Secukinumab long-term efficacy and safety in psoriasis through to year 5 of treatment: results of a randomized extension of the phase III ERASURE and FIXTURE trials.

BACKGROUND: In the long-term extension study of the ERASURE and FIXTURE trials, the efficacy of secukinumab (a fully human anti-interleukin-17A monoclonal antibody) was demonstrated to have been maintained through to year 3 of treatment in moderate-to-severe plaque psoriasis. OBJECTIVES: To assess the efficacy and safety of secukinumab through to year 5 of treatment in moderate-to-severe plaque psoriasis. METHODS: Responders with ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) from two core trials - ERASURE and FIXTURE - were randomized 2 : 1 at year 1 (end of core trials) to either the same dose (300 or 150 mg, continuous treatment) or placebo (treatment withdrawal) every 4 weeks, until year 3 or relapse (> 50% reduction in maximal PASI from core study baseline). Partial responders (achieving PASI 50 but not PASI 75) at year 1 continued at the same dose as in the core trials. At year 3, all patients received open-label secukinumab treatment, with those on secukinumab 300 mg continuing on their dose, while those on secukinumab 150 mg or placebo received secukinumab 150 or 300 mg based on the physician's discretion. The study is registered on ClinicalTrials.gov with the identifier NCT01544595. RESULTS: Most patients randomized to placebo at year 1 relapsed, but the response was rapidly recaptured upon reinitiation of treatment. PASI responses were sustained with secukinumab through to year 5. The PASI responses for the 300 mg responders + partial responders group at year 1 (PASI 75/90/100: 86.8%/72.8%/45.9%) trended downwards until year 3 (PASI 75/90/100: 82.3%/58.4%/32.7%) and then remained stable through year 4 (PASI 75/90/100: 83.3%/60.1%/32.2%) until year 5 (PASI 75/90/100: 81.1%/62.8%/35.1%). Dermatology Life Quality Index showed sustained benefit up to year 5. Absolute PASI responses were maintained throughout the study. The most common adverse events (AEs) were infections and infestations, nasopharyngitis, and upper respiratory tract infections (URTIs). The overall exposure-adjusted incidence rate (EAIR; with 95% confidence interval) for all AEs was 139.9 (130.3-149.9). EAIRs for Crohn's disease and neutropenia were 0.1 (0.0-0.3) and 0.5 (0.3-0.8), respectively. CONCLUSIONS: The 4-year extension of two pivotal phase III trials demonstrated that secukinumab treatment was effective through to year 5 and improved quality of life in patients with moderate-to-severe plaque psoriasis. The most common AEs were infections and infestations, nasopharyngitis, and URTIs. The safety profile was consistent with that in the secukinumab phase II/III clinical development programme.

Investigation of plaque psoriasis relapse after secukinumab withdrawal in patients from two Phase 3 studies.

BACKGROUND: Secukinumab is effective against a range of psoriatic manifestations. Investigating psoriasis (PsO) relapse following secukinumab discontinuation could provide insights into long-term PsO remission. OBJECTIVE: To examine PsO relapse rates upon treatment discontinuation following one year of secukinumab treatment. METHODS: This study (NCT01544595) is an extension of the Phase 3 ERASURE/FIXTURE studies in patients with moderate-to-severe plaque PsO. After one year of secukinumab 300 mg or 150 mg treatment, Week 52 PASI75 responders were randomly assigned to receive placebo. Upon relapse, patients receiving placebo were switched to their previous secukinumab dose. The study primary outcome was non-relapse rate after secukinumab withdrawal. RESULTS: Following the last dose of secukinumab 300 mg, 21% and 10% of patients who switched to placebo did not relapse at one and two years after discontinuation, respectively. Patients who received secukinumab 150 mg for one year showed a lower proportion of non-relapse following treatment discontinuation (14% and 6%) at one and two years, respectively). Non-relapsing patients maintained low mean PASI (2.8) at one year drug-free versus baseline (20.9); 1.7 at two years drug-free versus baseline (19.2). Disease duration (P=0.017) and severity (P=0.022) were significantly associated with time-to-relapse in patients initially treated with secukinumab 300 mg; patients with shorter disease duration and lower baseline PASI remained relapse-free for longer. CONCLUSIONS: Following discontinuation of secukinumab, a proportion of patients stayed relapse-free. Further, patients with shorter disease duration remained relapse-free for longer, suggesting that earlier treatment with secukinumab may result in long-term clinical control of moderate-to-severe PsO.

Secukinumab dosing every 2 weeks demonstrated superior efficacy compared with dosing every 4 weeks in patients with psoriasis weighing 90 kg or more: results of a randomized controlled trial.

BACKGROUND: Obesity is a common comorbidity of psoriasis and can attenuate response to biologic treatment. OBJECTIVES: To investigate the efficacy, safety and tolerability of secukinumab 300 mg every 2 weeks (Q2W) vs. secukinumab 300 mg every 4 weeks (Q4W) in patients with a higher bodyweight. METHODS: In this multicentre, double-blind, parallel-group trial, 331 patients with moderate-to-severe chronic plaque psoriasis weighing ≥ 90 kg were randomized to receive secukinumab 300 mg Q2W or secukinumab 300 mg Q4W. Patients who did not achieve Psoriasis Area and Severity Index (PASI) 90 at week 16 on the Q4W regimen were reallocated to remain on the Q4W regimen or uptitrate to Q2W. RESULTS: At week 16, Q2W dosing (n = 165) led to significantly higher PASI 90 responses vs. Q4W [n = 166; 73.2% vs. 55.5%, one-sided P-value = 0.0003, odds ratio estimate (95% confidence intervals): 2.3 (1.4-3.8)]. At week 52, higher efficacy responses were maintained in the Q2W arm (n = 165) vs. Q4W (n = 83); PASI 75: 88.9% vs. 74.8%; PASI 90: 76.4% vs. 52.4%; PASI 100: 46.7% vs. 27.3%; Investigator's Global Assessment 0/1: 75.9% vs. 55.6% and Dermatology Life Quality Index 0/1: 66.1% vs. 48.8%. PASI 90 nonresponders at week 16 who uptitrated to Q2W (n = 31) showed higher efficacy responses at week 32 (16 weeks post-uptitration, PASI 90: 38.7% vs. 16.5%) vs. those who remained on Q4W (n = 40). Safety results were comparable across treatment arms and consistent with the established secukinumab safety profile. CONCLUSIONS: Secukinumab 300 mg Q2W demonstrated superior and sustained efficacy compared with Q4W in patients with moderate-to-severe plaque psoriasis weighing ≥ 90 kg. PASI 90 nonresponders derived additional benefits from uptitration to a Q2W regimen (ClinicalTrials.gov identifier: NCT03504852). What is already known about this topic? Obesity is a common comorbidity of psoriasis and can attenuate response to biologic treatment. Secukinumab is a fully human monoclonal antibody that selectively neutralizes interleukin-17A in the treatment of moderate-to-severe plaque psoriasis. Subgroup analyses of previous study results and pharmacokinetic/pharmacodynamic modelling data suggest that heavier patients may benefit from higher exposure to secukinumab through an increased dosing frequency [300 mg every 2 weeks (Q2W) vs. every 4 weeks (Q4W)]. What does this study add? Over 52 weeks, secukinumab 300 mg Q2W demonstrated superior efficacy compared with secukinumab 300 mg Q4W in patients with moderate-to-severe plaque psoriasis weighing ≥90 kg, with comparable safety results, consistent with the established secukinumab safety profile. In patients who did not achieve PASI 90 at week 16 on the Q4W regimen, uptitration to the Q2W regimen at week 16 resulted in improved efficacy responses through week 52 after switching.

Secukinumab shows significant efficacy in palmoplantar psoriasis: Results from GESTURE, a randomized controlled trial.

BACKGROUND: Plaque psoriasis affecting palms and soles is disabling and often resistant to treatment. OBJECTIVE: Evaluate the efficacy and safety of secukinumab, an anti-interleukin 17A antibody, in subjects with palmoplantar psoriasis. METHODS: In this double-blinded, randomized controlled trial, 205 subjects were randomized 1:1:1 to secukinumab 300 mg, 150 mg, or placebo. The primary endpoint was Palmoplantar Investigator's Global Assessment (ppIGA) 0 (clear) or 1 (almost clear/minimal) response at week 16. RESULTS: At week 16, the percentage of subjects who achieved clear or almost clear palms and soles (or ppIGA 0/1) with secukinumab 300 mg (33.3%) and 150 mg (22.1%) was superior to the percentage achieved with placebo (1.5%, P < .001). Palmoplantar Psoriasis Area and Severity Index (ppPASI) was significantly reduced with secukinumab 300 mg (-54.5%) and 150 mg (-35.3%) compared with placebo (-4.0%, P < .001). Dermatology Life Quality Index (DLQI) 0/1 responses from subjects in the secukinumab groups were also significantly higher compared with placebo at week 16 (P < .01) and pain and function of palms and soles was markedly improved with secukinumab as measured by the palmoplantar Quality-of-Life Instrument. Secukinumab 300 mg consistently showed the best outcomes. The safety profile was favorable and similar to previous studies. LIMITATIONS: Lack of active comparator. CONCLUSION: In GESTURE, the largest randomized controlled trial in palmoplantar psoriasis, secukinumab demonstrated the greatest efficacy to date for treating difficult-to-treat psoriasis.

Secukinumab is superior to ustekinumab in clearing skin of subjects with moderate-to-severe plaque psoriasis up to 1 year: Results from the CLEAR study.

BACKGROUND: Secukinumab demonstrated superior efficacy to ustekinumab at week 4 and week 16 of the CLEAR study, with comparable safety, in subjects with moderate-to-severe plaque psoriasis. OBJECTIVE: To compare the efficacy and safety of secukinumab and ustekinumab use over 52 weeks. METHODS: Analysis of 52-week data from CLEAR, a randomized, double-blind, phase 3b study. RESULTS: Among 676 randomized subjects, secukinumab demonstrated superiority to ustekinumab at week 52 in the proportion of subjects with ≥90% improvement in Psoriasis Area and Severity Index (PASI 90) (76% vs 61% [P < .0001]); PASI 100 responses were 46% versus 36% (P = .0103) and Investigator's Global Assessment responses of clear/almost clear skin were 80% versus 65% (P < .0001). Subjects on secukinumab reported greater reductions in psoriasis-related pain, itching, and scaling, and greater improvement across all quality-of-life measures evaluated (Dermatology Life Quality Index [DLQI], EuroQoL 5-Dimension Health Questionnaire, Work Productivity and Activity Impairment Questionnaire-Psoriasis, and Health Assessment Questionnaire-Disability Index). At week 52, 72% of subjects on secukinumab versus 59% on ustekinumab (P = .0008) reported no impact of skin disease on their lives (DLQI 0/1 response). Safety and tolerability was comparable. LIMITATIONS: There was no placebo arm. CONCLUSION: In this head-to-head, double-blind study, secukinumab demonstrated sustained superior efficacy in comparison with ustekinumab in clearing skin through week 52, greater improvement in quality of life, and a favorable and comparable safety profile.

Secukinumab is superior to ustekinumab in clearing skin of subjects with moderate to severe plaque psoriasis: CLEAR, a randomized controlled trial.

BACKGROUND: Secukinumab, a fully human anti-interleukin-17A monoclonal antibody, has shown superior efficacy to etanercept with similar safety in moderate to severe plaque psoriasis (FIXTURE study). OBJECTIVE: We sought to directly compare efficacy and safety of secukinumab versus ustekinumab. METHODS: In this 52-week, double-blind study (NCT02074982), 676 subjects were randomized 1:1 to subcutaneous injection of secukinumab 300 mg or ustekinumab per label. Primary end point was 90% or more improvement from baseline Psoriasis Area and Severity Index (PASI) score (PASI 90) at week 16. RESULTS: Secukinumab (79.0%) was superior to ustekinumab (57.6%) as assessed by PASI 90 response at week 16 (P < .0001). The 100% improvement from baseline PASI score at week 16 was also significantly greater with secukinumab (44.3%) than ustekinumab (28.4%) (P < .0001). The 75% or more improvement from baseline PASI score at week 4 was superior for secukinumab (50.0%) versus ustekinumab (20.6%) (P < .0001). Percentage of subjects with the Dermatology Life Quality Index score 0/1 (week 16) was significantly higher with secukinumab (71.9%) than ustekinumab (57.4%) (P < .0001). The safety profile of secukinumab was comparable with ustekinumab and consistent with pivotal phase III secukinumab studies. LIMITATIONS: The study was not placebo-controlled and of short-term duration. CONCLUSIONS: Secukinumab is superior to ustekinumab in clearing skin of subjects with moderate to severe psoriasis and improving health-related quality of life with a comparable safety profile over 16 weeks.

Innovative Pediatric Development for Secukinumab in Psoriasis: Faster Patient Access, Reduction of Patients on Control.

This paper describes the innovative pediatric development strategy of secukinumab in psoriasis. Initially, this pediatric development had been planned early during the adult development program. This is common for most development programs as it is required by law in major regions worldwide. At that time, only limited experience with secukinumab's mechanism of action was available, especially in the pediatric population for which no data had been collected yet. Pediatric extrapolation frameworks were not in use. As a result, a standard pediatric program had initially been proposed requiring two relatively large placebo-controlled pivotal trials. However, as experience with the use of secukinumab grew, so did experience with-and regulatory openness to-innovative quantitative approaches, such as extrapolation. It became clear that the pediatric development of secukinumab could be substantially accelerated by these novel ideas. Here, we report how these concepts were implemented in the pediatric development program of secukinumab in psoriasis, using a wide range of innovative quantitative techniques. This strategy led to the removal of the placebo arm from one trial, a substantial reduction of the overall sample size in this program, and a significantly faster approval of secukinumab for the pediatric psoriasis population.

Conjugate heat transfer study of various cooling structures and sensitivity analysis of overall cooling effectiveness.

The conjugate heat transfer of a turbine blade is influenced by several factors. To analyze the influence of each factor, the published one-dimensional conjugate heat transfer model was improved through theoretical analysis in this study. An overall cooling effectiveness equation containing three dimensionless parameters (adiabatic film cooling effectiveness η, Biot number on the mainstream side Big, and ratio between the heat transfer coefficients of the external and internal walls hg/hi) was obtained. The sensitivity of the overall cooling effectiveness ϕ to these three parameters was obtained through a multi-parameter sensitivity analysis. The results showed that increasing η could improve ϕ the most effectively. The interactions between the dimensionless parameters were analyzed by developing sensitivity charts. The results showed that increasing η from 0.4 to 0.5 could reduce the sensitivity of ϕ to the other two parameters by approximately 15%, whereas increasing Big had little effect on the sensitivity of ϕ to each dimensionless parameter. Increasing hg/hi could improve the sensitivity to η. The above conclusions could also be applied to the plate film hole and plate impingement effusion structures. The effects of different internal cooling structures and film hole structures on the three dimensionless parameters were studied by performing numerical simulations, which verified the accuracy of the one-dimensional conjugate heat transfer model in this study. The results showed that the internal cooling structures had little effect on the distribution of η and Big. The heat transfer coefficient on the coolant side could be effectively improved by installing film holes. The film hole structures mainly affected ϕ by influencing the distribution of η.

Area level deprivation and drinking patterns among adolescents.

OBJECTIVE: To assess relationships between area level deprivation and drinking patterns among adolescents. METHOD: This study uses data from the national New Zealand Alcohol Survey 2004 comprising 1828, age range 12-19 years. A multilevel linear regression was conducted using NZDep2001 (a composite deprivation measure) as the exposure and alcohol use (quantity and frequency) as outcome. RESULTS: A J-shaped association was observed between area level deprivation and quantity of adolescents' alcohol use after controlling for age, sex, ethnicity, and individual socioeconomic position; where adolescents living in the most deprived areas consumed the heaviest quantities of alcohol. No association was found for frequency of drinking. CONCLUSION: This study found a J-shaped relationship between area-level disadvantage and increased quantities consumed, where adolescents living in the most deprived areas typically consumed the heaviest quantities of alcohol. However, our study has also highlighted that future research may better isolate an independent relationship between deprivation and consumption in adolescents by accounting for structural variables related to both deprivation and consumption, such as alcohol outlet density.