Tuesday, 8 November 2011

ECTRIMS 2011: B cell targeting can trigger relapses

L. Kappos, H-P. Hartung, M. S. Freedman, A. Boyko, D. Mikol, U. Freudensprung, T. Plitz for the ATAMS study group ATAMS: a randomised trial of the B-cell-targeting agent atacicept in patients with relapsing multiple sclerosis.

As has been shown that depleting B cells with anti-CD20 antibodies inhibits MS, other B cell targeting agents have been developed with a view they will also halt MS.


BACKROUND: 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 a proliferation-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)

AIM: To assess the immunomodulatory effect of atacicept in relapsing multiple sclerosis (RMS).

METHODS: ATAMS (ATAcicept in MS) was a randomized, double-blind (DB), Phase II trial of atacicept 25, 75 and 150mg (weekly subcutaneous injection) vs placebo (plc) in RMS over 36 weeks.


RESULTS:
Independent Data Safety Monitoring Board review showed increased MS disease activity in the atacicept arms, so further dosing and patient enrolment were stopped prematurely and the protocol amended with a 60-wk safety follow-up (SFU), allowing use of approved disease-modifying therapy. Of the 255 patients enrolled, 35% completed 36-weeks treatment; 54% discontinued treatment early due to premature study discontinuation (PSD); overall, 72% entered the SFU. In the DB period, the total number of relapses was 12, 24, 24, 31 for Placebo, atacicept 25, 75, 150mg, respectively. Patients with multiple relapses were exclusively in the atacicept groups. Mean annualized relapse rates (ARR; negative binomial regression [95% confidence interval]) were: 0.38 (0.20–0.72), 0.86 (0.53–1.37; p=0.040 vs plc), 0.79 (0.49–1.25; p=0.066 vs plc), 0.96 (0.64–1.45; p=0.015 vs plc) for placebo, atacicept 25, 75, 150mg. Time to 1st relapse (log-rank test) was shorter for atacicept 150mg vs placebo (p=0.013). Despite a 2–2.5 times increase in ARR across atacicept groups vs placebo, a significant increase in T1 Gadolium positive lesions was only seen with the 75mg dose (mean no. of Gadolium positive lesions for placebo, atacicept 25, 75, 150mg: 1.14, 1.35 [p=0.631 vs placebo], 2.64 [p=0.017 vs placebo], 1.74 [p=0.227 vs placebo]). Atacicept reduced the number of mature peripheral B cells across all dosing groups and dose dependently reduced serum immunoglobulin (Ig) levels. Interim analysis of SFU at 36 weeks off atacicept showed a reduction in ARR in the atacicept groups during the SFU vs DB period and a return of Ig and B cells to pre-treatment levels.



CONCLUSIONS: Initiation of atacicept treatment was associated with increased exacerbation rates that were not fully reflected by increased numbers of Gadolium positive lesions, reduction in mature B cells and a dose-dependent reduction in serum Ig. These effects were reversible after treatment cessation. These findings suggest that targeting B cells and B-cell function in MS therapy is complex.


FUDING: This study was supported by Merck Serono

CoI: None

"A
tacicept is a B cell depleting agent, but in contrast to Rituximab/ocrelizumab
which is also a B cell depleting agent, atacicept triggered excaserbation of disease and the study was prematurely terminated. If we could understand why this worsening occurred it could teach us alot. But it tells us that disease is complex, as not all B cell depleting agents behave the same".

It shows that there are risks, as well as benefits, to being involved in trials. We really appreciate the contribution of everybody who contributes to trials of drugs in MS.

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