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Safety and efficacy of ixekizumab in patients with PsA and previous inadequate response to TNF inhibitors: week 52 results from SPIRIT-P2.

ABSTRACT: Objectives:To assess the long-term safety and efficacy of ixekizumab, an IL-17A antagonist, in patients with active PsA. Methods:In SPIRIT-P2 (NCT02349295), patients (n = 363) with previous inadequate response to TNF inhibitors entered the double-blind period (weeks 0-24) and received placebo or ixekizumab 80 mg every 4 weeks (IXEQ4W) or every 2 weeks (IXEQ2W) following a 160-mg starting dose at week 0. During the extension period (weeks 24-156), patients maintained their original ixekizumab dose, and placebo patients received IXEQ4W or IXEQ2W (1:1). We present the accumulated safety findings (week 24 up to 156) at the time of this analysis for patients who entered the extension period (n = 310). Exposure-adjusted incidence rates (IRs) per 100 patient years are presented. ACR responses are presented on an intent-to-treat basis using non-responder imputation up to week 52. Results:From week 24 up to 156 (with 228 patient years of ixekizumab exposure), 140 [61.3 IR] and 15 (6.6 IR) patients reported infections and serious adverse events, respectively. Serious adverse events included one death and four serious infections. In all patients initially treated with IXEQ4W and IXEQ2W at week 0 (non-responder imputation), ACR20 (61 and 51%), ACR50 (42 and 33%) and ACR70 (26 and 18%) responses persisted out to week 52. Placebo patients re-randomized to ixekizumab demonstrated efficacy as measured by ACR responses at week 52. Conclusion:During the extension period, the overall safety profile of ixekizumab remained consistent with that observed with the double-blind period, and clinical improvements persisted up to 1 year.

SUBMITTER: Genovese MC

PROVIDER: S-EPMC6199530 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Safety and efficacy of ixekizumab in patients with PsA and previous inadequate response to TNF inhibitors: week 52 results from SPIRIT-P2.

Genovese Mark C MC Combe Benard B Kremer Joel M JM Tsai Tsen-Fang TF Behrens Frank F Adams David H DH Lee Chin C Kerr Lisa L Nash Peter P

Rheumatology (Oxford, England) 20181101 11

<h4>Objectives</h4>To assess the long-term safety and efficacy of ixekizumab, an IL-17A antagonist, in patients with active PsA.<h4>Methods</h4>In SPIRIT-P2 (NCT02349295), patients (n = 363) with previous inadequate response to TNF inhibitors entered the double-blind period (weeks 0-24) and received placebo or ixekizumab 80 mg every 4 weeks (IXEQ4W) or every 2 weeks (IXEQ2W) following a 160-mg starting dose at week 0. During the extension period (weeks 24-156), patients maintained their original ...[more]

PMID: 30053162

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Project description:PurposeIxekizumab 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.MethodsIn 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.ResultsOf 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).ConclusionIn 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 registrationClinicalTrials.gov identifier: NCT02349295.

Project description:IntroductionIn 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.MethodsIn 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.ResultsBy 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.ConclusionIn 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.

Project description:Introduction/objectivesTo evaluate the three-year efficacy and safety of ixekizumab with and without concomitant conventional synthetic disease-modifying antirheumatic drug (csDMARD) use in patients with active psoriatic arthritis (PsA).MethodPatients with PsA who were biologic-naïve (SPIRIT-P1, NCT01695239) or had prior inadequate response to tumor necrosis factor inhibitors (SPIRIT-P2, NCT02349295) were randomized to receive 80-mg ixekizumab every four weeks after receiving 160-mg ixekizumab at baseline. Efficacy, safety, and immunogenicity were evaluated in this post-hoc analysis in three subgroups: (1) ixekizumab monotherapy, (2) ixekizumab and methotrexate (MTX), (3) ixekizumab and any csDMARD (including MTX). Missing data were imputed using multiple imputation for continuous variables and modified non-responder imputation for categorical variables.ResultsEfficacy was similar across the three subgroups with 59.1%, 67.0%, and 66.1% of ixekizumab-treated patients achieving 20% improvement in the American College of Rheumatology scale score at week 156. Radiographic progression of structural joint damage (SPIRIT-P1 only) was similarly inhibited across the three subgroups with several outliers. No new safety signals were reported, and 91.0%, 84.1%, and 83.2% in the three subgroups reported ≥ 1 treatment-emergent adverse event. At week 156, 15.9%, 13.1%, and 11.0% in the three subgroups had antidrug antibodies; most had low titer status.ConclusionsIxekizumab showed sustained efficacy in treating patients with PsA for up to three years in monotherapy or in combination with MTX or any csDMARD. The three subgroups had similar safety and immunogenicity profiles, which supports that the use of concomitant MTX or csDMARDs does not seem to impact the benefit/risk profile of ixekizumab. Key Points • Ixekizumab treatment led to improved clinical responses over time when used as monotherapy or in combination with concomitant MTX or any concomitant csDMARD (including MTX) in patients with active PsA. • Ixekizumab monotherapy has similar radiographic efficacy as ixekizumab with MTX or ixekizumab with other csDMARDs (including MTX); similar inhibition of radiographic progression was observed between the subgroups of patients receiving ixekizumab monotherapy or ixekizumab with MTX or other csDMARDs. • The long-term safety profile of ixekizumab used as monotherapy or in combination with MTX or any other csDMARDs is consistent with what has been previously reported. The addition of MTX or any csDMARD to ixekizumab treatment did not negatively impact the favorable long-term safety profile of ixekizumab.

Project description:BackgroundThis analysis assessed improvements in patients with radiographic axial spondyloarthritis (r-axSpA) treated with ixekizumab in the Assessment of Spondyloarthritis International Society (ASAS) treatment response domains and additional patient-reported outcomes at 1 year of treatment.MethodsCOAST-V and COAST-W were 52-week, phase 3, randomized controlled trials evaluating the efficacy and safety of ixekizumab in biologic disease-modifying antirheumatic drug (bDMARD)-naïve and tumor necrosis factor inhibitor (TNFi)-experienced patients with radiographic spondyloarthritis, respectively. Patients were treated with 80-mg ixekizumab either every 2 weeks or every 4 weeks. Patient-reported outcomes included Patient Global Disease Activity, Spinal Pain, stiffness as measured by Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) Questions 5 and 6, function as measured by the Bath Ankylosing Spondylitis Functional Index, fatigue as measured by the Fatigue Numeric Rating Scale and BASDAI question 1, Spinal Pain at Night, and sleep quality as measured by the Jenkins Sleep Evaluation Questionnaire. Mixed-effects models for repeated measures were used to analyze changes from baseline in patient-reported outcomes from weeks 1 to 16, and descriptive statistics were reported from weeks 20 to 52. Analysis of covariance with Scheffé's method was used for the ASAS response association analyses.ResultsThis study assessed 341 bDMARD-naïve and 316 TNFi-experienced patients in the placebo-controlled blinded treatment dosing period (weeks 1-16) as well as 329 bDMARD-naïve and 281 TNFi-experienced patients in the dose double-blind extended treatment period (weeks 20-52). bDMARD-naïve or TNFi-experienced patients treated with ixekizumab every 2 weeks and every 4 weeks reported improvements in patient global disease activity, spinal pain, function, stiffness, fatigue, spinal pain at night, and sleep quality through week 52. Greater correlations with improvements in all response domains were seen when comparing ASAS40 responders to ASAS20 non-responders (p < 0.001), with up to 10.5-fold greater improvements observed in ASAS40 responses compared with ASAS20 non-responders. Function and fatigue demonstrated the highest values.ConclusionsIxekizumab-treated bDMARD-naïve and TNFi-experienced patients with radiographic axial spondyloarthritis achieving ASAS40 reported sustained and consistent improvement in all ASAS response domains and other patient-reported outcomes though week 52, with spinal pain, function, and stiffness as major drivers of the response.Trial registrationNCT02696785 and NCT02696798 , March 2, 2016.

Project description:ObjectiveTo evaluate the effect of ixekizumab on self-reported functioning and health in patients with active nonradiographic axial spondyloarthritis (SpA).MethodsCOAST-X was a randomized, controlled trial conducted in patients with nonradiographic axial SpA over 52 weeks. Participants were randomized at a ratio of 1:1:1 to receive 80 mg of ixekizumab subcutaneously every 4 weeks or 2 weeks or placebo for 52 weeks. Self-reported functioning and health end points included the Medical Outcomes Study Short Form 36 (SF-36) health survey, Assessment of Spondyloarthritis International Society (ASAS) health index, and European Quality of Life-5 Dimensions-5 Level (EQ-5D-5L) health-utility descriptive system.ResultsCompared to placebo, ixekizumab treatment resulted in improvement of SF-36 physical component summary scores from baseline, with a score of 4.7 improving to 8.9 with ixekizumab therapy every 4 weeks (P < 0.05) and a score of 9.3 with ixekizumab therapy every 2 weeks (P < 0.01); the greatest improvements were observed in the domains of physical functioning, role-physical, and bodily pain at weeks 16 and 52. A higher proportion of patients receiving ixekizumab therapy every 2 weeks reported ≥3 improvements based on the ASAS health index from baseline to weeks 16 and 52 (P < 0.05). Significantly more patients receiving ixekizumab every 4 weeks reported improvements in "good health status" on the ASAS health index (ASAS score of ≤5) at weeks 16 and 52 (P < 0.05). Patients receiving ixekizumab reported improvements on the EQ-5D-5L compared to those who received placebo at week 16 (0.11 versus 0.17 for patients receiving treatment every 4 weeks and 0.19 for patients receiving treatment every 2 weeks; P < 0.05), which remained consistent at week 52. There were no clinical meaningful differences in responses based on the ixekizumab dosing regimen for patients who received ixekizumab therapy every 2 weeks or every 4 weeks.ConclusionIn patients with nonradiographic axial SpA, therapy with ixekizumab was superior to placebo in the improvement of self-reported functioning and health at weeks 16 and 52.

Project description:IntroductionA previous network meta-analysis established 16-week relative efficacy with bimekizumab, an inhibitor of interleukin (IL)-17F in addition to IL-17A, versus other treatments for patients with radiographic axial spondyloarthritis (r-axSpA; i.e., ankylosing spondylitis), including the IL-17A inhibitors secukinumab and ixekizumab. This matching-adjusted indirect comparison (MAIC) assessed 52-week relative efficacy of bimekizumab versus secukinumab and ixekizumab.MethodsIndividual patient data from BE MOBILE 2 (bimekizumab 160 mg; N = 220) were matched to pooled summary data from MEASURE 1/2/3/4 (secukinumab 150 mg), MEASURE 3 (secukinumab 300 mg; escalated dose for inadequate responders), COAST-V (ixekizumab) and COAST-V/-W (ixekizumab). BE MOBILE 2 patients were reweighted using propensity score weights based on age, sex, ethnicity, tumor necrosis factor inhibitor (TNFi) exposure, weight, baseline ASDAS and BASFI (secukinumab) and baseline BASDAI (ixekizumab), and 52-week efficacy outcomes from the trial recalculated. Odds ratios (OR) or mean difference for unanchored comparisons are reported with 95% confidence intervals (CI).ResultsAt week 52, MAIC demonstrated that patients may have higher likelihood of improvement in key efficacy outcomes with bimekizumab versus secukinumab 150 mg (e.g., ASAS40: [OR (95% CI): 1.48 (1.05, 2.10); p = 0.026]; effective sample size [ESS] = 177). Differences in 52-week efficacy outcomes between bimekizumab and secukinumab 300 mg dose escalation were non-significant (ESS = 120). Bimekizumab versus ixekizumab 80 mg comparisons (COAST-V only; ESS = 84) also suggested that differences were non-significant for most key efficacy outcomes. Other ixekizumab comparisons (COAST-V/-W; ESS = 45) suggested bimekizumab may have higher comparative efficacy for many of the same efficacy outcomes, however ixekizumab analyses were limited by poor population overlap, likely due to the greater proportion of patients with previous TNFi exposure.ConclusionsPatients treated with bimekizumab may have a higher likelihood of achieving improved longer-term efficacy versus secukinumab 150 mg, suggesting bimekizumab may be a favorable therapeutic option for r-axSpA. Differences in efficacy outcomes with bimekizumab versus ixekizumab 80 mg were mostly non-significant, depending on the populations considered.

Dataset Information

Safety and efficacy of ixekizumab in patients with PsA and previous inadequate response to TNF inhibitors: week 52 results from SPIRIT-P2.

Publications

Safety and efficacy of ixekizumab in patients with PsA and previous inadequate response to TNF inhibitors: week 52 results from SPIRIT-P2.

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