Elsevier

The Lancet

Volume 395, Issue 10235, 9–15 May 2020, Pages 1496-1505
The Lancet

Articles
Secukinumab versus adalimumab for treatment of active psoriatic arthritis (EXCEED): a double-blind, parallel-group, randomised, active-controlled, phase 3b trial

https://doi.org/10.1016/S0140-6736(20)30564-XGet rights and content

Summary

Background

Head-to-head trials in psoriatic arthritis are helpful in guiding clinical decision making. The EXCEED study evaluated the efficacy and safety of secukinumab versus adalimumab as first-line biological monotherapy for 52 weeks in patients with active psoriatic arthritis, with a musculoskeletal primary endpoint of American College of Rheumatology (ACR) 20 response.

Methods

This parallel-group, double-blind, active-controlled, phase-3b, multicentre (168 sites in 26 countries) trial enrolled patients aged at least 18 years with active psoriatic arthritis. Eligible patients were randomly assigned (1:1) by means of interactive response technology to receive secukinumab or adalimumab. Patients, investigators, site personnel, and those doing the assessments (except independent study drug administrators) were masked to study assignment. 300 mg secukinumab was administered subcutaneously at baseline, weeks 1, 2, 3, and 4, and then every 4 weeks until week 48 as a pre-filled syringe. Adalimumab was administered every 2 weeks from baseline until week 50 as 40 mg per 0·4 mL citrate free subcutaneous injection. The primary outcome was the proportion of patients with at least 20% improvement in the ACR response criteria (ACR20) at week 52. Patients were analysed according to the treatment to which they were randomly assigned. Safety analyses included all safety data reported up to and including the week 52 visit for each patient who received at least one dose of study drug. The trial is registered at ClinicalTrials.gov, NCT02745080.

Findings

Between April 3, 2017 and Aug 23, 2018, we randomly assigned 853 patients to receive secukinumab (n=426) or adalimumab (n=427). 709 (83%) of 853 patients completed week 52 of the study, of whom 691 (81%) received the last study treatment at week 50. 61 (14%) of 426 patients in the secukinumab group discontinued treatment by week 52 versus 101 (24%) of 427 patients in the adalimumab group. The primary endpoint of superiority of secukinumab versus adalimumab for ACR20 response at week 52 was not met. 67% of patients in the secukinumab group achieved an ACR20 response at week 52 versus 62% of patients in the adalimumab group (OR 1·30, 95% CI 0·98–1·72; p=0·0719). The safety profiles of secukinumab and adalimumab were consistent with previous reports. Seven (2%) of 426 patients in the secukinumab group and six (1%) of 427 patients in the adalimumab group had serious infections. One death was reported in the secukinumab group due to colon cancer and was assessed as not related to the study drug by the investigator.

Interpretation

Secukinumab did not meet statistical significance for superiority versus adalimumab in the primary endpoint of ACR20 response at week 52. However, secukinumab was associated with a higher treatment retention rate than adalimumab. This study provides comparative data on two biological agents with different mechanisms of action, which could help guide clinical decision making in the management of patients with psoriatic arthritis.

Funding

Novartis Pharma.

Introduction

Psoriatic arthritis is clinically heterogeneous, comprising musculoskeletal and dermatological manifestations that might involve arthritis, spondylitis, enthesitis, dactylitis, and psoriasis of skin and nails, and is associated with impaired physical function and poor quality of life.1 Non-steroidal anti-inflammatory drugs (NSAIDs) are typically the first choice in treating psoriatic arthritis symptoms, but have associated safety issues of cardiovascular risk and gastrointestinal toxicity; therefore, physicians initiate conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), preferably methotrexate, early in patients with poor prognostic factors and relevant skin involvement to modify underlying musculoskeletal and skin inflammation.2, 3

Several biological disease modifying anti-rheumatic drugs (bDMARDs) targeting inflammatory cytokines are recommended for patients with psoriatic arthritis with inadequate response to csDMARDs.3, 4 Adalimumab, a human monoclonal antibody against tumour necrosis factor (TNF), is widely used as a first line bDMARD in the treatment of patients with psoriatic arthritis as monotherapy or an add-on to methotrexate.5 Secukinumab, a human monoclonal antibody that directly inhibits IL-17A, has shown substantial improvement in the key clinical domains of psoriatic arthritis, including signs and symptoms, radiographic progression, physical functioning, and quality of life.6, 7, 8 In the treatment of patients with moderate to severe psoriasis and plaque psoriasis, secukinumab has shown greater efficacy versus a TNF inhibitor (etanercept) and an IL-12/23 inhibitor (ustekinumab).9, 10, 11

Research in context

Evidence before this study

Many patients with psoriatic arthritis who have active psoriasis and musculoskeletal symptoms show inadequate clinical responses to conventional synthetic disease-modifying antirheumatic agents (csDMARDs), including methotrexate, in all manifestations of psoriatic arthritis, including arthritis, spondylitis, enthesitis, dactylitis, and psoriasis. Several biological disease-modifying anti-rheumatic drugs (bDMARDs) that target different inflammatory cytokines are recommended for patients with psoriatic arthritis with inadequate response to csDMARDs. Adalimumab, a human monoclonal antibody against tumour necrosis factor (TNF), is widely used as a first-line bDMARD in the treatment of patients with psoriatic arthritis in monotherapy or in combination with methotrexate. We searched PubMed using the terms “psoriatic arthritis”, “biologic”, and “head-to-head” for English language articles published from inception up to Jan 13, 2020, with no limitation or restriction for year of publication or article type. The search results yielded 30 articles, of which nine used matching adjusted indirect comparisons to compare two biologicals, 20 were review articles, and one was a head-to-head comparison of two biologicals in psoriatic arthritis. However, matching adjusted indirect comparisons have an inherent limitation of the methodology used and might lead to different conclusions; therefore, prospective head-to-head trials in psoriatic arthritis are needed to help guide physicians in clinical decision making. A 2020 head-to-head, open label, 24-week trial compared the efficacy and safety of two biologicals—adalimumab and ixekizumab (an IL-17A inhibitor)—in psoriatic arthritis and supported that ixekizumab was superior to adalimumab in achieving combined American College of Rheumatology 50 (ACR50) and Psoriasis Area and Severity Index 100 responses at week 24.

Added value of this study

To our knowledge, EXCEED is the first fully blinded head-to-head trial to evaluate the efficacy and safety of secukinumab (an IL-17A inhibitor) versus adalimumab (an anti-TNF agent) as first-line biological monotherapy in patients with active psoriatic arthritis with a musculoskeletal primary endpoint of ACR20 at week 52. The efficacy data in this study suggest that secukinumab was at least as efficacious as adalimumab in improving musculoskeletal endpoints, provided better responses on skin endpoints, and had a higher retention rate at week 52. No new safety signals were reported for secukinumab and adalimumab.

Implications of all the available evidence

This study presents a considerable volume of comparative efficacy and safety data on two biologicals with different mechanisms of action in the treatment of patients with psoriatic arthritis.

Both adalimumab and secukinumab are approved for treatment of patients with active psoriatic arthritis with or without the use of concomitant methotrexate.5, 6, 12 More than 40% of patients treated with methotrexate discontinue treatment or are non-compliant because of poor tolerability or toxicity, or cannot receive methotrexate because of liver abnormalities related to psoriatic arthritis or concomitant alcohol abuse.13, 14, 15 The European League Against Rheumatism (EULAR) and Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) recommendations differ. EULAR proposes a treatment algorithm, whereas GRAPPA proposes an evidence-based clinical domain approach that includes biologicals with novel mechanisms of action.3, 16 However, there is a paucity of trials to determine which biological treatment should be the initial treatment in patients with psoriatic arthritis upon csDMARD failure or intolerance. The advent of biological therapies with selective mechanisms of action that are approved and widely used in clinical practice has prompted indirect comparison approaches to guide therapy, but these comparisons have methodological limitations.17

Head-to-head trials have shown that IL-17A inhibitors have higher efficacy in treatment of patients with moderate to severe psoriasis and on the skin manifestations of patients with psoriatic arthritis. However, comparative data are lacking on the efficacy of these drugs on musculoskeletal manifestations of psoriatic arthritis and are urgently required. The aim of the EXCEED study was to investigate whether secukinumab 300 mg monotherapy was superior to adalimumab 40 mg monotherapy as first-line bDMARD treatment, thus testing the musculoskeletal endpoint of the American College of Rheumatology (ACR) 20 response as the primary objective in a fully blinded manner. Safety of secukinumab and adalimumab was also assessed.

Section snippets

Study design and participants

EXCEED is a randomised, double-blind, active-controlled, phase-3b, multicentre (168 sites in 26 countries; appendix p 19), parallel-group, 52-week study that evaluated secukinumab monotherapy and adalimumab monotherapy in patients with active psoriatic arthritis who were naive to biological therapy for psoriatic arthritis and psoriasis, and who were intolerant or had an inadequate response to csDMARDs.

Patients fulfilling all the following criteria were included in the study: aged at least 18

Results

Between April 3, 2017, and Aug 23, 2018, we randomly assigned 853 patients to receive secukinumab (n=426) or adalimumab (n=427). 709 (83%) of 853 patients completed week 52 of the study (figure 1), of whom 691 (81%) received the last study treatment at week 50 (appendix p 20). 61 (14%) of 426 patients in the secukinumab group discontinued treatment by week 52 versus 101 (24%) of 427 patients in the adalimumab group. Major reasons for discontinuation of treatment were adverse events (15 [4%] of

Discussion

With increased availability of approved medicines that have distinct mechanisms of action, head-to-head trials can be useful to help guide clinical decision making in the management of psoriatic arthritis after csDMARD (including methotrexate) failure, intolerance, or contraindication.3, 21 To our knowledge, EXCEED is the first head-to-head, double-blind, randomised trial to compare secukinumab and adalimumab, and tested a musculoskeletal primary endpoint of ACR20 response in psoriatic

Data sharing

The datasets generated and analysed during the current study are not publicly available. Novartis is committed to sharing access to patient-level data and supporting clinical documents from eligible studies with qualified external researchers. These requests are reviewed and approved based on scientific merit. All data provided are anonymised to respect the privacy of patients who have participated in the trial, in line with applicable laws and regulations. The data can be requested from the

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