Secukinumab in enthesitis-related arthritis and juvenile psoriatic arthritis: a randomised, double-blind, placebo-controlled, treatment withdrawal, phase 3 trial.

BACKGROUND: Treatment options in patients with enthesitis-related arthritis (ERA) and juvenile psoriatic arthritis (JPsA) are currently limited. This trial aimed to demonstrate the efficacy and safety of secukinumab in patients with active ERA and JPsA with inadequate response to conventional therapy. METHODS: In this randomised, double-blind, placebo-controlled, treatment-withdrawal, phase 3 trial, biologic-naïve patients (aged 2 to <18 years) with active disease were treated with open-label subcutaneous secukinumab (75/150 mg in patients <50/≥50 kg) in treatment period (TP) 1 up to week 12, and juvenile idiopathic arthritis (JIA) American College of Rheumatology 30 responders at week 12 were randomised 1:1 to secukinumab or placebo up to 100 weeks. Patients who flared in TP2 immediately entered open-label secukinumab TP3 that lasted up to week 104. Primary endpoint was time to disease flare in TP2. RESULTS: A total of 86 patients (median age, 14 years) entered open-label secukinumab in TP1. In TP2, responders (ERA, 44/52; JPsA, 31/34) received secukinumab or placebo. The study met its primary end point and demonstrated a statistically significant longer time to disease flare in TP2 for ERA and JPsA with secukinumab versus placebo (27% vs 55%, HR, 0.28; 95% CI 0.13 to 0.63; p<0.001). Exposure-adjusted incidence rates (per 100 patient-years (PY), 95% CI) for total patients were 290.7/100 PY (230.2 to 362.3) for adverse events and 8.2/100 PY (4.1 to 14.6) for serious adverse events in the overall JIA population. CONCLUSIONS: Secukinumab demonstrated significantly longer time to disease flare than placebo in children with ERA and JPsA with a consistent safety profile with the adult indications of psoriatic arthritis and axial spondyloarthritis. TRIAL REGISTRATION NUMBER: NCT03031782.

Secukinumab provides sustained improvement in nail psoriasis, signs and symptoms of psoriatic arthritis and low rate of radiographic progression in patients with concomitant nail involvement: 2-year results from the Phase III FUTURE 5 study.

OBJECTIVES: To evaluate the impact of secukinumab on nail psoriasis and other psoriatic disease manifestations in patients with psoriatic arthritis (PsA) with concomitant nail psoriasis from the FUTURE 5 study. METHODS: Eligible patients were randomly allocated to receive subcutaneous secukinumab (300 mg load [300 mg], 150 mg load [150 mg], and 150 mg [no load]) or placebo weekly and then every 4 weeks starting Week 4. Key assessments through Week 104 in this post hoc analysis included modified Nail Psoriasis Severity (mNAPSI), Psoriasis Area and Severity Index (PASI 90), resolution of dactylitis and enthesitis, Dermatology Life Quality Index (DLQI) and radiographic progression (assessed by vdH-mTSS). RESULTS: At baseline, 66.6% patients (663/996) had concomitant nail psoriasis. Baseline characteristics were balanced in the nail subset and comparable with the overall population. Secukinumab reduced mNAPSI score at Week 16 versus placebo: -8.71 (300 mg), -8.95 (150 mg), -7.55 (150 mg no load) versus -2.34 (placebo); all p<0.0001. Mean change from baseline in DLQI at Week 16 was -8.5 (300 mg), -7.4 (150 mg), -7.3 (150 mg no load) versus -2.4 (placebo); all p<0.0001. Overall, the improvements reported at Week 16 sustained through Week 104. The proportion of patients with no radiographic progression (change from baseline in vdH-mTSS≤0.5) at Week 104 was 91.9% (300 mg) 78.9% (150 mg), and 82.4% (150 mg no load). CONCLUSIONS: Secukinumab provided sustained improvements in nail disease, signs and symptoms of PsA, and a low rate of radiographic progression through 2 years in patients with concomitant nail psoriasis.

Long-term Safety of Secukinumab Over Five Years in Patients with Moderate-to-severe Plaque Psoriasis, Psoriatic Arthritis and Ankylosing Spondylitis: Update on Integrated Pooled Clinical Trial and Post-marketing Surveillance Data.

Secukinumab, a selective interleukin (IL)-17A inhibitor, is approved for use in adult and paediatric psoriasis, psoriatic arthritis, ankylosing spondylitis and non-radiographic axial spondyloarthritis. The aim of this study was to report the long-term safety of secukinumab in pooled data from 28 clinical trials and a post-marketing safety surveillance in psoriasis, psoriatic arthritis and ankylosing spondylitis patients. Analyses included 12,637 secukinumab-treated patients, corresponding to 15,063, 5,985 and 3,527 patient-years of exposure in psoriasis, psoriatic arthritis and ankylosing spondylitis patients, respectively. Incidences of serious adverse events were low, with no identifiable patterns across indications. Active tuberculosis or latent tuberculosis infections were rare. The incidence of opportunistic infections was < 0.2/100 patient-years, the incidence of malignancy was ≤ 1/100 patient-years, and the incidence of major adverse cardiovascular events was < 0.7/100 patient-years, with no apparent increases over time. Secukinumab demonstrated a favourable safety profile for up to 5 years of treatment across the 3 indications, and no new safety signals were identified.

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

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.

Sequential knockoffs for continuous and categorical predictors: With application to a large psoriatic arthritis clinical trial pool.

Knockoffs provide a general framework for controlling the false discovery rate when performing variable selection. Much of the Knockoffs literature focuses on theoretical challenges and we recognize a need for bringing some of the current ideas into practice. In this paper we propose a sequential algorithm for generating knockoffs when underlying data consists of both continuous and categorical (factor) variables. Further, we present a heuristic multiple knockoffs approach that offers a practical assessment of how robust the knockoff selection process is for a given dataset. We conduct extensive simulations to validate performance of the proposed methodology. Finally, we demonstrate the utility of the methods on a large clinical data pool of more than 2000 patients with psoriatic arthritis evaluated in four clinical trials with an IL-17A inhibitor, secukinumab (Cosentyx), where we determine prognostic factors of a well established clinical outcome. The analyses presented in this paper could provide a wide range of applications to commonly encountered datasets in medical practice and other fields where variable selection is of particular interest.

Secukinumab's effect on structural damage progression in psoriatic arthritis: longitudinal mixture modelling of FUTURE-1 and FUTURE-5.

OBJECTIVES: Peripheral and axial manifestations of psoriatic arthritis (PsA) can lead to irreversible structural damage and chronic disability. Our objective was to explore predictors of radiographic progression and to increase our understanding of treatment effects in subgroups of patients with different rates of structural damage progression. METHODS: We analysed data from two large Phase-3 trials of secukinumab in PsA patients, FUTURE-1 (NCT01392326, n=606) and FUTURE-5 (NCT02404350, n=996), where different posologies ranging from 75 mg to 300 mg were used. We applied a longitudinal Bayesian mixture model with random effects to account for the variability in the repeated radiographic assessments. "Fast progressors" were defined post hoc as patients with a 50% model-estimated probability to progress at least 0.5 mTSS/year faster than an average patient. RESULTS: Higher baseline inflammation and higher body weight were identified as significant predictors of radiographic progression (multivariate model). Model-estimated structural damage progression in an average patient treated with secukinumab 150 mg subcutaneous (s.c.) was slower (0.04 mTSS/year; 95% CI -0.28, 0.34) compared to a patient treated with placebo (0.94 mTSS/year; 95% CI 0.45, 1.45). According to the model, the subgroup of "fast progressors" (hsCRP ≥26 mg/L, body weigth ≥94 kg, inadequate response to prior anti-TNF-alpha, structural damage ≥42 mTSS) treated with secukinumab 150 mg s.c. progressed at 0.56 mTSS/year (95% CI 0.02, 1.09) and 1.46 mTSS/year (95% CI 0.81, 2.11) when treated with placebo. CONCLUSIONS: Greater systemic inflammation and higher body weight at baseline were identified as significant predictors of progression. Even patients with fast radiographic progression could experience a beneficial effect with secukinumab that holds promise to prevent further mobility loss.

Secukinumab Efficacy in Psoriatic Arthritis: Machine Learning and Meta-analysis of Four Phase 3 Trials.

BACKGROUND: Using a machine learning approach, the study investigated if specific baseline characteristics could predict which psoriatic arthritis (PsA) patients may gain additional benefit from a starting dose of secukinumab 300 mg over 150 mg. We also report results from individual patient efficacy meta-analysis (IPEM) in 2049 PsA patients from the FUTURE 2 to 5 studies to evaluate the efficacy of secukinumab 300 mg, 150 mg with and without loading regimen versus placebo at week 16 on achievement of several clinically relevant difficult-to-achieve (higher hurdle) endpoints. METHODS: Machine learning employed Bayesian elastic net to analyze baseline data of 2148 PsA patients investigating 275 predictors. For IPEM, results were presented as difference in response rates versus placebo at week 16. RESULTS: Machine learning showed secukinumab 300 mg has additional benefits in patients who are anti-tumor necrosis factor-naive, treated with 1 prior anti-tumor necrosis factor agent, not receiving methotrexate, with enthesitis at baseline, and with shorter PsA disease duration. For IPEM, at week 16, all secukinumab doses had greater treatment effect (%) versus placebo for higher hurdle endpoints in the overall population and in all subgroups; 300-mg dose had greater treatment effect than 150 mg for all endpoints in overall population and most subgroups. CONCLUSIONS: Machine learning identified predictors for additional benefit of secukinumab 300 mg compared with 150 mg dose. Individual patient efficacy meta-analysis showed that secukinumab 300 mg provided greater improvements compared with 150 mg in higher hurdle efficacy endpoints in patients with active PsA in the overall population and most subgroups with various levels of baseline disease activity and psoriasis.

Secukinumab provides sustained low rates of radiographic progression in psoriatic arthritis: 52-week results from a phase 3 study, FUTURE 5.

OBJECTIVE: To evaluate the effect of secukinumab on radiographic progression through 52 weeks in patients with PsA from the FUTURE 5 study. METHODS: Patients with active PsA, stratified by prior anti-TNF use (naïve or inadequate response), were randomized to s.c. secukinumab 300 mg load (300 mg), 150 mg load (150 mg), 150 mg no load regimens or placebo at baseline, at weeks 1, 2 and 3 and every 4 weeks starting at week 4. Radiographic progression was assessed by change in van der Heijde-modified total Sharp score (vdH-mTSS; mean of two readers). Statistical analysis used a linear mixed-effects model (random slope) at weeks 24 and 52, and observed data at week 52. Assessments at week 52 included additional efficacy endpoints (non-responders imputation and mixed-effects models for repeated measures) and safety. RESULTS: The majority (86.6%) of patients completed 52 weeks of treatment. The proportion of patients with no radiographic progression (change from baseline in vdH-mTSS ⩽0.5) was 91.8, 85.2 and 87.2% in 300, 150 and 150 mg no load groups, respectively, at week 52. The change in vdH-mTSS from baseline to week 52 using random slope [mean change (s.e.)] was -0.18 (0.17), 0.11 (0.18) and -0.20 (0.18) in 300, 150 and 150 mg no load groups, respectively; the corresponding observed data [mean change (s.d.)] was -0.09 (1.02), 0.13 (1.39) and 0.21 (1.15). Clinical efficacy endpoints were sustained, and no new or unexpected safety signals were reported through 52 weeks. CONCLUSION: Secukinumab 300 and 150 mg with or without s.c. loading regimen provided sustained low rates of radiographic progression through 52 weeks of treatment. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT02404350.

Incidence rates of inflammatory bowel disease in patients with psoriasis, psoriatic arthritis and ankylosing spondylitis treated with secukinumab: a retrospective analysis of pooled data from 21 clinical trials.

OBJECTIVES: Here, we present the reported incidence rates of inflammatory bowel disease (IBD) in patients receiving treatment with secukinumab for psoriasis (PsO), psoriatic arthritis (PsA) or ankylosing spondylitis (AS), in a pooled analysis of 21 clinical trials. METHODS: Data from all patients who had received at least one dose of secukinumab were included. Safety analyses were conducted to evaluate cumulative IBD rates as well as per-year rates, by indication. Crohn's disease (CD), ulcerative colitis (UC) and IBD unclassified (IBDU) events were analysed using exposure-adjusted incidence rates (patient incidence rates per 100 patient-years (PY)). RESULTS: A total of 7355 patients with a cumulative exposure of 16 226.9 PY were included in the pooled analysis. Among 5181 patients with PsO, there were 14 cases of UC, 5 cases of CD and 1 case of IBDU, with exposure adjusted incidence rates (EAIRs) of 0.13, 0.05 and 0.01, respectively. Of these 20 cases, 14 were new-onset. In 1380 patients with PsA, there were 3 cases of UC, 3 cases of CD and 2 cases of IBDU (EAIRs 0.08, 0.08 and 0.05); 7 of these represented new-onset cases. Among 794 patients with AS, there were 4 cases of UC, 8 cases of CD and 1 case of IBDU (EAIRs 0.2, 0.4 and 0.1); 9 were new-onset cases. In the per year analysis, the EAIRs for each indication did not increase over time with secukinumab treatment. CONCLUSIONS: In this pooled secukinumab safety analysis of 7355 patients across 21 clinical trials, cases of IBD events (including CD, UC and IBDU) were uncommon.

Secukinumab Inhibition of Interleukin-17A in Patients with Psoriatic Arthritis.

BACKGROUND: In a phase 2 study, the inhibition of the interleukin-17A receptor improved signs and symptoms of psoriatic arthritis. We sought to evaluate the efficacy and safety of secukinumab, an anti-interleukin-17A monoclonal antibody, in such patients. METHODS: In this double-blind, phase 3 study, 606 patients with psoriatic arthritis were randomly assigned in a 1:1:1 ratio to receive intravenous secukinumab (at a dose of 10 mg per kilogram) at weeks 0, 2, and 4, followed by subcutaneous secukinumab at a dose of either 150 mg or 75 mg every 4 weeks, or placebo. Patients in the placebo group were switched to subcutaneous secukinumab at a dose of 150 mg or 75 mg at week 16 or 24, depending on clinical response. The primary end point was the proportion of patients with an American College of Rheumatology 20 (ACR20) response at week 24, defined as a 20% improvement from baseline in the number of tender and swollen joints and at least three other important domains. RESULTS: ACR20 response rates at week 24 were significantly higher in the group receiving secukinumab at doses of 150 mg (50.0%) and 75 mg (50.5%) than in those receiving placebo (17.3%) (P<0.001 for both comparisons with placebo). Secondary end points, including the ACR50 response and joint structural damage, were significantly better in the secukinumab groups than in the placebo group. Improvements were sustained through 52 weeks. Infections, including candida, were more common in the secukinumab groups. Throughout the study (mean secukinumab exposure, 438.5 days; mean placebo exposure, 128.5 days), four patients in the secukinumab groups had a stroke (0.6 per 100 patient-years; 95% confidence interval [CI], 0.2 to 1.5), and two had a myocardial infarction (0.3 per 100 patient-years; 95% CI, 0.0 to 1.0), as compared with no patients in the placebo group. CONCLUSIONS: Secukinumab was more effective than placebo in patients with psoriatic arthritis, which validates interleukin-17A as a therapeutic target. Infections were more common in the secukinumab groups than in the placebo group. The study was neither large enough nor long enough to evaluate uncommon serious adverse events or the risks associated with long-term use. (Funded by Novartis Pharma; ClinicalTrials.gov number, NCT01392326.).

Secukinumab improves active psoriatic arthritis symptoms and inhibits radiographic progression: primary results from the randomised, double-blind, phase III FUTURE 5 study.

OBJECTIVES: To evaluate the effect of subcutaneous (s.c.) secukinumab, an interleukin-17A inhibitor, on clinical signs and symptoms and radiographic progression in patients with psoriatic arthritis (PsA). METHODS: Adults (n=996) with active PsA were randomised 2:2:2:3 to s.c. secukinumab 300 mg or 150 mg with loading dose (LD), 150 mg without LD or placebo. All groups received secukinumab or placebo at baseline, weeks 1, 2 and 3 and then every 4 weeks from week 4. The primary endpoint was the proportion of patients achieving an American College of Rheumatology 20 (ACR20) response at week 16. RESULTS: Significantly more patients achieved an ACR20 response at week 16 with secukinumab 300 mg with LD (62.6%), 150 mg with LD (55.5%) or 150 mg without LD (59.5%) than placebo (27.4%) (p<0.0001 for all; non-responder imputation). Radiographic progression, as measured by van der Heijde-modified total Sharp score, was significantly inhibited at week 24 in all secukinumab arms versus placebo (p<0.01 for 300 mg with LD and 150 mg without LD and p<0.05 for 150 mg with LD; linear extrapolation). Adverse event rates at week 24 were similar across treatment arms: 63.1% (300 mg with LD), 62.7% (150 mg with LD), 61.1% (150 mg without LD) and 62.0% (placebo). No deaths or new safety signals were reported. CONCLUSION: S.c. secukinumab 300 mg and 150 mg with and without LD significantly improved clinical signs and symptoms and inhibited radiographic structural progression versus placebo at week 24 in patients with PsA. TRIAL REGISTRATION NUMBER: NCT02404350; Results.

Secukinumab improves patient-reported outcomes in subjects with active psoriatic arthritis: results from a randomised phase III trial (FUTURE 1).

OBJECTIVE: To evaluate the effect of secukinumab on patient-reported outcomes (PROs) in subjects with active psoriatic arthritis (PsA) in the FUTURE 1 study. METHODS: Subjects were randomised 1:1:1 to receive intravenous (i.v.) secukinumab 10 mg/kg at weeks 0, 2 and 4 followed by subcutaneous secukinumab 150 or 75 mg every 4 weeks or matching placebo until week 24. RESULTS: At week 24, subjects receiving secukinumab i.v.→150 mg or i.v.→75 mg reported greater least squares mean changes from baseline than those receiving placebo in patient global assessment of disease activity (-20.6 and -20.0 vs -7.4, respectively), patient assessment of pain (-20.8 and -20.4 vs -6.7), psoriatic arthritis quality of life (-3.5 and -3.2 vs -0.4), Dermatology Life Quality Index (-8.8 and -7.9 vs 0.7); p<0.0001 vs placebo for both secukinumab groups for above PROs and Functional Assessment of Chronic Illness Therapy-Fatigue (6.74 (p<0.05 vs placebo) and 6.03 vs 4.00); all of which well exceeded minimum clinically important differences. CONCLUSIONS: In subjects with PsA, secukinumab treatment resulted in clinically meaningful improvements in global disease activity, pain, generic and disease-specific measures of health-related quality of life and fatigue. TRIAL REGISTRATION NUMBER: NCT01392326; Results.

Secukinumab sustains improvement in signs and symptoms of psoriatic arthritis: 2 year results from the phase 3 FUTURE 2 study.

Objectives: To assess long-term efficacy, safety and tolerability of secukinumab up to 104 weeks in patients with active PsA. Methods: Patients with PsA (n = 397) were randomized to s.c. secukinumab 300, 150 or 75 mg or placebo at baseline, weeks 1, 2, 3 and 4 and every 4 weeks thereafter. Placebo-treated patients were re-randomized to receive secukinumab 300 or 150 mg s.c. from week 16 (placebo non-responders) or week 24 (placebo responders). Exploratory endpoints at week 104 included 20, 50 and 70% improvement in ACR criteria (ACR20, 50, 70); 75 and 90% improvement in the Psoriasis Area Severity Index, 28-joint DAS with CRP, presence of dactylitis and enthesitis and other patient-reported outcomes. For binary variables, missing values were imputed; continuous variables were analysed by a mixed-effects model for repeated measures. Results: A total of 86/100 (86%), 76/100 (76%) and 65/99 (66%) patients in the secukinumab 300, 150 and 75 mg groups, respectively, completed 104 weeks. At week 104, ACR20 response rates after multiple imputation in the 300, 150 and 75 mg groups were 69.4, 64.4 and 50.3%, respectively. Sustained clinical improvements were observed through week 104 with secukinumab across other clinically important domains of PsA. Responses were sustained through week 104 regardless of prior anti-TNF-α use. Over the entire treatment period the incidence, type and severity of adverse events were consistent with those reported previously. Conclusion: Secukinumab provided sustained improvements in signs and symptoms and multiple clinical domains in patients of active PsA through 2 years of therapy. Secukinumab was well tolerated, with a safety profile consistent with that reported previously. Trial registration: ClinicalTrials.gov (https://clinicaltrials.gov), NCT01752634.

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

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.

Efficacy and Safety of Secukinumab in US Patients with Psoriatic Arthritis: A Subgroup Analysis of the Phase 3 FUTURE Studies.

INTRODUCTION: The aim of this work is to evaluate secukinumab vs. placebo in a challenging-to-treat and smaller US patient subpopulation of the international FUTURE 2-5 studies in patients with psoriatic arthritis (PsA). METHODS: Data were pooled from US patients enrolled in the phase 3 FUTURE 2-5 studies (NCT01752634, NCT01989468, NCT02294227, and NCT02404350). Patients received secukinumab 300 or 150 mg with subcutaneous loading dose, secukinumab 150 mg without subcutaneous loading dose, or placebo. Categorical efficacy and health-related quality-of-life (QoL) outcomes and safety were evaluated at week 16. Subgroup analyses were performed based on tumor necrosis factor inhibitor (TNFi) status and body mass index (BMI). For hypothesis generation, odds ratios (ORs) for American College of Rheumatology (ACR) 20/50/70 and Psoriasis Area and Severity Index (PASI) 75/90/100 responses by treatment were estimated using logistic regression without adjustment for multiple comparisons. RESULTS: Of 2148 international patients originally randomized, 279 US patients were included in this pooled analysis. Mean BMI was > 30 kg/m2 and 55.2% had prior TNFi treatment. ORs for ACR20/50/70 significantly favored patients receiving secukinumab 300 mg and 150 mg with loading dose vs. placebo (P < 0.05), but not those receiving secukinumab 150 mg without loading dose vs. placebo. For PASI75, ORs favored all secukinumab groups over placebo (P < 0.05); for PASI90 and PASI100, only the secukinumab 300-mg group was significantly favored over placebo (P < 0.05). CONCLUSIONS: In this challenging sub-population of US patients with PsA, secukinumab provided rapid improvements in disease activity and QoL. Patients with PsA and active psoriasis might benefit more from secukinumab 300 mg than 150 mg.

Correlation of 18F-FDG PET/CT assessments with disease activity and markers of inflammation in patients with early rheumatoid arthritis following the initiation of combination therapy with triple oral antirheumatic drugs.

PURPOSE: This study evaluated the potential of functional imaging to monitor disease activity and response to treatment with disease-modifying antirheumatic drugs (DMARD) in DMARD-naive patients with early rheumatoid arthritis (RA). METHODS: The study involved 17 patients with active RA in whom combination therapy was initiated with methotrexate, sulfasalazine, hydroxychloroquine, and low-dose oral prednisolone. Clinical disease activity was assessed at screening, at baseline and after 2, 4, 8 and 12 weeks of therapy. (18)F-FDG PET/CT of all joints was performed at baseline and after 2 and 4 weeks of therapy. RESULTS: (18)F-FDG maximum standardized uptake values showed a reduction of 22 ± 13 % in 76 % of patients from baseline to week 2 and a reduction of 29 ± 13 % in 81 % of patients from baseline to week 4. The percentage decrease in (18)F-FDG uptake from baseline to week 2 correlated with clinical outcome, as measured by the disease activity score (DAS-28) at week 12. In addition, changes in C-reactive protein levels and erythrocyte sedimentation rate were positively associated with changes shown by PET. CONCLUSION: (18)F-FDG PET/CT findings after 2 and 4 weeks of triple combination oral DMARD therapy correlated with treatment efficacy and clinical outcome in patients with early RA. (18)F-FDG PET/CT may help predict the therapeutic response to novel drug treatments.

Quantification of pre-existing radiographic damage and its relationship with joint activity and long-term clinical outcomes with secukinumab therapy in patients with psoriatic arthritis.

BACKGROUND: Psoriatic arthritis (PsA) patient data from two phase 3 secukinumab trials (FUTURE 1, 5) were analysed to quantify the prevalence and extent of pre-existing radiographic damage (RD) at baseline; investigate the association of RD with swollen/tender joint counts (SJC/TJC) at baseline; and investigate the extent to which RD at baseline correlated with response to secukinumab. METHODS: Pooled data (N = 1554) provided baseline radiographic bone erosion and joint space narrowing (JSN) scores at pre-specified locations per the van der Heijde-modified total Sharp score (vdH-mTSS) for PsA and swollen and tender joint scores in the same joints at multiple visits. Overall patient RD and individual joints RD bone erosion and JSN scores were assessed. The association between joint activity (tenderness, swelling) and vdH-mTSS was assessed at the overall patient-level and individual joint tender, swollen scores (yes/no) and RD joint JSN and bone erosion scores at the individual joint-level. Treatment response was assessed using SJC/TJC at weeks 16 and 52 and the proportion of patients achieving minimal disease activity (MDA) over all assessments within 1 year from FUTURE 5 alone. RESULTS: A substantial prevalence of pre-existing RD with higher prevalence of erosion than JSN was observed (86% and 60% of patients had positive erosion and JSN scores, respectively); higher RD prevalence was associated with longer time since PsA diagnosis. Joint activity was weakly associated with RD at baseline at the patient-level (Pearson's coefficients: range 0.12-0.18), but strongly associated at the individual joint-level, with a higher probability of tender/swollen joints to associate with higher JSN/erosion scores: all 42 analysed joints showed statistical significance at the 0.05 level (unadjusted) for the relationship between joint tenderness (yes/no) and its JSN score, all but one for tenderness and bone erosion scores, and all but 2 for swollen and JSN scores and for swollen and bone erosion score. Secukinumab (150/300 mg), reduced TJC and SJC across all values of baseline erosion and JSN scores at weeks 16 and 52. Patients with higher levels of RD were less likely to achieve zero tender/zero swollen joint status and had lower chance of achieving MDA. CONCLUSIONS: PsA patients showed substantial prevalence of RD at baseline that correlated with time since diagnosis, but patient's individual joint activity was strongly associated with pre-existing RD at those joints. Patients with the highest RD at baseline had a reduced likelihood of achieving zero joint count status.

Accelerated pathological and clinical nephritis in systemic lupus erythematosus-prone New Zealand Mixed 2328 mice doubly deficient in TNF receptor 1 and TNF receptor 2 via a Th17-associated pathway.

TNF-alpha has both proinflammatory and immunoregulatory functions. Whereas a protective role for TNF administration in systemic lupus erythematosus (SLE)-prone (New Zealand Black x New Zealand White)F(1) mice has been established, it remains uncertain whether this effect segregates at the individual TNFR. We generated SLE-prone New Zealand Mixed 2328 mice genetically deficient in TNFR1, in TNFR2, or in both receptors. Doubly-deficient mice developed accelerated pathological and clinical nephritis with elevated levels of circulating IgG anti-dsDNA autoantibodies and increased numbers of CD4(+) T lymphocytes, especially activated memory (CD44(high)CD62L(low)) CD4(+) T cells. We show that these cells expressed a Th17 gene profile, were positive for IL-17 intracellular staining by FACS, and produced exogenous IL-17 in culture. In contrast, immunological, pathological, and clinical profiles of mice deficient in either TNFR alone did not differ from those in each other or from those in wild-type controls. Thus, total ablation of TNF-alpha-mediated signaling was highly deleterious to the host in the New Zealand Mixed 2328 SLE model. These observations may have profound ramifications for the use of TNF and TNFR antagonists in human SLE and related autoimmune disorders, as well as demonstrate, for the first time, the association of the Th17 pathway with an animal model of SLE.

Clinically relevant patient clusters identified by machine learning from the clinical development programme of secukinumab in psoriatic arthritis.

OBJECTIVES: Identify distinct clusters of psoriatic arthritis (PsA) patients based on their baseline articular, entheseal and cutaneous disease manifestations and explore their clinical and therapeutic value. METHODS: Pooled baseline data in PsA patients (n=1894) treated with secukinumab across four phase 3 studies (FUTURE 2-5) were analysed to determine phenotypes based on clusters of clinical indicators. Finite mixture models methodology was applied to generate clinical clusters and mean longitudinal responses were compared between secukinumab doses (300 vs 150 mg) across identified clusters and clinical indicators through week 52 using machine learning (ML) techniques. RESULTS: Seven distinct patient clusters were identified. Cluster 1 (very-high (VH) - SWO/TEN (swollen/tender); n=187) was characterised by VH polyarticular burden for both tenderness and swelling of joints, while cluster 2 (H (high) - TEN; n=251) was marked by high polyarticular burden in tender joints and cluster 3 (H - Feet - Dactylitis; n=175) by high burden in joints of feet and dactylitis. For cluster 4 (L (Low) - Nails - Skin; n=209), cluster 5 (L - skin; n=283), cluster 6 (L - Nails; n=294) and cluster 7 (L; n=495) articular burden was low but nail and skin involvement was variable, with cluster 7 marked by mild disease activity across all domains. Greater improvements in the longitudinal responses for enthesitis in cluster 2, enthesitis and Psoriasis Area and Severity Index (PASI) in cluster 4 and PASI in cluster 6 were shown for secukinumab 300 mg compared with 150 mg. CONCLUSIONS: PsA clusters identified by ML follow variable response trajectories indicating their potential to predict precise impact on patients' outcomes. TRIAL REGISTRATION NUMBERS: NCT01752634, NCT01989468, NCT02294227, NCT02404350.

Secukinumab provides sustained improvement in signs and symptoms and low radiographic progression in patients with psoriatic arthritis: 2-year (end-of-study) results from the FUTURE 5 study.

OBJECTIVE: Secukinumab provided sustained efficacy, low radiographic progression and consistent safety over 52 weeks in patients with psoriatic arthritis (PsA) in the FUTURE 5 study. Here, we report 2-year (end-of-study) results from this study. METHODS: Adults with active PsA were randomised 2:2:2:3 to receive subcutaneous secukinumab 300 mg load (300 mg), 150 mg load (150 mg), 150 mg no load or placebo at baseline; weeks 1, 2, 3 and 4; and every 4 weeks thereafter. Secukinumab could be escalated from 150 mg to 300 mg starting at week 52, if active signs of disease were observed based on physician's assessment. Assessments at week 104 (2 years) included clinical end points and radiographic damage (mean change in van der Heijde-modified total Sharp score (vdH-mTSS)). Safety analysis included all patients who received ≥1 dose of study medication. RESULTS: Of the 996 patients randomised, 783 patients (78.6%) completed 2 years of treatment. Improvement in clinical end points was sustained through 2 years. The vdH-mTSS (mean change (SD)) was 0.10 (1.74; 300 mg), 0.52 (2.66; 150 mg) and 0.41 (2.20; 150 mg no load) at 2 years. The proportion of patients with no radiographic progression (change from baseline in vdH-mTSS ≤0.5) at 2 years was 89.5% (300 mg), 82.3% (150 mg) and 81.1% (150 mg no load). CONCLUSION: Secukinumab with and without loading regimen provided sustained clinical efficacy and low radiographic progression through 2 years in patients with PsA. No new safety findings were reported. TRIAL REGISTRATION NUMBER: NCT02404350.