Incidence of Uveitis in Secukinumab-treated Patients With Ankylosing Spondylitis: Pooled Data Analysis From Three Phase 3 Studies.

OBJECTIVE: The objective of this study was to report the incidence of uveitis in secukinumab-treated patients with ankylosing spondylitis (AS) in a pooled analysis of three phase 3 trials (MEASURE 1-3 [ClinicalTrials.gov identifiers NCT01358175, NCT01649375, NCT02008916]). METHODS: Analysis included pooled patient-level data from all patients (N = 794) who received any dose (one or more) of secukinumab up to the last patient attending the week 156 study visit in MEASURE 1 and up to the week 156 visit in MEASURE 2 and the week 104 visit in MEASURE 3 for each patient. Postmarketing data were from the periodic safety update report. Incidence of uveitis is reported as the exposure-adjusted incidence rate (EAIR) per 100 patient-years of secukinumab exposure. RESULTS: Overall, 135 (17%) patients reported preexisting (but not active or ongoing) uveitis at baseline, and 589 (74.2%) patients were HLA antigen B27 positive. The EAIR for uveitis was 1.4 per 100 patient-years over the entire treatment period. Among all cases of uveitis (n = 26), 14 (54%) were flares. The exposure-adjusted reporting rate of uveitis in the postmarketing data (which included patients across the three approved indications of psoriasis, psoriatic arthritis, and AS) was 0.03 per 100 patient-years based on cumulative secukinumab exposure of 96 054 patient-years. CONCLUSION: The incidence rate of uveitis in secukinumab-treated patients with active AS does not suggest an increased risk with secukinumab treatment.

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).

Inhibition of IL-17A by secukinumab shows no evidence of increased Mycobacterium tuberculosis infections.

Secukinumab, a fully human monoclonal antibody that selectively neutralizes interleukin-17A (IL-17A), has been shown to have significant efficacy in the treatment of moderate to severe psoriasis, psoriatic arthritis and ankylosing spondylitis. Blocking critical mediators of immunity may carry a risk of increased opportunistic infections. Here we present clinical and in vitro findings examining the effect of secukinumab on Mycobacterium tuberculosis infection. We re-assessed the effect of secukinumab on the incidence of acute tuberculosis (TB) and reactivation of latent TB infection (LTBI) in pooled safety data from five randomized, double-blind, placebo-controlled, phase 3 clinical trials in subjects with moderate to severe plaque psoriasis. No cases of TB were observed after 1 year. Importantly, in subjects with a history of pulmonary TB (but negative for interferon-γ release and receiving no anti-TB medication) or positive for latent TB (screened by interferon-γ release assay and receiving anti-TB medication), no cases of active TB were reported. Moreover, an in vitro study examined the effect of the anti-tumor necrosis factor-α (TNFα) antibody adalimumab and secukinumab on dormant M. tuberculosis H37Rv in a novel human three-dimensional microgranuloma model. Auramine-O, Nile red staining and rifampicin resistance of M. tuberculosis were measured. In vitro, anti-TNFα treatment showed increased staining for Auramine-O, decreased Nile red staining and decreased rifampicin resistance, indicative of mycobacterial reactivation. In contrast, secukinumab treatment was comparable to control indicating a lack of effect on M. tuberculosis dormancy. To date, clinical and preclinical investigations with secukinumab found no evidence of increased M. tuberculosis infections.

A multicentre, prospective study to evaluate costs of septic patients in Brazilian intensive care units.

BACKGROUND: Sepsis has a high prevalence within intensive care units, with elevated rates of morbidity and mortality, and high costs. Data on sepsis costs are scarce in the literature, and in developing countries such as Brazil these data are largely unavailable. OBJECTIVES: To assess the standard direct costs of sepsis management in Brazilian intensive care units (ICUs) and to disclose factors that could affect those costs. METHODS: This multicentre observational cohort study was conducted in adult septic patients admitted to 21 mixed ICUs of private and public hospitals in Brazil from 1 October 2003 to 30 March 2004. Complete data for all patients admitted to the ICUs were obtained until their discharge or death. We collected only direct healthcare-related costs, defined as all costs related to the ICU stay. Enrolled patients were assessed daily in terms of cost-related expenditures such as hospital fees, operating room fees, gas therapy, physiotherapy, blood components transfusion, medications, renal replacement therapy, laboratory analysis and imaging. Standard unit costs (year 2006 values) were based on the Brazilian Medical Association (AMB) price index for medical procedures and the BRASINDICE price index for medications, solutions and hospital consumables. Medical resource utilization was also assessed daily using the Therapeutic Intervention Scoring System (TISS-28). Indirect costs were not included. RESULTS: With a mean (standard deviation [SD]) age of 61.1 +/- 19.2 years, 524 septic patients from 21 centres were included in this study. The overall hospital mortality rate was 43.8%, the mean Acute Physiology And Chronic Health Evaluation II (APACHE II) score was 22.3 +/- 5.4, and the mean Sequential Organ Failure Assessment (SOFA) score at ICU admission was 7.5 +/- 3.9. The median total cost of sepsis was $US 9632 (interquartile range [IQR] 4583-18 387; 95% CI 8657, 10 672) per patient, while the median daily ICU cost per patient was $US 934 (IQR 735-1170; 95% CI 897, 963). The median daily ICU cost per patient was significantly higher in non-survivors than in survivors, i.e. $US 1094 (IQR 888-1341; 95% CI 1058, 1157) and $US 826 (IQR 668-982; 95% CI 786, 854), respectively (p < 0.001). For patients admitted to public and private hospitals, we found a median SOFA score at ICU admission of 7.5 and 7.1, respectively (p = 0.02), and the mortality rate was 49.1% and 36.7%, respectively (p = 0.006). Patients admitted to public and private hospitals had a similar length of stay of 10 (IQR 5-19) days versus 9 (IQR 4-16) days (p = 0.091), and the median total direct costs for public ($US 9773; IQR 4643-19 221; 95% CI 8503, 10 818) versus private ($US 9490; IQR 4305-17 034; 95% CI 7610, 11 292) hospitals did not differ significantly (p = 0.37). CONCLUSIONS: The present study provides the first economic analysis of direct costs of sepsis in Brazilian ICUs and reveals that the cost of sepsis treatment is high. Despite similar ICU management, there was a significant difference regarding patient outcome between private and public hospitals. Finally, the median daily costs of non-survivor patients were higher than survivors during ICU stay.