Atacicept Phase 2 Trial Yields Disappointing Results for MS
Atacicept, which targets B cells, increased rather than decreased exacerbations in relapsing MS
Results from a phase 2 trial of the recombinant fusion protein atacicept raise significant questions about its potential use in managing relapsing multiple sclerosis (MS).
As MSDF has reported, it’s known that depletion of B lymphocytes is associated with decreased inflammatory activity in MS. In addition, previous studies with the monoclonal antibodies rituximab (Hauser et al., 2008) and ocrelizumab (Kappos et al., 2011), both of which target the CD20 receptors, have shown those agents to be robust in their therapeutic effect on MRI lesion activity and relapses.
Studies focusing on atacicept have shown that it suppresses the production of autoreactive antibodies and inhibits the development of more mature spleen B cells by blocking the evolution of immature B cells from stage T1 to stage T2. Atacicept has also been shown to inhibit disease progression in mouse models of rheumatoid arthritis and systemic lupus erythematosus.
Hopes for atacicept appear to have been quashed by a study appearing in the current issue of The Lancet Neurology by Ludwig Kappos, M.D., of University Hospital in Basel, Switzerland, along with colleagues, which aimed to evaluate the safety and efficacy of atacicept in treating relapsing MS (Kappos et al., 2014).
The investigators designed a randomized, double-blind, placebo-controlled trial to gauge the short-term safety and tolerability of atacicept. The trial was also aimed at assessing the protein's capability to decrease CNS inflammation, as determined by frequent MRI assessments.
The Atacicept in Multiple Sclerosis trial (ATAMS) enrolled patients from Australia, Canada, the U.S., and 14 European countries.
Between April 2008 and September 2009, investigators randomly assigned 255 patients with confirmed relapsing MS to one of four groups. Three received weekly subcutaneous doses of atacicept (25, 75, or 150 mg). The fourth group received placebo.
During an initial study period of 36 weeks, patients underwent frequent neurologic evaluations, laboratory studies, and MRIs to assess CNS inflammation.
The investigators said the results were unexpected.
They reported that in patients who completed the initial 36 weeks of the trial, annualized relapse rates more than doubled in all the atacicept groups, compared to placebo (atacicept 25 mg, 0.86, 95% CI 0.43–1.74; 75 mg, 0.79, 0.40–1.58; 150 mg, 0.98, 0.52–1.81; placebo, 0.38, 0.17–0.87).
Of note, however, MRI findings did not appear to reflect those differences in relapse rates: Mean numbers of gadolinium-enhancing T1 lesions per scan were similar in all the groups, the researchers reported.
Based on those disappointing findings, the researchers terminated the initial phase of the study. They followed up, however, by revising the study parameters to include a 60-week safety follow-up period. During that time, annualized relapse rates did not differ significantly among the groups, the researchers said. Also, temporary increases in disease activity did not translate into differences in time to disability progression or to the number of patients who had progressed by the end of the safety follow-up phase of the study, the researchers said.
They concluded, "Increased clinical disease activity associated with atacicept suggests that the role of B cells and humoral immunity in multiple sclerosis is complex." They stressed that future studies of immune response in MS need to include rigorous monitoring for negative effects.
In comments accompanying the ATAMS study (Lühder and Gold, 2014), Fred Lühder, Ph.D., of the University of Göttingen Medical School in Göttingen, Germany, and Ralf Gold, M.D., of Ruhr-University Bochum in Bochum, Germany, asked, "What happened in the ATAMS study, and what could account for the differences between atacicept and the anti-CD20 drugs that showed benefits in previous trials?"
They said one possible explanation might have to do with the specific types of B cells atacicept preferentially depletes. They noted that animal studies have suggested that antigen-specific B cells might help provide a necessary stimulus for antigen-specific T cells. However, B cells that produce interleukin-10 might have a regulatory effect, thereby curbing activation of antigen-specific T cells and reducing inflammation.
"Finally," the commentators noted, "pathogenic T-cell responses are diminished and regulatory T cells are expanded in response to rituximab, which could be the result of B-cell depletion or of an unidentified mechanism; this effect could very well aid the therapeutic efficacy of anti-CD20 monoclonal antibodies, but be absent in the case of atacicept."
Key open questions
- What might account for the difference between atacicept and the anti-CD20 drugs that showed benefits in previous studies?
- Why did findings on MRI fail to reflect differences in relapse rates?
- What differences exist between the pathogenesis of MS and other autoimmune diseases?
- What different therapeutic strategies would be most effective in targeting B cells during various points in their development?
Disclosures and sources of funding
This study was funded by Merck Serono (Geneva, Switzerland) and EMD Serono (Rockland, MA, USA), both subsidiaries of Merck KgaA (Darmstadt, Germany).
Some of the authors of the study disclosed competing interests involving a variety of commercial entities including Basilea Pharmaceutica, Bayer Schering, Biogen Idec, Celgene, EMD Canada, EMD Serono, Genzyme, Glycominds, Merck Serono, Novartis, Opexa, Roche, Sanofi-Aventis, Teva, and Teva Canada Innovation.
Authors of the comments accompanying the study in The Lancet also disclosed competing interests involving a variety of commercial entities, including Baxter, Bayer Schering, Biogen Idec, CLB Behring, Genzyme, Merck Serono, Sanofi-Genzyme, Novartis, Talecris, Teva, and Wyeth.