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ObjectivesIxekizumab, a high-affinity monoclonal antibody that selectively targets interleukin 17A (IL-17A), has shown significant efficacy in the treatment of psoriatic arthritis (PsA) and sustained long-term clinical response without unexpected new safety outcome for an IL-17A inhibitor. Here, we report the updated safety profile of ixekizumab up to 3 years in patients with PsA.MethodsThis is an integrated safety analysis from four clinical trials in patients with PsA who received at least one dose of ixekizumab. Treatment-emergent adverse events (TEAEs) and selected adverse events (AEs) exposure-adjusted incidence rates (EAIRs) per 100 patient-years up to 3 years of exposure are reported.ResultsA total of 1401 patients with a cumulative ixekizumab exposure of 2247.7 patient-years were included in this analysis. The EAIR of patients with ≥1 TEAE was 50.3 per 100 patient-years and most TEAEs were mild to moderate in severity. Serious AEs were reported by 134 patients (EAIR=6.0). The most reported TEAEs were nasopharyngitis (EAIR=9.0) and upper respiratory tract infection (EAIR=8.3). Infections in general and injection site reactions were the most common TEAEs; the incidence rates of serious cases were low (EAIR ≤1.2). The EAIRs of malignancies (EAIR=0.7), inflammatory bowel disease (EAIR=0.1) including ulcerative colitis and Crohn’s disease, depression (EAIR=1.6), and major adverse cerebro-cardiovascular events (EAIR=0.5) were low. As assessed, based on year of exposure, incidence rates were decreasing or constant over time.ConclusionsIn this analysis, the overall safety profile and tolerability of ixekizumab are consistent with the known safety profile in patients with PsA. No new or unexpected safety events were detected.Trial registration numberNCT01695239,NCT02349295,NCT02584855,NCT03151551.

Objective To evaluate the efficacy of ixekizumab (IXE), a monoclonal antibody selectively targeting interleukin-17A, in patients with inadequate response to one or two TNF inhibitors (TNFi). Methods A phase 3 study (SPIRIT-P2; NCT02349295) randomized patients with PsA with inadequate response or intolerance to one or two TNFi to receive 80-mg IXE every 2 weeks (n = 123) or every 4 weeks (n = 122) after a 160-mg starting dose or placebo (PBO; n = 118) through week 24. This post hoc analysis used data from inadequate responders to one or two TNFi, measuring the percentage achieving: ≥50% improvement in ACR response criteria (ACR50) and 100% improvement from baseline in the Psoriasis Area and Severity Index (PASI 100), ACR50, improvement in HAQ-Disability Index (HAQ-DI) ≥0.35, minimal disease activity (MDA), European League Against Rheumatism (EULAR) Good Response Criteria [improvement in Disease Activity Score 28 CRP (DAS28-CRP) >1.2], and Disease Activity in PsA (DAPSA) ≤14. Results There were no significant differences in baseline characteristics between inadequate responders to one and two TNFi. At week 24, significantly more patients irrespective of previous TNFi experience receiving IXE than PBO achieved ACR50, HAQ-DI ≥0.35 improvement, MDA, EULAR good response, and DAPSA ≤14, and significantly more patients with inadequate response to one TNFi receiving IXE than PBO achieved ACR50 and PASI 100. Improvement persisted in all measures through week 52. Conclusion IXE improved the signs and symptoms of PsA in a population of difficult-to-treat patients with inadequate response to one or two TNFi.

Introduction In the SPIRIT-H2H (ClinicalTrials.gov: NCT03151551) trial in biologic-naïve patients with active psoriatic arthritis (PsA), ixekizumab (IXE) was superior to adalimumab (ADA) at week 24 in terms of achieving a combined endpoint of ≥ 50% improved response in the American College of Rheumatology scale score (ACR50) and 100% improvement in the Psoriasis Areas and Severity Index (PASI100), and was non-inferior in terms of achieving ACR50. IXE resulted in similar improvements of PsA manifestations irrespective of the use of concomitant conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), while ADA response was higher with concomitant csDMARD use. The aim of this study was to determine the efficacy and safety of treatment with IXE and ADA with or without methotrexate (MTX), the most commonly use csDMARD, through week 52 in patients with PsA. Methods In the open-label, rater-blinded, head-to-head SPIRIT-H2H trial, randomization of patients was stratified by concomitant use of csDMARD and moderate-to-severe plaque psoriasis involvement. In the post-hoc subgroup analysis presented here, subgroups were defined as with/without concomitant MTX use at baseline. Treatment group effects within subgroups were tested using Fisher’s exact test. Missing data were imputed using non-responder imputation. Results By week 52, IXE provided similar improvements in the combined ACR50 and PASI100 endpoint, ACR50, and other PsA-related domains regardless of whether IXE was used with or without MTX, while ADA efficacy appeared to be improved with concomitant MTX use. When used without concomitant MTX, IXE resulted in significantly higher response versus ADA in terms of the combined ACR50 and PASI100 (p = 0.002) endpoint, minimal disease activity (p = 0.016), and very low disease activity (p = 0.037). The safety of both agents was consistent with their known safety profiles regardless of concomitant MTX use. Conclusion In PsA patients with inadequate control of the disease, IXE delivers consistent efficacy in several clinical domains of the disease regardless of concomitant MTX use. The efficacy of ADA is increased by the concomitant use of MTX. These findings can inform treatment decisions when considering the need for concomitant MTX use with IXE or ADA at initiation or for long-term maintenance. Electronic supplementary material The online version of this article (10.1007/s40744-020-00250-3) contains supplementary material, which is available to authorized users.

Differences in psoriatic arthritis (PsA) treatment response between sexes for ixekizumab, an interleukin-17A antagonist, are largely unexplored. This analysis used data from randomized clinical trials (RCTs) evaluating ixekizumab to study differences in treatment response between male and female patients with PsA.We used pooled data from patients enrolled in SPIRIT-P1 and SPIRIT-P2 (NCT01695239 and NCT02349295, respectively), phase 3 RCTs evaluating ixekizumab every 4 and 2 weeks in patients with active PsA. Subgroups of patients were defined by sex (male, female). Efficacy was measured by the proportion of male and female patients achieving American College of Rheumatology 20%/50%/70% improvement criteria (ACR20/50/70), minimal disease activity or very low disease activity (MDA/VLDA), and Disease Activity Index for Psoriatic Arthritis (DAPSA) scores representing low disease activity (LDA) or remission through week 156. Changes from baseline in components of the above measures were also assessed through week 156.Compared to male patients at baseline, female patients were older, had higher body mass index and lower C-reactive protein levels, and had worse tender joint count, Health Assessment Questionnaire Disability Index, and Leeds Enthesitis Index scores. Through week 156, female patients in all treatment arms had lower response rates than male patients in all analyzed composite measures (ACR20/50/70; MDA/VLDA; DAPSA LDA/remission), with significant differences observed at multiple timepoints in both ixekizumab treatment arms. Female patients also had smaller numeric changes from baseline in the composite measures' individual components.Compared to female patients, male patients had greater response rates in ACR20/50/70, MDA/VLDA, and DAPSA LDA/remission and numerically larger improvements in these measures' individual components, although clinical significance is unclear. Continued efforts to understand sex differences in treatment response may provide insights that can help optimize clinical decision making.ClinicalTrials.gov identifiers, NCT01695239 and NCT02349295.

Purpose Ixekizumab is a high-affinity monoclonal antibody that selectively targets interleukin-17A. The objective of this study was to assess the long-term efficacy and safety (to week 156) of ixekizumab in patients with active psoriatic arthritis and inadequate response or intolerance to one or two tumor necrosis factor inhibitors. Methods In the SPIRIT-P2 study (ClinicalTrials.gov ID: NCT02349295), patients were randomized to placebo or ixekizumab 80 mg every 4 weeks (IXE Q4W) or every 2 weeks (IXE Q2W) following a 160-mg starting dose. During the extension period (weeks 24–156), patients maintained their original ixekizumab dose, and placebo patients received IXE Q4W or IXE Q2W (1:1). Exposure-adjusted incidence rates (IRs) per 100 patient-years (PY) are presented. Results Of 363 patients enrolled in the study, 310 entered the extension period. In all patients treated with IXE Q4W and IXE Q2W at week 0, responses persisted to week 156. At week 156, clinical responses (observed) in patients treated with IXE Q4W and IXE Q2W were assessed [American College of Rheumatology (ACR) response criteria and minimal disease activity (MDA) criteria]: 84 and 85% showed 20% improvement (ACR20); 60 and 58% showed 50% improvement (ACR50); 35 and 47% showed 70% improvement (ACR70), respectively; and 48 and 54% showed MDA. Placebo patients re-randomized to ixekizumab also demonstrated sustained efficacy, as measured by ACR and MDA responses. In the All Ixekizumab Exposure Safety Population (n = 337), with 644 PY of ixekizumab exposure, treatment-emergent adverse events (TEAEs) were reported by 286 patients (44.4 IR). The most common TEAEs were upper respiratory tract infection (9.80 IR), nasopharyngitis (8.2 IR), sinusitis (6.2 IR), and bronchitis (4.5 IR). Serious adverse events were reported by 42 (6.5 IR) patients (included 3 deaths and 10 infections). Conclusion In this 156-week study of ixekizumab, improvements in signs and symptoms of psoriatic arthritis and the safety profile remained consistent with those in previous reports. Trial registration ClinicalTrials.gov identifier: NCT02349295. Electronic supplementary material The online version of this article (10.1007/s40744-020-00261-0) contains supplementary material, which is available to authorized users.

To analyse the onset and sustainability of patient-reported improvements in symptoms of psoriatic arthritis (PsA) following treatment with ixekizumab (IXE) up to Week 108.In patients with active PsA, either naive to biological DMARDs (SPIRIT-P1) or having inadequate response or intolerance to 1 or 2 prior TNF-inhibitors (TNFi‑experienced; SPIRIT-P2), we analysed the change from baseline in joint pain visual analogue scale (VAS; 0-100 scale), patient global assessment (PatGA VAS; 0-100 scale), fatigue numerical rating scale (NRS; 0 [no fatigue] to 10 [worst imaginable]), and Health Assessment Questionnaire-Disability Index (HAQ-DI; 0-3), up to Week 108.IXE-treated patients compared to placebo reported rapid and statistically significant improvement in pain VAS, PatGA, and HAQ-DI as early as Week 1 and this benefit was sustained or increased through Week 108. Fatigue scores improved in IXE-treated patients compared to placebo in both studies; results were statistically significant at Week 24 only in SPIRIT-P2. Improvements in fatigue with IXE were sustained over 2 years. The improvements observed in these patient-reported outcomes (PROs) were consistent in biologic-naive or TNFi-experienced patients.Patients treated with IXE versus PBO achieved significantly greater improvements and showed faster onset of improvements in patient-reported outcomes measuring symptoms and impact of PsA. Responses were sustained over 2 years and were generally consistent regardless of prior TNFi experience.

Background:Patients with psoriatic arthritis (PsA) require long-term treatment, which may lead to adverse events (AEs). Ixekizumab, an interleukin-17A antagonist, is approved for the treatment of adults with active PsA.Objectives:We report a summary of safety outcomes for patients enrolled in 4 PsA studies with up to 3 years of exposure to ixekizumab.Methods:This integrated safety analysis included all patients with PsA who received at least 1 dose of ixekizumab (80 mg every 2 or 4 weeks) in 4 clinical trials (NCT01695239, NCT02349295, NCT02584855, NCT03151551). Safety outcomes included treatment-emergent adverse events (TEAEs), serious AEs (SAEs), discontinuations due to AEs, deaths, and AEs of special interest.Results:A total of 1401 patients were included in this safety analysis (51.5% female; mean age 49 years), with 2247.6 patient-years of exposure (Table 1). In all, 1131 patients (80.7%) reported ≥1 TEAE (exposure-adjusted incidence rate per 100 patient-years [IR] 50.3, 95% CI 47.5–53.3), mostly mild (32.9%) or moderate (39.7%) in severity. The most common TEAEs were nasopharyngitis (n=202, IR 9.0), upper respiratory infections (n=186, IR 8.3), and injection site reaction (n=156, IR 6.9). SAEs were reported by 134 patients (IR 6.0, 95% CI 5.0–7.1). 115 (8.2%) patients discontinued due to AEs (IR 5.1, 95% CI 4.3–6.1). Six deaths were reported (IR 0.3, 95% CI 0.1–0.6). Allergic reactions/hypersensitivity were reported in 102 patients (IR 4.5, 95% CI 3.7–5.5). Three cases were adjudicated as de novo inflammatory bowel disease (IR 0.13, 95% CI 0.04–0.41); 1 was ulcerative colitis (IR 0.04, 95% CI 0.01–0.32), 2 were Crohn’s disease (IR 0.09, 95% CI 0.02–0.36). Major adverse cardiac events occurred in 12 patients (IR 0.5) and malignancies in 15 (IR 0.7), 9 of which were non-melanoma skin cancer. Opportunistic infections occurred in 40 (2.9%) patients (IR 1.8, 95% CI 1.3–2.4). Candidiasis occurred in 24 patients (oral: IR 0.7, 95% CI 0.4–1.2; oral fungal infection: IR 0.3, 95% CI 0.1–0.6; esophageal infection: IR 0.1, 95% CI 0.0–0.4). No active or reactive cases of tuberculosis were reported. Other opportunistic infections included hepatitis B (IR 0.0, 95% CI 0.0–0.3), herpes simplex (IR 1.8, 95% CI 1.3–2.5), and herpes zoster (IR 0.7, 95% CI 0.4–1.2).Conclusion:The safety profile of ixekizumab across 4 clinical trials and up to 3 years of continuous treatment in patients with active PsA was consistent with the known safety profile reported in previous studies for psoriasis and PsA. No new safety events were found in this analysis.Pooled Ixekizumab(N=1401; Total Patient-Years=2247.6)n (IR)95% CIYear 0–1(n=1401)n (IR)95% CIYear 1–2(n=946)n (IR)95% CIYear 2–3(n=510)n (IR)95% CIYear ≥3(n=89)n (IR)95% CITotal Patient-Years2247.71207.3689.8347.72.9Patients with ≥1 TEAE1131 (50.3)1050 (87.0)496 (71.9)234 (67.3)6 (206.2)47.5–53.381.9–92.465.9–78.559.2–76.592.6–458.9SAEs134 (6.0)72 (6.0)53 (7.7)19 (5.5)1 (34.4)5.0–7.14.7–7.55.9–10.13.5–8.64.8–243.9Discontinuations due to AEs115 (5.1)61 (5.1)37 (5.4)17 (4.9)0 (0)4.3–6.13.9–6.53.9–7.43.0–7.90.0–274.7Hepatic reactions112 (5.0)80 (6.6)32 (4.6)14 (4.0)0 (0)4.1–6.05.3–8.33.3–6.62.4–6.80.0–274.7Allergic reaction/hypersensitivity102 (4.5)83 (6.9)23 (3.3)5 (1.4)0 (0)3.7–5.55.5–8.52.2–5.00.6–3.50.0–274.7Serious infection28 (1.2)18 (1.5)9 (1.3)3 (0.9)0 (0)0.9–1.80.9–2.40.7–2.50.3–2.70.0–274.7Malignancies15 (0.7)4 (0.3)8 (1.2)4 (1.2)0 (0)0.4–1.10.1–0.90.6–2.30.4–3.10.0–274.7Major adverse cardiac events12 (0.5)3 (0.2)8 (1.2)1 (0.3)0 (0)0.3–0.90.1–0.80.6–2.30.0–2.00.0–274.7Inflammatory bowel disease3 (0.1)3 (0.2)1 (0.1)0 (0.0)0 (0.0)0.0–0.40.1–0.80.0–1.00.0–2.30.0–274.7 Ulcerative colitis1 (0.0)1 (0.1)1 (0.1)0 (0.0)0 (0.0)0.0–0.30.0–0.60.0–1.00.0–2.30.0–274.7 Crohn’s disease2 (0.1)2 (0.2)0 (0.0)0 (0.0)0 (0.0)0.0–0.40.0–0.70.0–1.20.0–2.30.0–274.7AE, adverse event; CI, confidence interval; IR, exposure-adjusted incidence rate per 100 patient-years; SAE, serious adverse event; TEAE, treatment-emergent adverse event.Disclosure of Interests:Carlos Sesin Speakers bureau: Amgen, AbbVie, Sanofi, Radius, Pfizer, Eli Lilly and Company, Novartis, Gaia Gallo Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Amanda Gellett Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Andris Kronbergs Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Aubrey Trevelin Sprabery Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Wen Xu Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Himanshu Patel Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Atul Deodhar Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Galapagos, Glaxo Smith & Kline, Janssen, Novartis, Pfizer, UCB, Grant/research support from: AbbVie, Eli Lilly and Company, Glaxo Smith & Kline, Novartis, Pfizer, UCB, Bernard Combe Speakers bureau: AbbVie, BMS, Gilead-Galapagos, Eli Lilly and Company, MSD, Pfizer, Roche Chugai, Consultant of: AbbVie, Bayer, Gilead-Galapagos, Janssen, Eli Lilly and Company, Novartis, Roche Chugai, Grant/research support from: AbbVie, Eli Lilly and Company, Pfizer, Roche Chugai, Gerd Rüdiger Burmester Speakers bureau: AbbVie, Janssen, Novartis, Eli Lilly and Company, MSD, Pfizer, Consultant of: AbbVie, Janssen, Novartis, Eli Lilly and Company, MSD, Pfizer.

Background:Ixekizumab (IXE), a high-affinity monoclonal antibody that selectively targets IL-17A, has shown improvements compared to placebo (PBO) not only in disease activity but also in various patient-reported outcomes (PROs) assessing physical function, quality of life (QoL), and work productivity in PsA patients treated for 24 weeks and sustained up to 52 weeks.1, 2Objectives:To report the effects of treatment with IXE on these PROs after up to 3 years of treatment.Methods:In SPIRIT-P2 (NCT02349295), a Phase 3 trial, 363 adult patients with active PsA and prior inadequate response or intolerance to 1 or 2 TNF inhibitors (TNFis) were randomized 1:1:1 to IXE 80 mg every 4 weeks (IXEQ4W; N=122) or every 2 weeks (IXEQ2W; N=123), or PBO (N=118) in the double-blind treatment period (Weeks 0-24). Both IXE regimens had a starting dose of 160 mg. Results are reported from a subset of the intent-to-treat population who were randomized to IXE at baseline (Week 0). The following PROs were assessed during Weeks 0-156: HAQ-DI (minimally clinically important difference [MCID] an improvement ≥0.35), medical outcomes survey Short Form-36 (SF-36) Physical and Mental Component Summary (PCS and MCS), European Quality of Life 5 Dimensions Visual Analog Scale (EQ-5D VAS), and Work Productivity and Activity Impairment Questionnaire-Specific Health Problem (WPAI-SHP; absenteeism, presenteeism, work productivity, and activity impairment). Missing values were imputed by observed analysis and modified baseline observation carried forward (mBOCF) for continuous data or by modified non-responder imputation (mNRI) for categorical data.Results:Mean baseline scores for SF-36 (PCS and MCS), EQ-5D VAS, and WPAI-SHP (Figure 1) and HAQ-DI (mean [SD]: IXEQ4W=1.2 [0.6]; IXEQ2W=1.2 [0.6]), indicated impaired physical function and QoL. The percentage of patients of who completed 156 weeks of the study in IXEQ4W and IXEQ2W arms were 57.4% (n=70) and 44.7% (n=55), respectively. Patients receiving IXE treatment up to 3 years reported sustained improvements in SF-36 (PCS and MCS), EQ-5D VAS, and WPAI-SHP (presenteeism, work productivity, and activity impairment) (Figure 1). Observed HAQ-DI mean change from baseline in IXEQ4W: -0.46 (0.62) and IXEQ2W: -0.48 (0.55). The percentage of IXE treated patients achieving MCID for HAQ-DI (improvement ≥0.35) was sustained at 3 years (Figure 2).Figure 1.Summary of Patient-Reported Outcomes presented as change from baseline at Week 156 (Observed and mBOCF): Intent-to-Treat Population (Patients Randomized to IXE at Baseline)Figure 2.Patients achieving HAQ-DI MCID Response up to Week 156 (Observed) and at Week 156 (mNRI) among patients with HAQ-DI≥0.35 at baseline: Intent-to-Treat Population (Patients Randomized to IXE at Baseline)Conclusion:Improvements in PROs, measuring physical and mental function, quality of life, and work productivity are maintained up to 3 years with IXE treatment in patients with active PsA who have had an inadequate response or intolerance to 1 or 2 TNFis.References:[1]Nash P, et al. Lancet. 2017;389(10086):2317-2327.[2]Genovese MC, et al. Rheumatology (Oxford). 2018;57(11):2001-2011.Disclosure of Interests:Ana-Maria Orbai Grant/research support from: Abbvie, Eli Lilly and Company, Celgene, Novartis, Janssen, Horizon, Consultant of: Eli Lilly; Janssen; Novartis; Pfizer; UCB. Ana-Maria Orbai was a private consultant or advisor for Sun Pharmaceutical Industries, Inc, not in her capacity as a Johns Hopkins faculty member and was not compensated for this service., Jordi Gratacos-Masmitja Grant/research support from: a grant from Pfizzer to study implementation of multidisciplinary units to manage PSA in SPAIN, Consultant of: Pfizzer, MSD, ABBVIE, Janssen, Amgen, BMS, Novartis, Lilly, Speakers bureau: Pfizzer, MSD, ABBVIE, Janssen, Amgen, BMS, Novartis, Lilly, Eva Dokoupilova Grant/research support from: Eli Lilly and Abbvie, Bernard Combe Grant/research support from: Novartis, Pfizer, Roche-Chugai, Consultant of: AbbVie; Gilead Sciences, Inc.; Janssen; Eli Lilly and Company; Pfizer; Roche-Chugai; Sanofi, Speakers bureau: Bristol-Myers Squibb; Gilead Sciences, Inc.; Eli Lilly and Company; Merck Sharp & Dohme; Pfizer; Roche-Chugai; UCB, Arnaud Constantin Grant/research support from: Study was sponsored by Sanofi Genzyme, Consultant of: Consulting fees from Abbvie, BMS, Celgene, Gilead, Janssen, Lilly, Novartis, Pfizer, Roche, Sanofi, UCB, Amanda M. Gellett Shareholder of: Eli Lilly and company, Employee of: Eli Lilly and company, Aubrey Trevelin Sprabery Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Julie Birt Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Vladimir Geneus Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Peter Nash Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Gilead, Janssen, MSD, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, MSD, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, MSD, Novartis, Pfizer Inc, Roche, Sanofi, UCB

Background:Ixekizumab (IXE), a high-affinity monoclonal antibody selectively targeting IL-17A, was superior to adalimumab (ADA) at Week (Wk) 24 for simultaneous achievement of ACR50 and 100% improvement from baseline in the Psoriasis Area and Severity Index (PASI 100) (primary endpoint) in patients (pts) with active PsA from SPIRIT-H2H1. SPIRIT-H2H had two major secondary endpoints and achieved both: noninferiority of IXE to ADA for ACR50 at Wk 24, and superiority of IXE to ADA for PASI 100 at Wk 24.Objectives:To determine how concomitant conventional synthetic DMARD (csDMARD) use affects safety and efficacy of IXE and ADA in prespecified subgroups defined by biologic monotherapy, concomitant MTX use, and concomitant csDMARD use through Wk 52 in SPIRIT-H2H.Methods:SPIRIT-H2H (NCT03151551) was a 52-week, multicentre, randomised, open-label, assessor-blinded, parallel-group study evaluating the efficacy and safety of IXE versus ADA in adults with PsA and naïve to biologic DMARDs. Patients were required to have active PsA fulfilling Classification for Psoriatic Arthritis (CASPAR) criteria and ≥3/68 tender and ≥3/66 swollen joints, ≥3% plaque psoriasis BSA involvement, no prior treatment with bDMARDs, and with prior inadequate response to ≥1 csDMARD (but not necessarily current treatment with csDMARDs). Randomization (1:1) was stratified by concomitant use of csDMARD and the presence/absence of moderate to severe PsO (baseline: BSA≥10% + PASI≥12, + static Physician’s Global Assessment≥3). Patients (N=566) received IXE/ADA through 52 wks according to the labelled dose dependent on presence/absence of moderate-to-severe PsO. In this prespecified subgroup analysis by presence or absence of csDMARDs, efficacy outcomes through wk 52 were compared between IXE and ADA using logistic regression models and Fisher’s exact tests. Missing data were imputed using non-responder imputation.Results:At baseline, 167 of 283 IXE-treated patients and 169 of 283 ADA-treated patients had concomitant MTX use. Of these, 9.0% (15/167) and 7.1% (12/169) treated with IXE and ADA, respectively, were taking an additional csDMARD (sulfasalazine, cyclosporine, or leflunomide). A significantly greater proportion of patients on IXE versus ADA achieved the primary endpoint or PASI 100 when used as monotherapy or in combination with csDMARD (Figure 1A and 1C). At Wk 52, the proportion of patients achieving ACR50 was not statistically different between IXE and ADA, regardless of monotherapy or concomitant csDMARD use (Figure 1B). A significantly higher proportion of patients achieved MDA on IXE compared to ADA in the monotherapy subgroup (49% vs 33%), while the response rates were similar in both combination subgroups (Figure 1D). These data support consistent ACR50, PASI 100, and MDA response for IXE across all three subgroups. Frequencies of adverse events were similar across the three subgroups for IXE and ADA (Figure 2).Conclusion:As with prior studies,2,3consistent efficacy across multiple PsA disease-specific endpoints was observed with IXE in SPIRIT-H2H, regardless of whether IXE was taken as monotherapy or in combination with MTX or another csDMARD. No unexpected safety signals were found for either agent.References:[1]Mease et al, Ann Rheum Dis 2020;79:123-31.[2]Coates et al, RMD Open 2017;3:e000567.[3]Nash et al, RMD Open 2018;4:e000692.Disclosure of Interests:Josef S. Smolen Grant/research support from: AbbVie, AstraZeneca, Celgene, Celltrion, Chugai, Eli Lilly, Gilead, ILTOO, Janssen, Novartis-Sandoz, Pfizer Inc, Samsung, Sanofi, Consultant of: AbbVie, AstraZeneca, Celgene, Celltrion, Chugai, Eli Lilly, Gilead, ILTOO, Janssen, Novartis-Sandoz, Pfizer Inc, Samsung, Sanofi, Anthony Sebba Consultant of: Genentech, Gilead, Lilly, Regeneron Pharmaceuticals Inc., Sanofi, Speakers bureau: Lilly, Roche, Sanofi, Eric Ruderman Consultant of: Pfizer, Amanda Gellett Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Christophe Sapin Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Aubrey Trevelin Sprabery Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Soyi Liu Leage Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Sreekumar Pillai Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Paulo Reis Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Peter Nash Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Gilead, Janssen, MSD, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, MSD, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, MSD, Novartis, Pfizer Inc, Roche, Sanofi, UCB

Background Ixekizumab (IXE), a high-affinity monoclonal antibody that selectively targets interleukin-17A, was superior to placebo (PBO) in two randomized Phase 3 studies in patients (pts) with active psoriatic arthritis (PsA).1,2 Objectives To assess the consistency of response of IXE across subgroups of pts defined by specific baseline disease characteristics. Methods Data were analyzed from an integrated database of 2 randomized, double-blind, Phase 3 studies in pts who were either biologic Disease Modifying Anti-Rheumatic Drug (bDMARD)-naive (SPIRIT-P1) or who had prior inadequate response or intolerance to TNF inhibitors (SPIRIT-P2). Analyses included pts randomly assigned to the approved dosing regimen of IXE (80 mg IXE every 4 wks [IXE Q4W] with a starting dose of 160 mg IXE) or to PBO through Wk 24. Efficacy was measured as the percentage of pts achieving ≥20%, 50%, or 70% improvement from baseline in the American College of Rheumatology criteria (ACR20/50/70) or minimal disease activity (MDA) in subgroups of pts defined by baseline presence of enthesitis, dactylitis, psoriasis body surface area (BSA) involvement ( 6 or ≤6 mg/L). Missing data were imputed by nonresponder imputation. Results Clinical response rates at Wk 24 in each subgroup are summarized (Table). Significantly (p Conclusion At Wk 24, IXE was superior to placebo for the treatment of PsA signs and symptoms regardless of baseline presence of dactylitis or enthesitis, BSA involvement, or CRP levels. References [1] Mease, et al. Ann Rheum Dis. 2017 [2] Nash, et al. Lancet. 2017 Disclosure of Interests Hans-Peter Tony Consultant for: Eli Lilly and Company, Speakers bureau: Eli Lilly and Company, Eva Galindez: None declared, Aubrey Trevelin Sprabery Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Amanda M. Gellett Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Chen-Yen Lin Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, So Young Park Employee of: Eli Lilly and Company, Clinton C Bertram Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Alexis Ogdie Grant/research support from: (To my university) Novartis, Pfizer, Grant/research support from: Novartis, Pfizer, Grant/research support from: Novartis, Pfizer, Grant/research support from: Novartis, Pfizer, Consultant for: AbbVie, Bristol-Myers Squibb, Celgene, Corrona, Eli Lilly and Company, Novartis, Pfizer, and Takeda, Consultant for: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Corrona, Eli Lilly, Novartis, Pfizer Inc, Takeda, Consultant for: Abbvie, Amgen, BMS, Celgene, Corrona, Lilly, Novartis, Pfizer, Takeda, Consultant for: Abbvie, Amgen, BMS, Celgene, Corrona, Lilly, Novartis, Pfizer, Takeda

Background Psoriatic arthritis (PsA) is a progressive, chronic inflammatory disease often treated with tumor necrosis factor inhibitors (TNFi) when conventional treatments fail. Patients with inadequate response to TNFi represent a more difficult-to-treat population. Objectives To report the efficacy of ixekizumab (IXE), a monoclonal antibody that selectively targets interleukin-17A, in patients with inadequate response to 1 TNFi or 2 TNFi. Methods In a Phase 3 study (SPIRIT-P2; NCT02349295), patients who had an inadequate response or intolerance to 1 or 2 TNFi were randomized to receive subcutaneous IXE 80 mg every 2 weeks (IXEQ2W; N=123) or every 4 weeks (IXEQ4W; N=122), after a 160-mg starting dose, or placebo (PBO; N=118) for up to 24 weeks. At Week 16, patients not meeting predefined criteria ( Results At baseline, 1-TNFi inadequate responders were, on average, 52 years of age with a PsA diagnosis for 10 years; 40% were using MTX, and HAQ-DI was 1.2. 2-TNFi inadequate responders were 52 years of age with a PsA diagnosis for 11 years; 42% were using MTX, and HAQ-DI was 1.3. Regardless of inadequate response to 1 or 2 TNFi, at Week 24 significantly more patients receiving Q4W or Q2W than PBO attained ACR50, improvement in HAQ-DI ≥0.35, MDA, DAS28-CRP, and DAPSA ≤14. Improvement persisted on all measures through Week 52. Conclusion Both IXE Q4W and Q2W improved the signs and symptoms of PsA in a population of difficult-to-treat patients who have had inadequate response to 1 or 2 TNFi. Disclosure of Interests: L Bruce Kirkham Grant/research support from: Investigator for Janssen Research & Development, LLC, Consultant for: Abbvie, Eli Lilly and Company, Janssen, Novartis, Carlos Sesin Grant/research support from: Eli Lilly and Company, Novartis, Roche, Consultant for: Eli Lilly and Company, Novartis, Pfizer, Amgen, Abbvie, Janssen, Speakers bureau: Eli Lilly and Company, Novartis, Pfizer, Celgene, Abbvie, Amgen, Radius, Regeneron/Sanofi Genzyme, Janssen, Aubrey Trevelin Sprabery Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Chen-Yen Lin Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Amanda M. Gellett Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Anthony Turkiewicz Grant/research support from: Janssen, Eli Lilly and Company, UCB, Pfizer, Regeneron Sanofi-Genzyme, Novartis, Consultant for: Janssen, Eli Lilly and Company, UCB, Pfizer, Regeneron Sanofi-Genzyme, Novartis, Abbvie, Medac, Horizon, Genentech

Background Ixekizumab (IXE) is a high-affinity monoclonal antibody that selectively targets interleukin-17A. During 24 weeks (wks) of treatment, IXE resulted in significantly greater improvements versus placebo (PBO) in the signs and symptoms of active psoriatic arthritis (PsA) in two randomized Phase 3 studies.1,2 Objectives To evaluate the consistency of clinical response with IXE in demographic subsets of patients (pts) with active PsA. Methods Clinical response to IXE was analyzed from an integrated database of 2 randomized, double-blind, Phase 3 studies in biologic Disease Modifying Anti-Rheumatic Drug (bDMARD)-naive (SPIRIT-P1) pts or in pts with prior inadequate response or intolerance to TNF inhibitors (SPIRIT-P2). Analyses were conducted on subgroups defined by sex, body mass index (BMI), and duration of disease ( Results Response rates at Wk 24 (Table) were significantly (p Conclusion IXE was superior to PBO in the treatment of pts with active PsA at Wk 24 regardless of sex or disease duration, as well as in normal, overweight, and obese BMI subgroups. References [1] Mease, et al. Ann Rheum Dis. 2017 [2] Nash, et al. Lancet. 2017 Disclosure of Interests Lihi Eder Grant/research support from: AbbVie, Eli Lilly and Company, Amgen, Celgene, UCB, Janssen, Novartis, and Pfizer, Consultant for: AbbVie, Eli Lilly and Company, Amgen, Celgene, UCB, Janssen, Novartis, and Pfizer, Satish Odhav Grant/research support from: AbbVie, Ardea Biosciences, AstraZeneca, BMS, Celgene Corporation, Centocor, Eli Lilly and Company, Galapagos, Genentech, GSK, Human Genome Sciences, Janssen, Merck, Mesoblast, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi-Aventis, Takeda Pharmaceuticals, UCB, and Vertex Pharmaceuticals, Consultant for: AbbVie, Ardea Biosciences, AstraZeneca, BMS, Celgene Corporation, Centocor, Eli Lilly and Company, Galapagos, Genentech, GSK, Human Genome Sciences, Janssen, Merck, Mesoblast, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi-Aventis, Takeda Pharmaceuticals, UCB, and Vertex Pharmaceuticals, Speakers bureau: AbbVie, Ardea Biosciences, AstraZeneca, BMS, Celgene Corporation, Centocor, Eli Lilly and Company, Galapagos, Genentech, GSK, Human Genome Sciences, Janssen, Merck, Mesoblast, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi-Aventis, Takeda Pharmaceuticals, UCB, and Vertex Pharmaceuticals, Mariusz Korkosz Consultant for: Eli Lilly and Company, Novartis, Roche, MSD, UCB, and AbbVie, Speakers bureau: Eli Lilly and Company, Novartis, Roche, MSD, UCB, and AbbVie, Aubrey Trevelin Sprabery Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Amanda M. Gellett Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Chen-Yen Lin Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, So Young Park Employee of: Eli Lilly and Company, Clinton C Bertram Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Alexis Ogdie Grant/research support from: (To my university) Novartis, Pfizer, Grant/research support from: Novartis, Pfizer, Grant/research support from: Novartis, Pfizer, Grant/research support from: Novartis, Pfizer, Consultant for: AbbVie, Bristol-Myers Squibb, Celgene, Corrona, Eli Lilly and Company, Novartis, Pfizer, and Takeda, Consultant for: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Corrona, Eli Lilly, Novartis, Pfizer Inc, Takeda, Consultant for: Abbvie, Amgen, BMS, Celgene, Corrona, Lilly, Novartis, Pfizer, Takeda, Consultant for: Abbvie, Amgen, BMS, Celgene, Corrona, Lilly, Novartis, Pfizer, Takeda

Background:Ixekizumab (IXE) is a high affinity monoclonal antibody that selectively targets interleukin-17A. In the SPIRIT-P2 study, IXE every 4 (Q4W) or 2 (Q2W) weeks was superior to placebo (PBO) in improving the signs and symptoms of psoriatic arthritis (PsA) at Week 24 in patients (pts) with prior inadequate response or intolerance to 1 or 2 tumor necrosis factor inhibitors (TNFi).Objectives:To determine efficacy and safety of IXE treatment up to 3 years in pts with PsA.Methods:In SPIRIT-P2 (NCT02349295), 310 pts entered the extension period where pts maintained their original ixekizumab dose, and placebo pts received IXEQ4W or IXEQ2W (1:1). Pts failing to demonstrate ≥20% improvement in both tender and swollen joint counts at Week 32, or any subsequent visit, were discontinued (mandatory discontinuation criteria). Efficacy outcomes were ACR20/50/70 response, Psoriasis Area and Severity Index (PASI) 75/90/100 response, Leeds Enthesitis Index (LEI), Leeds Dactylitis Index-Basic (LDI-B), Minimal Disease Activity (MDA), and Disease Activity in Psoriatic Arthritis (DAPSA). Ad-hoc efficacy data are presented for intent-to-treat (ITT) pts initially randomized to IXE at Week 0. Observed and modified non-responder imputation (mNRI; missing data treated as non-response for pts discontinued due to lack of efficacy or adverse events [AEs]) was applied to categorical measures. Observed and modified baseline observation carried forward (mBOCF) was applied to continuous efficacy measures. Safety was analysed in pts exposed to at least one dose of IXE.Results:Of the 245 pts initially randomized to IXE at Week 0 (ITT), 64 (26.1%) pts discontinued due to lack of efficacy and 22 (9.0%) pts due to mandatory discontinuation criteria. Efficacy results are summarized below (Figure 1). Pts in SPIRIT-P2 who received IXEQ4W and IXEQ2W for 156 weeks reported sustained improvement in ACR responses and manifestations of PsA, including enthesitis, dactylitis, and skin outcomes. Treat-to-target measures such as MDA and DAPSA (Low Disease Activity or Remission) were achieved by 30.8% and 47.7% of pts, respectively on IXEQ4W, and by 29.2% and 40.7% of pts, respectively on IXEQ2W. Incidence rates (IR) of treatment-emergent adverse events (TEAEs) are provided below (Figure 2). Most TEAEs were mild or moderate in severity, and 38 out of 337 (5.9%) pts (safety population) discontinued due to AEs. The most common TEAEs were infections (IR=33.1) and injection site reactions (IR=5.4). Three deaths were reported in the study.Figure 1.Efficacy Outcome Measures at Week 156 (Intent-to-treat Population).ACR=American College of Rheumatology; IXE=ixekizumab; LEI=Leeds Enthesitis Index; LDI-B=Leeds Dactylitis Index-Basic; mNRI=modified non-responder imputation; PASI=Psoriasis Area and Severity Index; Q2W=every two weeks; Q4W=every four weeks.Figure 2.Safety Outcome Measures (Weeks 0-156).Safety was analysed in patients exposed to at least one dose of ixekizumab. During the double-blind treatment period (Weeks 0-24), one patient reported serious adverse events of anal fistula and anal abscess, which were considered by the sponsor to be IBD; however, an independent adjudication committee of external experts reviewed the case and determined the events to be “Not IBD.”Conclusion:In pts treated with IXE who had prior inadequate response or intolerance to 1 or 2 TNFi, improvements in the signs and symptoms of PsA persisted up to 3 years. No unexpected safety signals were observed, and the safety profile was consistent with previous studies of IXE.Disclosure of Interests:Jordi Gratacos-Masmitja Grant/research support from: a grant from Pfizzer to study implementation of multidisciplinary units to manage PSA in SPAIN, Consultant of: Pfizzer, MSD, ABBVIE, Janssen, Amgen, BMS, Novartis, Lilly, Speakers bureau: Pfizzer, MSD, ABBVIE, Janssen, Amgen, BMS, Novartis, Lilly, Anthony Turkiewicz Grant/research support from: Received research grants from AbbVie, Eli Lilly and Company, Janssen, Novartis, and Pfizer, Consultant of: Received consulting fees from AbbVie, Eli Lilly and Company, Janssen, Novartis, and Pfizer, Speakers bureau: On speaker bureau for Abbvie, Eli Lilly and Company, Janssen, Novartis, Pfizer, Eva Dokoupilova Grant/research support from: Eli Lilly, AbbVie, Novartis, Amanda M. Gellett Shareholder of: Eli Lilly and company, Employee of: Eli Lilly and company, Aubrey Trevelin Sprabery Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Vladimir J. Geneus Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Arnaud Constantin Grant/research support from: Study was sponsored by Sanofi Genzyme, Consultant of: Consulting fees from Abbvie, BMS, Celgene, Gilead, Janssen, Lilly, Novartis, Pfizer, Roche, Sanofi, UCB

S1P (sphingosine 1-phosphate) is a pleiotropic lipid mediator involved in numerous cellular and physiological functions. Of note among these are cell survival and migration, as well as lymphocyte trafficking. S1P, which exerts its effects via five GPCRs (G-protein-coupled receptors) (S1P1–S1P5), is formed by the action of two SphKs (sphingosine kinases). Although SphK1 is the more intensively studied isotype, SphK2 is unique in it nuclear localization and has been reported to oppose some of the actions ascribed to SphK1. Although several scaffolds of SphK1 inhibitors have been described, there is a scarcity of selective SphK2 inhibitors that are necessary to evaluate the downstream effects of inhibition of this isotype. In the present paper we report a cationic amphiphilic small molecule that is a selective SphK2 inhibitor. In the course of characterizing this compound in wild-type and SphK-null mice, we discovered that administration of the inhibitor to wild-type mice resulted in a rapid increase in blood S1P, which is in contrast with our SphK1 inhibitor that drives circulating S1P levels down. Using a cohort of F2 hybrid mice, we confirmed, compared with wild-type mice, that circulating S1P levels were higher in SphK2-null mice and lower in SphK1-null mice. Thus both SphK1 and SphK2 inhibitors recapitulate the blood S1P levels observed in the corresponding null mice. Moreover, circulating S1P levels mirror SphK2 inhibitor levels, providing a convenient biomarker of target engagement.

Lysophosphatidic acid (LPA) designates a family of bioactive phosphoglycerides that differ in the length and degree of saturation of their radyl chain. Additional diversity is provided by the linkage of the radyl chain to glycerol: acyl, alkyl, or alk-1-enyl. Acyl-LPAs are the predominate species in tissues and biological fluids. Alkyl-LPAs exhibit distinct pharmacodynamics at LPA receptors, potently drive platelet aggregation, and contribute to ovarian cancer aggressiveness. Multiple biosynthetic pathways exist for alkyl-LPA production. Herein we report that diacylglycerol kinases (DGKs) contribute to cell-associated alkyl-LPA production involving phosphorylation of 1-alkyl-2-acetyl glycerol and document the biosynthesis of alkyl-LPA by DGKs in SKOV-3 ovarian cancer cells, specifically identifying the contribution of DGKα. Concurrently, we discovered that treating SKOV-3 ovarian cancer cell with a sphingosine analog stimulates conversion of exogenous 1-alkyl-2-acetyl glycerol to alkyl-LPA, indicating that DGKα contributes significantly to the production of alkyl-LPA in SKOV-3 cells and identifying cross-talk between the sphingolipid and glycerol lipid pathways.

S1P (sphingosine 1-phosphate) is a signalling molecule involved in a host of cellular and physiological functions, most notably cell survival and migration. S1P, which signals via a set of five G-protein-coupled receptors (S1P1–S1P5), is formed by the action of two SphKs (sphingosine kinases) from Sph (sphingosine). Interfering RNA strategies and SphK1 (sphingosine kinase type 1)-null (Sphk1−/−) mouse studies implicate SphK1 in multiple signalling cascades, yet there is a paucity of potent and selective SphK1 inhibitors necessary to evaluate the effects of rapid onset inhibition of this enzyme. We have identified a set of submicromolar amidine-based SphK1 inhibitors and report using a pair of these compounds to probe the cellular and physiological functions of SphK1. In so doing, we demonstrate that our inhibitors effectively lower S1P levels in cell-based assays, but we have been unable to correlate SphK1 inhibition with changes in cell survival. However, SphK1 inhibition did diminish EGF (epidermal growth factor)-driven increases in S1P levels and Akt (also known as protein kinase B)/ERK (extracellular-signal-regulated kinase) phosphorylation. Finally, administration of the SphK1 inhibitor to wild-type, but not Sphk1−/−, mice resulted in a rapid decrease in blood S1P levels indicating that circulating S1P is rapidly turned over.

The synthesis of a new unnatural amino acid, Nα-Ne-(ferrocene-1-acetyl)- l -lysine, was achieved by coupling a ferroceneacetic acid molecule onto the side chain amine of a lysine. The structure of the compound provides options for incorporation of the molecule into peptides or large proteins. In addition, Nα-Ne-(ferrocene-1-acetyl)- l -lysine exhibits nuclease activity. It is expected that incorporation of this ferrocenyl amino acid into any nucleic acid-binding protein will endow the protein with nuclease capability.

The nucleolytic activity of an unnatural ferrocenyl amino acid can be significantly enhanced under reducing or Fenton conditions while exploiting different mechanisms of DNA cleavage. In addition, results from high resolution electrophoresis indicate that the ferrocenyl amino acid exhibits non-sequence specific cleavage of the DNA backbone.