induction regimens of adalimumab were investigated: 160 mg at week 0, 80 mg at week 2 and 40 mg at week 4 or 6 (160/80 mg) and 80 mg at week 0 and 40 mg at weeks 2, 4 and 6 (80/40 mg). At week 8, higher proportions of patients in the 160/80 mg group (18.5%) and the 80/40 mg group (10.0%) were in clinical remission compared with the placebo group (9.2%) (Reinisch et al. Gut 2010. doi:10.1136/gut.2010.221127). Dr. Reinisch announced that after open-label treatment with 40 mg eow or weekly, 29.5% of patients maintained clinical remission and other efficacy end points. Patients in both M06-826 and M06-827 have been entered into an open-label, long-term extension study (M10-223) which will provide long-term data.

Summary

Two anti-TNF agents, infliximab and adalimumab, are approved for treatment of adults with moderate to severe CD who have had an inadequate response to corticosteroids and/or immunosuppressants. Adalimumab is also indicated in CD patients if they have lost response or are intolerant to infliximab.

Outlining treatment expectations for 2011 and beyond, Dr. Subrata Ghosh, University of Calgary, told delegates, “In both CD and UC, we must aim for long-term remission, avoidance of repeated need for steroids, avoidance of surgery and hospitalization, and good quality of life, with the ability to achieve personal ambitions. In children, we must also aim for normal growth and maturation.”