Efficacy and safety of atacicept for prevention of flares in patients with moderate-to-severe systemic lupus erythematosus (SLE): 52-week data (APRIL-SLE randomised trial)

David Isenberg, Caroline Gordon, Daiana Licu, Samuel Copt, Claudia Pena Rossi, David Wofsy, David Isenberg, Caroline Gordon, Daiana Licu, Samuel Copt, Claudia Pena Rossi, David Wofsy

Abstract

Objectives: Despite advances in systemic lupus erythematosus (SLE) treatment, many patients suffer from the disease and side effects. Atacicept is a fusion protein that blocks B-lymphocyte stimulator and a proliferation-inducing ligand, which are increased in patients with SLE.

Methods: In this double-blind, placebo-controlled study, patients with moderate-to-severe SLE were randomised to atacicept 75 mg or atacicept 150 mg administered subcutaneously, or placebo twice-weekly for 4 weeks, then weekly for 48 weeks. Primary and secondary efficacy measures were the proportion of patients experiencing at least one flare of British Isles Lupus Assessment Group A or B, and time to first flare, respectively.

Results: Enrolment in the atacicept 150 mg arm was discontinued prematurely due to two deaths. In the intention-to-treat population (n=461), there was no difference in flare rates or time to first flare between atacicept 75 mg and placebo. Analysis of patients treated with atacicept 150 mg suggested beneficial effect versus placebo in flare rates (OR: 0.48, p=0.002) and time to first flare (HR: 0.56, p=0.009). Both atacicept doses were associated with reductions in total Ig levels and anti-dsDNA antibodies, and increases in C3 and C4 levels. Most treatment-emergent adverse events were mild or moderate.

Conclusions: There was no difference between atacicept 75 mg and placebo for flare rate or time to first flare. Analysis of atacicept 150 mg suggested benefit.

Trial registration number: EudraCT: 2007-003698-13; NCT00624338.

Keywords: Autoantibodies; Autoimmunity; B cells; Infections; Systemic Lupus Erythematosus.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Figures

Figure 1
Figure 1
Patient disposition. *Includes potential completer (PC) population, n=81; **Includes PC population, n=84; †Includes PC population, n=81.
Figure 2
Figure 2
Analysis of the primary and the main secondary outcome measure. (A) Proportion of patients who experienced a flare during the 52-week treatment period in the ITT population; (B) proportion of patients who experienced a flare during the 52-week treatment period in the potential completer analysis; (C) time to first new flare in the ITT population; (D) time to first new flare in the potential completer population. ITT, intention-to-treat.
Figure 3
Figure 3
Change from baseline (median) in (A) IgG, (B) IgA and (C) IgM levels (treatment completer population). IgG, immunoglobulin G; IgA, immunoglobulin A; IgM, immunoglobulin M.
Figure 4
Figure 4
Median change from baseline in anti-dsDNA and complement in the treatment completer population (all 285 subjects who completed 52 weeks of trial treatment). (A) Change in anti-dsDNA in patients positive at screening (≥30 IU/mL); (B) change in C3 in patients with below normal C3 levels at screening (

References

    1. Bernatsky S, Leung D, Ramsey-Goldmann R, et al. Mortality in SLE. Dubois’ Lupus Erythematosus. 8th edn Amsterdam: Elsevier, 2013:666–75.
    1. Croca S, Rodrigues T, Isenberg DA. Assessment of lupus nephritis cohort over a 30-year period. Rheumatology 2011;50:1424–30.
    1. Stamatis-Nick C, Tsokos GC. B cells in systemic lupus erythematosus. In: Wallace DJ, Hahn BH. eds. Dubois Lupus Erythematosus. 7th edn Philadelphia, PA: Lippincott, Williams & Wilkins, 2007:176–90.
    1. Furtado J, Isenberg DA. B cell elimination in systemic lupus erythematosus. Clin Immunol 2013;146:90–103.
    1. Merrill JT, Neuelt CM, Wallace DJ, et al. Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum 2010;62:222–33.
    1. Rovin BH, Furie R, Latinis K, et al. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum 2012;64:1215–26.
    1. Navarra SV, Guzmán RM, Gallacher AE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomized placebo-controlled, phase 3 trial. Lancet 2011;377:721–31.
    1. Furie R, Petri M, Zamani O, et al. A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum 2011;63:3918–30.
    1. Dall'Era M, Chakravarty E, Wallace D, et al. Reduced B lymphocyte and immunoglobulin levels after atacicept treatment in patients with systemic lupus erythematosus: results of a multicentre, phase 1b, double-blind, placebo-controlled, dose-escalating trial. Arthritis Rheum 2007;56:4142–50.
    1. Roschke V, Sosnovtseva S, Ward CD, et al. BLyS and APRIL form biologically active heterotrimers that are expressed in patients with systemic immune-based rheumatic diseases. J Immunol 2002;169:4314–21.
    1. O'Connor BP, Raman VS, Erickson LD, et al. BCMA is essential for the survival of long-lived bone marrow plasma cells. J Exp Med 2004;199:91–8.
    1. Hay EM, Bacon P, Gordon C, et al. The BILAG index: a reliable and valid instrument for measuring clinical disease activity in systemic lupus erythematosus. QJ Med 1993;86:447–58.
    1. Isenberg DA, Gordon C; on behalf of the BILAG group. From BILAG to BLiPS—disease activity assessment in lupus past, present and future. Lupus 2000;9:651–4.
    1. Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982;25:1271–2.
    1. Hochberg MC. Updating the American College of Rheumatology Revised Criteria for the Classification of Systemic Lupus Erythematosus (letter). Arthritis Rheum 1997;40:1725.
    1. Isenberg DA, Manson JJ, Ehrenstein MR, et al. Fifty years of anti-dsDNA antibodies—are we approaching journey's end? Rheumatology 2007;46:1052–6.
    1. Anthera updates phase 3 plans following results from the phase 2b PEARL-SC dose ranging study of blisibimod (press release) 2012.
    1. Ginzler EM, Wax S, Rajeswaran A, et al. Atacicept in combination with MMF and corticosteroids in lupus nephritis: results of a prematurely terminated trial. Arthritis Res Ther 2012;14:R33.
    1. van Vollenhoven RF, Kinnman N, Vincent E, et al. Atacicept in patients with rheumatoid arthritis and an inadequate response to methotrexate: results of a phase II, randomized, placebo-controlled trial. Arthritis Rheum 2011;63:1782–92.
    1. Merrill JT, Neuwelt CM, Wallace DJ, et al. Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum 2010;62:222–33.
    1. Gordon C, Sutcliffe N, Skan J, et al. Definition and treatment of lupus flare measured by the BILAG index. Rheumatology 2003;42:1372–9.

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren