Downloaded from http://ard.bmj.com/ on December 8, 2016 - Published by group.bmj.com Clinical and epidemiological research EXTENDED REPORT Sifalimumab, an anti-interferon-α monoclonal antibody, in moderate to severe systemic lupus erythematosus: a randomised, double-blind, placebo-controlled study Munther Khamashta,1 Joan T Merrill,2 Victoria P Werth,3,4 Richard Furie,5 Kenneth Kalunian,6 Gabor G Illei,7 Jorn Drappa,7 Liangwei Wang,8 Warren Greth,7 on behalf of the CD1067 study investigators Handling editor Tore K Kvien ABSTRACT remains challenging because of the suboptimal effi- ▸ Additional material is Objectives The efficacy and safety of sifalimumab cacy of standard-of-care medications and the – published online only. To view were assessed in a phase IIb, randomised, double-blind, serious adverse events associated with their use.4 6 – please visit the journal online placebo-controlled study (NCT01283139) of adults with Several studies, reviewed elsewhere,7 9 have sug- (http://dx.doi.org/10.1136/ moderate to severe active systemic lupus erythematosus gested a role for interferon-α (IFN-α) in the patho- annrheumdis-2015-208562). – (SLE). genesis of SLE.10 16 Distinct patterns of gene fi – For numbered af liations see Methods 431 patients were randomised and received expression induced by type I IFN11 17 19 are sub- end of article. monthly intravenous sifalimumab (200 mg, 600 mg or stantially upregulated in blood, skin biopsies and Correspondence to 1200 mg) or placebo in addition to standard-of-care synovial biopsies of patients with SLE compared Professor Munther Khamashta, medications. Patients were stratified by disease activity, with healthy controls.20 This study aimed to inves- Graham Hughes Lupus interferon gene-signature test (high vs low based on the tigate whether blocking the type I IFN pathway is Research Laboratory, Division of Women’s Health, King’s expression of four genes) and geographical region. The an effective approach for the treatment of SLE. College London, The Rayne primary efficacy end point was the percentage of Sifalimumab is a fully human, immunoglobulin Institute, Lambeth Wing 4th patients achieving an SLE responder index response at G1 κ monoclonal antibody that binds to and neu- Floor, St Thomas’ Hospital, week 52. tralises the majority of IFN-α subtypes. Clinical London SE1 7EH, UK; Results Compared with placebo, a greater percentage trials of sifalimumab have established its safety [email protected] of patients who received sifalimumab (all dosages) met profile and its suppression of IFN-α-induced genes, Received 10 September 2015 the primary end point (placebo: 45.4%; 200 mg: and have suggested favourable effects on clinical Revised 15 February 2016 58.3%; 600 mg: 56.5%; 1200 mg 59.8%). Other outcome measures.21 22 This phase IIb trial was Accepted 21 February 2016 improvements were seen in Cutaneous Lupus conducted to evaluate the efficacy and safety of Published Online First fi 23 March 2016 Erythematosus Disease Area and Severity Index score three xed intravenous dosages of sifalimumab in (200 mg and 1200 mg monthly), Physician’s Global adults with moderate to severe active SLE with Assessment (600 mg and 1200 mg monthly), British inadequate responses to standard-of-care Isles Lupus Assessment Group-based Composite Lupus treatments. Assessment (1200 mg monthly), 4-point reductions in the SLE Disease Activity Index−2000 score and reductions in counts of swollen joints and tender joints. METHODS Serious adverse events occurred in 17.6% of patients on Eligible patients were male or female, aged 18– placebo and 18.3% of patients on sifalimumab. Herpes 75 years, weighing ≥40 kg, fulfilling ≥4 of the 11 zoster infections were more frequent with sifalimumab American College of Rheumatology (ACR) SLE 23 24 treatment. classification criteria, and receiving stable Conclusions Sifalimumab is a promising treatment for dosages of one or more of the following: oral pred- adults with SLE. Improvement was consistent across nisone (≤20 mg/day, or equivalent); azathioprine various clinical end points, including global and organ- (≤150 mg/day); antimalarial treatment; mycophe- specific measures of disease activity. nolate mofetil/mycophenolic acid (≤3.0 g/day); or Trial registration number NCT01283139; Results. subcutaneous/oral methotrexate (≤20 mg/week). Administration of stable dosages of non-steroidal anti-inflammatory drugs was permitted. Prior to enrolment, biological therapies had to be discontin- INTRODUCTION ued for a sufficient period to ensure they would no ▸ http://dx.doi.org/10.1136/ Systemic lupus erythematosus (SLE) is a chronic, longer have any pharmacodynamic and/or clinical annrheumdis-2016-209345 multisystem, autoimmune disease that predomin- effect. antly affects women of childbearing age. Its clinical At screening, patients had to have positive ser- manifestations (eg, arthritis, rashes, alopecia, vascu- ology for antinuclear (≥1:40), anti-Smith or fi ≥ To cite: Khamashta M, litis, nephritis, serositis) lead to signi cant morbid- anti-double-stranded DNA (dsDNA) ( 100 IU/mL) Merrill JT, Werth VP, et al. ity, reduced physical function, loss of employment, antibodies by the AtheNA Multi-Lyte ANA-II Plus Ann Rheum Dis impaired quality of life, high risk of permanent dis- test system (Alere, Waltham, Massachusetts, USA). – – 2016;75:1909 1916. ability and shortened life span.1 3 Treatment of SLE Patients also had to meet the following disease Khamashta M, et al. Ann Rheum Dis 2016;75:1909–1916. doi:10.1136/annrheumdis-2015-208562 1909 Downloaded from http://ard.bmj.com/ on December 8, 2016 - Published by group.bmj.com Clinical and epidemiological research activity criteria: SLE Disease Activity Index 2000 (≥10 mg/day, or equivalent, at baseline to ≤7.5 mg/day by week (SLEDAI-2K)25 score ≥6 with at least two points from a clinical 52); ≥4-point reduction in Cutaneous Lupus Erythematosus component (excluding SLE headache or organic brain syn- Disease Area and Severity Index (CLASI)30 31 for patients with drome), a British Isles Lupus Assessment Group at least moderate skin involvement (CLASI ≥10); and >3-point (BILAG)-200426 score of ≥1A or ≥2B organ system scores27 improvement in Functional Assessment of Chronic Illness and a Physician’s Global Assessment (PGA) of disease activity Therapy-Fatigue.32 Other prespecified efficacy end points ≥1 (scale: 0 (none) to 3 (severe)). Patients with active and severe included SLEDAI-2K25; modified SRI (mSRI) requiring lupus nephritis or neuropsychiatric SLE were excluded from the SLEDAI-2K reductions of 5–8 points; BILAG-based Combined study. At randomisation, the overall SLEDAI-2K clinical compo- Lupus Assessment (BICLA)33; PGA; numbers of swollen and nent score was required to be at or above the screening value. tender joints; dsDNA; and C3 and C4 complement Additional study exclusion criteria are provided in the online concentrations. supplementary material. Safety end points included reporting of adverse events (Medical Dictionary for Regulatory Activities, V.17), laboratory Study design assessments and vital signs. This study (NCT01283139), conducted at 107 sites in 20 coun- tries, consisted of a 52-week, randomised, double-blind, placebo-controlled, parallel-group treatment phase, followed by Statistical analysis a 22-week safety follow-up phase, and was conducted between Analysis of the primary end point compared response rates at March 2011 and April 2014. All sites received ethics committee week 52 between each sifalimumab group and placebo using a or independent institutional review board approval before com- logistic regression model with independent variables of treat- mencement of the study. ment group and randomisation stratification factors. Patients Dosages of oral corticosteroids were required to remain stable who withdrew from treatment had increased use of corticoster- throughout the study, with the exception of limited, protocol- oids beyond that permitted (see online supplementary material), defined, oral corticosteroid burst (followed by a taper) for or initiated or increased immunosuppressant dosage any time increased SLE disease activity or protocol-permitted oral cor- after baseline were considered non-responders. Analyses were ticosteroid tapering (see online supplementary material). performed in the modified intention-to-treat (mITT) population The study was monitored by an independent data safety and (all randomised patients who received any investigational monitoring board, which included a rheumatologist and an product and had a baseline primary efficacy measurement) and infectious disease expert. An independent external adjudication an mITT subpopulation of patients with a high IFN gene signa- group confirmed SLE organ system involvement and disease ture. The study result was considered positive if the primary activity at screening, approved randomisation, and monitored end point was met in either of the two study populations. assessments and adherence throughout the trial. The type-I error rate (α level) was controlled at approximately This study was conducted in accordance with the principles 0.10 (two-sided), within each of the populations for the of the Declaration of Helsinki and the International Conference primary end point analysis, by performing a Cochran−Armitage on Harmonisation Guidance for Good Clinical Practice. trend test of all treatment groups prior to performing pairwise Independent ethics committee approval was obtained and all comparisons between each sifalimumab group and placebo. No patients provided written