AMSTERDAM – While the B-cell targeted drug atacicept failed to improve disease activity in patients with relapsing remitting multiple sclerosis and even may have made the patients’ conditions worse, another anti–B-cell drug, ocrelizumab, is showing positive signs of being a future treatment for the disease.
Even though atacicept decreased mature B-cell proliferation and levels of serum immunoglobulins in the ATAMS (Atacicept in Multiple Sclerosis) randomized, phase II study – as would have been expected – patients who received atacicept had a higher annualized relapse rate (ARR) and more gadolinium-enhancing (GdE) lesions than did those on placebo. Atacicept is a recombinant fusion protein containing the soluble TACI receptor. It binds to and neutralizes the B-cell stimulatory cytokines B-Lymphocyte Stimulator and A Proliferation-Inducing Ligand and also blocks the activation of TACI receptors on mature B cells.
Data from a separate multicenter, randomized trial with ocrelizumab appear in stark contrast to the ATAMS study, as ocrelizumab clearly had a beneficial effect on the number of GdE lesions and ARR, and the findings appear to persist in the long term. Ocrelizumab is a humanized monoclonal antibody that targets CD-20 on the surface of B cells, much like rituximab (Rituxan), which has also been investigated as a potential MS therapy.
At the joint triennial congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS), where the ATAMS results were presented, Dr. Ralf Gold of St. Josef Hospital and St. Elisabeth Hospital, both in Bochum, Germany, commented that the ATAMS findings came as a surprise because multiple studies have indicated a clear rationale for targeting B cells in MS.
"B cells have regulatory capacities [and] it may be that [with atacicept] you may impair regulatory pathways rather than silence the active and putative pathogenic B cells," Dr. Gold suggested. "Our immune system is very selective," he said, adding that there may be other explanations that would no doubt be discussed when the ATAMS data are published.
"B cells play a multifaceted role in the immune system and ... there can be unintended consequences for a therapy based on our incomplete understanding of B-cell biology," said Timothy Coetzee, Ph.D., the chief research officer of the National MS Society in the United States.
Dr. Coetzee, who was not involved in either study, noted in an interview that the ATAMS findings in particular highlight the complexity of B-cell signaling in MS.
"Although there is much we know about B cells, our understanding of these cells continues to evolve as we discover that they have new and unexpected roles to play." he said. "I suspect that that is what we saw with ATAMS. This doesn’t mean that we won’t have B-cell specific treatments for MS; however, we have more work to do in this area."
"B cells play a multifaceted role in the immune system."
In ATAMS, the ARR for atacicept after 36 weeks was 0.86 with the 25-mg dose, 0.79 with the 75-mg dose, and 0.96 with the 150-mg dose, compared with 0.38 for placebo. In addition, patients who were given the experimental drug showed evidence of more, not fewer, GdE T1 lesions on MRI, which was the study’s primary end point.
The ATAMS study was halted early, in September 2009, after an independent data safety monitoring board identified these negative findings, Dr. Ludwig Kappos, chair of neurology at the University Hospital Basel (Switzerland), said at the congress.
Speaking on behalf of the ATAMS study group, Dr. Kappos noted that the apparently detrimental effects of atacicept appear to be reversed in the long term once treatment has stopped. The ATAMS trial protocol was amended to allow all patients who had been randomized into the trial to participate in an extended follow-up study for safety.
Of 255 patients who were enrolled in the trial, 184 underwent an extended 60-week evaluation. During this time, the mean ARR seen with two of the three doses of atacicept fell to rates similar to placebo, at 0.25 for the 25-mg dose (P less than .001 vs. placebo) and 0.29 for the 75-mg dose (P equals .014 vs. placebo), and 0.27 for placebo. The ARR for the 150-mg dose was 0.45.
"At least it was reassuring to observe that the negative effect that we might have had with this agent was reversed and did not persist over the end of treatment period," Dr. Kappos said.
He noted that at baseline there were higher percentages of patients in the atacicept groups who had no signs of GdE T1 lesions than there were in patients who received placebo (61.5% to 68.3% vs. 54%). There also was prior to treatment a higher mean number of GdE T1 lesions in placebo-treated patients, compared with patients who received atacicept at a dose of 25 mg or 75 mg (4.1 vs. 2.1 and 3.7, respectively). There were 4.7 GdE T1 lesions at baseline in patients treated with 150 mg.