Elsevier

The Lancet

Volume 386, Issue 9999, 19–25 September 2015, Pages 1137-1146
The Lancet

Articles
Secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis (FUTURE 2): a randomised, double-blind, placebo-controlled, phase 3 trial

https://doi.org/10.1016/S0140-6736(15)61134-5Get rights and content

Summary

Background

Interleukin 17A is a proinflammatory cytokine that is implicated in the pathogenesis of psoriatic arthritis. We assessed the efficacy and safety of subcutaneous secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis.

Methods

In this phase 3, double-blind, placebo-controlled study undertaken at 76 centres in Asia, Australia, Canada, Europe, and the USA, adults (aged ≥18 years old) with active psoriatic arthritis were randomly allocated in a 1:1:1:1 ratio with computer-generated blocks to receive subcutaneous placebo or secukinumab 300 mg, 150 mg, or 75 mg once a week from baseline and then every 4 weeks from week 4. Patients and investigators were masked to treatment assignment. The primary endpoint was the proportion of patients achieving at least 20% improvement in the American College of Rheumatology response criteria (ACR20) at week 24. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01752634.

Findings

Between April 14, and Nov 25, 2013, 397 patients were randomly assigned to receive secukinumab 300 mg (n=100), 150 mg (n=100), 75 mg (n=99), or placebo (n=98). A significantly higher proportion of patients achieved an ACR20 at week 24 with secukinumab 300 mg (54 [54%] patients; odds ratio versus placebo 6·81, 95% CI 3·42–13·56; p<0·0001), 150 mg (51 [51%] patients; 6·52, 3·25–13·08; p<0·0001), and 75 mg (29 [29%] patients; 2·32, 1·14–4·73; p=0·0399) versus placebo (15 [15%] patients). Up to week 16, the most common adverse events were upper respiratory tract infections (four [4%], eight [8%], ten [10%], and seven [7%] with secukinumab 300 mg, 150 mg, 75 mg, and placebo, respectively) and nasopharyngitis (six [6%], four [4%], six [6%], and eight [8%], respectively). Serious adverse events were reported by five (5%), one (1%), and four (4%) patients in the secukinumab 300 mg, 150 mg, and 75 mg groups, respectively, compared with two (2%) in the placebo group. No deaths were reported.

Interpretation

Subcutaneous secukinumab 300 mg and 150 mg improved the signs and symptoms of psoriatic arthritis, suggesting that secukinumab is a potential future treatment option for patients with this disorder.

Funding

Novartis.

Introduction

Psoriatic arthritis, a chronic inflammatory disease that can affect peripheral and axial joints, entheses, and the skin, is associated with impaired physical function and poor quality of life.1, 2 Pathogenesis-based interventions, particularly therapies targeting tumour necrosis factor (TNF), have improved outcomes in patients with psoriatic arthritis.3, 4, 5, 6, 7 Recently, the interleukin 12/23 inhibitor ustekinumab and the phosphodiesterase-4 inhibitor apremilast have also shown efficacy.8, 9, 10 Despite this progress, not all patients respond to or tolerate therapy, and clinical needs are largely unmet.

Interleukin 17A and its receptor are expressed in synovial tissues and as such the interleukin-17 pathway is proposed to contribute to the pathogenesis of psoriatic arthritis.11, 12, 13, 14, 15 Interleukin 17A can mediate a variety of effector biological functions that can result in joint and enthesial inflammation, damage, and tissue remodelling.16

Secukinumab, a human monoclonal antibody that inhibits the effector function of interleukin 17A, has been shown to be better than placebo and etanercept in improving the signs and symptoms of psoriasis.17 In the phase 3 FUTURE 1 study of 606 patients with psoriatic arthritis, intravenous loading with secukinumab followed by subcutaneous maintenance dosing significantly improved key clinical domains of disease versus placebo, including signs and symptoms, radiographic disease progression, physical functioning, and quality of life.18

We report the main results from FUTURE 2, an ongoing phase 3 trial of the efficacy and safety of subcutaneous loading and maintenance dosing of secukinumab versus placebo in patients with psoriatic arthritis.

Section snippets

Study design and participants

This randomised, double-blind, placebo-controlled phase 3 trial was done at 76 centres in Asia, Australia, Canada, Europe, and the USA. Changes to the protocol after the start of the study are summarised in the appendix. The study protocol is available from the funder.

Research in context

Evidence before this study

We searched PubMed using the terms “psoriatic arthritis (PsA)”, “biologic”, and “interleukin-17 (IL-17)” for English language articles published up to April 29, 2015, with no limitation

Results

Between April 14, and Nov 25, 2013, 397 patients were randomly assigned to receive secukinumab 300 mg (n=100), 150 mg (n=100), 75 mg (n=99), or placebo (n=98); 373 (94%) of these patients completed week 24 treatment (figure 1). No patients were excluded from the efficacy and safety analyses.

Baseline demographics, disease characteristics, and previous or concomitant medication use were similar across the study groups, except for imbalances in baseline PASI score, proportion of female patients,

Discussion

In this phase 3 trial, subcutaneous administration of the anti-interleukin-17A monoclonal antibody secukinumab significantly improved the signs and symptoms of psoriatic arthritis versus placebo. ACR20 response rates at week 24 were better with all secukinumab doses than with placebo. Additional efficacy outcomes at week 24 also showed significant benefits with secukinumab 300 mg and 150 mg versus placebo, but responses with secukinumab 75 mg were lower and not significantly different from

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