High BMI is associated with lower TNF-α inhibitor serum trough levels and higher disease activity in patients with axial spondyloarthritis.

BACKGROUND: TNF-α inhibitor (TNFi) serum trough levels have previously been found to be related to disease activity in axial spondyloarthritis (axSpA). However, most research regarding serum trough levels has been conducted in patients who only recently started TNFi therapy. Therefore, our objective was to explore TNFi serum trough level measurements in relation to disease activity and BMI in the total axSpA population in daily clinical practice, also including patients on long-term TNFi therapy. METHODS: Consecutive patients from the Groningen Leeuwarden Axial Spondyloarthritis (GLAS) cohort were approached for a TNFi serum trough level measurement during their regular outpatient visit at the UMCG. Spearman's correlation coefficient was used to analyse the relation of serum trough levels with disease activity and BMI. Logistic regression was performed to analyse the relation between therapeutic drug levels and disease activity, corrected for potential confounders, including BMI. RESULTS: Thirty-four patients on adalimumab and 21 patients on etanercept were included. Mean age was 45 ± 12 years, 47% were male, median BMI was 26.4 (IQR 23.9-32.5) and median treatment duration was 41 months (range 2-126). According to definitions of Sanquin, 47% of patients had therapeutic serum trough levels. No significant correlations were found between TNFi levels and disease activity (ASDAS-CRP: adalimumab: ρ = -0.16, p = 0.39; etanercept: ρ = -0.29, p = 0.20). TNFi levels were moderately correlated with BMI (adalimumab: ρ = -0.48, p = 0.004; etanercept: ρ = -0.50, p = 0.021). Patients with active disease (ASDAS ≥ 2.1) showed higher BMI than patients with inactive disease (median 29.7 vs. 24.6, p = 0.015). In multivariable regression analyses, BMI was identified as the only confounder for the relationship between therapeutic drug levels and ASDAS. CONCLUSION: In this cross-sectional, observational study of axSpA patients mainly on long-term treatment with TNFi, higher BMI was significantly associated with lower adalimumab and etanercept serum trough levels and higher disease activity.

N-terminus of Etanercept is Proteolytically Processed by Dipeptidyl Peptidase-4.

PURPOSE: Biologics are structurally heterogeneous and can undergo biotransformation in the body. Etanercept (ETN) is a fusion protein composed of a soluble tumor necrosis factor (TNF) receptor and the Fc portion of human immunoglobulin G1. The N-terminus of ETN has a putative sequence cleaved by dipeptidyl peptidase-4 (DPP-4). The purpose of this study was to investigate the biotransformation of ETN in humans and mice and evaluate its effects on functional properties. METHODS: An analytical method using liquid chromatography-mass spectrometry (LC-MS/MS) was established. The N-terminal heterogeneity of ETN was assessed in the serum of patients with rheumatoid arthritis or mice receiving ETN. The in vitro N-terminal truncation was explored using recombinant DPP-4. The binding affinity to TNF-α or TNF-ß was investigated using an in-house enzyme-linked immunosorbent assay. RESULTS: In the formulations, about 90% of ETN had an intact N-terminus, while the N-terminal truncated form was most abundant in the serum of the patients with rheumatoid arthritis and mice. Recombinant human DPP-4 cleaved two amino acids from the N-terminus of ETN in vitro. Sitagliptin, a DPP-4 inhibitor, inhibited N-terminal truncation both in vivo and in vitro. However, N-terminal truncation did not affect the binding ability to TNF-α or TNF-ß and the pharmacokinetics of ETN. ETN biosimilars exhibited similar characteristics to the reference product in vivo and in vitro. CONCLUSIONS: ETN undergoes N-terminal truncation in the body, and DPP-4 cleaves exogenous ETN via N-terminal proteolysis. The application of an MS-based assay will detect novel biotransformation of therapeutic proteins.

A novel method for the storage and transport of biological samples of therapeutic proteins prior to the detection of analytes using ELISA.

Therapeutic proteins have exhibited promising clinical applications in the diagnosis and treatment of some diseases. Prior to the detection of analytes using enzyme-linked immunosorbent assay, biological samples of therapeutic proteins are conventionally frozen at temperatures ranging from - 20 to - 80 °C to increase the stability of analytes. However, therapeutic proteins destabilization and aggregation may occur during the frozen storage or the freeze-thawing step. In this work, an effective method was proposed to freeze-dry therapeutic protein samples to allow subsequent storage or transport of samples without freezing them. This new method was validated with quality control samples of adalimumab and etanercept, and it was also used in the bioanalysis of adalimumab and etanercept in pharmacokinetic (PK) studies. Adalimumab and etanercept were stable for 14 days at 4 °C after being prepared and stored using the new method, with detection that was accurate and repeatable. Studies of adalimumab and etanercept in animals and humans showed that the PK parameters of the analytes stored with the new method were consistent with those of analytes stored using the conventional method. This effective method will be attractive for facilitating the storage and transport of plasma samples containing therapeutic proteins.

Biologic TNF-α inhibitors reduce microgliosis, neuronal loss, and tau phosphorylation in a transgenic mouse model of tauopathy.

BACKGROUND: Tumor necrosis factor-α (TNF-α) plays a central role in Alzheimer's disease (AD) pathology, making biologic TNF-α inhibitors (TNFIs), including etanercept, viable therapeutics for AD. The protective effects of biologic TNFIs on AD hallmark pathology (Aß deposition and tau pathology) have been demonstrated. However, the effects of biologic TNFIs on Aß-independent tau pathology have not been reported. Existing biologic TNFIs do not cross the blood-brain barrier (BBB), therefore we engineered a BBB-penetrating biologic TNFI by fusing the extracellular domain of the type-II human TNF-α receptor (TNFR) to a transferrin receptor antibody (TfRMAb) that ferries the TNFR into the brain via receptor-mediated transcytosis. The present study aimed to investigate the effects of TfRMAb-TNFR (BBB-penetrating TNFI) and etanercept (non-BBB-penetrating TNFI) in the PS19 transgenic mouse model of tauopathy. METHODS: Six-month-old male and female PS19 mice were injected intraperitoneally with saline (n = 12), TfRMAb-TNFR (1.75 mg/kg, n = 10) or etanercept (0.875 mg/kg, equimolar dose of TNFR, n = 10) 3 days/week for 8 weeks. Age-matched littermate wild-type mice served as additional controls. Blood was collected at baseline and 8 weeks for a complete blood count. Locomotion hyperactivity was assessed by the open-field paradigm. Brains were examined for phosphorylated tau lesions (Ser202, Thr205), microgliosis, and neuronal health. The plasma pharmacokinetics were evaluated following a single intraperitoneal injection of 0.875 mg/kg etanercept or 1.75 mg/kg TfRMAb-TNFR or 1.75 mg/kg chronic TfRMAb-TNFR dosing for 4 weeks. RESULTS: Etanercept significantly reduced phosphorylated tau and microgliosis in the PS19 mouse brains of both sexes, while TfRMAb-TNFR significantly reduced these parameters in the female PS19 mice. Both TfRMAb-TNFR and etanercept treatment improved neuronal health by significantly increasing PSD95 expression and attenuating hippocampal neuron loss in the PS19 mice. The locomotion hyperactivity in the male PS19 mice was suppressed by chronic etanercept treatment. Equimolar dosing resulted in eightfold lower plasma exposure of the TfRMAb-TNFR compared with etanercept. The hematological profiles remained largely stable following chronic biologic TNFI dosing except for a significant increase in platelets with etanercept. CONCLUSION: Both TfRMAb-TNFR (BBB-penetrating) and non-BBB-penetrating (etanercept) biologic TNFIs showed therapeutic effects in the PS19 mouse model of tauopathy.

Lymphatic Distribution of Etanercept Following Intravenous and Subcutaneous Delivery to Rats.

PURPOSE: The purpose of this work was to investigate the role of the lymphatic system in the pharmacokinetics of etanercept, a fusion protein. METHODS: Etanercept 1 mg/kg was administered intravenously (IV) and subcutaneously (SC) to thoracic lymph duct-cannulated and sham-operated control rats. Blood and lymph samples were obtained for up to 6 days. RESULTS: Model-based SC bioavailability of etanercept was 65.2% in the control group. In lymph-cannulated rats, etanercept concentration in the lymph was consistently lower than in serum following IV dosing; and the concentration in the lymph was significantly higher than in serum after SC injection. The absorption occurred predominantly through the lymphatic pathway (82.7%), and only 17.3% by direct uptake into the central compartment (blood pathway). Lymphatic cannulation reduced the area under the serum concentration-time curve by 28% in IV group and by 91% in SC group. A mechanistic pharmacokinetic model that combined dual absorption pathways with redistribution of the systemically available protein drug into lymph was developed. The model successfully captured serum and lymph data in all groups simultaneously, and all parameters were estimated with sufficient precision. CONCLUSIONS: Lymphatic system was shown to play an essential role in systemic disposition and SC absorption of etanercept.

Assessment of Placental Disposition of Infliximab and Etanercept in Women With Autoimmune Diseases and in the Ex Vivo Perfused Placenta.

Tumor necrosis factor (TNF) inhibitors are increasingly applied during pregnancy without clear knowledge of the impact on placenta and fetus. We assessed placental transfer and exposure to infliximab (n = 3) and etanercept (n = 3) in women with autoimmune diseases. Furthermore, we perfused healthy term placentas for 6 hours with 100 µg/mL infliximab (n = 4) or etanercept (n = 5). In pregnant women, infliximab transferred into cord blood but also entered the placenta (cord-to-maternal ratio of 1.6 ± 0.4, placenta-to-maternal ratio of 0.3 ± 0.1, n = 3). For etanercept, a cord-to-maternal ratio of 0.04 and placenta-to-maternal ratio of 0.03 was observed in one patient only. In ex vivo placenta perfusions, the extent of placental transfer did not differ between the drugs. Final concentrations in the fetal compartment for infliximab and etanercept were 0.3 ± 0.3 and 0.2 ± 0.2 µg/mL, respectively. However, in placental tissue, infliximab levels exceeded those of etanercept (19 ± 6 vs. 1 ± 3 µg/g, P < 0.001). In conclusion, tissue exposure to infliximab is higher than that of etanercept both in vivo as well as in ex vivo perfused placentas. However, initial placental transfer, as observed ex vivo, does not differ between infliximab and etanercept when administered in equal amounts. The difference in placental tissue exposure to infliximab and etanercept may be of clinical relevance and warrants further investigation. More specifically, we suggest that future studies should look into the occurrence of placental TNF inhibition and possible consequences thereof.

An Open-Label, Randomized, Single-Dose, Crossover, Comparative Pharmacokinetics Study of YLB113 and the Etanercept Reference Product in Healthy Adult Male Subjects.

BACKGROUND AND OBJECTIVES: YLB113 is being developed as a biosimilar of the antitumor necrosis factor-alpha antagonist etanercept, which is approved for the treatment of moderate-to-severe rheumatoid arthritis (RA) and other chronic immune-mediated inflammatory diseases. An open-label, crossover, pharmacokinetic study was conducted to compare the relative bioavailability and safety of YLB113 and the etanercept reference product (RP) Enbrel®. METHODS: Healthy male subjects aged 18-50 years were randomized to receive a single subcutaneous dose of YLB113 in one period and the etanercept RP in another period. A washout period of 28 days separated the two treatment periods. Blood samples were collected for pharmacokinetic analysis predose and until 480 h postdose during both periods. RESULTS: Overall, 52 subjects were enrolled, including 51 subjects who completed the first period and 43 subjects who completed the second period. The 90% confidence intervals for the least squares means derived from an analysis of the log-transformed pharmacokinetic parameters maximum serum concentration (Cmax), area under the serum concentration-time curve (AUC) from 0 to the last measurable concentration (AUC(0-t)) and AUC from 0 to infinity (AUC(0-∞)) for etanercept were between the limits of 80 and 125%. Thus, YLB113 met the bioequivalence criterion. YLB113 and the etanercept RP were well tolerated, with 24 subjects reporting 53 adverse events, including 42 mild and 11 moderate events. Treatment-emergent adverse events were reported by 14 and 16 subjects following the administration of YLB113 and the etanercept RP, respectively. CONCLUSIONS: A single dose of YLB113 exhibited pharmacokinetic and safety profiles comparable with those of the etanercept RP in healthy adult male subjects. Therefore, YLB113 and the etanercept RP can be considered bioequivalent. These findings support the continued development of YLB113 for use in patients with RA. JORDAN FOOD & DRUG ADMINISTRATION UNIQUE TRIAL NUMBER: 31/Clinical/2018.

Comparison of the Pharmacokinetics, Safety, and Tolerability of the Autoinjector (AI) and Pre-Filled Syringe (PFS) of SB4 in Healthy Subjects.

PURPOSE: SB4 is an etanercept biosimilar, approved by the European Commission (EC) and the US Food and Drug Administration (FDA) following a demonstration of equivalent efficacy and safety and comparable quality data to the reference product. This study aimed to demonstrate equivalent pharmacokinetic (PK) profiles, safety, and tolerability between SB4 autoinjector (AI) and SB4 pre-filled syringe (PFS). PATIENTS AND METHODS: This was an open-label, two-period, two-sequence, single-dose, cross-over study to evaluate bioequivalence of PK profiles, safety, and tolerability between SB4 AI and PFS in healthy adults. Treatment periods were separated by 14 days resulting in a 35-day washout between investigational product (IP) administration in Periods 1 and 2. RESULTS: A total of 50 subjects were randomized: 24 subjects in Sequence I and 26 in Sequence II, and 6 subjects discontinued from the study. The primary PK endpoints including area under the concentration-time curve from time zero to infinity (AUCinf) and to the last quantifiable concentration (AUClast), and maximum serum concentration (Cmax) were all within the equivalence margin of 80.00-125.00%. Safety and tolerability were comparable between the two treatments. CONCLUSION: PK profiles showed that SB4 AI and PFS were bioequivalent in healthy subjects. Safety assessment was also comparable between the two treatments.

Switch from reference etanercept to SDZ ETN, an etanercept biosimilar, does not impact efficacy, safety, and immunogenicity of etanercept in patients with moderate-to-severe rheumatoid arthritis: 48-week results from the phase III, randomized, double-blind EQUIRA study.

BACKGROUND: Sandoz etanercept (SDZ ETN; GP2015) is an etanercept biosimilar with equivalent efficacy and comparable safety and immunogenicity to reference etanercept (ETN) in patients with moderate-to-severe chronic plaque-type psoriasis. METHODS: EQUIRA was a phase III, double-blind study conducted in patients with moderate-to-severe rheumatoid arthritis and inadequate response to disease-modifying anti-rheumatic drugs. Eligible patients were randomized 1:1 to receive subcutaneous 50 mg SDZ ETN or ETN, once-weekly, for 24 weeks. At week 24, patients with at least moderate EULAR response in the SDZ ETN group continued SDZ ETN treatment, and those in the ETN group were switched to receive 50 mg SDZ ETN, for up to 48 weeks. Patients received concomitant methotrexate at a stable dose (10-25 mg/week) and folic acid (≥ 5 mg/week). Equivalence between SDZ ETN and ETN for change from baseline in disease activity score including 28 joint count C-reactive protein (DAS28-CRP) at week 24 (primary endpoint) and comparable safety and immunogenicity profile of SDZ ETN and ETN have previously been demonstrated at week 24. Herein, we present the 48-week results of the study after a single switch from ETN to its biosimilar at week 24. RESULTS: The least squares mean (standard error) change in DAS28-CRP from baseline up to week 48 was comparable between "continued SDZ ETN" (- 2.90 [0.12], n = 148) and "switched to SDZ ETN" (- 2.78 [0.13], n = 131) groups. The proportion of patients achieving EULAR good/moderate responses based on DAS28-erythrocyte sedimentation rate and ACR20/50/70 response rates were comparable between the two groups. The proportion of patients with at least one treatment-emergent adverse event was 42.9% in the "continued SDZ ETN" and 38.0% in the "switched to SDZ ETN" groups. Serious adverse events occurred in 4 patients in each of the two groups. After week 24, none of the patients in the switched group developed anti-drug antibodies (ADAs), while 4 patients in the continued SDZ ETN group had single-event, very low titer, non-neutralizing ADAs detected. CONCLUSIONS: The 48-week results from the EQUIRA study demonstrate that switch from ETN to SDZ ETN in patients with moderate-to-severe rheumatoid arthritis does not impact the efficacy, safety, or immunogenicity of etanercept. TRIAL REGISTRATION: EudraCT number 2012-002009-23 , Registered 19 April 2012-prospectively registered.

Long-term efficacy, safety and immunogenicity in patients with rheumatoid arthritis continuing on an etanercept biosimilar (LBEC0101) or switching from reference etanercept to LBEC0101: an open-label extension of a phase III multicentre, randomised, double-blind, parallel-group study.

BACKGROUND: To evaluate the long-term efficacy, safety and immunogenicity of continuing LBEC0101; the etanercept (ETN) biosimilar; or switching from the ETN reference product (RP) to LBEC0101 in patients with rheumatoid arthritis (RA). METHODS: This multicentre, single-arm, open-label extension study enrolled patients who had completed a 52-week randomised, double-blind, parallel phase III trial of LBEC0101 vs ETN-RP. Patients treated with ETN-RP during the randomised controlled trial switched to LBEC0101; those treated with LBEC0101 continued to receive LBEC0101 in this study. LBEC0101 (50 mg) was administered subcutaneously once per week for 48 weeks with a stable dose of methotrexate. Efficacy, safety and immunogenicity of LBEC0101 were assessed up to week 100. RESULTS: A total of 148 patients entered this extension study (70 in the maintenance group and 78 in the switch group). The 28-joint disease activity scores (DAS28)-erythrocyte sedimentation rate (ESR) were maintained in both groups from week 52 to week 100 (from 3.068 to 3.103 in the maintenance group vs. from 3.161 to 3.079 in the switch group). ACR response rates at week 100 for the maintenance vs. switch groups were 79.7% vs. 83.3% for ACR20, 65.2% vs. 66.7% for ACR50 and 44.9% vs. 42.3% for ACR70. The incidence of adverse events and the proportion of patients with newly developed antidrug antibodies were similar in the maintenance and switch groups (70.0% and 70.5%, 1.4% and 1.3%, respectively). CONCLUSIONS: Administration of LBEC0101 showed sustained efficacy and acceptable safety in patients with RA after continued therapy or after switching from ETN-RP to LBEC0101. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02715908 . Registered 22 March 2016.

Prevalence of switching from two anti-TNF biosimilars back to biologic reference products in Germany
.

AIMS: Biosimilars are becoming more and more important for the treatment of many diseases. However, it is not understood how they are tolerated. Our aim was to analyze the behavior of switching from two anti-TNF biosimilars back to biologic reference products in German patients. MATERIALS AND METHODS: Patients switching from etanercept reference to an etanercept biosimilar between February 2016 and December 2017 and those switching from the infliximab reference product to an infliximab biosimilar between February 2015 and December 2017 were included in the study (index date). The main outcome of this study, the rate of switching from these two biosimilars back to reference products, was analyzed using Kaplan-Meier curves. A multivariate Cox regression model was used to predict the switch-back behavior. RESULTS: A total of 2,956 patients were included in this study. After 3 months, 14.7% and, after 12 months, 30.2% of them were switched back from a biosimilar to the reference product. Sex, age, physician specialty, and co-therapy were not significantly associated with this switch. CONCLUSION: Almost one third of the patients treated with one of two biosimilar drugs after previous biologic therapy are switched back to reference products in Germany.

Supervivencia a largo plazo de los fármacos biológicos anti-TNF subcutáneos administrados durante los años 2008-2012 en una cohorte de pacientes con artritis reumatoide / Long-term survival of subcutaneous anti-tumor necrosis factor biological drugs administered between 2008 and 2012 in a cohort of rheumatoid arthritis patients

Objetivo: Comparar la supervivencia de los anti-TNF subcutáneos utilizados durante el periodo 2008-2012 según práctica clínica. Material y métodos: Estudio observacional retrospectivo de todos los pacientes diagnosticados de AR que habían iniciado tratamiento con un anti-TNF subcutáneo y mantenido durante al menos 6 meses. Los datos fueron analizados mediante SPSS V17,0. Resultados: Cuarenta y nueve pacientes con AR iniciaron tratamiento con anti-TNF subcutáneo (32 con etanercept y 17 con adalimumab). La media de edad fue de 45,94 años (75,5% mujeres). La media de duración de la enfermedad previa al inicio del anti-TNF fue de 2,67 años. La media de edad al inicio del tratamiento fue de 51,84 años, índice de actividad de la enfermedad en 28 articulaciones medio de 4,93. La supervivencia media del tratamiento anti-TNF fue de 8,40 años, mostrando una mayor supervivencia etanercept. La principal razón de discontinuación fue por fallo secundario (90,9%). Conclusión: En la práctica clínica habitual, la supervivencia a largo plazo de los tratamientos anti-TNF subcutáneos fue elevada e independiente de que tuvieran o no tratamiento inmunosupresor concomitante

Objective:To compare the survival of subcutaneous anti-tumor necrosis factor (TNF) drugs used between 2008 and 2012 prescribed in accordance with clinical practice. Material and methods:Retrospective, observational study of the patients in our center diagnosed with rheumatoid arthritis (RA). We included patients who had received a subcutaneous anti-TNF agent for at least 6 months. The data were analyzed using the SPSS V17.0 statistical package. Results:Forty-nine RA patients started subcutaneous biological treatment with an anti-TNF agent (32 with etanercept and 17 with adalimumab). The mean age was 45.94 years (75.5% female). The mean disease duration prior to starting anti-TNF administration was 2.67 years. The mean age at the start of treatment was 51.84 years, and the average Disease Activity Score 28 was 4.93. The median survival of the anti-TNF treatment was 8.40 years; the survival of etanercept was the longer of the two. The main reason for discontinuation was secondary failure (90.9%). Conclusions:In routine clinical practice, the survival of subcutaneous anti-TNF treatment was extensive and was independent of whether or not the patients received concomitant immunosuppressive therapy

Etanercept biosimilar SB-4.

INTRODUCTION: Biosimilars are highly similar molecules to other biological medicines that have already been authorized for use. Etanercept (ETN) was the first anti-tumor necrosis factor inhibitor (TNFi) approved by the Food and Drug Administration for the treatment of moderate to severe rheumatoid arthritis (RA) in November 1998 and in February 2000 by the European Medicines Agency. Twenty years later, the first ETN biosimilar has come of age. Areas covered: In this review we examined SB-4 as a biosimilar candidate to ETN, focusing on the available data. Current data indicate that SB-4 is a highly similar alternative to ETN in terms of safety, efficacy, tolerability, and immunogenicity. SB-4 has already been approved by health authorities in Europe, South Korea, Australia, and Canada, as a subcutaneous therapy option for the treatment of patients with RA but also for the full spectrum approved for its bio-originator ETN. Expert opinion: The current body of evidence suggests that all biologic activities have been demonstrated to be equivalent between SB-4 and the originator, including pharmacodynamic and pharmacokinetic activities. In some areas, and more specifically when it comes to immunogenicity, SB-4 showed lower incidents. Therefore, it is fully expected to have same efficacy and safety in all indications.

Evolución a largo plazo de la calidad de vida en pacientes con artritis reumatoide tratados con terapias biológicas / Long-term changes in the quality of life of patients with rheumatoid arthritis treated with biological therapies

Objetivo: Analizar la evolución a largo plazo de la calidad de vida relacionada con la salud (CVRS) en pacientes con artritis reumatoide (AR) tratados con terapias biológicas. Método: Estudio observacional prospectivo realizado entre octubre de 2006 y mayo de 2011. Se seleccionó a pacientes mayores de edad, diagnosticados de AR, tratados durante al menos un año con anti-TNF (infliximab o etanercept) y que no hubieran recibido otros tratamientos biológicos previos. Completaron el estudio 41 pacientes, cumplimentando el cuestionario específico validado QOL-AR en 3ocasiones: E1 (entre septiembre de 2006 y febrero de 2007), E2 (entre abril de 2008 y enero de 2009) y E3 (entre julio de 2010 y mayo de 2011). Los datos se analizaron con Epi-Info versión 3.3-2004 para Windows (R) y Excel 2007; la comparación de las medias con la prueba t de Student y la relación entre valores de un mismo paciente, mediante regresión lineal. Resultados: Resultados globales: tendencia descendente no estadísticamente significativa: 7,09±1,15 en E1; 6,90±1,60 en E2 y 6,52±1,59 en E3. Los ítems con mayor puntuación fueron los relacionados con aspectos psicosociales (ayuda familiar, interacción con familia y amigos). La dimensión física fue la peor valorada (habilidad física, dolor artrítico, artritis). Entre E2 y E3 aumentó significativamente la valoración de la ayuda familiar (p=0,0008) y disminuyeron significativamente tensión nerviosa (p=0,0119) y estado de ánimo (p=0,0451). Conclusiones: La CVRS de los pacientes es buena y se ha mantenido prácticamente invariable tras unos 6años de estudio. Es probable que parte de la estabilidad en la CVRS sea atribuible al tratamiento

Objective: To analyze the changes in health-related quality of life (HRQoL) of patients with rheumatoid arthritis (RA) treated with biological therapies. Method: Observational prospective study performed from October 2006 to May 2011. The inclusion criteria were adult patients, diagnosed with RA, treated for at least one year with anti-tumor necrosis factor therapy (infliximab or etanercept), who had not received other biological treatments previously. A total of 41 patients who completed the study undertook the specific and validated questionnaire QoL-RA Scale 3 times: E1 (September 2006-February 2007), E2 (April 2008-January 2009) and E3 (July 2010- May 2011). Data analysis was conducted using Epi-Info version 3.3 2004 for Windows(R) and Excel 2007; mean comparisons were evaluated by Student's t-test and the relationship between the 3 outcomes for each patient by lineal regression. Results: Overall results show a downward trend which was not statistically significant: 7.09 (standard deviation [SD]=1.15) in E1; 6.90 (SD=1.60) in E2; and 6.52 (SD=1.59) in E3. Items with higher scores were those related to psychosocial aspects (help from family, interaction with family and friends), whereas the physical dimension was valued more poorly (physical ability, arthritis pain, arthritis). Between E2 and E3 there was a significant increase in help from family (P=.0008), whereas level of tension (P=.0119) and mood (P=.0451) decreased significantly. Conclusions: In all, HRQoL reported by patients is good and has remained unchanged after approximately 6 years of study. The stability of HRQoL is probably partly attributable to treatment

Uptake of rheumatology biosimilars in the absence of forced switching.

BACKGROUND: To describe the uptake and system-level effects of the introduction of biosimilars in a setting without forced switching. RESEARCH DESIGN AND METHODS: We used data from the Swedish Rheumatology Quality register from start of marketing of infliximab (Remsima® and Inflectra®) and etanercept (Benepali®) biosimilars until 31 December 2016. We compared users of each originator-product and its biosimilar(s) by line of treatment: bDMARD-naïve patients, non-medical switchers (vs. matched patients remaining on originator), and patients switching from a previous bDMARD of another type. RESULTS: From the start of marketing 1343 patients started an infliximab biosimilar (22 months) and 2691 started etanercept (9 months). Overall, the introduction of these biosimilars resulted in an increase of the total number of ongoing infliximab and etanercept treatments (originator + biosimilar) . At the end of the study period, biosimilars accounted for 31% of all infliximab treatments and 31% of all etanercept-treated patients. For each line of therapy, we noted only small differences in patient characteristics between those starting the originator product vs. its biosimilar(s). CONCLUSIONS: Introduction of biosimilars have effects beyond replacement of the originator product, in terms of an increased rate of bDMARD initiation. Selection to non-medical switching displayed no particular disease- or patient-characteristics.

GP2015 as a promising therapy for rheumatoid arthritis.

INTRODUCTION: Rheumatoid arthritis is a common inflammatory joint disease with a myriad of systemic manifestations. Over the last 20 years its treatment has been revolutionised by the introduction of a number of different biologic drugs, including the TNF-receptor Fc fusion protein, Etanercept. However, these drugs are expensive and their widespread use puts a financial burden on healthcare systems. As many biologic treatments begin to come off patent new 'biosimilar' versions are being developed which can lead to significant cost savings. GP2015 (Erelzi®) is the second biosimilar version of Etanercept which is licensed for the treatment of rheumatoid arthritis. Areas covered: We discuss the Chemistry, pharmacokinetics and pharmacodynamics of GP2015 in relation to reference Etanercept. Preclinical trials have shown pharmacokinetic equivalence between GP2015 and the reference drug. The recently completed Phase III, randomised, double blind EQUIRA study has shown equivalent efficacy and safety between GP2015 and Etanercept in patients with rheumatoid arthritis. Expert opinion: GP2015 has shown equivalent efficacy and safety to reference Etanercept. With a growing number of biosimilar medications becoming available and another biosimilar Etanercept already being widely prescribed it is likely to be the cost of the drug that will determine if it is used widely.

TNF-α level affects etanercept clearance: TNF-α concentration as a new correction factor of allometric scaling to predict individual etanercept clearances in patients with ankylosing spondylitis.

Etanercept (ETN) is a widely used anti-tumour necrosis factor-α (TNF-α) agent, which relieves the symptoms of ankylosing spondylitis (AS) by binding to TNF-α to inhibit its inflammation effects. In this study, the effect of TNF-α level on ETN clearance (CL) was investigated, and the TNF-α concentration was initially set as a correction factor for allometric scaling to improve the predictions of individual ETN CLs. Individual ETN CLs and TNF-α concentrations in healthy volunteers and patients with AS were determined by performing ETN pharmacokinetic studies in the two cohorts. Accordingly, individual ETN CLs in both healthy volunteers and patients with AS were predicted from data of two animal species using different methods, including simple allometric scaling, scaling with a correction factor of maximum life span potential or brain weight, and scaling with a correction factor of the TNF-α concentration. The accuracies of such predictions were evaluated by the percentage errors. Consequently, increased TNF-α concentration was shown to improve ETN CL, by comparing both ETN CLs and TNF-α concentrations between healthy volunteers and patients with AS. More importantly, better predictions of individual ETN CLs were achieved in patients with AS using allometric scaling with TNF-α concentration as the correction factor. In conclusion, in vivo levels of TNF-α can affect ETN CL, and allometric scaling corrected with the TNF-α concentration can be used to estimate the individual CLs of anti-TNF-α monoclonal antibodies based on preclinical data.

Pharmacokinetics, Immunogenicity, and Efficacy of Etanercept in Pediatric Patients With Moderate to Severe Plaque Psoriasis.

Etanercept has been recently approved in the United States for the treatment of moderate to severe plaque psoriasis in patients aged 4-17 years. The objective of this study was to characterize etanercept pharmacokinetics, immunogenicity, and efficacy in pediatric patients. Data from a phase 3 study and open-label extension study were analyzed. Etanercept serum concentrations in pediatric patients receiving etanercept 0.8 mg/kg (maximum, 50 mg) weekly were compared with adult psoriasis patients and pediatric patients with juvenile idiopathic arthritis (JIA) who received etanercept 0.4 mg/kg twice weekly. The developments of antietanercept antibodies and efficacy based on the Psoriasis Area and Severity Index were evaluated. Steady-state trough etanercept concentrations were similar across visits from weeks 12-48, between patients aged 4-11 and 12-17 years, between pediatric and adult psoriasis patients, and between pediatric patients with psoriasis or JIA. Etanercept serum concentrations and safety profiles were similar in patients with (15.9%) and without antietanercept antibodies. Dosing used in the study provided similar exposures and efficacy across ranges of weight and body mass index. Pharmacokinetic, immunogenicity, and efficacy data support 0.8 mg/kg (maximum, 50 mg) weekly dosing of etanercept in patients aged 4-17 years.

Phase III, multicentre, double-blind, randomised, parallel-group study to evaluate the similarities between LBEC0101 and etanercept reference product in terms of efficacy and safety in patients with active rheumatoid arthritis inadequately responding to methotrexate.

OBJECTIVE: To evaluate the similarities between LBEC0101 (etanercept biosimilar) and the etanercept reference product (ETN-RP) in terms of efficacy and safety, including immunogenicity, in patients with active rheumatoid arthritis despite methotrexate treatment. METHODS: This phase III, multicentre, randomised, double-blind, parallel-group, 54-week study was conducted in Japan and Korea. The primary efficacy endpoint was the change from baseline in the disease activity score in 28 joints based on erythrocyte sedimentation rate (DAS28-ESR) at week 24. American College of Rheumatology 20% (ACR20) response rate, adverse events (AEs), pharmacokinetics and development of antidrug antibodies (ADAs) were also evaluated. RESULTS: In total, 374 patients were randomised to LBEC0101 (n=187) or ETN-RP (n=187). The least squares mean changes from baseline in DAS28-ESR at week 24 in the per-protocol set were -3.01 (95% CI -3.198 to -2.820) in the LBEC0101 group and -2.86 (95% CI -3.051 to -2.667) in the ETN-RP group. The estimated between-group difference was -0.15 and its 95% CI was -0.377 to 0.078, which was within the prespecified equivalence margin of -0.6 to 0.6. ACR20 response rates at week 24 were similar between the groups (LBEC0101 93.3% vs ETN-RP 86.7%). The incidence of AEs up to week 54 was comparable between the groups (LBEC0101 92.0% vs ETN-RP 92.5%), although fewer patients in the LBEC0101 group (1.6%) than the ETN-RP group (9.6%) developed ADAs. CONCLUSION: The clinical efficacy of LBEC0101 was equivalent to that of ETN-RP. LBEC0101 was well tolerated and had a comparable safety profile to ETN-RP. TRIAL REGISTRATION NUMBER: NCT02357069.