NEW YORK (Reuters Health) Apr 29 - Atacicept lacks efficacy in patients with rheumatoid arthritis that shows an inadequate response to tumor necrosis factor (TNF) antagonist or methotrexate therapy, according to two studies in the March 30th online Arthritis & Rheumatism.
"Atacicept was developed as a specific inhibitor of the activation of B-cells through blocking the cytokines BAFF and APRIL," Dr. Ronald F. van Vollenhoven from The Karolinska Institute, Stockholm, Sweden, told Reuters Health in an email.
"It was postulated that such inhibition could be beneficial in a number of autoimmune conditions where autoreactive B-cells play a role. Because rheumatoid arthritis (RA) is frequently associated with autoantibodies (rheumatoid factor (RF) and/or ACPA (anti-citrullinated peptide antibodies)), and because another anti-B-cell agent (rituximab) is effective in this disease, it was decided to test the clinical efficacy of atacicept in such patients."
Atacicept had shown promise in an earlier phase I trial of patients with RA.
"However, in these trials atacicept did not demonstrate a clinically meaningful benefit over placebo in the primary outcome nor in the majority of secondary clinical outcomes. This disappointing result with respect to the clinical results was seen despite evidence for a robust biological effect of the drug, including decreases in immunoglobulins, RF, ACPA, and B-cells," Dr. van Vollenhoven said.
Dr. van Vollenhoven and colleagues investigated the efficacy, safety, and biological activity of atacicept in a phase II study of 311 patients with active RA who had an inadequate response to methotrexate but had never been treated with TNF antagonists.
In a similar study, Dr. Mark C. Genovese from Stanford University, Palo Alto, California, and colleagues investigated the effects of atacicept in 256 RA patients who had an inadequate response to TNF antagonists.
In both studies, atacicept failed to show a benefit over placebo in the primary endpoint, ACR20-CRP response at 26 weeks.
In contrast, atacicept showed significant biological activity, significantly reducing immunoglobulin levels and RF levels in both studies and significantly lowering mature B cell and plasma cell levels in the study of methotrexate-inadequate response patients.
Adverse events occurred with similar frequency in treatment and placebo groups, but more patients in both studies treated with atacicept experienced serious adverse events.
"Despite evidence to support biologic activity of atacicept, no significant evidence of efficacy was demonstrated in the TNF-inadequate response population," Dr. Genovese told Reuters Health by email. "Thus, there does not appear to be a role for atacicept in this population."
Dr. van Vollenhoven agreed: "These results do not support the hypothesis that atacicept would be a useful therapeutic agent for RA, at least not in the manner it was used in these two trials, and there is currently no role for this agent in RA."
"The evidence of biologic activity suggests that it might be possible to apply this therapy to other diseases," Dr. Genovese said. "I know that the company is exploring its potential in other diseases."
"Some sound ideas about what is going to work in the treatment of a disease may turn out not to work well in the actual trials," Dr. van Vollenhoven added. "A note of caution, in other words, against too much optimism before we know the data."
Some of the researchers in both studies report financial ties to Merck Serono, Roche, Genentech and Biogen-Idec. Both studies were supported by Merck Serono S.A. and EMD Serono Inc.
SOURCE: http://bit.ly/mO9Mv3
Arthritis Rheum 2011.