A preliminary trial by researchers at Cedars-Sinai Medical Center in Los Angeles California, has found that patients with active Crohn's disease who stopped responding to infliximab (RemicadeR) showed a demonstrable clinical response and a reduction in disease activity following treatment with adalimumab (HumiraR).

In the retrospective, 6-month study of 15 patients with active Crohn's disease who were unresponsive to infliximab, 11 of 13 (85%) who completed the study experienced a reduction in disease activity with adalimumab, according to a report in the January 2005 issue of the American Journal of Gastroenterology. Moreover, 54% of patients in the new study experienced a complete response, and 31% of patients showed a partial, symptomatic improvement.

Study Has Important Implications for Subset of Crohn's Patients

"Adalimumab appears to be effective in patients with an attenuated response to infliximab, although larger prospective studies with longer follow-up are required to determine if the efficacy of adalimumab is maintained over time," concludes lead researcher Konstantinos A. Papadakis, MD, a gastroenterologist at the Inflammatory Bowel Disease Center at Cedars-Sinai Medical Center. "These results have important clinical implications for a subset of patients with Crohn's for whom alternative anti-TNF therapies have not been available." As it stands, infliximab is the only approved biologic agent to treat Crohn's disease and it is considered the last-line pharmaceutical agent before considering surgery as an option.

Patients with extra-intestinal manifestations of Crohn's (arthralgias) improved or resolved their symptoms with adalimumab treatment, as did one patient who suffered from oral ulcers. Notably, the study showed that five of the 11 patients taking concomitant corticosteroid therapy were able to discontinue its use by week 14 of adalimumab treatment and three were able to decrease the dose at last follow-up visit.

Crohn's Disease Treatment May Follow RA Paradigm

"In the world of rheumatoid arthritis (RA), we have learned the principle that these drugs are not the same in that you can switch when a person either doesn't respond to one initially or loses response over time or, per chance, has side effects," says Phillip Mease, MD, of Seattle Rheumatology Associates in Washington state. "And when you switch to another agent, you can potentially achieve success.

"We have not done the same studies in psoriatic arthritis, psoriasis, or Crohn's," he tells CIAOMed. "[But] if the same principle holds true, it makes sense to consider doing this in other diseases. We have long known [that] the monoclonal antibody construct works well in Crohn's and the soluble receptor, etanercept, does not."

All patients in the new study had received a diagnosis of moderate-to-severe active Crohn's disease, were steroid-dependent and had failed standard immunomodulators, and/or had experienced draining fistula despite concomitant medical therapy. Patients selected for the study had received a median of five infliximab infusions prior to study treatment and had experienced reduced or loss of response to infliximab. Dr. Papadakis and colleagues used the Harvey-Bradshaw clinical activity index (HBI) to score disease activity. Complete response was defined as an HBI of <e;4 and withdrawal of corticosteroid treatment; partial response was defined as a decrease of at least 50% in HBI and reduction in corticosteroid dose. All other patients were considered nonresponders.

Patients received a loading dose of 80 mg subcutaneously followed by 40 mg every 2 weeks. To maintain clinical response, the dose and/or dosing frequency was increased during the study. Specifically, three patients received an increased dose of 80 mg every 2 weeks, two patients were given 80 mg weekly and one patient was given 120 mg every 2 weeks. Concomitant treatment with immunomodulators was continued. Two patients who had received the initial 80 mg loading dose could not be included in the evaluation because of inadequate follow-up.

The treatment was relatively safe, the study showed. No severe adverse events (AEs) were noted and there was no evidence of immediate or delayed-type hypersensitivity reactions. The most frequent AE was injection site reaction characterized by erythema and discomfort lasting less than 24 hours.

"Adalimumab is also a monoclonal antibody, but it's humanized, so the new data makes sense from the paradigm that we have been operating under," Dr. Mease points out. "It makes sense that it works and if the paradigm of switching established in RA holds true in Crohn's, as well, then it's very reasonable if a person doesn't respond or loses response, to try a different drug that can work."

The researchers note that while a small number of patients with an attenuated response to infliximab responded to adalimumab, larger prospective trials with a longer follow-up period are necessary before any determination can be made relative to the long-term efficacy in patients with Crohn's disease.

Reference:

Papadakis KA, Shaye OA, Vasiliauskas EA et al. Safety and efficacy of adalimumab (D2E7) in Crohn's disease patients with an attenuated response to infliximab. Am J Gastroenterol. 2005;100:75-79.