Friday, 21 March 2014

Blocking B cells is not always good news for MS

Kappos L, Hartung HP, Freedman MS, Boyko A, Radü EW, Mikol DD, Lamarine M, Hyvert Y, Freudensprung U, Plitz T, van Beek J; for the ATAMS Study Group. Atacicept in multiple sclerosis (ATAMS): a randomised, placebo-controlled, double-blind, phase 2 trial. Lancet Neurol. 2014 Mar. pii: S1474-4422(14)70028-6. doi: 10.1016/S1474-4422(14)70028-6. [Epub ahead of print]

BACKGROUND: Depletion of B lymphocytes is associated with suppression of inflammatory activity in multiple sclerosis. We aimed to assess the safety and efficacy of atacicept, a recombinant fusion protein that suppresses B-cell function and antibody production.
METHODS: In this placebo-controlled, double-blind, 36-week, phase 2 trial (ATAMS) in Australia, Canada, Europe, and the USA, patients aged 18-60 years with relapsing multiple sclerosis were randomly assigned via an interactive voice response system in a 1:1:1:1 ratio, stratified by geographical region, to receive weekly subcutaneous injections with atacicept (25, 75, or 150 mg) or placebo. Both patients and study personnel were masked to treatment assignment. The primary endpoint was the change in mean number of gadolinium-enhancing lesions on T1-weighted MRI per patient per scan between weeks 12 and 36. Efficacy endpoints were analysed in the intention-to-treat population. Patients who completed week 36 were eligible to participate in a long-term extension study (ATAMS EXT), consisting of a double-blind phase followed by an open-label phase, for a total study time of up to 5 years. The study was terminated early after the independent data and safety monitoring board noted an increased annualised relapse rate with atacicept. The protocol was subsequently amended to include a 60-week safety follow-up, to allow treatment with approved multiple sclerosisdrugs, and to change the primary endpoint to gadolinium-enhancing T1 lesions per scan during the entire double-blind period of ATAMS. Both the trial and the extension are registered with ClinicalTrials.gov, numbers NCT00642902 (ATAMS) and NCT00853762 (ATAMS EXT).
FINDINGS: Between April 23, 2008, and early study termination on Sept 11, 2009, 255 patients were randomly assigned: 63 to placebo, 63 to atacicept 25 mg, 64 to 75 mg, and 65 to 150 mg. 90 (35%) patients completed the week 36 treatment visit, 26 (10%) discontinued before study termination (including one who dropped out before receiving study treatment), and 139 (55%) discontinued because of study termination. During the double-blind period of ATAMS, annualised relapse rates were higher in the atacicept groups than in the placebo group (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). Mean numbers of gadolinium-enhancing T1 lesions per scan were similar in all groups (25 mg, 2·26, 0·97-5·27; 75 mg, 2·30, 1·08-4·92; 150 mg, 2·49, 1·18-5·27; placebo, 3·07, 1·40-6·77). Seven patients (one taking placebo and six atacicept) discontinued treatment because of adverse events. One death occurred in the placebo group. During the safety follow-up, immunoglobulin concentrations and B-cell counts returned towards predose values and annualised relapse rates in the atacicept groups decreased until they were similar to that of the placebo group
INTERPRETATION: Increased clinical disease activity associated with atacicept suggests that the role of B cells and humoral immunity in multiple sclerosis is complex. For studies that explore therapeutic immunomodulation in multiple sclerosis, rigorous monitoring for negative effects on clinical and MRI outcomes is warranted.



This study was first presented at ECTRIMS in 2011. Atacicept is a recombinant fusion protein made to inhibit B cells. The designer protein combines the binding site for two cytokines that regulate maturation, function, and survival of B cells, B-lymphocyte stimulator (BLyS) and aproliferation-inducing ligand (APRIL), with the constant region of the antibody molecule. Atacicept blocks activation of B cells by the tumor necrosis factor receptor superfamily member 13B (more commonly known as TACI), a transmembrane receptor protein found predominantly on the surface of B cells. Atacicept blocks the binding of BLyS and APRIL. Binding of these TACI binding-molecules induces proliferation, activation, and longevity of B cells and thus their production of antibodies. Atacicept is thought to selectively impair mature B cells and plasma cells (B cells that produce and secrete antibodies). It appeared to make MS worse so blocking B cell activity is not always a good move. 

Maybe it is affecting regulatory B cells

B-type suppression: A role played by "regulatory B cells" or "regulatory plasma cells"? Ries S, Hilgenberg E, Lampropoulou V, Shen P, Dang VD, Wilantri S, Sakwa I, Fillatreau S. Eur J Immunol. 2014 Mar 11. doi: 10.1002/eji.201343683. [Epub ahead of print]

8 comments:

  1. What does this mean for EBV? Black swan bites the dust?

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    1. Not at all..Until the reason why the worsening occurs and its relationship to EBV then it has not impact on the theory, however understanding the reasons would help us to understand MS much better

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    2. I don't understand. What is the difference between this and rituximab and how does it relate to ebv?

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    3. Rituximab depletes CD20Positive B cells and blocks relapsing MS. It may kill b cells that contain ebv . The idea with thid molecule is that it does the same and would work the same it didnot and made things worse

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    4. Rituximab also effects the tcell population by lowering Th and increasing Treg. Atacicept only effects bcells. I think the data speaks for itself.

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    5. Like it.....the T cell brigade will be happy but is it that simple?

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    6. It seems all of the immune system resetting therapies target both b and t cells. This is one of the only therapies that target b cells only and the results are not encouraging. It does not look good for the B cell and EBV brigade.

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    7. More suspicion about the b-cell brigade:

      http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)60508-X/fulltext

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