Abstract
Objective. To determine the effect of prior tumor necrosis factor inhibitor (TNFi) therapy on secukinumab efficacy in psoriatic arthritis (PsA).
Methods. Patients were randomized to secukinumab 300 mg, 150 mg, 75 mg, or placebo.
Results. American College of Rheumatology 20 responses at Week 24 with secukinumab 300 mg, 150 mg, 75 mg, and placebo were 58.2%, 63.5%, 36.9%, and 15.9% in TNFi-naive (n = 258), and 45.5%, 29.7%, 14.7%, and 14.3% in TNFi-exposed patients (n = 139), respectively. Week 52 responses with secukinumab 300 mg, 150 mg, and 75 mg were 68.7%, 79.4%, and 58.5% in TNFi-naive, and 54.5%, 37.8%, and 35.3% in TNFi-exposed patients, respectively.
Conclusion. Secukinumab was efficacious in TNFi-naive and TNFi-exposed patients with PsA, with greatest improvements in TNFi-naive patients.
Tumor necrosis factor inhibitors (TNFi) have proven efficacy in psoriatic arthritis (PsA)1,2. However, some patients are intolerant of TNFi or fail to achieve desired levels of disease control3. Alternative treatment options are therefore required.
The proinflammatory cytokine interleukin (IL)-17 is implicated in the pathophysiology of PsA4,5. Secukinumab, a human anti-IL-17A monoclonal antibody of the immunoglobulin (Ig) G1/κ isotype, is approved for the treatment of moderate to severe psoriasis and active PsA.
In the phase III FUTURE 2 (NCT01752634) study, secukinumab significantly improved signs and symptoms of disease, physical function, and quality of life in patients with PsA, with efficacy sustained through 52 weeks6. Here we describe efficacy outcomes in patients naive to TNFi therapy (TNFi-naive) and those previously treated with TNFi (TNFi-exposed).
MATERIALS AND METHODS
Patients and study design
FUTURE 2 is a 5-year, randomized, double-blind, multicenter, placebo-controlled, parallel-group study that is ongoing at the time of this analysis. Detailed patient eligibility criteria and study design have been reported previously6. Briefly, patients were ≥ 18 years old and had PsA fulfilling the ClASsification criteria for Psoriatic ARthritis (CASPAR) and active disease, defined as ≥ 3 tender and ≥ 3 swollen joints, despite previous treatment with conventional therapy. Patients were excluded if they had previously received biologics other than TNFi, or had received > 3 TNFi. Where applicable, TNFi were discontinued for 4–10 weeks before randomization. Concomitant methotrexate (MTX; ≤ 25 mg per week) was permitted.
Eligible patients were randomized (1:1:1:1) to receive subcutaneous (sc) doses of secukinumab 300 mg, 150 mg, 75 mg, or placebo at baseline, weeks 1, 2, 3, and 4, and every 4 weeks thereafter. At Week 16, placebo-treated patients were re-randomized (1:1) to receive secukinumab 300 mg or 150 mg sc from Week 16 (if they had < 20% improvement from baseline in tender and swollen joint counts) or Week 24. Randomization was stratified by previous TNFi use, with patients being TNFi-naive or TNFi-exposed (defined as having active disease despite having received an approved dose of a TNFi for ≥ 3 months or as having stopped treatment owing to safety and tolerability reasons).
The study was conducted in accordance with the Declaration of Helsinki principles and was approved by institutional review boards or independent ethics committees. Written informed consent was obtained from all patients.
Efficacy outcomes
Primary and secondary efficacy endpoints in the overall study population have been published6. Efficacy outcomes included proportion of patients with ≥ 20%, ≥ 50% or ≥ 70% improvement in American College of Rheumatology response criteria (ACR20, ACR50, and ACR70 responses, respectively); proportion of patients with ≥ 75% or ≥ 90% improvement in Psoriasis Area and Severity Index score (PASI75 and PASI90 responses, respectively: evaluated in patients with ≥ 3% body surface area affected with psoriasis); change in 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP); physical component summary score of the Medical Outcomes Study Short Form-36 health survey (SF36-PCS); Health Assessment Questionnaire–Disability Index (HAQ-DI); resolution of dactylitis and enthesitis among patients with these symptoms at baseline.
Assessment of efficacy in TNFi-naive and TNFi-exposed patients was prespecified, with analyses performed by intent-to-treat. Exploratory posthoc analyses were performed in TNFi-naive and TNFi-exposed patients based on concomitant MTX use, baseline weight (≥ 90 kg and < 90 kg), and disease activity (DAS28-CRP > 5.1 and ≤ 5.1).
Statistical analysis
Sample size calculations and analysis of primary and other efficacy endpoints have been reported6. For binary variables, patients with missing values and those with < 20% improvement in tender and swollen joint counts at Week 16 were imputed as nonresponders in the Week 24 analyses (nonresponder imputation). P values were computed for comparisons of secukinumab doses versus placebo from a logistic regression model with treatment and previous TNFi use as factors and the covariate being baseline weight. Baseline PASI score was a covariate in PASI75 and PASI90 analyses. For continuous variables at Week 24, a mixed-effect model repeated measures model was used, with treatment regimen, analysis visit, and previous TNFi use as factors, and weight and baseline score as continuous covariates.
Efficacy analyses at Week 52 are presented for patients originally randomized to secukinumab. Both imputed analyses and descriptive summaries (observed data) were performed on efficacy endpoints at Week 52.
RESULTS
Of 397 patients randomized, 258 (65.0%) were TNFi-naive and 139 (35.0%) were TNFi-exposed. The majority of patients completed 52 weeks of treatment [secukinumab 300 mg: 92/100 (92.0%); secukinumab 150 mg: 86/100 (86.0%); secukinumab 75 mg: 75/99 (75.8%)]. Lack of efficacy was the most common reason for discontinuation: 1 (1.0%) secukinumab 300 mg, 6 (6.0%) secukinumab 150 mg; 12 (12.1%) secukinumab 75 mg. More than half [13/19 (68.4%)] of the patients who discontinued because of lack of efficacy at Week 52 were in the TNFi-exposed subgroup.
Demographic and baseline characteristics were generally similar between TNFi-naive and TNFi-exposed, although some differences were noted in terms of weight and MTX use at baseline between the subgroups (Table 1).
Demographic and baseline characteristics.
In the overall population, ACR20 response rates (primary endpoint) were significantly higher in the secukinumab 300 mg (54.0%; p < 0.0001), 150 mg (51.0%; p < 0.0001), and 75 mg (29.3%; p < 0.05) groups versus placebo (15.3%) at Week 24. In the TNFi-naive subgroup, ACR20 response rates at Week 24 were 58.2% for secukinumab 300 mg group (p < 0.0001); 63.5% for the 150 mg group (p < 0.0001); and 36.9% for the 75 mg group (p < 0.01), compared with 15.9% in the placebo group (Table 2; Supplementary Figure 1, available online at jrheum.org). Improvements in multiple secondary endpoints were observed with secukinumab 300 mg and 150 mg versus placebo at Week 24 (Table 2).
Efficacy of secukinumab at weeks 24 and 52.
In the TNFi-exposed subgroup, ACR20 response rates at Week 24 were 45.5% in the secukinumab 300 mg group (p < 0.01), 29.7% in the 150 mg group (p = 0.12), and 14.7% in the 75 mg group (p = 0.96), versus 14.3% in the placebo group (Table 2; Supplementary Figure 1, available online at jrheum.org). Secukinumab 300 mg improved a number of secondary endpoints at Week 24 versus placebo (Table 2).
Clinical improvements observed with secukinumab at Week 24 were sustained or continued to improve through Week 52 in both TNFi-naive and TNFi-exposed patients (Table 2 and Table 3; Supplementary Figure 1, available online at jrheum.org). Using a conservative estimate of efficacy with missing values imputed as nonresponse, 68.7%, 79.4%, and 58.5% of TNFi-naive and 54.5%, 37.8%, and 35.3% of TNFi-exposed patients in the 300 mg, 150 mg, and 75 mg group, respectively, achieved an ACR20 response at Week 52 (Table 2). Observed data are presented in Table 3.
Efficacy of secukinumab at Week 52 (observed data).
In the posthoc analyses, improvements in ACR20 response rates in TNFi-naive patients at Week 24 versus placebo were observed with secukinumab 300 mg and 150 mg, irrespective of concomitant MTX use, body weight or baseline disease activity (Supplementary Figures 2, 3, and 4, available online at jrheum.org). In TNFi-exposed patients, improved ACR20 response rates at Week 24 versus placebo were achieved with secukinumab 300 mg in patients receiving concomitant MTX, patients weighing ≥ 90 kg, and patients with baseline DAS28-CRP ≤ 5.1. Across all of these subgroups, the clinical responses observed with secukinumab at Week 24 were generally sustained or improved through Week 52 (Supplementary Figures 2, 3, and 4, available online at jrheum.org).
DISCUSSION
Previous results from the FUTURE 2 study demonstrated that secukinumab 300 mg and 150 mg sc provide clinically meaningful and sustained improvements in key clinical domains of PsA6. Here, we expand upon those findings, demonstrating that secukinumab is effective in TNFi-naive patients and those who are intolerant of or who fail to achieve adequate disease control with TNFi. These data suggest that secukinumab 150 mg appears to be the most appropriate dose for TNFi-naive patients, but among the TNFi-exposed patients, the 300 mg dose seems to be more appropriate, especially among those patients with high levels of disease activity.
Despite the proven benefits of TNFi, not all treated patients achieve desired levels of disease control, and loss of efficacy can be a clinically relevant problem7. In an analysis of data from the Danish DANBIO registry, about 40% of patients with PsA receiving a TNFi switched to a second biologic within a median followup of 2.3 years8. Moreover, switching biologics was associated with decreasing ACR response rates and drug survival times; 47% of patients achieved an ACR20 response after 3–6 months of first-line TNFi therapy, reducing to 22% and 18% among patients switching to a second or third biologic, respectively8. These data suggest that targeting IL-17A with secukinumab may be a viable treatment option for patients with PsA, including those previously treated with TNFi.
Posthoc analyses indicate that secukinumab 300 mg and 150 mg was effective in TNFi-naive patients regardless of concomitant MTX use, weight, or baseline disease activity. In TNFi-exposed patients, the 300 mg dose appeared to be effective in those patients with concomitant MTX, increased weight (≥ 90 kg), and lower baseline disease activity.
The main limitation of these analyses is the small number of patients within each subgroup. This, along with the posthoc nature of some of the exploratory analyses by baseline disease characteristics, means these findings should be interpreted with caution.
Secukinumab 300 mg and 150 mg provided sustained improvements in the signs and symptoms of PsA in TNFi-naive patients. In TNF-exposed patients, improved clinical responses were consistently observed only with the 300 mg dose.
ONLINE SUPPLEMENT
Supplementary data for this article are available online at jrheum.org.
Acknowledgment
We thank John Gallagher, a medical consultant for Novartis Pharma; Chris Strutynskyj-Stannard (Seren Communications, an Ashfield Company, part of UDG Healthcare plc), and Neeta Pillai (Novartis Healthcare Pvt Ltd, India) for medical writing support.
Footnotes
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The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. A. Kavanaugh received research grants or consultation fees from Novartis. I.B. McInnes received research grants, consultation fees, or speaker honoraria from Novartis. P.J. Mease received research grants, consultation fees, or speaker honoraria from Novartis. H. Chinoy received consulting fees/grant support from Novartis. Z. Wang is an employee of Novartis. S. Mpofu is an employee of Novartis and owns Novartis stock.
- Accepted for publication May 9, 2016.
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