To assess the efficacy and safety of the subcutaneous (s.c.) secukinumab 150 mg with loading (150 mg) or without loading (150 mg no-load) regimen through 104 weeks in patients with active psoriatic arthritis (PsA) in the FUTURE 4 (NCT02294227) study. Patients with PsA (N = 341) were randomized to s.c. secukinumab 150 mg, 150 mg no-load or placebo at baseline, weeks 1, 2, 3 and every 4 weeks thereafter. All placebo patients were reassigned to secukinumab 150 mg no-load at either week 16 (non-responders) or week 24 (responders). The primary end point was ACR20 at week 16. Patients could have their dose escalated from 150 to 300 mg based on their physician’s decision starting at week 36. Pre- and post-escalation ACR and PASI responses were also assessed. A total of 95.6% (326/341), 84.5% (288/341) and 79.8% (272/341) patients completed 16, 52 and 104 weeks of treatment, respectively. The primary end point was met; ACR20 response rate at week 16 was 41.2% and 39.8% with the 150 mg and 150 mg no-load groups, respectively, versus placebo (18.4%; adjusted P value = 0.0003 for both treatment arms). Efficacy responses observed at week 16 in both treatment regimens were sustained up to week 52 and 104, with many patients continuing to show improvements up to week 104. After dose escalation to 300 mg, the proportion of patients with non-/low-level ACR/PASI response decreased with increasing proportions of patients having higher ACR/PASI responses. No new or unexpected safety signals were reported. The secukinumab 150 mg or 150 mg no-load regimen demonstrated significant and sustained improvements in the signs and symptoms of psoriatic arthritis through 104 weeks; the loading regimen was associated with numerically higher and earlier responses for some high-hurdle end points. Improved efficacy was observed upon dose escalation from 150 to 300 mg. The safety profile was consistent with previous reports. ClinicalTrials.gov identifier, NCT02294227. Novartis Pharma AG, Basel, Switzerland.

Background: Pooled safety data from secukinumab (SEC) studies in psoriasis and psoriatic arthritis (PsA) have been reported previously. Objectives: To report updated longer-term safety data with up to 5 years of SEC treatment from psoriasis and PsA studies. Methods: The moderate-to-severe plaque psoriasis and active PsA data pool consisted of 15 Phase 2 and 3 Phase 3 studies. Different SEC doses in the studies included intravenous (up to 10 mg/kg) or subcutaneous (s.c.; 75-300 mg) loading, followed by s.c. maintenance dosing (300, 150 or 75 mg). Placebo patients were rerandomised to SEC at 12-24 weeks depending on study design. Adverse events (AEs) were reported as exposure-adjusted incident rates (EAIR) per 100 patientyears and analyses included all patients who received ≥1 dose of SEC. Results: A total of 5,181 and 1,380 patients from psoriasis and PsA studies representing an exposure of 10,416.9 and 3,866.9 patient-years, respectively, were included in this study. The most frequently reported AE was viral upper respiratory tract infection (Table 1). EAIRs for serious infections, Candida infections, inflammatory bowel disease and major adverse cardiac events were low and similar in both psoriasis and PsA indications (Table 1). No cases of tuberculosis were reported. Conclusion: SEC demonstrated a favourable safety profile during long-term treatment (up to 5 years) in patients with moderate-to-severe plaque psoriasis or PsA, hence, supporting long-term use. The safety profile of SEC was consistent with previous reports and comparable across psoriasis and PsA patients.

Secukinumab, a fully human immunoglobulin G1-kappa monoclonal antibody that directly inhibits interleukin (IL)-17A, has been shown to have robust efficacy in the treatment of moderate-to-severe psoriasis (PsO), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) demonstrating a rapid onset of action and sustained long-term clinical responses with a consistently favorable safety profile in multiple Phase 2 and 3 trials. Here, we report longer-term pooled safety and tolerability data for secukinumab across three indications (up to 5 years of treatment in PsO and PsA; up to 4 years in AS). The integrated clinical trial safety dataset included data pooled from 21 randomized controlled clinical trials of secukinumab 300 or 150 or 75 mg in PsO (14 Phase 3 trials and 1 Phase 4 trial), PsA (3 Phase 3 trials), and AS (3 Phase 3 trials), along with post-marketing safety surveillance data with a cut-off date of June 25, 2017. Adverse events (AEs) were reported as exposure-adjusted incident rates (EAIRs) per 100 patient-years. Analyses included all patients who received ≥ 1 dose of secukinumab. A total of 5181, 1380, and 794 patients from PsO, PsA, and AS clinical trials representing secukinumab exposures of 10,416.9, 3866.9, and 1943.1 patient-years, respectively, and post-marketing data from patients with a cumulative exposure to secukinumab of ~ 96,054 patient-years were included in the analysis. The most frequent AE was upper respiratory tract infection. EAIRs across PsO, PsA, and AS indications were generally low for serious infections (1.4, 1.9, and 1.2, respectively), Candida infections (2.2, 1.5, and 0.7, respectively), inflammatory bowel disease (0.01, 0.05, and 0.1, respectively), and major adverse cardiac events (0.3, 0.4, and 0.6, respectively). No cases of tuberculosis reactivation were reported. The incidence of treatment-emergent anti-drug antibodies was low with secukinumab across all studies, with no discernible loss of efficacy, unexpected alterations in pharmacokinetics, or association with immunogenicity-related AEs. Secukinumab demonstrated a favorable safety profile over long-term treatment in patients with PsO, PsA, and AS. This comprehensive assessment demonstrated that the safety profile of secukinumab was consistent with previous reports in patients with PsO, PsA, and AS, supporting its long-term use in these chronic conditions.

BackgroundPooled safety data from secukinumab (SEC) studies in psoriasis and psoriatic arthritis (PsA) have been reported previously.1ObjectivesTo report updated longer-term safety data with up to 5 years of SEC treatment from psoriasis and PsA studies.MethodsThe moderate to severe plaque psoriasis and active PsA data pool consisted of 15 and 3 Phase III studies, respectively. Different SEC doses in the studies included intravenous (up to 10 mg/kg) or subcutaneous (s.c.; 75–300 mg) loading, followed by s.c. maintenance dosing (300, 150 or 75 mg). Placebo patients were re-randomised to SEC at 12–24 weeks depending on study design. Adverse events (AEs) were reported as exposure adjusted incident rates (EAIR) per 100 patient-years and analyses included all patients who received ≥1 dose of SEC.ResultsA total of 5181 and 1380 patients from psoriasis and PsA studies representing an exposure of 10416.9 and 3866.9 patient years, respectively, were included in this study. The most frequently reported AE was viral upper respiratory tract infection (table 1). EAIRs for serious infections, Candida infections, inflammatory bowel disease (IBD) and major adverse cardiac events (MACE) were low and similar in both psoriasis and PsA indications (table 1). No cases of tuberculosis were reported.ConclusionsSEC demonstrated a favourable safety profile during long-term treatment (up to 5 years) in patients with moderate to severe plaque psoriasis or PsA, hence, supporting long-term use. The safety profile was consistent with previous reports and comparable across psoriasis and PsA patients.Reference[1] Mease, et al. Arthritis Rheumatol2017; 69(suppl 10):A606.Disclosure of InterestP. Mease Grant/research support from: AbbVie, Amgen, BMS, Janssen, Lilly, Novartis, Pfizer, and UCB, Consultant for: AbbVie, Amgen, BMS, Celgene, Janssen, Lilly, Merck, Novartis, Pfizer, SUN Pharma, UCB,, Speakers bureau: AbbVie, Amgen, BMS, Janssen, Lilly, Pfizer, and UCB, I. McInnes Grant/research support from: AbbVie, Amgen, BMS, Celgene, Janssen, Lilly, Novartis, Pfizer, and UCB, Consultant for: AbbVie, Amgen, BMS, Celgene, Janssen, Lilly, Novartis, Pfizer, and UCB, Speakers bureau: AbbVie, Amgen, BMS, Celgene, Janssen, Lilly, Novartis, Pfizer, and UCB, K. Reich Consultant for: Abbvie, Affibody, Amgen, Biogen, Boehringer Ingelheim Pharma, Celgene, Centocor, Covagen, Forward Pharma, GlaxoSmithKline, Janssen-Cilag, Leo, Lilly, Medac, Merck Sharp and Dohme Corp., Novartis, Ocean Pharma, Pfizer, Regeneron, Sanofi, Takeda, UCB Pharma, Xenoport, Speakers bureau: Abbvie, Affibody, Amgen, Biogen, Boehringer Ingelheim Pharma, Celgene, Centocor, Covagen, Forward Pharma, GlaxoSmithKline, Janssen-Cilag, Leo, Lilly, Medac, Merck Sharp and Dohme Corp., Novartis, Ocean Pharma, Pfizer, Regeneron, Sanofi, Takeda, UCB Pharma, Xenoport., P. Nash Grant/research support from: AbbVie, Amgen, BMS, Celgene, Eli Lilly, Hospira, MSD, Pfizer, Janssen, UCB, Novartis, Roche, Consultant for: AbbVie, Amgen, BMS, Celgene, Eli Lilly, Hospira, MSD, Pfizer, Janssen, UCB, Novartis, Roche, Speakers bureau: AbbVie, Amgen, BMS, Celgene, Eli Lilly, Hospira, MSD, Pfizer, Janssen, UCB, Novartis, Roche, A. Widmer Shareholder of: Novartis Stock, Employee of: Novartis, K. Abrams Shareholder of: Novartis Stock, Employee of: Novartis, L. Pricop Shareholder of: Novartis Stock, Employee of: Novartis, T. Fox Shareholder of: Novartis Stock, Employee of: Novartis

Background The assessment of achieving, maintaining or improving clinical response to biologics in ankylosing spondylitis (AS) is a part of treat-to-target recommendations aimed at optimising treatment goals.1 Objectives To evaluate patient (pt)-level secukinumab data and assess the likelihood of achieving, maintaining or improving an Assessment of SpondyloArthritis international Society (ASAS) response from Week (Wk) 2 (early response) to Wk 16 (primary endpoint) and from Wk 16 to Wk 52 or 104 (sustained effect) in pts with active AS from the MEASURE 2 trial.2,3 Methods This is a post-hoc analysis of AS pts originally randomised to secukinumab 150mg (approved dose) who completed the 16-wk double-blind treatment period, followed by long-term uncontrolled treatment. Shift analyses on ASAS response between Wks 2 and 16 and Wks 16 and 52 or 104 were performed on subgroups of secukinumab 150mg treated pts categorised by their highest ASAS criteria response at the earlier time point (ASAS non-responder [ASAS NR], ASAS20 responder, ASAS40 responder) and evaluating whether this response was improved, sustained, or worsened at the later time point, based on observed analysis. Results Overall, 65, 61 and 59 pts treated with secukinumab 150mg had available data to determine ASAS responses for shift analyses from Wk 2 to 16 and Wk 16 to 52 or 104, respectively. At baseline, mean age was 41.9±12.5 years, mean time since diagnosis was 7.0±8.2 years and mean Bath Ankylosing Spondylitis Disease Activity Index score was 6.6±1.5. Approximately half of the ASAS NR pts at Wk 2 or 16 subsequently developed an ASAS 20 or 40 response at the later time point of Wk 16 or 52, respectively. A total of 79% pts improved their response from ASAS20 to ASAS40 at Wk 16 (Wk 2 to 16) and another 44% pts improved their response from ASAS20 to ASAS40 from Wk 16 to 52. A majority (64% and 84%) of ASAS40 responders at Wk 2 or 16 maintained this response at Wk 16 or 52, respectively. Similar trends were observed in responses from Wk 16 to 104 (Figure). Conclusions In this post-hoc pt-level analysis, the majority of secukinumab 150mg treated pts maintained or improved their ASAS responses over time, consistent with the sustainability of group-level ASAS responses reported previously.2,3 In particular, the majority of pts who achieved either an ASAS20 or ASAS40 response at Wk 2 or 16 maintained or improved their response at Wks 16, 52 or 104, respectively. References Smolen JS, et al. Ann Rheum Dis 2014;73:6–16. Baeten D, et al. N Engl J Med 2015;373:2534–48. Marzo-Ortega H, et al. Ann Rheum Dis 2016;75:812–3. Disclosure of Interest X. Baraliakos Grant/research support from: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB, Werfen, Consultant for: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB, Werfen, Speakers bureau: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB, Werfen, M. Schiff Consultant for: Abbvie, BMS, Lilly, J&J, Speakers bureau: Abbvie, K. Pavelka Speakers bureau: MSD, AbbVie, Roche, UCB, Amgen, Hospira, Egis, Pfizer, Medac, BMS, A. Widmer Shareholder of: Novartis, Employee of: Novartis, B. Porter Shareholder of: Novartis, Employee of: Novartis, C. Gaillez Shareholder of: Novartis, BMS, Employee of: Novartis

Objective. To evaluate the efficacy and safety of secukinumab, a fully human antiinterleukin-17A monoclonal antibody, administered with an intravenous (IV) or subcutaneous (SC) loading regimen versus placebo, in patients with active rheumatoid arthritis (RA). Methods. In this phase II, double-blind, double-dummy, 52-week study ( ClinicalTrials.gov NCT01359943 ), 221 patients with inadequate response to methotrexate were randomized (2:2:1) to secukinumab, IV loading 10 mg/kg at baseline, Weeks 2 and 4, then SC 150 mg every 4 weeks (n = 88); secukinumab SC loading 150 mg once weekly for 5 weeks, then every 4 weeks (n = 89); or a matching placebo (followed by secukinumab 150 mg every 4 weeks starting Week 16; n = 44). The primary endpoint was superior efficacy of pooled secukinumab versus placebo using American College of Rheumatology 20% response (ACR20) at Week 12. Results. The primary efficacy endpoint was not met: ACR20 response at Week 12 was 49.2% for pooled secukinumab versus 40.9% for placebo (p = 0.3559). These variables improved significantly with pooled secukinumab versus placebo at Week 12 (all p < 0.05): the 28-joint Disease Activity Score (DAS28), patient’s and physician’s global assessment of disease activity, patient’s assessment of RA pain, and high-sensitivity C-reactive protein levels. Results of continuous efficacy outcomes were similar between the IV and SC loading regimens. The most frequent adverse events were infections, with similar rates across secukinumab and placebo. Conclusion. Although the primary endpoint (ACR20) was not met, secukinumab demonstrated improved efficacy in reducing disease activity over placebo as measured by DAS28 and other secondary endpoints.

ObjectivesTo describe the safety profile of secukinumab, an anti–interleukin-17A monoclonal antibody, in patients (pts) with psoriatic arthritis (PsA) treated in phase 3 studies.MethodsSafety data from two randomized, double-blind, placebo (PBO)-controlled, phase 3 studies in pts with active PsA, FUTURE 1 (NCT01392326) and FUTURE 2 (NCT01752634), were pooled. In FUTURE 1, 606 pts were randomized to secukinumab or PBO. Pts on secukinumab received 10 mg/kg i.v at baseline, Week (Wk) 2, and 4, followed by 150 or 75 mg s.c. every 4 wks from Wk 8. PBO was given according to the same i.v. and s.c. schedule. In FUTURE 2, 397 pts were randomized to receive s.c. secukinumab (300, 150, or 75 mg) or PBO at baseline, Wk 1, 2, 3, 4, and every 4 wks thereafter. At Wk16, PBO pts with ≤20% reduction in both tender and swollen joint count (nonresponders) were re-randomized to receive secukinumab 150 or 75 mg s.c. in FUTURE 1, and secukinumab 300 or 150 mg s.c. in FUTURE 2; responders were re-randomized at Wk 24. Anti-drug antibodies (ADAs) were assessed using a Meso Scale Discovery bridging assay with a stepwise approach for screening, confirmation and titration. All randomized pts were included in the pooled safety analysis.Results974 pts received ≥1 dose of secukinumab (955 pt-years of exposure). Baseline demographics, disease/medical history and concomitant medications were similar between the pooled secukinumab and PBO populations. During the 16-wk PBO-controlled period, adverse events (AEs)/serious AEs (SAEs) were reported in 58.9%/3.4% and 58.3%/4.0% of pts in the pooled secukinumab and PBO groups, respectively. Exposure-adjusted AE/SAE incidence rates across the entire safety period (mean/max exposure: 358.1/721 days secukinumab; 128.6/233 days PBO) were 210.3/9.0 and 319.6/13.6 per 100 pt-years with secukinumab and PBO, respectively; 25 (2.6%) pts receiving secukinumab discontinued due to AEs during this period vs. 14 (4.7%) with PBO. Nasopharyngitis and upper respiratory tract infection (URTI) were the most frequent AEs with secukinumab and PBO in both the PBO-controlled period and throughout the entire safety period. There was one death due to intracranial hemorrhage in a pt with a history of CV disease who received secukinumab. The incidence of inflammatory bowel disease (IBD)/Crohn9s, Candida infections, neutropenia, MACE and malignancy was low with secukinumab (Table). Injection site reactions with secukinumab were observed in 26 (2.7%) pts vs. 3 (1.0%) with PBO. Treatment-emergent ADAs were detected in 1 (0.1%) pt, with no associated loss of efficacy.ConclusionsSecukinumab was well-tolerated in pts with active PsA, with a low incidence of SAEs and discontinuations due to AEs, and a low potential for immunogenicity.AcknowledgementsMedical writing support was provided by Chris Strutynskyj-Stannard at Seren Communications (Tytherington, UK), and was funded by Novartis.Disclosure of InterestP. Mease Grant/research support from: AbbVie, Amgen, Biogen Idec, BMS, Celgene, Crescendo, Janssen, Lilly, Merck, Novartis, Pfizer, UCB, and Vertex, Consultant for: AbbVie, Amgen, Biogen Idec, BMS, Celgene, Covagen, Crescendo, Janssen, Lilly, Merck, Novartis, Pfizer, UCB, and Vertex, Speakers bureau: AbbVie, Amgen, Biogen Idec, BMS, Crescendo, Janssen, Lilly, Pfizer, and UCB, I. McInnes Consultant for: Novartis, Amgen, Janssen, BMS, Pfizer, UCB, Abbvie, Celgene, and Lilly, H. Richards Employee of: Novartis, L. Pricop Shareholder of: Novartis, Employee of: Novartis, A. Widmer Employee of: Novartis, S. Mpofu Shareholder of: Novartis, Employee of: Novartis

Objective Longer-term effects of prolonged selective interleukin-1β blockade with canakinumab were evaluated in the largest cohort of cryopyrin-associated periodic syndrome (CAPS) patients studied to date. Methods Adult and paediatric CAPS patients (n=166, including canakinumab-naive and pretreated patients from previous studies) received canakinumab subcutaneously 150 mg or 2 mg/kg (≤40 kg) every 8 weeks for up to 2 years. Response and relapse was assessed using scores for disease activity, skin rash and C-reactive protein (CRP) and/or serum amyloid A (SAA) levels. Results Complete response was achieved in 85 of 109 canakinumab-naive patients (78%; 79/85 patients within 8 days, and five patients between days 10 and 21). Of 141 patients with an available relapse assessment, 90% did not relapse, their CRP/SAA levels normalised (<10 mg/l) by day 8, and remained in the normal range thereafter. Median treatment duration was 414 days (29–687 days). Upward adjustments of dose or frequency were needed in 24.1% patients; mostly children and those with severe CAPS. Predominant adverse events (AE) were infections (65.7%) of mostly mild-to-moderate severity. Serious AE reported in 18 patients (10.8%) were mainly infections and were responsive to standard treatment. The majority of patients (92%) reported having no injection-site reactions and only 8% patients reported mild-to-moderate reactions. Patients receiving vaccination (15%) showed normal immune response. Conclusions Subcutaneous canakinumab 150 mg every 8 weeks was well tolerated and provided substantial disease control in children and adults across all CAPS phenotypes. Higher canakinumab doses in younger patients and more severe CAPS disease were efficacious in achieving complete responses without evidence of increased AE. Trial registration number: NCT00685373 (clinicaltrials.gov)

Background: Activities of the anti-TNFs, certolizumab pegol (CZP), etanercept (ETA), infliximab (IFX) and adalimumab (ADA), have been compared in a range of in vitro assays. CZP is the only licensed PEGylated Fab’ anti-TNF; ETA is a fusion protein with an IgG1 Fc, and IFX and ADA are both antibodies with an IgG1 Fc. Golimumab (GLM) is a monoclonal IgG1 TNF inhibitor recently approved for a number of indications; it is thus of interest to assess the in vitro activity of GLM. In vitro assays previously used were neutralisation of TNF in the L929 bioassay, inhibition of LPS-driven cytokine production by monocytes, induction of apoptosis in activated lymphocytes and monocytes, and induction of neutrophil necrosis. Methods: Neutralisation of human TNF was assessed in the L929 bioassay using a range of concentrations of the anti-TNFs and a fixed concentration of TNF (100 pg/mL). Activity of the anti-TNFs at inhibiting LPS-driven IL-1β secretion by monocytes was assessed by incubating peripheral blood monocytes with various concentrations of the anti-TNF for 1 hour (hr) and then washing the cells. LPS was added for 4 hrs, the supernatants collected and the IL-1β level measured by ELISA. To assess induction of apoptosis, peripheral blood lymphocytes were activated for 2 days with 2 μg/mL CD3/CD28 and monocytes with 300 U/mL IL-4 and GMCSF for 3 days. The effect of the anti-TNFs on apoptosis was assessed by Annexin V staining using flow cytometry 24 hrs later. The effect of the anti-TNFs on neutrophil necrosis was determined by measuring myeloperoxidase release after 12 hrs. An isotype-matched control was used in all assays except the L929 bioassay. Results: IC90 neutralisation activity of the anti-TNFs in the L929 bioassay was 0.3 ng/mL for ETA, 4 ng/mL for GLM, 15 ng/mL for ADA, and 20 ng/mL for IFX, compared with 2.5 ng/mL for CZP. CZP was the most potent inhibitor of LPS-driven IL-1β secretion (IC50 ∼0.1 ng/mL), followed by GLM (20 ng/mL) and IFX (50 ng/mL). GLM, ADA, IFX and ETA induced apoptosis of monocytes and lymphocytes to a similar degree reaching a level of 23% and ∼40% at 100 μg/mL, respectively. CZP caused no increase in apoptosis above the levels seen with the isotype-matched control. In the neutrophil necrosis assay, ADA,IFX and GLM caused ∼70% necrosis at 100 μg/mL, and ETA 48%. CZP did not increase the level of necrosis above the level of the control. Conclusions: Bioactivity of the IgG1 molecules GLM, IFX and ADA in neutralising human TNF was inferior to that of CZP and ETA. CZP, the only PEGylated anti-TNF, had a different profile to the other anti-TNFs as it was the most potent at inhibiting LPS-driven IL-1β production by monocytes, did not induce apoptosis of activated monocytes and lymphocytes, and did not cause neutrophil necrosis. The clinical relevance of these in vitro effects is unknown. Nevertheless, these assays show interesting in vitro differences between the anti-TNFs. Disclosure statement: G.F. and A.N. are employees of UCB.