Subcutaneous dosing regimens of tocilizumab in children with systemic or polyarticular juvenile idiopathic arthritis.

OBJECTIVES: To determine s.c. tocilizumab (s.c.-TCZ) dosing regimens for systemic JIA (sJIA) and polyarticular JIA (pJIA). METHODS: In two 52-week phase 1 b trials, s.c.-TCZ (162 mg/dose) was administered to sJIA patients every week or every 2 weeks (every 10 days before interim analysis) and to pJIA patients every 2 weeks or every 3 weeks with body weight ≥30 kg or <30 kg, respectively. Primary end points were pharmacokinetics, pharmacodynamics and safety; efficacy was exploratory. Comparisons were made to data from phase 3 trials with i.v. tocilizumab (i.v.-TCZ) in sJIA and pJIA. RESULTS: Study participants were 51 sJIA patients and 52 pJIA patients aged 1-17 years who received s.c.-TCZ. Steady-state minimum TCZ concentration (Ctrough) >5th percentile of that achieved with i.v.-TCZ was achieved by 49 (96%) sJIA and 52 (100%) pJIA patients. In both populations, pharmacodynamic markers of disease were similar between body weight groups. Improvements in Juvenile Arthritis DAS-71 were comparable between s.c.-TCZ and i.v.-TCZ. By week 52, 53% of sJIA patients and 31% of pJIA patients achieved clinical remission on treatment. Safety was consistent with that of i.v.-TCZ except for injection site reactions, reported by 41.2% and 28.8% of sJIA and pJIA patients, respectively. Infections were reported in 78.4% and 69.2% of patients, respectively. Two sJIA patients died; both deaths were considered to be related to TCZ. CONCLUSION: s.c.-TCZ provides exposure and risk/benefit profiles similar to those of i.v.-TCZ. S.c. administration provides an alternative administration route that is more convenient for patients and caregivers and that has potential for in-home use. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT01904292 and NCT01904279.

Efficacy and Safety of Tocilizumab for Polyarticular-Course Juvenile Idiopathic Arthritis in the Open-Label Two-Year Extension of a Phase III Trial.

OBJECTIVE: To report the 2-year efficacy and safety of tocilizumab (TCZ) in patients with polyarticular-course juvenile idiopathic arthritis (JIA). METHODS: Patients ages 2-17 years with active polyarticular-course JIA, in whom treatment with methotrexate was unsuccessful, received 16 weeks of open-label intravenous TCZ in part 1 (once every 4 weeks: 8 mg/kg or 10 mg/kg for body weight [BW] <30 kg; 8 mg/kg for BW ≥30 kg). Assessments were based on the JIA-American College of Rheumatology (ACR) response (defined as percentage of improvement in ≥3 of the 6 JIA core response variables [CRVs]). Patients with at least a JIA-ACR30 response (defined as ≥30% improvement in ≥3 of the 6 JIA CRVs without worsening in >1 of the remaining JIA CRVs by >30%) at week 16 were randomly assigned (1:1) to receive TCZ or placebo in part 2. Patients remained in part 2 until either week 40 or the occurrence of JIA flare. Upon starting part 3, all patients received open-label TCZ. At week 104 of the study, efficacy was assessed using JIA-ACR50/70/90 response rates (defined as 50%, 70%, or 90% improvement, respectively), achievement of inactive disease, and the Juvenile Arthritis Disease Activity Score in 71 joints (JADAS-71). Safety was assessed in the all-exposure population per 100 patient-years of exposure. RESULTS: Overall, 188 patients entered part 1, 166 patients entered part 2, and 160 patients entered part 3. By week 104, among the 188 patients in the modified intent-to-treat group who received TCZ, JIA-ACR50/70/90 response rates were 80.3%/77.1%/59.6%, respectively, the median JADAS-71 score decreased from 3.6 at week 40 to 0.7 at week 104, 51.1% of patients had achieved inactive disease, and 31 of 66 patients who had been receiving glucocorticoids discontinued them. Adverse event (AE) and serious AE rates were 406.5 per 100 patient-years and 11.1 per 100 patient-years, respectively. The infection rate was 151.4 per 100 patient-years, and the serious infection rate was 5.2 per 100 patient-years. CONCLUSION: Patients treated with TCZ for polyarticular-course JIA showed high-level disease control for up to 2 years. The TCZ safety profile was consistent with that previously reported.

Tocilizumab may slow radiographic progression in patients with systemic or polyarticular-course juvenile idiopathic arthritis: post hoc radiographic analysis from two randomized controlled trials.

BACKGROUND: Few clinical trials have investigated the prevention of radiographic progression in children with juvenile idiopathic arthritis treated with antirheumatic drugs. This study aimed to investigate radiographic progression in patients with systemic juvenile idiopathic arthritis (sJIA) and patients with polyarticular-course juvenile idiopathic arthritis (pcJIA) treated with the anti-interleukin-6 receptor antibody tocilizumab for 2 years in the TENDER and CHERISH randomized controlled trials, respectively. METHODS: Standard radiographs of both wrists and both hands in the posteroanterior view were obtained within 4 weeks of baseline and were repeated at weeks 52 ± 4 and 104 ± 4 in both trials. All films were scored by two independent readers using the adapted Sharp-van der Heijde (aSH) and Poznanski scoring methods. Although the Poznanski score indicates bone growth limitation or cartilage growth decrease, which are not the same as joint space narrowing in rheumatoid arthritis, its change reflects damage to cartilage. Therefore, impairment in the Poznanski score as well as the aSH score was considered as a measure of structural joint damage. Radiographic progression was defined as worsening of radiographic scores beyond the smallest detectable difference. RESULTS: Poznanski and aSH scores were available at baseline and at one or more postbaseline time points for 33 and 47 of 112 sJIA patients and 61 and 87 of 188 pcJIA patients, respectively, providing a representative subset of the study populations. The inter-reader and intra-reader agreement intra-class correlation coefficient was > 0.8. Median baseline Poznanski and aSH scores, respectively, were - 2.4 and 24.6 for sJIA patients and - 1.5 and 8.0 for pcJIA patients. Compared with baseline, aSH scores remained stable for all sJIA patients at week 52, whereas 9.4% of sJIA patients had radiographic progression according to Poznanski scores at week 52; at 104 weeks, radiographic progression according to aSH and Poznanski scores was observed in 5.4% and 11.5%, respectively. In pcJIA patients, radiographic progression from baseline at 52 weeks and at 104 weeks was 12.5% and 2.9%, respectively, using aSH scoring and 6.5% and 4%, respectively, using Poznanski scoring. CONCLUSION: Tocilizumab may delay radiographic progression in children with sJIA and children with pcJIA. TRIAL REGISTRATION: Trial registration numbers and dates: TENDER, NCT00642460 (March 19, 2008); CHERISH, NCT00988221 (October 1, 2009).

Evidence of bioequivalence and positive patient user handling of a tocilizumab autoinjector.

BACKGROUND: The anti-interleukin-6 receptor antibody tocilizumab is approved for subcutaneous injection using a prefilled syringe (PFS). We report results from a bioequivalence study in healthy subjects and a user-handling study in patients with rheumatoid arthritis (RA) using an autoinjector (AI) for tocilizumab. METHODS: A randomized crossover study in healthy subjects (N = 161) examined the bioequivalence, safety, and tolerability of tocilizumab after a single subcutaneous injection by AI versus PFS. A nonrandomized observational, real-life human factors study in RA patients (N = 54) assessed user (RA patients, caregivers, health care providers) ability to administer tocilizumab effectively by AI. RESULTS: Bioequivalence criteria for tocilizumab AI versus PFS were met for key pharmacokinetic parameters. Safety was comparable between devices and consistent with the established tocilizumab profile. In the real-life human factors study, the proportion of users who successfully performed all essential tasks required to operate the AI to deliver the full dose was 92.3% at first assessment and 98.1% at second assessment, with no safety concerns. CONCLUSIONS: Tocilizumab administration by AI was bioequivalent to administration by PFS. Intended users were successful in performing the tasks required to administer tocilizumab by AI. No new safety signals were observed in either study. CLINICAL TRIAL REGISTRATION: NCT02678988, NCT02682823.

Intravenous dosing of tocilizumab in patients younger than two years of age with systemic juvenile idiopathic arthritis: results from an open-label phase 1 clinical trial.

BACKGROUND: The anti-interleukin-6 receptor-alpha antibody tocilizumab was approved for intravenous (IV) injection in the treatment of patients with systemic juvenile idiopathic arthritis (sJIA) aged 2 to 17 years based on results of a randomized controlled phase 3 trial. Tocilizumab treatment in systemic juvenile idiopathic arthritis (sJIA) patients younger than 2 was investigated in this open-label phase 1 trial and compared with data from the previous trial in patients aged 2 to 17 years. METHODS: Patients younger than 2 received open-label tocilizumab 12 mg/kg IV every 2 weeks (Q2W) during a 12-week main evaluation period and an optional extension period. The primary end point was comparability of pharmacokinetics during the main evaluation period to that of the previous trial (in patients aged 2-17 years), and the secondary end point was safety; pharmacodynamics and efficacy end points were exploratory. Descriptive comparisons for pharmacokinetics, pharmacodynamics, safety, and efficacy were made with sJIA patients aged 2 to 17 years weighing < 30 kg (n = 38) who received tocilizumab 12 mg/kg IV Q2W in the previous trial (control group). RESULTS: Eleven patients (mean age, 1.3 years) received tocilizumab during the main evaluation period. The primary end point was met: tocilizumab exposures for patients younger than 2 were within the range of the control group (mean [±SD] µg/mL concentration at the end-of-dosing interval [Cmin]: 39.8 [±14.3] vs 57.5 [±23.3]; maximum concentration [Cmax] postdose: 288 [±40.4] vs 245 [±57.2]). At week 12, pharmacodynamic measures were similar between patients younger than 2 and the control group; mean change from baseline in Juvenile Arthritis Disease Activity Score-71 was - 17.4 in patients younger than 2 and - 28.8 in the control group; rash was reported by 14.3 and 13.5% of patients, respectively. Safety was comparable except for the incidence of serious hypersensitivity reactions (27.3% in patients younger than 2 vs 2.6% in the control group). CONCLUSIONS: Tocilizumab 12 mg/kg IV Q2W provided pharmacokinetics, pharmacodynamics, and efficacy in sJIA patients younger than 2 comparable to those in patients aged 2 to 17 years. Safety was comparable except for a higher incidence of serious hypersensitivity events in patients younger than 2 years. CLASSIFICATION: Juvenile idiopathic arthritis. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01455701 . Registered, October 20, 2011, Date of enrollment of first participant: October 26, 2012.

Toward Accelerated Authorization and Access to New Medicines for Juvenile Idiopathic Arthritis.

A meeting was organized to bring together multiple stakeholders involved in the testing and authorization of new medications for juvenile idiopathic arthritis (JIA) to discuss current issues surrounding clinical trials and access to new medications for children and adolescents with JIA. The Childhood Arthritis and Rheumatology Research Alliance invited representatives of regulatory agencies (Food and Drug Administration and European Medicines Agency), and major pharmaceutical companies with JIA-approved products or products in development, patient and parent representatives, representatives of an advocacy organization (Arthritis Foundation), and pediatric rheumatology clinicians/investigators to a 1-day meeting in April 2018. The participants engaged in discussion regarding issues in clinical trials. As the pharmacologic options to treat inflammatory arthritis rapidly expand, registration trial designs to test medications in JIA patients must adapt. Many methodologies successfully used in the recent past are no longer feasible. The pool of patients meeting entry criteria who are willing to participate is shrinking while the number of medications to be tested is growing. Suggested solutions included proposing innovative clinical trial methods to regulatory agencies, as well as open discussions among stakeholders. Ensuring that new medications are authorized in a timely manner to meet the needs of JIA patients worldwide is critical. Approaches should include open dialog between regulatory agencies, pharmaceutical companies, and other stakeholders to develop and implement novel study designs, including patient and clinician perspectives to define meaningful trial outcomes, and changing existing study plans.

Pharmacokinetic and Pharmacodynamic Analysis of Subcutaneous Tocilizumab in Patients With Rheumatoid Arthritis From 2 Randomized, Controlled Trials: SUMMACTA and BREVACTA.

Tocilizumab is a humanized anti-interleukin-6 receptor antibody for treating rheumatoid arthritis. Pharmacokinetic/pharmacodynamic analysis was performed on the 24-week double-blind parts of 2 randomized, controlled trials: SUMMACTA and BREVACTA. SUMMACTA compared subcutaneous tocilizumab 162 mg every week to intravenous tocilizumab 8 mg/kg every 4 weeks, whereas BREVACTA evaluated 162 mg subcutaneous tocilizumab every 2 weeks versus placebo. In addition to noncompartmental analysis, a 2-compartment population pharmacokinetic model, with first-order absorption (for subcutaneous) and linear and Michaelis-Menten elimination was used. Mean observed steady-state predose tocilizumab concentrations in week 24 were 40 and 7.4 µg/mL for subcutaneous every-week and every-2-week dosing, respectively, and 18 µg/mL for intravenous dosing. In the population PK model, body weight was an important covariate affecting clearance and volume of distribution. Mean ± SD population-predicted predose concentration for patients ≥100 kg was 23.0 ± 13.5 µg/mL for subcutaneous tocilizumab every week and 1.0 ± 1.6 µg/mL for every 2 weeks. Efficacy was lowest with subcutaneous every-2-week dosing in patients > 100 kg, reflecting lower exposure. The subcutaneous every-2-week regimen is not recommended for these patients. Pharmacodynamic responses were comparable for the every-week subcutaneous and every-4-week intravenous regimens and less pronounced with the every-2-week subcutaneous regimen. No trend was observed for increased adverse events with increasing tocilizumab exposure. The results of this analysis are consistent with the noninferiority of efficacy of the every-week subcutaneous regimen to the every-4-week intravenous regimen and the superiority of the every-2-week subcutaneous regimen to placebo. These results support the label recommendations for subcutaneous dosing of tocilizumab in rheumatoid arthritis patients.