INTERVENTION: Product Name: Ixekizumab Product Code: LY2439821 Pharmaceutical Form: Solution for injection in pre‐filled syringe INN or Proposed INN: Ixekizumab CAS Number: 1143503‐69‐8 Current Sponsor code: LY2439821 Other descriptive name: Monoclonal Antibody (MAb) Concentration unit: ml millilitre(s) Concentration type: equal Concentration number: 80‐ Pharmaceutical form of the placebo: Solution for injection in pre‐filled syringe Route of administration of the placebo: Subcutaneous use Trade Name: Adalimumab Product Name: Adalimumab Pharmaceutical Form: Solution for injection in pre‐filled syringe INN or Proposed INN: ADALIMUMAB CAS Number: 331731‐18‐1 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 40‐ Pharmaceutical form of the placebo: Solution for injection in pre‐filled syringe Route of administration of the placebo: Subcutaneous use CONDITION: Arthritic Psoriasis ; MedDRA version: 14.1 Level: LLT Classification code 10037160 Term: Psoriatic arthritis System Organ Class: 100000004859 Therapeutic area: Diseases [C] ‐ Musculoskeletal Diseases [C05] PRIMARY OUTCOME: Main Objective: Efficacy of ixekizumab (LY2439821) compared to placebo in participants with active psoriatic arthritis based on ACR20 at 24 Weeks Primary end point(s): American College of Rheumatology 20 Index (ACR20) Secondary Objective: · Efficacy of ixekizumab (LY2439821) compared to placebo in participants with active psoriatic arthritis based on modified Total Sharp Score (mTSS) through 24 weeks; · Efficacy of ixekizumab (LY2439821) compared to placebo in participants with active psoriatic arthritis based on ACR20 through 24 Weeks; · Efficacy of ixekizumab (LY2439821) compared to placebo in participants with active psoriatic arthritis based on Non‐Arthritic Disease Assessments through 24 Weeks; · Efficacy of ixekizumab (LY2439821) compared to placebo in participants with active psoriatic arthritis based on Patient Reported Outcomes (PROs) through 24 Weeks Timepoint(s) of evaluation of this end point: At 24 Weeks SECONDARY OUTCOME: Secondary end point(s): · modified Total Sharp Score (mTSS) ; · ACR20 ; · Non‐Arthritic Disease Assessments ; · Patient Reported Outcomes (PRO) ; Timepoint(s) of evaluation of this end point: Baseline through 24 Weeks INCLUSION CRITERIA: • Presents with established diagnosis of active psoriatic arthritis for at least 6 months, and currently meets Classification for Psoriatic Arthritis (CASPAR) criteria • Active psoriatic arthritis (PsA) defined as the presence of at least 3 tender and at least 3 swollen joints • Presence of active psoriatic skin lesion or a history of plaque psoriasis (Ps) • Men must agree to use a reliable method of birth control or remain abstinent during the study • Women must agree to use reliable birth control or remain abstinent during the study and for at least 12 weeks after stopping treatment Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range 392 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 20
Background: Psoriatic arthritis (PsA) is a chronic immune-mediated inflammatory disease associated with psoriasis, peripheral arthritis, enthesitis, dactylitis, and spondylitis. Ixekizumab (IXE) is an IgG4 monoclonal antibody that binds with high affinity and specificity to the proinflammatory cytokine IL-17A. Results are presented for the phase 3 trial (SPIRIT-P1) with IXE treatment of patients with active PsA. Objectives: To evaluate the efficacy and safety of IXE when used alone or in combination with concomitant conventional DMARDs (cDMARDs). Methods: A total of 417 bDMARD-naive adult patients were randomly assigned 1:1:1:1 to subcutaneous administration of 80-mg IXE every 4 wks (Q4W) or every 2 wks (Q2W), each starting with a 160-mg dose at Wk 0; adalimumab (ADA) 40 mg Q2W (active comparator); or placebo (PBO) during the Double-Blind Treatment Period (DBTP; Wks 0 through 24). Of these patients, 267 were receiving a concomitant cDMARD at baseline, 149 were not, and 1 did not receive study drug; patients were stratified by cDMARD use, and were to remain on their cDMARD through the DBTP. At Wk 24, efficacy was evaluated by American College of Rheumatology (ACR) response; and progression of structural damage was assessed by the modified Total Sharp Score (mTSS). Safety assessments included the percentage of patients experiencing treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and discontinuations due to adverse events (AEs). Efficacy analyses were conducted on the Intent-to-Treat Population, defined as all randomly assigned patients; safety analyses were conducted on the Safety Population, defined as all randomly assigned patients who received at least 1 dose of study drug. Fisher's test was used for treatment comparisons in ACR and AE data, and an analysis of covariance model was used for mTSS data. Missing values were imputed by nonresponder imputation for ACR data and by linear extrapolation for mTSS data. Results: At Wk 24, compared with patients receiving PBO, significantly more patients receiving IXEQ4W or IXEQ2W (with/without concomitant cDMARD) achieved ACR20/50/70 responses (see Table for ADA results). Patients receiving IXEQ2W (with/without concomitant cDMARD) or IXEQ4W or ADA (with concomitant cDMARD) showed significantly less progression in mTSS from baseline compared with patients receiving PBO (Table). No treatment-by-subgroup effects were observed for ACR20/50/70 or mTSS (Table footnotes). In patients receiving concomitant cDMARDs, significantly more patients receiving IXE or ADA experienced ≥1 TEAE, compared with patients receiving PBO; the percentages of patients with SAEs or discontinuations due to an AE were comparable among treatment groups (Table). (Table presented) Conclusions: IXE demonstrated efficacy in improvement of PsA signs and symptoms and structural inhibition in bDMARD-naive patients with/without concomitant cDMARD use. With concomitant cDMARD use, although significantly more patients receiving IXE or ADA experienced ≥1 TEAE, compared with patients receiving PBO, the frequency of SAEs and discontinuations due to an AE were comparable among all treatment groups.
Background: Ixekizumab (IXE) is an IgG4 monoclonal antibody that binds with high affinity and specificity to the proinflammatory cytokine IL-17A. In this phase 3 study (SPIRIT-P1), IXE was superior to placebo (PBO) in achieving American College of Rheumatology 20 (ACR20) response at Week 24 in biologic disease-modifying antirheumatic drug-naive (bDMARD-naive) patients with active psoriatic arthritis (PsA)1. Objectives: To evaluate efficacy and safety of IXE over 52 weeks in patients with active PsA. Methods: A total of 417 bDMARD-naive patients with active PsA were randomized 1:1:1:1 to IXE 80 mg once every 4 weeks (Q4W) or once every 2 weeks (Q2W) including a 160 mg starting dose, to 40 mg adalimumab (ADA), or to PBO (all subcutaneous dosing) during the Double-Blind Treatment Period (DBTP: Weeks 0 to 24). Of these, 381 patients completed the DBTP and entered the Extension Period (EP: Weeks 24 to 52) where they were assigned to 80 mg IXE Q4W or Q2W. Patients randomized to IXE at Week 0 continued the same dose regimen in the EP. Patients randomized to PBO or ADA at Week 0 were re-randomized (1:1) to 80 mg IXE Q4W or Q2W at Week 16 (inadequate responders) or 24. Those patients who initially received PBO started IXE at Week 16 or 24; patients who initially received ADA started IXE at Week 24 or 32 after an 8 week wash out period. Efficacy measures included ACR20/50/70 response, Health Assessment Questionnaire-Disability Index (HAQ-DI) Score, Disease Activity Score 28 diarthrodial joint count based on C-reactive protein (DAS 28-CRP), Psoriasis Area and Severity Index 75, 90, 100 (PASI 75/90/100), Leeds Enthesitis Index (LEI), and Leeds Dactylitis Index-Basic (LDI-B). Efficacy and safety were analyzed using the EP population defined as all patients who received at least 1 dose of study drug in the EP. Missing values were imputed by nonresponder imputation for categorical data and modified baseline observation carried forward for continuous data. Results: A total of 304 patients completed the EP. Efficacy and safety results in the EP population are summarized in Table 1. Improvements from baseline in ACR20/50/70, HAQ-DI, DAS 28-CRP, PASI 75/90/100, LEI and LDI-B were observed at Week 52. The frequency of treatment-emergent adverse events (AEs) in the EP was similar to that observed in the DBTP; the majority were mild or moderate in severity. Serious AEs occurred in 12 patients and no deaths occurred in the EP population. Conclusions: IXE demonstrated clinically significant improvement in signs and symptoms of PsA including arthritis, dactylitis and enthesitis as well as skin manifestations across treatment groups in the EP. The safety profile of IXE observed in the EP was similar to that observed in the DBTP and other phase 3 studies of IXE in patients with plaque psoriasis (UNCOVER studies).
Introduction: Approximately 6% to 42% of patients with psoriasis suffer from comorbid PsA, a progressive and destructive auto‐inflammatory disease. PsA has a significant negative impact on patients' physical function, quality of life, and work productivity; therefore, improving patient‐reported outcomes (PROs) is critical in enhancing the lives of patients with PsA. Patients treated with ixekizumab (IXE), a high affinity monoclonal antibody that selectively targets interleukin‐17A, reported significant improvements in PROs during the 24‐week, placebo (PBO)‐controlled period of the Phase 3 SPIRIT‐P1 trial. Objectives: To evaluate whether an effect of IXE on improvement of PROs is also observed at week 52 in SPIRIT‐P1. Materials and Methods: 417 bDMARD‐naive patients with active PsA were randomly assigned to subcutaneous administration of 80 mg IXE every 4 weeks (Q4W) or 2 weeks (Q2W), each with a 160 mg starting dose at week 0, adalimumab (ADA) 40 mg Q2W (active control), or PBO in the Double‐Blind Treatment Period (weeks 0 through 24). 381 patients continued into the Extension Period (EP; weeks 24 through 52). PBO‐ and ADA‐ treated patients were randomly re‐assigned (to 80 mg IXEQ4W or IXEQ2W at week 24; ADA‐treated patients started IXE after an 8‐week wash‐out period at week 32. Analyses for the EP were conducted on the EP Population, patients who received at least 1 dose of study drug during the EP. Missing values were imputed by nonresponder imputation for categorical data and modified baseline observation carried forward for continuous data. Results: Physician‐assessed clinical efficacy was shown by achievement of American College of Rheumatology (ACR) 20 response by 69% of patients receiving IXE for 52 weeks. Patients treated with IXE for 52 weeks reported improvements (mean change from baseline [standard deviation]) in Health Assessment Questionnaire ‐ Disability Index (HAQ‐DI; IXEQ4W = ‐0.53 [0.56], IXEQ2W = ‐0.55 [0.52]); Short Form‐36 Health Survey Physical Component Summary (IXEQ4W = 9.5 [9.5], IXEQ2W = 9.2 [9.4]); itch numeric rating scale (IXEQ4W = ‐3.3 [2.51], IXEQ2W = ‐3.5 [3.06]); and Work Productivity and Activity Impairment‐Specific Health Problem (presenteeism: IXEQ4W = ‐23.6 [27.0], IXEQ2W = ‐25.4 [21.3]; work productivity: IXEQ4W = ‐25.3 [28.0], IXEQ2W = ‐24.9 [22.9]; and activity impairment: IXEQ4W = ‐26.2 [26.9], IXEQ2W = ‐29.1 [24.1]) that were similar to improvements reported at week 24 (see Introduction). The percentages of patients with improvement from baseline HAQ‐DI score >0.35 achieving minimally clinically important difference for HAQ‐DI were similar at week 52 (IXEQ4W = 57.1%, IXEQ2W = 57.1%) to the percentages observed at week 24. Conclusion: IXE provides sustained improvement through 52 weeks in physical function, quality of life, and work productivity in bDMARD‐naive patients with active PsA.
Background: Psoriatic arthritis (PsA) is a chronic immune-mediated inflammatory disease associated with psoriasis, peripheral arthritis, enthesitis, dactylitis, and spondylitis. PsA can be progressive and destructive, resulting in physical deformities, impaired function, decreased quality of life, and increased mortality. Ixekizumab (IXE) is an IgG4 monoclonal antibody that binds with high affinity and specificity to the proinflammatory cytokine IL-17A. Results are presented from a phase 3 trial (SPIRIT-P1; NCT01695239) with IXE in patients with active PsA. Objectives: To explore the impact of IXE, as assessed by disease activity composite measures, up to 52 weeks (wks). Methods: A total of 417 bDMARD-naive adult patients with active PSA, were randomly assigned 1:1:1:1 to subcutaneous administration of either 80-mg IXE every 4 wks (Q4W) or every 2 wks (Q2W), each with a 160-mg starting dose at Wk 0; adalimumab (ADA) 40 mg Q2W (active comparator); or placebo (PBO) in the Double-Blind Treatment Period (DBTP; Wks 0 through 24). Of these patients, 381 continued into the Extension Period (EP; Wks 24 through 52). PBO- and ADA-treated patients were randomly re-assigned (1:1) to 80 mg IXEQ4W or IXEQ2W at Wk 16 (inadequate responders) or Wk 24; ADA-treated patients started IXE, after an 8-wk wash-out period, at Wk 24 (inadequate responders) or Wk 32. Investigators were blinded as to the criteria for inadequate response. Disease activity was measured at Wks 24 and 52 by composite measures including the following: minimum disease activity (MDA) as measured with the Psoriasis Area and Severity Index (MDAPASI) and with the static Physician Global Assessment of psoriasis (MDAsPGA), and modified Composite Psoriatic Disease Activity Indices (CPDAI-12 and CPDAI-14 [see Table 1 footnote]). Analyses for the DBTP were conducted on the Intent-to-Treat Population, defined as all randomly assigned patients; analyses for the EP were conducted on the EP Population, defined as all patients who received at least 1 dose of study drug during the EP. In the DBTP, treatment comparisons were made by a logistic regression model for categorical data with missing values imputed by nonresponder imputation; a mixed model for repeated measures analysis was used for continuous data. Results: At Wk 24, CPDAI-12 and CPDAI-14 total scores (assesses domains of peripheral arthritis, skin disease, enthesitis, dactylitis [and spinal disease for CPDAI-14 only]) for patients receiving IXEQ4W, IXEQ2W, or ADA, were significantly improved compared with results for patients receiving PBO (Table 1). Similarly, at Wk 24, significantly more patients receiving IXEQ4W, IXEQ2W, or ADA achieved MDAsPGA and MDAPASI compared with patients receiving PBO (Table 1), and percentages of patients receiving IXEQ4W or IXEQ2W who achieved MDAsPGA and MDAPASI were sustained through Wk 52 (Table 2). Results for MDAsPGA were similar to results for MDAPASI within each treatment group. (Table presented) Conclusions: IXE provides sustained improvement of disease activity, as measured by various composite measures, for up to 52 wks in bDMARD-naive patients with active PsA.
<b>OBJECTIVE: </b>To assess the safety and efficacy of ixekizumab, a monoclonal antibody that inhibits interleukin-17A, in a double-blind phase III trial enrolling patients with active psoriatic arthritis (PsA).<b>METHODS: </b>Patients naive to biologic therapy with active PsA were randomised to subcutaneous injections of placebo (N=106), adalimumab 40 mg once every 2 weeks (active reference; N=101), ixekizumab 80 mg once every 2 weeks (IXEQ2W) (N=103), or ixekizumab 80 mg once every 4 weeks (IXEQ4W) (N=107). Both ixekizumab regimens included a 160-mg starting dose. The primary objective was to assess the superiority of IXEQ2W or IXEQ4W versus placebo as measured by the proportion of patients achieving an American College of Rheumatology 20 (ACR20) response at week 24.<b>RESULTS: </b>Significantly more patients treated with ixekizumab achieved an ACR20 response with IXEQ2W (62.1%) or IXEQ4W (57.9%) than placebo (30.2%) (p≤0.001; non-responder imputation method). Disease activity and functional disability were significantly improved with both ixekizumab doses versus placebo at weeks 12 and 24, and there was significantly less progression of structural damage at week 24 (p≤0.01). Clearance of plaque psoriasis was greater with ixekizumab than placebo (p≤0.001). Efficacy results with adalimumab, the active reference arm, showed significant improvements versus placebo. Treatment-emergent adverse events were more frequent with ixekizumab (65.7-66.4%) and adalimumab (64.4%) than placebo (47.2%) (p<0.05).<b>CONCLUSIONS: </b>In biologic-naive patients with active PsA, ixekizumab treatment resulted in improvements in disease activity and physical function, as well as in the inhibition of structural damage progression. Overall, adverse events were more frequent in all active groups compared with placebo.<b>Trial Registration Number: </b>NCT01695239; EudraCT2011-002326-49; Results.
OBJECTIVE: To evaluate the efficacy and safety of ixekizumab alone or with concomitant conventional disease-modifying antirheumatic drugs (cDMARDs) versus placebo in patients with active psoriatic arthritis (PsA) as part of a SPIRIT-P1 subgroup analysis (NCT01695239).
METHODS: Patients were stratified by cDMARD use (concomitant cDMARDs use (including methotrexate) or none (past or naïve use)) and randomly assigned to treatment groups (ixekizumab 80 mg every 4 weeks (IXEQ4W) or every 2 weeks (IXEQ2W) or placebo). Efficacy was evaluated versus placebo at week 24 by the American College of Rheumatology criteria (ACR20/50/70), modified total Sharp score and Health Assessment Questionnaire-Disability Index (HAQ-DI). Safety was assessed according to cDMARD status.
RESULTS: Regardless of concomitant cDMARD usage, ACR20, ACR50 and ACR70 response rates were significantly higher versus placebo with IXEQ4W and IXEQ2W. The proportion of patients achieving HAQ-DI minimal clinically important difference was significantly higher versus placebo with IXEQ4W with concomitant cDMARD use and IXEQ2W, regardless of concomitant cDMARD use. Treatment-emergent adverse events (AE) were more frequent versus placebo for either ixekizumab-dosing regimen, regardless of concomitant cDMARD use. Serious AEs were not higher versus placebo, regardless of concomitant cDMARD use.
CONCLUSION: Ixekizumab treatment improved measures of disease activity and physical function in patients with active PsA relative to placebo, when used with or without concomitant cDMARD therapy.
Background: Psoriatic arthritis (PsA) is a chronic, systemic, inflammatory disease with both articular and extra-articular symptoms including joint pain, enthesitis, dactylitis, and fatigue. Fatigue is increasingly recognised as a priority symptom to patients and has been added to the PsA core set of outcomes for clinical trials.1 The best instrument to assess fatigue has not yet been defined. Objectives: To assess fatigue improvement following treatment with ixekizumab (IXE), an anti-interleukin (IL)-17A monoclonal antibody, relative to placebo (PBO) in PsA patients. Methods: In two phase 3 randomised controlled trials, patients naïve to and experienced with biologic disease-modifying antirheumatic drugs (SPIRIT-P1, SPIRITP2, respectively) received subcutaneous PBO, ADA 40 mg every 2 weeks (SPIRIT-P1 only; reference arm), or IXE 80 mg every 2 weeks (Q2W) or every 4 weeks (Q4W) after a 160 mg starting dose for up to 24 weeks. At Week 16, all patients considered inadequate responders (IR) received rescue therapy. PBO and ADA patients were re-randomised (1:1) to Q2W or Q4W at Week 16 (IR) or Week 24; ADA patients underwent a washout prior to IXE treatment. Patients rated their worst level of fatigue during the past 24 hours at baseline, Week 4, 12, 16, 24, 32, and 52 on the 11-point Fatigue Severity Numeric Rating Scale (Fatigue NRS; not yet validated) where 0=no fatigue and 10=as bad as you can imagine. The minimal clinically important difference (MCID) was defined as an improvement ≥3 on the Fatigue NRS. Results: At Week 24 significantly more patients in both studies achieved fatigue improvements≥3 on the Fatigue NRS with both IXE doses versus PBO (table 1; NRI). When evaluating group level changes, statistically significant improvements on the Fatigue NRS were observed with both IXE doses versus PBO prior to Week 24 in both studies. At Week 24, significance was observed in the SPIRITP2 study only (table 1; MMRM). For patients who continued IXE treatment beyond Week 24, mean improvements on the Fatigue NRS persisted through Week 52 (table 1; MI). Conclusions: In a subset of PsA patients, clinically meaningful improvements in fatigue level were observed following IXE treatment. Fatigue improvement persisted with up to 1 year of IXE treatment. (Table Presented).
Background: Ixekizumab is a humanised monoclonal antibody, selectively targeting interleukin-17A with high affinity. At 24 weeks, ixekizumab was superior to placebo in achieving American College of Rheumatology (ACR) 20/50/70 response, resolution of enthesitis, dactylitis and inhibiting the progression of structural joint damage in biologic DMARD-naïve patients with active psoriatic arthritis. This analysis investigates the efficacy and safety of ixekizumab after 52 weeks of treatment. Methods: In a phase III, multicenter, double-blind randomised trial (SPIRIT-P1; NCT01695239), 417 patients were randomised to receive up to 24 weeks of treatment with placebo (N=106), adalimumab 40mg once every two weeks (Q2W; N=101), or ixekizumab 80mg every two weeks (Q2W; N=103) or every four weeks (Q4W; N=107) following an 160mg initial dose at baseline. Patients who completed the 24 week visit enrolled in the open-label extension period (EP), and received ixekizumab Q4W or Q2W up to one year. Efficacy and safety were analysed using the EP population, i.e. all patients who received at least one dose of study drug. Missing values were imputed by nonresponse-imputation for categorical variables and modified baselineobservation-carried-forward approach for continuous variables. Results: A total of 304 patients completed the EP. At week 52 for the Q4W/Q4W and Q2W/Q2W groups, the response rates for ACR 20/50/ 70 were 69.1/54.6/39.2% and 68.8/53.1/39.6%, respectively. Throughout 52w weeks, minimal changes in mTSS and improvement for enthesitis and dactylitis were observed. The improvement persisted through the EP in the Q4W/Q4W and Q2W/Q2W groups for Psoriasis Area and Severity Index 75/90/100 (78.8/66.7/56.1% and 81.8/78.2/ 67.3%), the changes from baseline to 52w for percent Body Surface Area involvement of psoriasis were -13.5% and -9.3%, respectively and for Nail Psoriasis Severity Index -16.5 and -21.6, respectively. The number of treatment-emergent adverse events in the EP was comparable to that observed in the first 24-week period; and the majority were mild or moderate in severity, see table for full results. Conclusion: Over a 52-week period, ixekizumab demonstrated sustained efficacy improving articular signs and symptoms of PsA, as well as plaque-psoriasis and patient reported outcomes with safety comparable to those reported at week 24. This study was sponsored by Eli Lilly and Company. (Table Presented).
Background: Treatment goals in psoriatic arthritis (PsA) are moving toward attainment of absolute therapeutic thresholds rather than relative improvement. Minimal disease activity (MDA) and very low disease activity (VLDA); Disease Activity in Psoriatic Arthritis (DAPSA) LDA and DAPSA Remission; and Psoriatic Arthritis Disease Activity Score (PASDAS) LDA and PASDAS VLDA are validated composite indices used to measure disease activity states in PsA. Objectives: The effect of ixekizumab (IXE), as assessed by composite endpoints that incorporate multiple disease domains, was explored up to 52 weeks for the SPIRIT-P11 and SPIRIT-P22 trials. Methods: Data were analysed from 2 double-blind, phase III SPIRIT trials investigating the efficacy and safety of IXE, a high-affinity monoclonal antibody selectively targeting interleukin-17A, for patients with active PsA. For SPIRIT-1 (NCT01695239), patients who were biologic disease-modifying antirheumatic drug (DMARD)-naive were randomised to placebo (n=106) or 80 mg IXE every 4 weeks (Q4W, n=107) or every 2 weeks (Q2W, n=103) after a 160 mg starting dose. For SPIRIT-2 (NCT02349295), patients who had an inadequate response or were intolerant to tumour necrosis factor inhibitors (TNFi) were randomised to placebo (n=118) or 80 mg IXE every 4 weeks (Q4W, n=122) or every 2 weeks (Q2W, n=123) after a 160 mg starting dose. MDA, MDA VLDA, DAPSA LDA, DAPSA Remission, PASDAS LDA, and PASDAS VLDA composite endpoints were evaluated. Imputation for categorical responses was non-responder imputation. Treatment comparisons (with respect to placebo up to Week 24) based on the intent-to-treat population were made using a logistic regression model. Data up to Week 52 are summarised descriptively. Results: The therapeutic threshold results are summarised in table 1. At Week 24, the percentage of patients achieving MDA, MDA VLDA, DAPSA LDA, DAPSA Remission, PASDAS LDA, and PASDAS VLDA was greater with IXE Q4W and IXE Q2W compared with placebo. In patients who continued treatment with IXE through Week 52, response rates of these therapeutic thresholds were either sustained or further improved. Conclusions: Regardless of previous TNFi exposure, in patients with active PsA, a higher proportion of IXE-treated compared with placebo-treated patients achieved MDA and MDA VLDA, DAPSA LDA and DAPSA Remission, and PASDAS LDA and PASDAS VLDA at Week 24. At Week 52, the extent of IXE clinical response was sustained or further improved.
Background/Purpose: The DAPSA is a composite tool that assesses several domains of psoriatic arthritis (PsA) manifestations and was developed as a disease activity measure for clinical trials and clinical practice. Ixekizumab is a high affinity mAb against IL‐17A recently approved for the treatment of PsA, and in this analysis, we evaluated the impact of ixekizumab treatment on disease activity assessed with the DAPSA through 52 weeks in patients who are biologic DMARD (bDMARD)‐naïve or TNF‐ inadequate responders (TNF‐IR). Methods: Data from the 24‐week, randomized, double‐blind, placebo‐controlled periods from 2 Phase 3 clinical trials (SPIRIT‐P1, NCT01695239; SPIRIT‐P2, NCT02349295) and their extension periods were analyzed. Patients from SPIRIT‐P1 were bDMARD‐naïve (N=417) and patients from SPIRIT‐P2 had inadequate response or intolerance to TNF inhibitors (N=363). Patients were randomized to receive subcutaneous placebo (PBO), adalimumab (ADA, SPIRIT P1 only) or 80 mg ixekizumab every 2 (IXE Q2W) or 4 wks (IXE Q4W), after a 160 mg starting dose. The components of the DAPSA (68 tender joint counts, 66 swollen joint counts, patient assessment of pain, patient global assessment and CRP) were assessed at each visit. Comparisons versus placebo were made on changes in each component of DAPSA and the composite DAPSA score through week 24 using mixed effects model for repeated measures. Mean change values were reported through week 52 for patients initially randomized to ixekizumab treatment arms for the intent‐to‐treat population using last observation carried forward for imputing the missing values. Results: Baseline DAPSA was 44.7 for bDMARD‐ naïve and 50.4 for TNF‐IR patients. After 24 weeks of treatment in bDMARD‐naive patients, the mean change from baseline in DAPSA was ‐25.7 (IXE Q4W), ‐30.0 (IXE Q2W), ‐22.6 (ADA) versus ‐10.7 (PBO; p<0.001 vs PBO for all comparisons; FIGURE). Similarly, in TNF‐IR patients, mean change from baseline in DAPSA was ‐30.6 (IXE Q4W), ‐27.7 (IXE Q2W) vs ‐14.7 (PBO; p<0.001 vs PBO for all comparisons; FIGURE). In both populations, significant differences versus PBO were observed as early as Week 1. Furthermore, improvements persisted through 52 weeks with changes of ‐31.0 (IXE Q4W) and ‐33.8 (IXE Q2W) in the bDMARD‐naive population and ‐31.7 (IXE Q4W) and ‐32.1 (IXE Q2W) in the TNF‐IR population from baseline to week 52. Consistent, rapid and sustained improvements were observed with each component of the DAPSA. Conclusion: Ixekizumab treatment resulted insignificant and rapid improvements in DAPSA and its components from week 1 to week 24 which persisted through 52 weeks in 2 independent trials, SPIRIT‐P1 (bDMARD‐naïve patients) and SPIRIT‐P2 (TNF‐IR patients).
Objective To report patient-reported outcomes of patients with PsA treated with ixekizumab up to 52 weeks. Methods In SPIRIT-P1, biologic-naïve patients with active PsA were randomized to ixekizumab 80 mg every 4 weeks (IXEQ4W; N = 107) or every 2 weeks (IXEQ2W; N = 103) following a 160 mg starting dose, adalimumab 40 mg every 2 weeks (ADA; N = 101) or placebo (PBO; N = 106) during the initial 24-week double-blind treatment period. At week 24 (week 16 for inadequate responders), ADA (8-week washout before starting ixekizumab) and PBO patients were re-randomized to IXEQ2W or IXEQ4W. Patients receiving ixekizumab at week 24 received the same dose during the extension period (EP) to week 52. Patients completed measures including the Dermatology Life Quality Index (DLQI), Itch Numeric Rating Scale, 36-Item Short Form Health Survey version 2, European Quality of Life 5 Dimensions Visual Analogue Scale and Work Productivity and Activity Impairment Questionnaire-Specific Health Problem. Results The IXEQ4W, IXEQ2W and ADA groups reported significant improvements in DLQI at week 24; 22% (PBO), 53% (IXEQ4W), 63% (IXEQ2W) and 54% (ADA) of patients reported DLQI scores of 0/1. The IXEQ4W, IXEQ2W and ADA groups reported significant improvements in Itch Numeric Rating Scale, 36-Item Short Form Health Survey version 2 physical component summary and some domain scores, and European Quality of Life 5 Dimensions Visual Analogue Scale at weeks 12 and 24; and in three of four Work Productivity and Activity Impairment Questionnaire-Specific Health Problem domains at week 24. Results are also presented through week 52 for the EP. Conclusion In biologic-naïve patients with active PsA, ixekizumab significantly improved skin symptoms, health-related quality of life and work productivity. Trial Registration ClinicalTrials.gov, http://clinicaltrials.gov, NCT01695239; EU Clinical Trials Register, https://www.clinicaltrialsregister.eu, EudraCT2011-002326-49
Background: Psoriatic arthritis (PsA) is a chronic inflammatory disease with heterogeneous musculoskeletal manifestations including enthesitis and dactylitis. Ixekizumab (IXE), an interleukin-17A antagonist, is approved in the USA for the treatment of PsA including patients with pre-existing enthesitis or dactylitis. Objectives: To investigate the impact of IXE treatment on the resolution of enthesitis or dactylitis and whether such improvements were associated with improved function and health-related quality of life (HRQoL). Methods: Patients with active PsA who were biologic-naïve (SPIRIT-P1; NCT01695239) or with prior inadequate response to tumour necrosis factor inhibitor( s) (SPIRIT-P2; NCT02349295) were randomised to placebo (PBO) or 80 mg IXE every 4 weeks (IXEQ4W) or 2 weeks (IXEQ2W), after a 160 mg starting dose. All patients who were inadequate responders at Week 16 received rescue therapy (changes in background therapy). Leeds Enthesitis Index (LEI), Leeds Dactylitis Index-Basic (LDI-B), Health Assessment Questionnaire Disability Index (HAQDI), and EuroQoL-5D Visual Analogue Scale (EQ-5D VAS) were measured at Week 24. Missing data or data from inadequate responders were considered nonresponse or imputed with last observation carried forward for categorical and continuous measures, respectively. Statistical comparisons between PBO and IXE treatment groups were performed with a logistic regression model using Wald's test with treatment and study as factors. In post hoc-analyses, associations between enthesitis and dactylitis with HAQ-DI and EQ-5D VAS are based on an ANCOVA model adjusting for study and Disease Activity of Psoriatic Arthritis (DAPSA). Results: In the integrated SPIRIT-P1 and -P2 dataset (n=679), 403 patients (59% of total) had baseline enthesitis (LEI >0) with a mean 2.9 LEI score, and 155 patients (23% of total) had baseline dactylitis (LDI-B >0) with a mean 56.4 LDI-B score. Relative to PBO, IXE treatment resulted in significantly higher resolution of enthesitis (SPIRIT-P1) and dactylitis (SPIRIT-P1 and -P2) after 24 weeks.1,2 In the integrated SPIRIT-P1 and -P2 dataset, both IXEQ4W and IXEQ2W had significantly higher enthesitis and dactylitis resolution than PBO treatment at Week 24 (Table). In ad-hoc analysis, IXE treatment had significantly higher resolution of enthesitis compared to PBO at the entheseal points comprising the LEI score (Table). For all PBO-and IXE-treated patients at Week 24, least squares mean (SE) HAQ-DI changes from baseline were -0.44 (0.05) and -0.25 (0.03; p<0.01) for patients who did and did not resolve enthesitis, and -0.41 (0.06) and -0.31 (0.07; p=0.34) for patients who did and did not resolve dactylitis. Corresponding EQ-5D VAS improvements were 12.3 (2.2) and 5.8 (1.5; p=0.02) for patients who did and did not resolve enthesitis, and 10.8 (2.8) and 9.8 (3.5; p=0.83) for patients who did and did not resolve dactylitis. Conclusions: Treatment with IXE resulted in significant improvement in enthesitis and dactylitis in patients with pre-existing enthesitis or dactylitis. Resolution of enthesitis symptoms was associated with improvements in patients' function and HRQoL (Table Presented).
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)-naïve (SPIRIT-P1) or who had prior inadequate response or intolerance to TNF inhibitors (SPIRITP2). 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 (<3% or ≥3%), and c-reactive protein (CRP >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<0.05) more patients achieved ACR20, ACR50, ACR70, and MDA with IXE compared to placebo across patient subgroups defined by presence of enthesitis, presence of dactylitis, percentage of psoriasis BSA involvement, and by CRP levels at baseline. 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.
Background: Ixekizumab improves signs/symptoms of psoriatic arthritis (PsA). We present an integrated analysis of baseline disease burden and post‐baseline outcomes in ixekizumab‐treated patients with enthesitis or dactylitis. Methods: Data from SPIRIT‐P1 and SPIRIT‐P2 were integrated. Patients with PsA were randomized to 80‐mg ixekizumab every 4 weeks (IXEQ4W) or 2 weeks (IXEQ2W), after a 160‐mg starting dose, or to placebo. Inadequate responders at week 16 received rescue therapy. Among patients with baseline enthesitis (Leeds Enthesitis Index [LEI] > 0) or dactylitis (Leeds Dactylitis Index‐Basic [LDI‐B] > 0), baseline characteristics and disease burden were reported. At week 24, LEI and LDI‐B (percentage of patients with resolution [LEI = 0, LDI‐B = 0]) were assessed. In pooled treatment groups, the impact of enthesitis or dactylitis resolution on health‐related quality of life (HRQoL) (EuroQol‐5 Dimensions Visual Analogue Scale [EQ‐5D VAS]), physical function (Health Assessment Questionnaire‐Disability Index [HAQ‐DI]), and pain was assessed. Results: The integrated analysis set comprised 679 patients; of these, 60% (n = 403 of 675) had baseline enthesitis (LEI > 0) and 23% (n = 155 of 676) had baseline dactylitis (LDI > 0). At week 24, ixekizumab‐treated patients experienced significantly more resolution than placebo of enthesitis (39% IXEQ4W, 35% IXEQ2W, 21% placebo) and dactylitis (78% IXEQ4W, 65% IXEQ2W, 24% placebo). Furthermore, at entheseal points measured by the LEI, ixekizumab‐treated patients had significantly higher resolution of enthesitis compared to placebo. At week 24, among all placebo‐ and ixekizumab‐treated patients, resolution of enthesitis was associated with improvements in function and HRQoL whereas dactylitis resolution was associated with more limited improvements. The least squares mean HAQ‐DI improvements from baseline were ‐ 0.44 and ‐ 0.25 for patients who did/did not resolve enthesitis, and ‐ 0.41 and ‐ 0.31 for patients who did/did not resolve dactylitis. EQ‐5D VAS improvements were 12.3 and 5.8 for patients who did/did not resolve enthesitis, and 10.8 and 9.8 for patients who did/did not resolve dactylitis. Conclusions: Among patients with pre‐existing enthesitis or dactylitis, IXEQ2W‐ and IXEQ4W‐treatment resulted in significant improvements in enthesitis and dactylitis. Enthesitis resolution was associated with improvements in patients' function, pain, and HRQoL. Trial registration: ClinicalTrials.gov, NCT01695239, registered on September 25, 2012, and NCT02349295, registered on October 10, 2014.
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)-naïve (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 (<5 or >5 years) at baseline for pts who were randomly assigned to either PBO or the approved dosing regimen of IXE (80 mg IXE every 4 wks [IXE Q4W] with a starting dose of 160-mg IXE). Efficacy in each subgroup was evaluated as the percentage of pts at Wk 24 achieving >20%, 50%, or 70% improvement from baseline in the American College of Rheumatology criteria (ACR20/50/70) or minimal disease activity. Missing data were imputed using nonres-ponder imputation (NRI). Results: Response rates at Wk 24 (Table) were significantly (p<0.05) greater in pts receiving IXE versus PBO across all endpoints assessed in subgroups defined by sex, disease duration, and in pts with overweight and obese BMI at baseline. Response rates were significantly greater with IXE compared to PBO for ACR20 and ACR50 in the normal BMI subgroup and for ACR50 in the extreme obese BMI subgroup. Assessment of superiority of IXE versus PBO in underweight and extreme obese subgroups was limited by small sample sizes; only three patients (all receiving IXE Q4W) had underweight BMI at baseline. For all endpoints assessed, numerically greater response rates were observed with IXE Q4W in male versus female pts. 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.
Background: The efficacy and safety of ixekizumab (IXE), an IL-17A antagonist, was investigated in patients with active psoriatic arthritis (PsA) in the SPIRIT-P1 and SPIRIT-P2 clinical trials. Objectives: To investigate the efficacy of ixekizumab on axial pain, fatigue, stiffness, and physical function in a subset of patients with PsA self-reporting axial pain starting before the age of 45 years at baseline. Methods: Patients with PsA in the intent-to-treat populations of SPIRIT-P1 (Biologic-naïve; NCT01695239) and SPIRIT-P2 (Inadequate responders or intolerant to 1 or 2 TNF inhibitors; NCT02349295) with baseline patientreported axial pain (≥4 Bath Ankylosing Spondylitis Disease Activity Index [BASDAI] question 2), high-sensitivity C-reactive protein (hsCRP) >5mg/L, and <45 years old were included in this post-hoc integrated analysis. SPIRIT-P1/P2 did not include axial imaging. Patients were treated with placebo (PBO) or ixekizumab 80-mg every 2 weeks (IXEQ2W) or 4 weeks (IXEQ4W) after a 160-mg starting dose for 24 weeks. The efficacy of ixekizumab on axial pain (BASDAI question 2), fatigue (BASDAI question 1), stiffness (mean of BASDAI questions 5/6), total BASDAI, Health Assessment Questionnaire Disability Index (HAQ-DI), and 36-Item Short Form Health Survey Physical Component Summary (SF-36 PCS) was analyzed at Weeks 16 and 24 using mixed model for repeated measures with treatment, region, baseline conventional DMARD experience, visit, and treatment-by-visit interaction as fixed factors, and response value at baseline as a covariate. Results: Axial pain and stiffness significantly improved at Weeks 16 and 24 in patients with PsA treated with IXEQ4W or IXEQ2W versus PBO (p<.05; Table 1). Fatigue significantly improved at Week 16 in patients treated with IXEQ4W or IXEQ2W versus PBO and at Week 24 with IXEQ2W versus PBO (p<.05). Total BASDAI scores significantly improved at Weeks 16 and 24 in patients treated with IXEQ4W or IXEQ2W versus PBO (p<.01). Physical function significantly improved at Weeks 16 and 24 in patients treated with IXEQ4W or IXEQ2W versus PBO when assessed by HAQ-DI or SF-36 PCS (p<.05). Conclusion: Ixekizumab treatment yielded significantly higher improvements than placebo in axial pain, fatigue, stiffness, and physical function at Weeks 16 and 24 in the integrated PsA subpopulation self-reporting axial pain at baseline. These analyses were limited by a lack of baseline axial imaging.
<b>OBJECTIVE: </b>To evaluate ixekizumab safety in adults with psoriatic arthritis (PsA).<b>METHODS: </b>Safety data from 2 integrated data sets are presented: 1) 24-week, double-blind, placebo-controlled period of SPIRIT-P1 and SPIRIT-P2; and 2) all ixekizumab-treated patients of SPIRIT-P1 and SPIRIT-P2 plus SPIRIT-P3 open-label period. We report adverse event (AE) frequency and exposure-adjusted incidence rates per 100 patient-years at 12-week intervals to week 96.<b>RESULTS: </b>The placebo-controlled period had 678 patients (safety population): 224 placebo, 229 ixekizumab every 4 weeks, and 225 ixekizumab every 2 weeks. Overall, 1,118 patients received ixekizumab (total exposure 1,373.4 patient-years). In the placebo-controlled period, the frequencies of ixekizumab-treated patients experiencing ≥1 treatment-emergent AE (TEAE) and those experiencing serious AEs were 68.1% (56.7% placebo) and 4.4% (2.7% placebo), respectively. Injection site reactions (ISRs) were very common (21.4% ixekizumab [4.5% placebo]), with ISR discontinuation rates of 1.1% (ixekizumab) and 0.4% (placebo). Through week 96, the incidence rates of ISRs decreased with increasing ixekizumab exposure. The frequencies of AEs of special interest were 32.8% (ixekizumab) and 27.7% (placebo); for serious infections, the frequencies were 1.3% and 0%, respectively; Candida infections, 2.6% and 0.4%; confirmed major adverse cardiac events, 0% and 0%; malignancy, 0.4% and 0%; hypersensitivities, 5.3% and 1.8%; and depression-related, 1.8% and 1.3%. The frequency of Crohn's disease and ulcerative colitis (investigator-reported) was 0% in both groups, and the frequencies of sponsor-determined inflammatory bowel disease were 0.2% in the ixekizumab group and 0% in the placebo group. Overall, no active tuberculosis, invasive Candida infections, anaphylaxis, or suicide/self-injury behaviors were reported.<b>CONCLUSION: </b>The PsA ixekizumab safety integrated data set reached 1,373.4 patient-years total exposure. Ixekizumab-treated patients had higher rates of overall TEAEs, serious infections, mucocutaneous Candida, hypersensitivities (non-anaphylactic), and ISRs than placebo-treated patients. No unexpected safety outcomes were reported.
Background/purpose: Ixekizumab (IXE) is approved for the treatment of moderate‐to‐ severe psoriasis and more recently for active psoriatic arthritis (PsA). Objective: To describe the efficacy of IXE at week 24 in PsA patients with different disease manifestations and characteristics. Methods: Biologic naïve patients (SPIRIT‐P1) were randomized to 80‐mg IXE (initial dose 160 mg) every 4 (Q4W; N = 107) or 2 weeks (Q2W; N = 103), to adalimumab 40‐mg IXE (Q2W; N = 101), or placebo (PBO; N = 106). Patients with an inadequate response or intolerance to TNF inhibitors (SPIRIT‐P2) were randomized to IXE Q4W (N = 122) or Q2W (N = 123), or PBO (N = 118). Patients had active disease with ≥3TJC and ≥3SJC and were classified according to the following phenotypes of PsA: polyarthritis (≥5TJC and/or ≥5SJC), oligoarthritis (<5TJC and <5SJC), DIP joint only, enthesitis and dactylitis. in each phenotype ACR 20, 50 and 70 response criteria, Minimal Disease Activity Psoriasis Area Severity Index (MDAPASI), and Disease Activity Psoriatic Arthritis (DAPSA) remission and low disease activity (LDA) response criteria were assessed to evaluate IXE effect at week 24 combining both doses. For each phenotype with a sufficient sample size, IXE‐and PBO‐treated patients' baseline characteristics were assessed. Treatment effects of IXE and PBO were compared using Chi‐square tests (or Fisher's exact tests) within each phenotype. Results: The largest phenotypes were polyarthritis (N = 662), enthesitis (investigator: N = 459; LEI > 0: N = 403), and dactylitis (investigator: N = 220; LDI‐B > 0: N = 155). Too small sample sizes due to inclusion criteria or low frequency were observed for “DIP joint only”, oligoarthritis and arthritis mutilans phenotypes (N = 22, N = 17 and N = 15). Baseline patient characteristics were generally balanced between treatment arms and similar between the 3 largest phenotypes, with no difference in disease activity and duration. Response rates were consistent to overall efficacy reported with IXE in SPIRIT trials. Conclusion: Treatment responses with IXE at week 24 were consistent across all phenotypes evaluated. (Table Presented).
Background/Purpose: Ixekizumab (IXE) is a high affinity anti-interleukin (IL)-17A monoclonal antibody approved for the treatment of moderate to severe psoriasis and active psoriatic arthritis (PsA). We evaluated the efficacy of IXE on signs and symptoms of PsA in biologic DMARD (bDMARD)-naïve patients (pts) (SPIRIT-P1; Trial registration number: NCT01695239) or TNF- inadequate responders (TNF-IR) (SPIRIT-P2; NCT02349295). Methods: The SPIRIT-P1 and -P2 study designs were reported previously. Pts with active PsA either bDMARD-naive or with inadequate response or intolerance to prior TNFi-IR were randomized to placebo (PBO), adalimumab (ADA; SPIRIT-P1 only) or 80 mg IXE every 4 (IXE Q4W) or 2 weeks (wks) (IXE Q2W) after a 160-mg starting dose. Efficacy measures included 20% improvement in ACR score and 75/90/100 percent improvement in PASI. Response rates were reported at Wk 108 for pts continuing on IXE treatment (intent-to-treat population). Missing values were imputed by nonresponder imputation for categorical data. Results: After 24 wks of treatment in bDMARD-naive pts (n = 210), ACR 20 response rates were 57.9% (IXE Q4W), 62.1% (IXE Q2W), 57.4% (ADA) versus 30.2% (PBO; P < .001 vs PBO for all comparisons). Among pts who continued on IXE for 108 wks, ACR 20 response rates sustained in 56.1% (IXE Q4W) and 58.3% (IXE Q2W) pts. Similarly, in TNF-IR pts (n = 363), ACR 20 response rates were 53.3% (IXE Q4W), 48.0% (IXE Q2W) vs 19.5% (PBO; P < .001 vs PBO for all comparisons) and these response rates (ACR 20) sustained for 108 wks in 51.6% and 41.5% in IXE Q4W and IXE Q2W arms respectively. In Bio-naïve pts, PASI 100 response rates at Wk 24 were 42.5% (IXE Q4W), 52.5% (IXE Q2W), 23.5% (ADA) versus 3.0% (PBO) and these response rates (PASI 100) sustained for 108 wks in 38.4% (IXE Q4W) and 59.3 % (IXE Q2W). In TNF-IR pts, PASI 100 response rates were 35.3% (IXE Q4W), 27.9% (IXE Q2W), versus 4.5% (PBO) (P < .001 vs PBO for all comparisons) and these response rates sustained for 108 wks in 38.4% (IXE Q4W) and 59.3% (IXE Q2W). In both populations, significant differences in ACR 20 and PASI 75 with IXE versus PBO were observed as early as Week 1. Conclusion: Ixekizumab treatment resulted in significant and rapid improvements in the signs and symptoms of peripheral joint and skin domains of PsA from Week 1 to Week 24, which persisted through 108 weeks in patients who are bDMARD-naïve and TNF-IR.
Objective The aim was to assess the safety and efficacy of up to 156 weeks of ixekizumab (an IL-17A antagonist) treatment in PsA patients. Methods In a phase III study, patients naïve to biologic treatment were randomized to placebo, adalimumab 40 mg every 2 weeks (ADA; active reference) or ixekizumab 80 mg every 2 weeks (IXEQ2W) or every 4 weeks (IXEQ4W) after an initial dose of 160 mg. At week 24 (week 16 for inadequate responders), ADA (after 8-week washout) and placebo patients were re-randomized to IXEQ2W or IXEQ4W. Outcomes were evaluated using a modified non-responder imputation [linear extrapolation for radiographic progression (modified total Sharp score = 0)] during extended treatment until week 156. Results Of 417 patients, 381 entered the extension, and 243 of 381 (63.8%) completed the 156-week study. Incidence rates of treatment-emergent and serious adverse events, respectively, were 38.0 and 5.2 with IXEQ2W (n = 189) and 38.1 and 8.0 with IXEQ4W (n = 197). One death occurred (IXEQ4W). With IXEQ2W and IXEQ4W, respectively, the response rates persisted to week 156 as measured by the ACR response ≥20% (62.5 and 69.8%), ≥50% (56.1 and 51.8%) and ≥70% (43.8 and 33.4%), psoriasis area and severity index (PASI) 75 (69.1 and 63.5%), PASI 90 (64.5 and 51.2%) and PASI 100 (60.5 and 43.6%). Inhibition of radiographic progression also persisted to week 156 in 61% of IXEQ2W and 71% of IXEQ4W patients. Conclusion In this 156-week study of ixekizumab, the safety profile remained consistent with previous reports, and improvements in signs and symptoms of PsA were observed, including persistent low rates of radiographic progression. Trial registration ClinicalTrials.gov, http://clinicaltrials.gov , NCT01695239, EudraCT 2011-002326-49.
OBJECTIVES: To determine the proportion of patients in Phase 3 studies (SPIRIT-P1 and SPIRIT-P2) who achieved minimal clinically important difference (MCID) for work productivity loss and activity impairment domains of Work Productivity and Activity Impairment Specific Health Problem (WPAI-SHP) questionnaire.
METHODS: In the SPIRIT-P1 study, comprising a 24-week double-blind treatment period, biologic-naive patients with active psoriatic arthritis (PsA) were randomised to ixekizumab 80 mg every 4 weeks (IXEQ4W) or every 2 weeks (IXEQ2W) (starting dose of 160 mg), adalimumab 40 mg every 2 weeks (ADAQ2W), or placebo. SPIRIT-P2 enrolled tumour necrosis factor inhibitor (TNFi)-experienced patients who were randomised to receive IXEQ4W, IXEQ2W or placebo for 24 weeks of double-blind treatment. In this post-hoc analysis, we investigated the proportion of patients in SPIRIT-P1 and P2 studies who achieved 15% improvement in work productivity loss and 20% improvement in activity impairment domains of WPAI-SHP during double- blind treatment period.
RESULTS: In SPIRIT-P1, at Week 24, 57.1% and 55.8% of biologic-naive patients on IXEQ4W and ADAQ2W respectively, achieved MCID estimates for work productivity loss compared to 25.6% of patients treated with placebo. The proportion of ixekizumab- and adalimumab-treated patients achieving MCIDs for activity impairment were significantly higher (IXEQ4W: p<0.001; ADAQ2W: p=0.001) com- pared to placebo-treated patients at Week 24. In SPIRIT-P2, significantly more TNFi-experienced patients on IXEQ4W (p<0.001) achieved MCIDs compared to placebo at Week 24.
CONCLUSIONS: Treatment with ixekizumab was associated with clinically meaningful improvements in WPAI-SHP domains in biologic-naive and TNFi- experienced patients with active PsA.
OBJECTIVES: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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: The efficacy and safety of ixekizumab (IXE) with and without continuous concomitant methotrexate (MTX), for up to 52 weeks of treatment, were evaluated in patients with active psoriatic arthritis (PsA).
METHODS: Patients with active PsA who were biologic-naive (SPIRIT-P1) or had prior inadequate response to tumor necrosis factor inhibitors (SPIRIT-P2) were randomized to 80 mg IXE every 4 (IXE Q4W) or 2 weeks (IXE Q2W), after a 160-mg initial dose. In this post hoc analysis, efficacy and safety were assessed up to week 52 in the subgroups of patients who received (i) IXE as monotherapy and (ii) IXE along with a stable dose of MTX (no dose tapering or increase). Efficacy outcomes included, but were not limited to, the percentage of patients achieving the American College of Rheumatology (ACR) responses.
RESULTS: Out of 455 patients initially randomized to IXE, 177 (38.9%) received monotherapy, 230 (50.5%) had concomitant MTX use, and 48 (10.5%) had other concomitant medication. Overall, 183 (40.2%) received IXE with a stable dose of concomitant MTX for 1 year. At week 52, the percentage of patients achieving ACR20/50/70 responses in IXE Q4W monotherapy versus concomitant MTX groups were 66.3% versus 55.3%, 48.4% versus 38.8%, and 35.8% versus 27.1%, respectively; these responses were generally similar with IXE Q2W. The safety profiles were similar between patients receiving IXE with or without concomitant MTX.
CONCLUSIONS: In this post hoc analysis, treatment with IXE demonstrated sustained efficacy in patients with PsA up to 1 year of treatment, with or without concomitant MTX therapy.
TRIAL REGISTRATION: ClinicalTrials.gov NCT01695239 and NCT02349295 .
