Post Hoc Analysis of the Phase II/III APRIL-SLE Study: Association Between Response to Atacicept and Serum Biomarkers Including BLyS and APRIL

Caroline Gordon, David Wofsy, Stephen Wax, Yong Li, Claudia Pena Rossi, David Isenberg, Caroline Gordon, David Wofsy, Stephen Wax, Yong Li, Claudia Pena Rossi, David Isenberg

Abstract

Objective: To assess the relationship between treatment response, baseline biomarker levels, and atacicept exposure in patients with systemic lupus erythematosus (SLE) in the phase II/III APRIL-SLE study.

Methods: We performed a post hoc analysis of patients who received placebo, atacicept 75 mg, or atacicept 150 mg in a randomized, controlled, 52-week trial. Serum levels of BlyS and APRIL were measured at baseline, and serum levels of Ig and the numbers of naive B cells and plasma cells were measured at baseline and during treatment. Atacicept exposure was determined by assessment of the serum trough concentrations throughout the 52-week trial period. Associations between these parameters, treatment response (reduction in British Isles Lupus Assessment Group A or B flare), and infection rates were explored.

Results: Recurrent high baseline levels of both BLyS (≥1.6 ng/ml) and APRIL (≥2.2 ng/ml) correlated with a greater treatment response (flare rate 75.7% with placebo, and 50.0% and 32.0% with atacicept 75 mg and atacicept 150 mg, respectively) compared with lower baseline levels of both. Increased atacicept exposure correlated with reduced flare rates (60.5% with placebo; 63.4%, 61.0%, 48.8%, and 29.3% in the 4 quartiles, from lowest to highest atacicept exposure). Greater pharmacodynamic responses (reduced Ig levels and naive B cell and plasma cell numbers) were associated with greater reductions in the flare rate. Infection rates were similar regardless of biomarker levels at baseline or at the time of atacicept exposure.

Conclusion: These post hoc analyses demonstrate a dose-response relationship between atacicept concentrations, reduced Ig levels, and reduced flare rates and suggest that baseline biomarkers such as elevated serum levels of BLyS and APRIL may help to identify the patients who are most likely to benefit from atacicept treatment.

© 2016 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.

Figures

Figure 1
Figure 1
Atacicept treatment is associated with disease flare reduction in patients with high baseline serum levels of BLyS and APRIL (potential completer population). A, Flare rate (proportion of atacicept‐ and placebo‐treated patients with a new flare) according to baseline levels of BLyS and APRIL. Lines represent the 90% confidence limit. B, Mean IgG reduction from baseline to week 52 in atacicept‐ and placebo‐treated patients, according to baseline levels of BLyS and APRIL. The cutoff for high versus low BLyS levels was defined as ≥1.6 ng/ml. The cutoff for high versus low APRIL levels was defined as ≥2.2 ng/ml. Values are the mean ± SD.

References

    1. Lisnevskaia L, Murphy G, Isenberg D. Systemic lupus erythematosus. Lancet 2014;384:1878–88.
    1. Cervera R, Khamashta MA, Hughes GR. The Euro‐lupus project: epidemiology of systemic lupus erythematosus in Europe. Lupus 2009;18:869–74.
    1. Bernatsky S, Boivin JF, Joseph L, Manzi S, Ginzler E, Gladman DD, et al. Mortality in systemic lupus erythematosus. Arthritis Rheum 2006;54:2550–7.
    1. Urowitz MB, Gladman DD, Tom BD, Ibanez D, Farewell VT. Changing patterns in mortality and disease outcomes for patients with systemic lupus erythematosus. J Rheumatol 2008;35:2152–8.
    1. Dobkin PL, da Costa D, Fortin PR, Edworthy S, Barr S, Esdaile JM, et al. Living with lupus: a prospective pan‐Canadian study. J Rheumatol 2001;28:2442–8.
    1. Mazzoni D, Cicognani E. Social support and health in patients with systemic lupus erythematosus: a literature review. Lupus 2011;20:1117–25.
    1. Arnaud L, Mathian A, Boddaert J, Amoura Z. Late‐onset systemic lupus erythematosus: epidemiology, diagnosis and treatment. Drugs Aging 2012;29:181–9.
    1. Lateef A, Petri M. Unmet medical needs in systemic lupus erythematosus. Arthritis Res Ther 2012;14 Suppl 4:S4.
    1. Postal M, Costallat LT, Appenzeller S. Biological therapy in systemic lupus erythematosus. Int J Rheumatol 2012;2012:578641.
    1. Tieng AT, Peeva E. B cell‐directed therapies in systemic lupus erythematosus. Semin Arthritis Rheum 2008;38:218–27.
    1. Liossis SN, Melissaropoulos K. Molecular abnormalities of the B cell in systemic lupus erythematosus are candidates for functional inhibition treatments. Expert Opin Pharmacother 2014;15:833–40.
    1. Dillon SR, Gross JA, Ansell SM, Novak AJ. An APRIL to remember: novel TNF ligands as therapeutic targets. Nat Rev Drug Discov 2006;5:235–46.
    1. Wallace DJ, Stohl W, Furie RA, Lisse JR, McKay JD, Merrill JT, et al. A phase II, randomized, double‐blind, placebo‐controlled, dose‐ranging study of belimumab in patients with active systemic lupus erythematosus. Arthritis Rheum 2009;61:1168–78.
    1. Dall'Era M, Chakravarty E, Wallace D, Genovese M, Weisman M, Kavanaugh A, et al. Reduced B lymphocyte and immunoglobulin levels after atacicept treatment in patients with systemic lupus erythematosus: results of a multicenter, phase Ib, double‐blind, placebo‐controlled, dose‐escalating trial. Arthritis Rheum 2007;56:4142–50.
    1. Koyama T, Tsukamoto H, Miyagi Y, Himeji D, Otsuka J, Miyagawa H, et al. Raised serum APRIL levels in patients with systemic lupus erythematosus. Ann Rheum Dis 2005;64:1065–7.
    1. Matthes T, Dunand‐Sauthier I, Santiago‐Raber ML, Krause KH, Donze O, Passweg J, et al. Production of the plasma‐cell survival factor a proliferation‐inducing ligand (APRIL) peaks in myeloid precursor cells from human bone marrow. Blood 2011;118:1838–44.
    1. Avery DT, Kalled SL, Ellyard JI, Ambrose C, Bixler SA, Thien M, et al. BAFF selectively enhances the survival of plasmablasts generated from human memory B cells. J Clin Invest 2003;112:286–97.
    1. Hoyer BF, Moser K, Hauser AE, Peddinghaus A, Voigt C, Eilat D, et al. Short‐lived plasmablasts and long‐lived plasma cells contribute to chronic humoral autoimmunity in NZB/W mice. J Exp Med 2004;199:1577–84.
    1. Roschke V, Sosnovtseva S, Ward CD, Hong JS, Smith R, Albert V, 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. Pers JO, Daridon C, Devauchelle V, Jousse S, Saraux A, Jamin C, et al. BAFF overexpression is associated with autoantibody production in autoimmune diseases. Ann N Y Acad Sci 2005;1050:34–9.
    1. Isenberg D, Gordon C, Licu D, Copt S, Rossi CP, Wofsy D. 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). Ann Rheum Dis 2015;74:2006–15.
    1. Isenberg DA, Gordon C, British Isles Lupus Assessment Group . From BILAG to BLIPS: disease activity assessment in lupus past, present and future. Lupus 2000;9:651–4.
    1. Boghdadi G, Elewa EA. Increased serum APRIL differentially correlates with distinct cytokine profiles and disease activity in systemic lupus erythematosus patients. Rheumatol Int 2014;34:1217–23.
    1. McCarthy EM, Lee RZ, Ni Gabhann J, Smith S, Cunnane G, Doran MF, et al. Elevated B lymphocyte stimulator levels are associated with increased damage in an Irish systemic lupus erythematosus cohort. Rheumatology (Oxford) 2013;52:1279–84.
    1. Petri MA, van Vollenhoven RF, Buyon J, Levy RA, Navarra SV, Cervera R, et al. Baseline predictors of systemic lupus erythematosus flares: data from the combined placebo groups in the phase III belimumab trials. Arthritis Rheum 2013;65:2143–53.
    1. Yee CS, Su L, Toescu V, Hickman R, Situnayake D, Bowman S, et al. Birmingham SLE cohort: outcomes of a large inception cohort followed for up to 21 years. Rheumatology (Oxford) 2015;54:836–43.
    1. Mosca M, Tani C, Aringer M, Bombardieri S, Boumpas D, Brey R, et al. European League Against Rheumatism recommendations for monitoring patients with systemic lupus erythematosus in clinical practice and in observational studies. Ann Rheum Dis 2010;69:1269–74.

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