Sarilumab for the treatment of ankylosing spondylitis: results of a Phase II, randomised, double-blind, placebo-controlled study (ALIGN)

Joachim Sieper, Jürgen Braun, Jonathan Kay, Salvatore Badalamenti, Allen R Radin, Lixia Jiao, Stefano Fiore, Tanya Momtahen, George D Yancopoulos, Neil Stahl, Robert D Inman, Joachim Sieper, Jürgen Braun, Jonathan Kay, Salvatore Badalamenti, Allen R Radin, Lixia Jiao, Stefano Fiore, Tanya Momtahen, George D Yancopoulos, Neil Stahl, Robert D Inman

Abstract

Objectives: The ALIGN study (NCT01061723) evaluated the efficacy and safety of sarilumab, the first fully human monoclonal antibody against interleukin-6 receptor-α (IL-6Rα), in patients with ankylosing spondylitis (AS).

Methods: Patients with active AS despite conventional treatment were randomised to placebo, or one of five subcutaneous dose regimens of sarilumab (100, 150 or 200 mg every other week, or 100 or 150 mg every week), for 12 weeks. The primary efficacy end point was the percentage of patients achieving the Axial SpondyloArthritis international Society (ASAS) 20 response criteria at week 12. Secondary endpoints included ASAS40 response, ASAS partial remission, AS Disease Activity Score, high-sensitivity C-reactive protein (hs-CRP) value, and safety.

Results: Baseline demographic and disease characteristics of the 301 patients enrolled were similar across treatment groups. At week 12, there was no statistically significant difference in ASAS20 response rate between placebo (ASAS20 = 24.0%) and any sarilumab dose group. A significantly greater reduction in hs-CRP value was achieved with the higher sarilumab doses versus placebo. No other statistically significant differences were evident for secondary efficacy endpoints. The most common treatment-emergent adverse events reported for sarilumab included infections (non-serious), neutropenia, and increase in alanine aminotransferase. No cases of tuberculosis, opportunistic, or fungal infections, or bowel perforations were reported. Seven patients experienced a treatment-emergent serious adverse event (all in sarilumab treatment groups). No deaths occurred.

Conclusions: The ALIGN study shows that IL-6Rα blockade with sarilumab was not an effective treatment for AS. Sarilumab was generally well tolerated with a manageable safety profile.

Keywords: Ankylosing Spondylitis; Autoimmune Diseases; Cytokines; DMARDs (biologic); Inflammation.

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. SC, subcutaneous; q2w, every 2 weeks; qw, every week.
Figure 2
Figure 2
Incidence of ASAS20 response – ITT population. Percentage response calculated using the number of ITT patients in the corresponding treatment group within each subgroup as denominator. At week 12, p>0.05 (nominal and adjusted) for all sarilumab-treated groups vs placebo. CRP, high sensitivity C-reactive protein; ITT, intent-to-treat.

References

    1. Braun J, Bollow M, Remlinger G, et al. Prevalence of spondylarthropathies in HLA-B27 positive and negative blood donors. Arthritis Rheum 1998;41:58–67.
    1. Sieper J, Rudwaleit M, Khan MA, et al. Concepts and epidemiology of spondyloarthritis. Best Pract Res Clin Rheumatol 2006;20:401–17.
    1. Zink A, Braun J, Listing J, et al. Disability and handicap in rheumatoid arthritis and ankylosing spondylitis—results from the German rheumatological database. German Collaborative Arthritis Centers. J Rheumatol 2000;27:613–22.
    1. Reveille JD. HLA-B27 and the seronegative spondyloarthropathies. Am J Med Sci 1998;316:239–49.
    1. Braun J, Sieper J. Ankylosing spondylitis. Lancet 2007;369:1379–90.
    1. Mansour M, Cheema GS, Naguwa SM, et al. Ankylosing spondylitis: a contemporary perspective on diagnosis and treatment. Semin Arthritis Rheum 2007;36:210–23.
    1. Braun J, Sieper J. Editorial: What is the most important outcome parameter in ankylosing spondylitis. Rheumatology 2008;47:1738–40.
    1. Haberhauer G, Strehblow C, Fasching P. Observational study of switching anti-TNF agents in ankylosing spondylitis and psoriatic arthritis vs. rheumatoid arthritis. Wien Med Wochenschr 2010;160:220–4.
    1. Rajalingham S, Das S. Antagonizing IL-6 in ankylosing spondylitis: a short review. Inflamm Allergy Drug Targets 2012;11:262–5..
    1. Smolen JS, Aletaha D, Koeller M, et al. New therapies for treatment of rheumatoid arthritis. Lancet 2007;370:1861–74.
    1. Braun J, Bollow M, Neure L, et al. Use of immunohistologic and in situ hybridization techniques in the examination of sacroiliac joint biopsy specimens from patients with ankylosing spondylitis. Arthritis Rheum 1995;38:499–505.
    1. Bal A, Unlu E, Bahar G, et al. Comparison of serum IL-1 beta, sIL-2R, IL-6, and TNF-alpha levels with disease activity parameters in ankylosing spondylitis. Clin Rheumatol 2007;26:211–15.
    1. Visvanathan S, Wagner C, Marini JC, et al. Inflammatory biomarkers, disease activity and spinal disease measures in patients with ankylosing spondylitis after treatment with infliximab. Ann Rheum Dis 2008;67:511–17.
    1. Pedersen SJ, Sørensen IJ, Lambert RG, et al. Radiographic progression is associated with resolution of systemic inflammation in patients with axial spondylarthritis treated with tumor necrosis factor α inhibitors: a study of radiographic progression, inflammation on magnetic resonance imaging, and circulating biomarkers of inflammation, angiogenesis, and cartilage and bone turnover. Arthritis Rheum 2011;63:3789–800.
    1. Actemra Prescribing Information 2010. (accessed July 2012).
    1. Henes JC, Horger M, Guenaydin I, et al. Mixed response to tocilizumab for ankylosing spondylitis. Ann Rheum Dis 2010;69:2217–8.
    1. Brulhart L, Nissen MJ, Chevallier P, et al. Tocilizumab in a patient with ankylosing spondylitis and Crohn's disease refractory to TNF antagonists. Joint Bone Spine 2010;77:625–6.
    1. Cohen JD, Ferreira R, Jorgensen C. Ankylosing spondylitis refractory to tumor necrosis factor blockade responds to tocilizumab. J Rheumatol 2011;38:1527.
    1. Shima Y, Tomita T, Ishii T, et al. Tocilizumab, a humanized anti-interleukin-6 receptor antibody, ameliorated clinical symptoms and MRI findings of a patient with ankylosing spondylitis. Mod Rheumatol 2011;21:436–9.
    1. Sieper J, Porter-Brown B, Thompson L, et al. Assessment of short-term symptomatic efficacy of tocilizumab in ankylosing spondylitis: results of randomised, placebo-controlled trials. Ann Rheum Dis 2014;73:95–100.
    1. Garrett S, Jenkinson T, Kennedy LG, et al. A new approach to defining disease status in ankylosing spondylitis: the Bath Ankylosing Spondylitis Disease Activity Index. J Rheumatol 1994;21:2286–91.
    1. Anderson JJ, Baron G, van der Heijde D, et al. Ankylosing Spondylitis Assessment Group preliminary definition of short-term improvement in ankylosing spondylitis. Arthritis Rheum 2001;44:1876–86.
    1. Calin A, Garrett S, Whitelock H, et al. A new approach to defining functional ability in ankylosing spondylitis: the development of the Bath Ankylosing Spondylitis Functional Index. J Rheumatol 1994;21:2281–5.
    1. Braun J, Baraliakos X, Golder W, et al. Magnetic resonance imaging examinations of the spine in patients with ankylosing spondylitis, before and after successful therapy with infliximab: evaluation of a new scoring system. Arthritis Rheum 2003;48:1126–36.
    1. Genovese MC, McKay JD, Nasonov EL, et al. Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. Arthritis Rheum 2008;58:2968–80.
    1. Smolen JS, Beaulieu A, Rubbert-Roth A, et al. OPTION Investigators. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet 2008;371:987–97.
    1. Huizinga TW, Fleischmann RM, Jasson M, et al. Sarilumab, a fully human monoclonal antibody against IL-6Rα in patients with rheumatoid arthritis and an inadequate response to methotrexate: efficacy and safety results from the randomised SARIL-RA-MOBILITY Part A trial. Ann Rheum Dis 2014;73: 1626–34.
    1. Kiltz U, Heldmann F, Baraliakos X, et al. Treatment of ankylosing spondylitis in patients refractory to TNF-inhibition: are there alternatives? Curr Opin Rheumatol 2012;24:252–60.
    1. Miossec P, Kolls JK. Targeting IL-17 and TH17 cells in chronic inflammation. Nat Rev Drug Discov 2012;11:763–76.
    1. Busquets-Perez N, Marzo-Ortega H, Emery P. Emerging drugs for axial spondyloarthritis including ankylosing spondylitis. Expert Opin Emerging Drugs 2013;18:71–86.
    1. Baeten D, Baraliakos X, Braun J, et al. Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind placebo-controlled trial. Lancet 2013;382:1705–13.

Source: PubMed

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