Efficacy and Safety of Atacicept in Patients With Systemic Lupus Erythematosus: Results of a Twenty-Four-Week, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Arm, Phase IIb Study

Joan T Merrill, Daniel J Wallace, Stephen Wax, Amy Kao, Patricia A Fraser, Peter Chang, David Isenberg, ADDRESS II Investigators, Joan T Merrill, Daniel J Wallace, Stephen Wax, Amy Kao, Patricia A Fraser, Peter Chang, David Isenberg, ADDRESS II Investigators

Abstract

Objective: To evaluate the efficacy and safety of atacicept, an antagonist of B lymphocyte stimulator/APRIL-mediated B cell activation, in patients with systemic lupus erythematosus (SLE).

Methods: ADDRESS II is a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-arm, phase IIb study evaluating the safety and efficacy of atacicept in patients with SLE (ClinicalTrials.gov identifier NCT01972568). Patients with active, autoantibody-positive SLE receiving standard therapy were randomized (1:1:1) to receive atacicept (75 mg or 150 mg) or placebo for 24 weeks. The primary end point was the SLE responder index 4 (SRI-4) at week 24.

Results: The intent-to-treat (ITT) population included 306 patients. There was a trend toward an improved SRI-4 response rate with atacicept 75 mg (57.8%; adjusted odds ratio [OR] 1.78, P = 0.045) and 150 mg (53.8%; adjusted OR 1.56, P = 0.121) at week 24 as compared with placebo (44.0%) (primary analysis; using the screening visit as baseline). In a prespecified sensitivity analysis using study day 1 as baseline, a significantly larger proportion of patients receiving atacicept 75 mg and 150 mg achieved an SRI-4 response at week 24 compared with placebo. In predefined subpopulations with high levels of disease activity (HDA) at baseline, serologically active disease, or both, statistically significant improvements in the SRI-4 and SRI-6 response rates were seen with atacicept versus placebo. A severe risk of disease flare was reduced with atacicept therapy in both the ITT and the HDA populations. The risks of serious adverse events and serious or severe infection were not increased with atacicept as compared with placebo.

Conclusion: Atacicept treatment showed evidence of efficacy in SLE, particularly in HDA and serologically active patients. Reductions in disease activity and severe flare were observed with atacicept treatment, with an acceptable safety profile.

© 2017, American College of Rheumatology.

Figures

Figure 1
Figure 1
Effect of atacicept on the disease response of patients with systemic lupus erythematosus (SLE), as determined by the SLE Responder Index 4 (SRI‐4). A, Proportion of SRI‐4 responders in the intent‐to‐treat (ITT) population. B, Proportion of SRI‐4 responders in the high disease activity (HDA) subpopulation. Values at the right are the effect size (Δ) for the indicated treatment groups. * = P < 0.05 versus placebo. D1= treatment day 1.
Figure 2
Figure 2
Effect of atacicept on the disease response of patients with systemic lupus erythematosus (SLE), as determined by the SLE Responder Index 6 (SRI‐6). A, Proportion of SRI‐6 responders in the intent‐to‐treat (ITT) population. B, Proportion of SRI‐6 responders in the high disease activity (HDA) subpopulation. C, Proportion of SRI‐6 responders in the serologically active subgroup (anti–double‐stranded DNA [anti‐dsDNA] antibody positive [≥15 IU/ml] and low levels of complement) of the ITT population. D, Proportion of SRI‐6 responders in the serologically active subgroup (anti‐dsDNA antibody positive and low levels of complement) of the HDA subpopulation. * = P < 0.05 versus placebo. D1 = treatment day 1.
Figure 3
Figure 3
Kaplan‐Meier analysis of time to first severe flare according to scores on the British Isles Lupus Assessment Group (BILAG) A grade manifestations. A, Intent‐to‐treat (ITT) population. B, High disease activity (HDA) subpopulation. Numbers across the bottom of the x‐axes are the numbers of patients at the indicated time points. HR = hazard ratio; 95% CI = 95% confidence interval.
Figure 4
Figure 4
Changes in serum biomarkers over time. The median percentage change from baseline over 24 weeks is shown for A, serum complement C3 levels (C3‐low patients), B, serum complement C4 levels (C4‐low patients), C, anti–double‐stranded DNA (anti‐dsDNA) antibody levels (anti‐dsDNA antibody–positive patients), and D, serum IgG levels.

References

    1. Rekvig OP, Van der Vlag J. The pathogenesis and diagnosis of systemic lupus erythematosus: still not resolved. Semin Immunopathol 2014;36:301–11.
    1. Bertsias G, Cervera T, Boumpas D. Systemic lupus erythematosus: pathogenesis and clinical features. 2012. URL: .
    1. Lisnevskaia L, Murphy G, Isenberg D. Systemic lupus erythematosus. Lancet 2014;384:1878–88.
    1. Bertsias G, Ioannidis JP, Boletis J, Bombardieri S, Cervera R, Dostal C, et al. EULAR recommendations for the management of systemic lupus erythematosus: report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics. Ann Rheum Dis 2008;67:195–205.
    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. Cervera R, Khamashta MA, Font J, Sebastiani GD, Gil A, Lavilla P, et al. Morbidity and mortality in systemic lupus erythematosus during a 10‐year period: a comparison of early and late manifestations in a cohort of 1,000 patients. Medicine (Baltimore) 2003;82:299–308.
    1. Lateef A, Petri M. Unmet medical needs in systemic lupus erythematosus. Arthritis Res Ther 2012;14 Suppl 4:S4.
    1. Schmeding A, Schneider M. Fatigue, health‐related quality of life and other patient‐reported outcomes in systemic lupus erythematosus. Best Pract Res Clin Rheumatol 2013;27:363–75.
    1. Gordon C, Isenberg D, Lerstrom K, Norton Y, Nikai E, Pushparajah DS, et al. The substantial burden of systemic lupus erythematosus on the productivity and careers of patients: a European patient‐driven online survey. Rheumatology (Oxford) 2013;52:2292–301.
    1. Thamer M, Hernan MA, Zhang Y, Cotter D, Petri M. Prednisone, lupus activity, and permanent organ damage. J Rheumatol 2009;36:560–4.
    1. Salazar‐Camarena DC, Ortiz‐Lazareno PC, Cruz A, Oregon‐Romero E, Machado‐Contreras JR, Munoz‐Valle JF, et al. Association of BAFF, APRIL serum levels, BAFF‐R, TACI and BCMA expression on peripheral B‐cell subsets with clinical manifestations in systemic lupus erythematosus. Lupus 2016;25:582–92.
    1. Hegazy M, Darwish H, Darweesh H, El‐Shehaby A, Emad Y. Raised serum level of APRIL in patients with systemic lupus erythematosus: correlations with disease activity indices. Clin Immunol 2010;135:118–24.
    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. Zhang J, Roschke V, Baker KP, Wang Z, Alarcon GS, Fessler BJ, et al. Cutting edge: a role for B lymphocyte stimulator in systemic lupus erythematosus. J Immunol 2001;166:6–10.
    1. Stohl W, Metyas S, Tan SM, Cheema GS, Oamar B, Roschke V, et al. Inverse association between circulating APRIL levels and serological and clinical disease activity in patients with systemic lupus erythematosus. Ann Rheum Dis 2004;63:1096–103.
    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. Navarra SV, Guzmán RM, Gallacher AE, Hall S, Levy RA, Jimenez RE, et al, for the BLISS‐52 Study Group . Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo‐controlled, phase 3 trial. Lancet 2011;377:721–31.
    1. Furie R, Petri M, Zamani O, Cervera R, Wallace DJ, Tegzová D, 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, 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. Pena‐Rossi C, Nasonov E, Stanislav M, Yakusevich V, Ershova O, Lomareva N, et al. An exploratory dose‐escalating study investigating the safety, tolerability, pharmacokinetics and pharmacodynamics of intravenous atacicept in patients with systemic lupus erythematosus. Lupus 2009;18:547–55.
    1. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982;25:1271–7.
    1. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997;40:1725.
    1. Isenberg DA, Rahman A, Allen E, Farewell V, Akil M, Bruce IN, et al. BILAG 2004: development and initial validation of an updated version of the British Isles Lupus Assessment Group's disease activity index for patients with systemic lupus erythematosus. Rheumatology (Oxford) 2005;44:902–6.
    1. Van Vollenhoven RF, Petri MA, Cervera R, Roth DA, Ji BN, Kleoudis CS, et al. Belimumab in the treatment of systemic lupus erythematosus: high disease activity predictors of response. Ann Rheum Dis 2012;71:1343–9.
    1. Furie RA, Leon G, Thomas M, Petri MA, Chu AD, Hislop C, et al. A phase 2, randomised, placebo‐controlled clinical trial of blisibimod, an inhibitor of B cell activating factor, in patients with moderate‐to‐severe systemic lupus erythematosus, the PEARL‐SC study. Ann Rheum Dis 2015;74:1667–75.
    1. Ota M, Duong BH, Torkamani A, Doyle CM, Gavin AL, Ota T, et al. Regulation of the B cell receptor repertoire and self‐reactivity by BAFF. J Immunol 2010;185:4128–36.
    1. Yu G, Boone T, Delaney J, Hawkins N, Kelley M, Ramakrishnan M, et al. APRIL and TALL‐I and receptors BCMA and TACI: system for regulating humoral immunity. Nat Immunol 2000;1:252–6.
    1. Ju S, Zhang D, Wang Y, Ni H, Kong X, Zhong R. Correlation of the expression levels of BLyS and its receptors mRNA in patients with systemic lupus erythematosus. Clin Biochem 2006;39:1131–7.
    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. Van Vollenhoven RF, Kinnman N, Vincent E, Wax S, Bathon J. 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. Van Vollenhoven RF, Wax S, Li Y, Tak PP. Safety and efficacy of atacicept in combination with rituximab for reducing the signs and symptoms of rheumatoid arthritis: a phase II, randomized, double‐blind, placebo‐controlled pilot trial. Arthritis Rheumatol 2015;67:2828–36.
    1. Isenberg DA, Petri M, Kalunian K, Tanaka Y, Urowitz MB, Hoffman RW, et al. Efficacy and safety of subcutaneous tabalumab in patients with systemic lupus erythematosus: results from ILLUMINATE‐1, a 52‐week, phase III, multicentre, randomised, double‐blind, placebo‐controlled study. Ann Rheum Dis 2016;75:323–31.
    1. Benson MJ, Dillon SR, Castigli E, Geha RS, Xu S, Lam KP, et al. Cutting edge: the dependence of plasma cells and independence of memory B cells on BAFF and APRIL. J Immunol 2008;180:3655–9.
    1. Belnoue E, Pihlgren M, McGaha TL, Tougne C, Rochat AF, Bossen C, et al. APRIL is critical for plasmablast survival in the bone marrow and poorly expressed by early‐life bone marrow stromal cells. Blood 2008;111:2755–64.

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner