Atacicept, a drug designed to interfere with B-cell differentiation and maturation, was associated with up to twice as many relapses as placebo among patients with multiple sclerosis in the 36-week, phase II ATAMS (Atacicept in Multiple Sclerosis Extension Study).
Interim findings were enough to halt the drug’s placebo-controlled dose-ranging study, Dr. Ludwig Kappos of the University Hospital Basel, Switzerland, and his colleagues reported (Lancet Neurol. 2014 [doi: 10.1016/S1474-4422(14)70028-6]). The trial results were originally reported at the 2011 joint triennial congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis.
Dr. Ludwig Kappos
The increase in disease activity was surprising, wrote Dr. Kappos and his coauthors, especially because atacicept did not cause such problems in other studies.
"Studies of atacicept in other autoimmune diseases, including rheumatoid arthritis and systemic lupus erythematosus, had not suggested that such B-cell-targeted interventions might enhance, rather than suppress, inflammatory activity," they said.
"Our finding of an early and robust increase in relapse activity with atacicept treatment in a typical population with relapsing-remitting multiple sclerosis was therefore unexpected. This increase in clinical disease activity occurred in parallel with reductions in serum immunoglobulin concentrations and mature B-cell counts of the same dynamics and degree as reported in previous atacicept studies."
Fortunately, the authors noted, the relapses didn’t translate into any increase in disease severity, and measurements of all the affected immune factors returned to normal shortly after treatment ceased.
In an editorial accompanying the published paper, Dr. Fred Lühder and Dr. Ralf Gold wrote that there’s little doubt that B cells are a valid therapeutic target in multiple sclerosis. But they seem to exist in a fine-tune balance that, if disrupted, can harm, rather than help (Lancet Neurol. 2014 March 6 [doi: 10.1016/S1474-4422(14)70050-X]).
Atacicept binds to B-lymphocyte stimulator (BLyS), a cytokine that helps control B-cell differentiation, maturation, and survival. But unlike other B-cell modulators, it doesn’t kill all of them immediately. In ATAMS, the maximum reduction was 60%-70%.
Dr. Ralf Gold
"A probably more important issue is the types of B cell that are preferentially depleted," Dr. Lühder and Dr. Gold wrote. "Experimental evidence in animal models suggests that B cells potentially have a dual role in the pathogenesis of neuroinflammation. ... Spontaneous demyelinating disease occurs when both receptors are brought together, suggesting that antigen-specific B-cells could provide the essential stimulus for antigen-specific T-cells."
The second type of B cells, which produce interleukin-10, exert a regulatory effect, controlling the action of activated T cells, and thus reduce disease severity.
"Since BLyS is believed to be involved in the differentiation of these regulatory B-cells, the targeting of BLyS might disturb the fine-tuned balance of conventional and regulatory B-cells in favor of the conventional cells, eventually resulting in increased disease activity, as seen in ATAMS," they wrote.
Researchers will learn as much from this failed trial as they would from any successful trial, Dr. Lühder and Dr. Gold said. "Many other candidates have gone the same way. B-cells should still be regarded as a valid target, but there are good and bad B-cells in multiple sclerosis, and the net effect of a particular treatment on this complex scenario can be unpredictable."
Dr. Lühder is with the neuroimmunology department at the Institute for Multiple Sclerosis Research and the Max Planck Institute for Experimental Medicine at the University of Göttingen, Germany. Dr. Gold is with the department of neurology, St. Josef-Hospital, Ruhr-University Bochum, Germany.
The study was sponsored by Merck Serono. Dr. Kappos’s institution has received Merck grant money. Most of the coauthors reported numerous financial disclosures, including financial relationships with Merck Serono.