Secukinumab for Long-Term Treatment of Psoriatic Arthritis: A Two-Year Followup From a Phase III, Randomized, Double-Blind Placebo-Controlled Study

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1 Arthritis Care & Research Vol. 69, No. 3, March 2017, pp DOI /acr VC 2016, American College of Rheumatology ORIGINAL ARTICLE Secukinumab for Long-Term Treatment of Psoriatic Arthritis: A Two-Year Followup From a Phase III, Randomized, Double-Blind Placebo-Controlled Study ARTHUR KAVANAUGH, 1 PHILIP J. MEASE, 2 ANDREAS M. REIMOLD, 3 HASAN TAHIR, 4 J URGEN RECH, 5 STEPHEN HALL, 6 PIET GEUSENS, 7 ZAILONG WANG, 8 LUMINITA PRICOP, 8 AND SHEPHARD MPOFU, 8 FOR THE FUTURE-1 STUDY GROUP Objective. To assess the 2-year efficacy and safety of the interleukin-17a inhibitor, secukinumab, in active psoriatic arthritis (PsA). Methods. In the FUTURE-1 study, 606 patients with active PsA were randomized to secukinumab 10 mg/kg intravenously at baseline, and at weeks 2 and 4, followed by 150 mg or 75 mg subcutaneously (SC) every 4 weeks from week 8, or matching placebo. Patients receiving placebo were re-randomized to secukinumab 150 mg or 75 mg SC from week 16 or week 24, depending upon clinical response. Treatment continued to week 104. Exploratory analysis of all primary and secondary end points, on an intent-to-treat basis, continued to week 104. Results. A total of 476 patients (78.5%) completed 104 weeks of treatment. Secukinumab showed sustained efficacy across multiple domains of PsA through week 104, including signs and symptoms, disease activity, quality of life, physical function, skin symptoms, dactylitis, and enthesitis. American College of Rheumatology criteria for 20% improvement response rates were 66.8% with secukinumab 150 mg and 58.6% with secukinumab 75 mg at week 104; Psoriasis Area and Severity Index criteria for 75% improvement response rates were 74.6% and 63.0%, respectively (multiple imputed data). At week 104, 84.3% of patients in the secukinumab 150 mg group and 83.8% in the secukinumab 75 mg group showed no radiographic disease progression (observed data). No new or unexpected safety signals were reported during 2 years of treatment. Immunogenicity to secukinumab was low. Conclusion. Secukinumab provided sustained improvements in PsA at 2 years, with very little radiographic progression. Treatment was well tolerated over the long term. INTRODUCTION Psoriatic arthritis (PsA) is a heterogeneous condition, characterized by not only peripheral arthritis, but also dactylitis, enthesitis, axial arthritis, and skin and nail psoriasis. As a chronic, systemic inflammatory disorder, management aims to suppress inflammation to minimize articular and dermatologic symptoms, prevent structural damage, and maximize quality of life (1 4). Ideally, for patients with active disease in various domains, treatments that address both articular and extraarticular manifestations should be preferred (2,3). Clinical Trials.gov identifier: NCT The FUTURE-1 study was supported by Novartis Pharma, who was also responsible for analyzing the data. 1 Arthur Kavanaugh, MD: University of California at San Diego, La Jolla, California; 2 Philip J. Mease, MD: Swedish Medical Center and University of Washington School of Medicine, Seattle; 3 Andreas M. Reimold, MD: Dallas VA Medical Center and University of Texas Southwestern Medical Center, Dallas; 4 Hasan Tahir, MD: Whipps Cross University Hospital, London, UK; 5 J urgen Rech, MD: Friedrich Alexander University, Erlangen-N urnberg (FAU), Universit atsklinikum Erlangen, Germany; 6 Stephen Hall, MBBS, FRACP: Cabrini Monash University, Victoria, Australia; 7 Piet Geusens, MD: CAPHRI/NUTRIM, Maastricht University Medical Centre, Maastricht, The Netherlands; 8 Zailong Wang, PhD, Luminita Pricop, MD, Shephard Mpofu, MD: Novartis Pharma, East Hanover, New Jersey. Dr. Kavanaugh has received consultant fees, speaking fees, and/or honoraria from AbbVie, Amgen, Janssen, Lilly, Novartis, UCB, and Pfizer (less than $10,000 each). Dr. Mease has received consultant fees, speaking fees, and/or honoraria from Celgene and Crescendo (less than $10,000 each) and from Lilly, AbbVie, Amgen, BMS, Novartis, UCB, and Pfizer (more than $10,000 each). Dr. Tahir has received speaking fees from AbbVie, Lilly, and Novartis (less than $10,000 each). Dr. Rech has received speaking and/or consultant fees from 347

2 348 Kavanaugh et al Significance & Innovations Secukinumab is an interleukin-17a inhibitor that has shown efficacy in treating inflammatory diseases such as psoriasis, ankylosing spondylitis, and psoriatic arthritis (PsA). This article presents the first 2-year efficacy and safety clinical trial data for this monoclonal antibody in PsA. These data show that secukinumab provides sustained improvements at 2 years across multiple clinical domains in patients with active PsA and inhibits radiographic progression of the disease. Secukinumab is a high affinity, human immunoglobulin G1 monoclonal antibody that selectively binds to and neutralizes interleukin-17a (IL-17A). It has shown efficacy in treating inflammatory diseases such as psoriasis and ankylosing spondylitis (5 10), as well as PsA (11 13). Primary analysis of the phase III FUTURE-1 study (ClinicalTrials.gov identifier: NCT ) reported rapid and significant improvements in key clinical domains of PsA with secukinumab at week 24, which were sustained through week 52 (13). Here we present efficacy and safety data for up to 104 weeks of treatment for patients enrolled in FUTURE-1. PATIENTS AND METHODS Study population. The design of FUTURE-1 has been described in detail elsewhere (13). In brief, participants were adults with PsA according to the Classification Criteria for Psoriatic Arthritis (14), with moderate to severe symptoms for $6 months,$3 tender joints of 78, and $3 swollen joints of 76 at baseline despite treatment with nonsteroidal antiinflammatory drugs, disease-modifying antirheumatic drugs, or anti tumor necrosis factor (anti-tnf) therapies. Patients taking an anti-tnf agent must have experienced an inadequate response to treatment given at an adequate dose for $3 months or have stopped treatment due to tolerability issues (thereby designated anti-tnf inadequate responders [anti-tnf-ir]). Concomitant use of stable doses of oral glucocorticoids (up to 10 mg/day of prednisone or equivalent) and methotrexate (up to 25 mg/week) were permitted. Key AbbVie, BMS, Celgene, MSD, Novartis, Pfizer, Roche, and UCB (less than $10,000 each). Drs. Hall, Wang, and Pricop are employed by Novartis and own stock in Novartis. Dr. Geusens has received consultant fees, speaking fees, and/or honoraria from AbbVie, Amgen, BMS, Lilly, MSD, Novartis, Pfizer, Roche, UCB, and Will Pharma (less than $10,000 each). Address correspondence to Arthur Kavanaugh, MD, Division of Rheumatology, Allergy and Immunology, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, Mail Code 0943, La Jolla, CA akavanaugh@ucsd.edu. Submitted for publication May 3, 2016; accepted in revised form September 27, exclusion criteria included previous therapy with biologic agents other than anti-tnf agents, treatment with.3 anti- TNF therapies, active inflammatory disease other than PsA, and active/history of ongoing infection. Study oversight and design. The study was approved by institutional review boards or ethics committees for each study center and conducted according to the Declaration of Helsinki. All patients provided written informed consent prior to participation. FUTURE-1 was a randomized, double-blind, placebocontrolled multicenter trial. The study began with a 4-week screening period, and patients who had received prior TNF inhibitors completed a washout period of 4 to 10 weeks. Eligiblepatientswerethenrandomizedto1of3armsina1:1:1 ratio, to receive either secukinumab 10 mg/kg intravenous (IV) loading dose at baseline, at weeks 2 and 4, and followed by 150 mg subcutaneous (SC), secukinumab 10 mg/kg IV loading dose at baseline, at weeks 2 and 4, and followed by 75 mg SC every 4 weeks from week 8, or matching placebo on the same IV-to-SC dosing schedule. Randomization stratified patients as anti-tnf-ir or anti- TNF-naive, with approximately 70% required to be anti- TNF-naive. At week 16, patients were classified as responders ($20% improvement from baseline in both tender and swollen joint counts) or nonresponders. All patients in the placebo group were re-randomized to receive secukinumab 150 mg SC or 75 mg SC from week 16 for nonresponders or from week 24 for responders. Treatment continued to week 104. Rescue medication, either as a new intervention or a change to ongoing therapy, was not allowed until after week 24. Outcome measures. The primary efficacy end point was the proportion of patients achieving $20% improvement in the American College of Rheumatology criteria for 20% improvement (ACR20) at week 24. Secondary objectives included efficacy versus placebo at week 24 in ACR50 response; $75% and90% improvementonthepsoriasis Area and Severity Index criteria for improvement (PASI 75/ 90) in patients with psoriasis affecting $3% body surface area; change from baseline in the Disease Activity Score in 28 joints (DAS28) including levels of C-reactive protein (CRP); and incidence of dactylitis and enthesitis. Quality of life was measured as the change from baseline in the physical component summary score (PCS) of the Medical Outcomes Study 36-Item Short Form health survey (SF-36). Physical function was assessed as the change from baseline in the Health Assessment Questionnaire (HAQ) disability index (DI) score. The modified total Sharp/van der Heijde score (SHS) was used to assess radiographic progression. Exploratory objectives included ACR70 response at week 24 and evidence of no radiographic disease progression (defined as #0.5 increase in SHS) (13). For the 2-year analysis, exploratory analysis of all primary and secondary end points continued to week 104. Safety was assessed by frequency of adverse events (AEs), laboratory abnormalities, electrocardiogram findings, and vital signs. Biochemical investigations were classified according to the Common Terminology Criteria for Adverse Events (version 4) (15). Blood samples were collected at baseline, immediately before dosing at weeks 24 and 52, and at weeks 104 and

3 PsA and Long-Term Treatment With Secukinumab for assessment of secukinumab immunogenicity using a Meso Scale Discovery bridging immunoassay (16). Statistical analysis. Statistical analyses at week 24 have been previously described and used the imputation of missing values as a nonresponse for binary variables and a mixed-effects repeated-measures (MMRM) model for continuous variables (13). Week 104 exploratory analyses were carried out on data from patients originally randomized to secukinumab. Evaluations of efficacy were performed on the full analysis set, which comprised all randomized patients to whom treatment had been assigned. Safety analyses were carried out on all randomized patients receiving at least 1 dose of study medication. Subgroup analyses were carried out on the basis of previous anti-tnf therapy and concomitant methotrexate treatment for key efficacy end points. At week 104, data were also analyzed with imputation and as observed. If all postbaseline values were missing, then the missing values were not imputed and the patient was removed from the analysis. RESULTS Patients. Of the 606 adults enrolled in FUTURE-1, 476 (78.5%) completed 104 weeks of the study (Figure 1). In total, 130 patients discontinued before week 104. The most common reason for discontinuation before 104 weeks was lack of efficacy (5.0% in the secukinumab 150 mg group, 6.9% in the secukinumab 75 mg group, and 7.4% in the placebo group). Demographic and disease characteristics at baseline were similar across groups (13). In both secukinumab groups, 108 patients (53.5%) had psoriasis affecting $3% of body surface area at baseline, and 104 patients (51.5%) had dactylitis. In addition, 126 patients (62.4%) in the secukinumab 150 mg group and 129 (63.9%) in the 75 mg group had enthesitis at baseline (13). Efficacy. Consistent with clinical benefits reported previously at weeks 24 and 52 (13), secukinumab showed efficacy across the multiple clinically relevant domains of PsA through week 104 (see Table 1 for summary of results, including both imputed and observed data). ACR20, ACR50, and ACR70 response rates were sustained from week 24 to week 104. ACR20 response rates were 66.8% for secukinumab 150 mg and 58.6% for secukinumab 75 mg at week 104. ACR50 and ACR70 response rates at this time point were 39.0% and 22.4%, respectively, for secukinumab 150 mg, and 29.7% and 17.6% for the 75 mg group (multiple imputation data) (Figure 2). Generally, a higher proportion of patients who were anti- TNF-naive achieved an ACR20 response versus patients who were anti-tnf-ir. ACR20 response rates at week 104 Figure 1. Patient flow through the study from randomization to week 104. * 5 1 patient was dosed up to week 12, attended the week 16 visit, and was re-randomized as a placebo responder. However, this patient was discontinued the same day and did not receive active treatment (i.e., reached but did not complete week 16); IV 5 intravenous.

4 350 Kavanaugh et al Table 1. Summary of efficacy results (data with missing values imputed using multiple imputation and observed data) at week 104* Imputation Observed Efficacy end point 150 mg 75 mg 150 mg 75 mg Patients randomized, no ACR response Patients, no ACR20 response, % ACR50 response, % ACR70 response, % PASI response Patients, no PASI75 response, % PASI90 response, % DAS28-CRP Patients, no Mean 6 SE/SD change from baseline Dactylitis resolution rate among patients with dactylitis at baseline Patients, no Resolution rate, % Enthesitis resolution rate among patients with enthesitis at baseline Patients, no Resolution rate, % SF-36 PCS Patients, no Mean 6 SE/SD change from baseline HAQ DI Patients, no Mean 6 SE/SD change from baseline * ACR 5 American College of Rheumatology; ACR20/50/70 5 ACR criteria for 20%/50%/70% improvement; PASI 5 Psoriasis Area and Severity Index; PASI 75/90 5 PASI criteria for 75%/90% improvement; DAS28 5 Disease Activity Score in 28 joints; CRP 5 C-reactive protein; SF-36 5 Medical Outcomes Study Short Form 36 health survey; PCS 5 physical component summary score; HAQ 5 Health Assessment Questionnaire; DI 5 disability index. Patients with evaluable data. SE values are presented for imputed data and SD values for observed data. were 75.2% for anti-tnf-naive patients and 48.0% for anti- TNF-IR patients for the secukinumab 150 mg group, and 63.7% for anti-tnf-naive patients and 46.9% for anti-tnf- IR patients for the secukinumab 75 mg group (multiple imputation data; see Supplementary Tables 1 and 2, available on the Arthritis Care & Research web site at onlinelibrary.wiley.com/doi/ /acr.23111/abstract). In patients taking concomitant methotrexate, the ACR20 response rate at week 104 was 69.6% for secukinumab 150 mg versus 54.2% for secukinumab 75 mg. In those not taking methotrexate, rates were 62.7% and 65.2% for secukinumab 150 mg and 75 mg, respectively (multiple imputation data) (Supplementary Table 1, available at onlinelibrary.wiley.com/doi/ /acr.23111/abstract). High PASI75 and PASI90 response rates were seen in patients with concurrent psoriasis. At week 104, PASI75 response rates were 74.6% for secukinumab 150 mg and 63.0% for secukinumab 75 mg; PASI90 rates were 61.0% and 44.6%, respectively (multiple imputation data) (Table 1). Disease activity, as assessed by DAS28-CRP, remained low from week 24 to week 104 in patients given secukinumab. Both treatment groups showed a similar mean change from baseline in this parameter (21.66 for secukinumab 150 mg and for the 75 mg dose) at week 104 (MMRM data). A high proportion of patients in both secukinumab groups showed complete resolution of dactylitis and enthesitis at week 104. Resolution of dactylitis among the subset of patients with this symptom at baseline occurred in 82.6% of patients treated with secukinumab 150 mg and 84.6% of those treated with secukinumab 75 mg at week 104 (multiple imputation data). Similarly, resolution of enthesitis at week 104 among the cohort with this symptom at baseline occurred in 73.7% and 76.8% of patients treated with secukinumab 150 mg and 75 mg, respectively (multiple imputation data). The improvement in quality of life achieved with secukinumab during the first 24 weeks was maintained through week 104, with a mean improvement in SF-36 PCS score of just below 5 points seen with both doses of secukinumab by the 104-week analysis point (4.89 and 4.67 for 150 mg and 75 mg, respectively) (MMRM data). Sustained improvements in physical function were also apparent with the mean change from baseline in HAQ DI score remaining at approximately 20.4 from week 24 through week 104 in both treatment groups (MMRM data).

5 PsA and Long-Term Treatment With Secukinumab shows the cumulative probability plot for SHS at week 104. Outlier patients influenced the trend for greater change in SHS from baseline to week 104 with secukinumab 150 mg compared with secukinumab 75 mg. Figure 2. Response rates for A, American College of Rheumatology criteria for 20% improvement (ACR20), B, 50% improvement (ACR50), and C, 70% improvement (ACR70) improvement to week 104 (multiple imputed data from weeks ; full analysis set). Missing ACR component variables imputed by nonresponder imputation during weeks 0 24 and multiple imputation for weeks Similarly, the low rate of progression of joint structural damage achieved in patients treated with secukinumab during the first 24 weeks was maintained through week 104. Minimal mean changes from baseline to week 104 in SHS were observed for both secukinumab doses, demonstrating limited radiographic progression over the long term (1.00 for the 150 mg group and 0.48 for the 75 mg group) (observed data) (Table 2). At week 104, 84.3% of patients in the secukinumab 150 mg group and 83.8% in the secukinumab 75 mg group had no radiographic disease progression (#0.5 change in SHS from baseline values) (observed data). Figure Safety. The type, incidence, and severity of AEs over the 104-week treatment period (with a mean exposure to secukinumab of days or 1,007.9 patient-years) were consistent with that reported at week 52 (Table 3 and Supplementary Table 3, available on the Arthritis Care & Research web site at /abstract) (13). Exposure-adjusted rates of AEs were per 100 patient-years (95% confidence interval [95% CI] ) in those receiving secukinumab 150 mg and per 100 patient-years (95% CI ) in those on the lower dose. AEs were mostly mild or moderate in severity (Supplementary Table 4, available at wiley.com/doi/ /acr.23111/abstract). The exposureadjusted rate of serious adverse events (SAEs) was 11.0 per 100 patient-years (95% CI ) in the secukinumab 150 mg group and 6.7 per 100 patient-years (95% CI ) in the secukinumab 75 mg group. Discontinuations due to AEs occurred at a rate of 3.4% and 5.8%, respectively. AEs leading to discontinuation were reported by no more than 1 2 patients in either treatment group. There were 2 deaths: 1 in the first 52 weeks (stroke/cerebrovascular death) and 1 between weeks 52 and 104 (myocardial infarction). Both these deaths were in the secukinumab 75 mg group, but neither were considered to be related to study treatment and occurred in patients with underlying disease that put them at increased risk for such events. No suicides or suicide attempts were reported. Infections and infestations were the most commonly reported events with secukinumab, with an exposureadjusted incidence rate of 67.9 per 100 patient-years (95% CI ) across both dose groups. The most common AEs were nasopharyngitis (13.4 per 100 patient-years; 95% CI ) and upper respiratory tract infection (12.6 per 100 patient-years; 95% CI ). Candida infections were seen in 14 patients in any secukinumab group. Oral candidiasis occurred in 5 patients receiving secukinumab 150 mg and in 4 patients in the secukinumab 75 mg group. None of these cases was serious. Esophageal candidiasis and vulvovaginal candidiasis each occurred in 2 patients treated with secukinumab 150 mg. Skin candida infection was experienced by 1 patient in the secukinumab 150 mg group. All cases of candida resolved, typically with concomitant treatment, with the exception of 1 case of untreated oral candidiasis that was first reported on day 737. There were no discontinuations due to candida. No new cases of tuberculosis (TB) were reported, and no reactivation of latent TB occurred. Neutropenia developed in 6 patients treated with secukinumab 150 mg and in 8 patients receiving the 75 mg dose (1.4 per 100 patient-years; 95% CI ). Eleven of the 14 patients were taking concomitant methotrexate. Most cases were grade 1 or 2 in severity, with only 3 patients developing grade 3 neutropenia. Crohn s disease was reported by 1 patient in the secukinumab 75 mg group and 1 patient in the placebo group. In the secukinumab-treated patient, severe Crohn s disease was reported on day 202. Although this was not considered treatment related, study treatment was

6 352 Kavanaugh et al Table 2. Modified total Sharp/van der Heijde score change from baseline through week 104 (evaluable cases, observed data)* Secukinumab 150 mg (n 5 202) Secukinumab 75 mg (n 5 202) Baseline, mean 6 SD Change, mean 6 SD Baseline, mean 6 SD Change, mean 6 SD Baseline Week Week Change from week to week 52 Week Change from week to week 104 Change from week 52 to week permanently discontinued and concomitant treatment for Crohn s disease was given. The initial flare was reported as resolved after 8 days of treatment for Crohn s disease. In the patient receiving placebo, the incidence of Crohn s disease was a moderate exacerbation of a preexisting condition that was first reported at day 31, lasted for 10 weeks, and resolved upon concomitant medication. Three myocardial infarctions were reported in 2 patients in the secukinumab 150 mg group and in 1 patient in the 75 mg group by week 104 (rate 0.3 per 100 patient-years; 95% CI ). Four strokes occurred in patients by week 104; all were in the secukinumab 75 mg group (0.4 per 100 patient-years [95% CI ] and 0.0 per 100 patient-years [95% CI ] for the secukinumab 150 mg group). Malignant or unspecified tumors were reported in 2 patients treated with secukinumab 150 mg and in 4 patients treated with secukinumab 75 mg, which equated to 0.6 per 100 patient-years (95% CI ) across secukinumab groups. Basal cell carcinoma was the most frequently reported malignancy (3 patients). Prostate cancer Figure 3. Cumulative probability plot of change from baseline of modified total Sharp/van der Heijde score at week 104 (observed data; full analysis set). occurred in 2 patients, and metastases to bone, skin cancer, and pleomorphic adenoma of the salivary gland were reported in 1 patient each. No cases of hepatitis were reported. Three patients developed antidrug antibodies on treatment: 1 patient treated with secukinumab 150 mg and 2 treated with secukinumab 75 mg. Two of these patients were taking concomitant methotrexate during the study. Only 2 patients (1 in each treatment group) remained antidrug antibody positive at week 104. Neutralizing antibodies were found in only 1 patient with treatment-emergent antidrug antibodies at week 24, and these had no effect on efficacy. Pharmacokinetics and efficacy were not adversely altered in patients with antidrug antibodies postbaseline. There was no relationship between antidrug antibody formation and hypersensitivity-related SAEs. DISCUSSION Understanding of the potential role of IL-17A inhibitors in the treatment of PsA is growing, and their use has now been included in the European League Against Rheumatism and Group for Research and Assessment of Psoriasis and Psoriatic Arthritis management guidelines (3,17). FUTURE-1 has shown, in a population with significant disease burden despite prior treatment, that secukinumab is associated with a wide range of clinical benefits. Prior analyses of the FUTURE-1 study found this IL-17A inhibitor to be significantly better than placebo at improving signs and symptoms of PsA in patients at week 24, with responses maintained over 52 weeks of treatment (13). In the first year of this study, secukinumab treatment improved joint and extraarticular signs and symptoms, physical function, and quality of life, and slowed the rate of progression of joint structural damage (13). Here we present followup data that show that the beneficial effects of secukinumab are retained long term, with no new safety signals reported. All measures of efficacy were sustained or continued to improve over 2 years of treatment (13). These are the first 2-year data for secukinumab in PsA and provide further evidence supporting use of IL-17A inhibitors in PsA.

7 PsA and Long-Term Treatment With Secukinumab 353 Table 3. Adverse events (AEs) through week 104* 150 mg (n 5 295) 75 mg (n 5 292) Any secukinumab, (n 5 587) Duration of exposure, mean 6 SD days Exposure, no. patient-years Patients reporting any AE 258 (199.4) 238 (155.9) 496 (175.8) Serious AEs 51 (11.0) 32 (6.7) 83 (8.8) Death 0 (0.0) 2 (0.4) 2 (0.2) Discontinuation due to AEs 10 (3.4) 17 (5.8) 27 (4.6) Common AEs Nasopharyngitis 54 (12.3) 61 (14.5) 115 (13.4) Upper RTI 60 (13.6) 52 (11.7) 112 (12.6) Headache 25 (5.2) 27 (5.8) 52 (5.5) Back pain 23 (4.7) 29 (6.2) 52 (5.5) Diarrhea 21 (4.3) 21 (4.4) 42 (4.4) Hypertension 18 (3.7) 22 (4.6) 40 (4.1) Nausea 11 (2.2) 16 (3.3) 27 (2.8) Hypercholesterolemia 15 (3.0) 11 (2.3) 26 (2.7) * Values are the number of patients (number of events per 100 patient-years) unless indicated otherwise. RTI 5 respiratory tract infection. Includes patients randomized to placebo and then switched to secukinumab. Exposure-adjusted incidence rates were not calculated for study drug discontinuations owing to AEs. Percentages are shown. AEs reported by at least 2% of patients in the combined secukinumab group during the initial treatment period or events with incidence of at least 5 cases per 100 patient-years in the combined secukinumab group at week 104. Almost 80% of patients remained in the FUTURE-1 study through 2 years. While ACR20 response at week 104 was not seen in all patients, those remaining in the study may have had improvement in skin symptoms, enthesitis, dactylitis, and fatigue at time points prior to week 104, showing some clinical improvement (18). This is an area in which further investigation would be interesting. As in the analyses at weeks 24 and 52, sustained efficacy was shown in patients naive to prior anti-tnf therapy as well as in those with prior incomplete response, although it was more marked in the former population (13). Efficacy in patients with prior inadequate response to anti-tnf treatments is important given the number of patients who discontinue biologic therapy due to lack of efficacy or tolerability issues (2,19 21). Better clinical responses in patients naive to other biologic therapies is also of interest, since it may indicate a potential utility in using secukinumab prior to other anti-tnf agents in PsA. Data at week 24 suggest that response to secukinumab was not affected by concurrent methotrexate treatment (13). This was also true at weeks 52 and 104, consistent with findings of studies of anti-tnf treatments in PsA. However, the design of this study precludes the ability to define the additive effect of methotrexate since patients were required to have active disease despite methotrexate upon study entry. Background methotrexate is sometimes used alongside anti-tnf agents in PsA to reduce immunogenicity and resultant loss of response over time, and studies with anti-tnf agents have suggested that drug persistence may be longer with concurrent methotrexate use (22 27). In this 2-year study, immunogenicity to secukinumab was low (with,1% of patients developing antidrug antibodies on treatment), which is consistent with what has been seen with this treatment in psoriasis and ankylosing spondylitis (5,10,28). Furthermore, treatmentemergent antidrug antibody formation did not affect efficacy, pharmacokinetics, or the incidence of AEs. Both doses of secukinumab were associated with a low rate of radiographic progression over the long term, with outlier patients influencing the difference between dosage groups in the cumulative probability of progression. Analysis of SHS data at week 52 has suggested that patients who showed the most radiographic progression had low plasma concentrations of secukinumab (C min,10 mg/ml), were anti-tnf-ir, and had high CRP levels (.10 mg/liter) at baseline (29). ACR and PASI response rates were numerically higher for the 150 mg dose versus the 75 mg dose. Other reported variables showed no marked difference between the doses. However, the study was not powered to detect statistically significant differences between the doses. The ongoing FUTURE-2 study, which is investigating a 300 mg SC dose alongside 150 mg and 75 mg doses in PsA, will further explore any dose-related effects of long-term treatment with secukinumab (12). Indeed, short-term (24-week) data from this study have demonstrated greater clinical improvements with secukinumab 300 mg versus 150 mg in psoriasis symptoms and ACR scores in anti-tnf-ir patients (12). In addition to broad and sustained efficacy, the high retention rate in FUTURE-1 also reflects the acceptable tolerability and safety profile of secukinumab, which was consistent with that previously reported (6,10,11,13). Incidence rates of AEs and SAEs were similar at 104 weeks to those at 52 weeks, and the overall incidence of AEs with secukinumab showed no dose dependence. The most

8 354 Kavanaugh et al common AEs and SAEs observed (e.g., infections, cardiac disorders, musculoskeletal and connective disorders, and gastrointestinal disorders) are similar to the data in patients receiving secukinumab and placebo presented previously (13). Limitations of the study included a lack of a long-term comparator, although continuation of a placebo arm long term would be unethical. The majority of patients randomized to placebo switched to secukinumab at week 16, with the remaining switching by week 24. Since all patients originally randomized to placebo had switched to secukinumab by week 24, the statistical analysis of data at week 24 differed from that at week 104 (13). Although the dose of secukinumab remained blinded, treatment following the switch was open-label. As such, meaningful comparisons between patients randomized to placebo and those receiving secukinumab from week 0 cannot be made. Furthermore, end points in the week 104 analysis were exploratory, and so were not powered to detect statistically significant differences in efficacy between the doses. However, as a followup study, FUTURE-1 provides key data regarding the long-term efficacy and safety of secukinumab of relevance to treating a chronic disease. In summary, secukinumab provided sustained improvements at 2 years across multiple clinical domains in the treatment of patients with active PsA, including very little radiographic progression in patients maintained on treatment for 2 years. The safety profile of both doses of secukinumab showed no new or unexpected safety signals during this time. ACKNOWLEDGMENTS We thank the patients who participated in the study and the study investigators. AUTHOR CONTRIBUTIONS All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication. Dr. Kavanaugh had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study conception and design. Kavanaugh, Mease, Wang, Pricop, Mpofu. Acquisition of data. Mease, Reimold, Tahir, Rech, Geusens, Pricop, Mpofu. Analysis and interpretation of data. Kavanaugh, Mease, Reimold, Tahir, Rech, Hall, Geusens, Wang, Pricop, Mpofu. ROLE OF THE STUDY SPONSOR Novartis was the sponsor and designed the study. All authors were investigators in the study, collected the data, and contributed to the interpretation of the data and preparation and approval of the manuscript. Medical writing was supported by Lyndsey Wood, Product Lifecycle Services, Novartis, and medical consulting was provided by John Gallagher, Novartis. Publication of this article was not contingent upon approval by Novartis. REFERENCES 1. Gottlieb A, Korman NJ, Gordon KB, Feldman SR, Lebwohl M, Koo JY, et al. 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