B-lymphocyte Targeted Therapies for MS — Paradoxical Effect of Atacicept
Abstract & Commentary
By Jai S. Perumal, MD
Assistant Professor of Neurology, Weill Cornell Medical
College
Dr. Perumal is on the speakers bureau for Biogen Idec, Teva Pharmaceuticals, Genzyme Corp., and Acorda Therapeutics.
Synopsis: A Phase 2 trial of atacicept, a humanized recombinant protein that suppresses B cell function, demonstrated a negative impact on clinical disease activity in relapsing-remitting multiple sclerosis.
Source: Kappos L, et al. Atacicept in multiple sclerosis (ATAMS): A randomized, placebo-controlled, double-blind, phase 2 trial. Lancet Neurol 2014;13:353-363.
The traditional view regarding the pathogenesis of multiple sclerosis (MS) postulated a T-cell mediated disease, but several lines of evidence now point to a significant role of B-lymphocytes in the pathogenesis of MS. B-cell targeted therapies such as rituximab, which is an anti-CD20 monoclonal antibody, have demonstrated high efficacy for suppression of inflammatory injury in MS as evidenced by a beneficial effect in reducing relapses and MRI lesions. Ocrelizumab, a humanized anti-CD20 monoclonal antibody, is currently in Phase 3 trials for MS. Studies showing a prominent role for B-cells in the immunopathogenesis of MS and the established efficacy of prior B-cell targeted therapies provided the rationale for exploring atacicept, which is a recombinant protein that suppresses B-cell function, for the treatment of MS. Atacicept binds to and blocks B-lymphocyte stimulator and a proliferation-inducing ligand, which serve key functions in B-cell maturation and survival. Atacicept was specifically designed for the treatment of autoimmune diseases including systemic lupus erythematosus and rheumatoid arthritis and is being explored for those indications as well.
Atacicept in Multiple Sclerosis (ATAMS) was a randomized, double-blind, placebo-controlled, 36-week, Phase 2 trial to assess the short-term efficacy and tolerability of atacicept in patients with relapsing-remitting MS. Patients enrolled in the study were randomized in a 1:1:1:1 manner to atacicept 25 mg, 75 mg, 150 mg, or placebo, administered as weekly subcutaneous injections after the initial escalation phase. The originally planned primary endpoint for the study was the change in mean number of gadolinium-enhancing lesions on T1 weighted MRI per patient, per scan, between weeks 12 and 36. Secondary endpoints were the mean number of gadolinium-enhancing T1 lesions per patient per scan from weeks 24 to 36; numbers of new T1 hypointense lesions per patient at weeks 12, 24, and 36; and the proportion of patients free from relapse. Tertiary endpoint was the annualized relapse rate.
The study was terminated early after an independent data and safety monitoring board noted an increased annualized relapse rate in the atacicept groups. The results reported are based on an intention-to-treat population of 255 patients with a median duration of 211 days in the double-blind phase. Of these 255 patients, 63 were randomized to the 25 mg group, 64 to the 75 mg group, 65 to the 150 mg group, and 63 to placebo. Ninety (35%) patients completed the originally planned 36 weeks, 26 (10%) discontinued before study termination due to lack of efficacy or other reasons, and 139 (55%) discontinued because of study termination. The annualized relapse rate was higher in the atacicept groups compared to placebo, with the difference being statistically significant for the 25 and 150 mg groups (0.38 for placebo, 0.86 for the 25 mg group, 0.79 for the 75 mg group, and 0.98 for the 150 mg group). The proportion of relapse-free patients was also higher in the placebo group compared to the atacicept groups (81% for placebo, 70% for the 25 mg, 72% for the 75 mg, and 62% for the 150 mg group). The mean number of gadolinium-enhancing lesions per patient per scan, which was the originally intended primary endpoint, did not differ between the treatment groups.
Commentary
ATAMS was a Phase 2 trial of atacicept, a B-cell targeted therapy for relapsing MS, that was terminated early, as it appeared to have deleterious effects on relapses. Prior data from clinical trials and real world experience, which demonstrated high efficacy of B-cell targeted therapies such as rituximab, led to the hypothesis that atacicept, which suppresses B cell function, would have a positive effect as well. The reasons for this negative clinical effect are being investigated and not known yet. While anti-CD 20 therapies like rituximab result in B-cell depletion with selective sparing of some progenitor B-cells and plasma cells, atacicept targets mature B-cells and plasma cells while sparing B-cell progenitors and memory cells. The differential influence of these therapies on B-cell sub-populations and the variable effects of the individual B-cell sub-populations on inflammation and regulation and repair might explain some of contrasting effects. The paradoxical and unexpected effect of atacicept highlights the limitations of our current understanding of the immune mechanisms involved in MS. A more comprehensive knowledge will help us develop better targets for intervention in the treatment of MS.
