Secukinumab immunogenicity over 52 weeks in patients with psoriatic arthritis and ankylosing spondylitis

Objective. Secukinumab, a fully human antiinterleukin 17A monoclonal antibody, is efficacious for the treatment of psoriatic arthritis (PsA) and ankylosing spondylitis (AS). This study examined the immunogenicity of secukinumab in patients with PsA and AS exposed to secukinumab for up to 52 weeks. Methods. Antibody bridging assays were used to assess the immunogenicity of secukinumab in patients with PsA [FUTURE 1–3 studies, and AS (MEASURE 1–4 studies)]. Evaluations were at baseline and at weeks 16 (AS only), 24, and 52. Treatment-emergent antidrug antibodies (TE-ADA) were defined as a positive ADA signal in ≥ 1 posttreatment sample in patients negative at baseline. Positive samples were analyzed for drug-neutralizing potential, and effect of TE-ADA on secukinumab pharmacokinetics, immunogenicity-related adverse events (AE), and efficacy through Week 52 were assessed. Results. Of 1414 treated PsA and 1164 treated AS patients with samples available for immunogenicity evaluation, 5 (0.35%) and 8 (0.69%), respectively, developed TE-ADA. All but 1 PsA patient were biologic-naive; two of the 5 PsA and one of the 8 AS patients received concomitant methotrexate, and two of the 8 AS patients received concomitant sulfasalazine. Associations between TE-ADA and secukinumab dose, frequency, or administration mode were not observed. Other than one PsA patient, all TE-ADA were non-neutralizing. No TE-ADA were associated with any AE. All TE-ADA were associated with normal secukinumab pharmacokinetics and none were associated with loss of secukinumab efficacy. Conclusion. Secukinumab treatment was associated with a low (< 1%) incidence of immunogenicity in patients with PsA or AS. (clinicaltrials.gov: NCT01392326; NCT01752634; NCT01989468; NCT01358175; NCT01649375; NCT02008916; NCT02159053)

Secukinumab shows sustained efficacy and low structural progression in ankylosing spondylitis: 4-year results from the MEASURE 1 study.

Objectives:To evaluate the effect of secukinumab, a fully human anti-interleukin-17A monoclonal antibody, on efficacy, imaging outcomes, and safety through 4 years (208 weeks) in patients with ankylosing spondylitis. Methods:Patients opting to enrol had completed 2 years' treatment in the MEASURE 1 core study with subcutaneous secukinumab 150 or 75 mg every 4 weeks (q4Wk), following intravenous loading to Week (Wk) 4, or placebo treatment to Wk16/24. Up-titration from secukinumab 75-150 mg q4Wk was permitted following a protocol amendment. Efficacy is reported for patients originally randomized to secukinumab. Radiographic changes were assessed using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) and changes in MRI measures of inflammation using the Berlin scoring method. Safety and tolerability were evaluated. Results:Among 274 extension study participants, 89.7% (78/87) and 93.0% (93/100) originally randomized to secukinumab 150 and 75 mg, respectively, completed 208Wk. Through Wk208, Assessment of Spondyloarthritis International Society 20/40 (observed) were 79.7%/60.8% (150 mg), 71.0%/43.5% (75 mg) and 80.0%/76% (up-titrators; n = 25). Mean (s.d.) changes in mSASSS were 1.2 (3.91) (150 mg), 1.8 (4.32) (75 mg) and 1.6 (5.67) (up-titrators). No radiographic progression (mSASSS change from Baseline < 2) was observed in 79% of patients receiving either secukinumab dose. Exposure-adjusted incidence rates per 100 patient-years were: serious infections (1.0), Candida infections (0.4), Crohn's disease (0.6), ulcerative colitis (0.2), and malignant/unspecified tumours (0.5), with no new safety signals. Conclusion:Through 4 years, secukinumab provided sustained efficacy on signs and symptoms, and MRI outcomes, a low rate of radiographic progression and a consistent safety profile. Trial registration:NCT01863732

Efficacy and safety of secukinumab in Asian patients with active ankylosing spondylitis: 52-week pooled results from two phase 3 studies

Aim: To evaluate efficacy and safety of secukinumab in Asian patients with active ankylosing spondylitis (AS) via a pooled subgroup analysis from two phase 3 studies, MEASURE 1 (NCT01358175) and MEASURE 2 (NCT01649375). Methods: In MEASURE 1, patients were randomized to intravenous secukinumab 10 mg/kg or placebo at baseline, Weeks 2 and 4, followed by subcutaneous (s.c.) secukinumab 150 mg, 75 mg or placebo every 4 weeks (q4w) at Week 8. In MEASURE 2, patients were randomized to s.c. secukinumab 150 mg, 75 mg or placebo at baseline, Weeks 1, 2 and 3, and q4w starting at Week 4. Efficacy outcomes were SpondyloArthritis International Society (ASAS) 20/40, high-sensitivity C-reactive protein (hsCRP), ASAS5/6, Bath Ankylosing Spondylitis Disease Activity Index, Short Form-36 physical component summary, AS quality of life (QoL), ASAS partial remission, and Ankylosing Spondylitis Disease Activity Score -CRP at Weeks 16 and 52. Due to lack of efficacy, the secukinumab 75 mg dose in MEASURE 2 was excluded from this pooled Asian subgroup analysis. Safety analysis included patients who received >= 1 dose of study treatment. Results: Of 517 patients enrolled into the MEASURE studies, 69 (13.3%) were Asians: 46 in pooled secukinumab and 23 in placebo. At Week 16, ASAS20/40 responses in Asian patients were 69.6%/43.5% with pooled secukinumab versus 26.1%/17.4% with placebo, which were comparable with rates reported in the overall study population. Secukinumab improved predefined efficacy endpoints at Week 16, with responses sustained through Week 52. Secukinumab was well tolerated in Asian patients, with a safety profile consistent with that reported in the overall study population. Conclusion: Secukinumab improved signs and symptoms, physical function, and disease-specific QoL in Asian patients with active A

Impact of baseline C-reactive protein levels on the response to secukinumab in ankylosing spondylitis: 3-year pooled data from two phase III studies

Objective To evaluate the magnitude of response to secukinumab treatment over 3 years in patients with ankylosing spondylitis (AS) grouped by baseline C-reactive protein (CRP) levels in a pooled study of two pivotal phase III studies: MEASURE 1 (NCT01358175) and MEASURE 2 (NCT01649375). Methods This post hoc analysis pooled data from all patients with available baseline CRP in the two studies who received subcutaneous secukinumab 150mg (approved dose; N=197) or placebo (N=195). Assessed efficacy endpoints included Assessments of SpondyloArthritis international Society (ASAS)20/40, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), BASDAI50, AS Disease Activity Score inactive disease and ASAS partial remission among patients grouped by baseline CRP based on central laboratory cut-off <5mg/L (normal) or ≥5mg/L (elevated) and a cut-off <10mg/L or ≥10mg/L. Results At baseline, 36.5% (143/392) patients had normal and 63.5% (249/392) had elevated CRP. At week 16, ASAS20/40 response rates were higher for secukinumab versus placebo in normal (56.9%/34.7% vs 28.2%/7.0%; p<0.01/p<0.001) and in elevated (63.2%/42.4% vs 29.0%/15.3%; both p<0.0001) CRP groups. Improvement was reported for all outcomes (p<0.05) in both groups, except for ASAS partial remission in the normal CRP group, where a numerical difference 12.5% vs 2.8%, p=0.07) was observed. Similar trends of improvement were observed in the <10and ≥10mg/L groups across all efficacy outcomes at week 16. Treatment responses to secukinumab in all CRP groups further improved over 156 weeks. Conclusion Secukinumab 150mg demonstrated rapid and sustained efficacy in patients with AS irrespective of baseline CRP, with greater magnitude of response in patients with more elevated CRP

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

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

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

Background: Head-to-head trials in psoriatic arthritis are helpful in guiding clinical decision making. The EXCEED study evaluated the efficacy and safety of secukinumab versus adalimumab as first-line biological monotherapy for 52 weeks in patients with active psoriatic arthritis, with a musculoskeletal primary endpoint of American College of Rheumatology (ACR) 20 response. Methods: This parallel-group, double-blind, active-controlled, phase-3b, multicentre (168 sites in 26 countries) trial enrolled patients aged at least 18 years with active psoriatic arthritis. Eligible patients were randomly assigned (1:1) by means of interactive response technology to receive secukinumab or adalimumab. Patients, investigators, site personnel, and those doing the assessments (except independent study drug administrators) were masked to study assignment. 300 mg secukinumab was administered subcutaneously at baseline, weeks 1, 2, 3, and 4, and then every 4 weeks until week 48 as a pre-filled syringe. Adalimumab was administered every 2 weeks from baseline until week 50 as 40 mg per 0·4 mL citrate free subcutaneous injection. The primary outcome was the proportion of patients with at least 20% improvement in the ACR response criteria (ACR20) at week 52. Patients were analysed according to the treatment to which they were randomly assigned. Safety analyses included all safety data reported up to and including the week 52 visit for each patient who received at least one dose of study drug. The trial is registered at ClinicalTrials.gov, NCT02745080. Findings: Between April 3, 2017 and Aug 23, 2018, we randomly assigned 853 patients to receive secukinumab (n=426) or adalimumab (n=427). 709 (83%) of 853 patients completed week 52 of the study, of whom 691 (81%) received the last study treatment at week 50. 61 (14%) of 426 patients in the secukinumab group discontinued treatment by week 52 versus 101 (24%) of 427 patients in the adalimumab group. The primary endpoint of superiority of secukinumab versus adalimumab for ACR20 response at week 52 was not met. 67% of patients in the secukinumab group achieved an ACR20 response at week 52 versus 62% of patients in the adalimumab group (OR 1·30, 95% CI 0·98–1·72; p=0·0719). The safety profiles of secukinumab and adalimumab were consistent with previous reports. Seven (2%) of 426 patients in the secukinumab group and six (1%) of 427 patients in the adalimumab group had serious infections. One death was reported in the secukinumab group due to colon cancer and was assessed as not related to the study drug by the investigator. Interpretation: Secukinumab did not meet statistical significance for superiority versus adalimumab in the primary endpoint of ACR20 response at week 52. However, secukinumab was associated with a higher treatment retention rate than adalimumab. This study provides comparative data on two biological agents with different mechanisms of action, which could help guide clinical decision making in the management of patients with psoriatic arthritis. Funding: Novartis Pharma