Open-label phase 3 study of intravenous golimumab in patients with polyarticular juvenile idiopathic arthritis.

OBJECTIVES: To assess efficacy, pharmacokinetics (PK) and safety of intravenous (i.v.) golimumab in patients with polyarticular-course JIA (pc-JIA). METHODS: Children aged 2 to <18 years with active pc-JIA despite MTX therapy for ≥2 months received 80 mg/m2 golimumab at weeks 0, 4, then every 8 weeks through week 52 plus MTX weekly through week 28. The primary and major secondary endpoints were PK exposure and model-predicted steady-state area under the curve (AUCss) over an 8-week dosing interval at weeks 28 and 52, respectively. JIA ACR response and safety were also assessed. RESULTS: In total, 127 children were treated with i.v. golimumab. JIA ACR 30, 50, 70, and 90 response rates were 84%, 80%, 70% and 47%, respectively, at week 28 and were maintained through week 52. Golimumab serum concentrations and AUCss were 0.40 µg/ml and 399 µg ⋅ day/ml at week 28. PK exposure was maintained at week 52. Steady-state trough golimumab concentrations and AUCss were consistent across age categories and comparable to i.v. golimumab dosed 2 mg/kg in adults with rheumatoid arthritis. Golimumab antibodies and neutralizing antibodies were detected via a highly sensitive drug-tolerant assay in 31% (39/125) and 19% (24/125) of patients, respectively. Median trough golimumab concentration was lower in antibody-positive vs antibody-negative patients. Serious infections were reported in 6% of patients, including one death due to septic shock. CONCLUSION: Body surface area-based dosing of i.v. golimumab was well tolerated and provided adequate PK exposure for clinical efficacy in paediatric patients with active pc-JIA.ClinicalTrials.gov number NCT02277444.

Safety and efficacy of intravenous belimumab in children with systemic lupus erythematosus: results from a randomised, placebo-controlled trial.

OBJECTIVES: This ongoing Phase-2, randomised, placebo-controlled, double-blind study evaluated the efficacy, safety and pharmacokinetics of intravenous belimumab in childhood-onset systemic lupus erythematosus (cSLE). METHODS: Patients (5 to 17 years) were randomised to belimumab 10 mg/kg intravenous or placebo every 4 weeks, plus standard SLE therapy. Primary endpoint: SLE Responder Index (SRI4) response rate (Week 52). Key major secondary endpoints: proportion of patients achieving the Paediatric Rheumatology International Trials Organisation/American College of Rheumatology (PRINTO/ACR) response using 50 and '30 alternative' definitions (Week 52), and sustained response (Weeks 44 to 52) by SRI4 and Parent Global Assessment of well-being (Parent-global). Safety and pharmacokinetics were assessed. Study not powered for statistical testing. RESULTS: Ninety-three patients were randomised (belimumab, n=53; placebo, n=40). At Week 52, there were numerically more SRI4 responders with belimumab versus placebo (52.8% vs 43.6%; OR 1.49 (95% CI 0.64 to 3.46)). PRINTO/ACR 30 alternative (52.8% vs 27.5%; OR 2.92 (95% CI 1.19 to 7.17)) and PRINTO/ACR 50 (60.4% vs 35.0%; OR 2.74 (95% CI 1.15 to 6.54)) responses were more frequent with belimumab than placebo, as were sustained responses for SRI4 (belimumab, 43.4%; placebo, 41.0%; OR 1.08 (95% CI 0.46 to 2.52)) and Parent-global (belimumab, 59.1%; placebo, 33.3%; OR 3.49 (95% CI 1.23 to 9.91)). Serious adverse events were reported in 17.0% of belimumab patients and 35.0% of placebo patients; one death occurred (placebo). Week-52, geometric mean (95% CI) belimumab trough concentration was 56.2 (45.2 to 69.8) µg/mL. CONCLUSION: The belimumab intravenous pharmacokinetics and benefit-risk profile in cSLE are consistent with adult belimumab studies and the 10 mg/kg every 4 weeks dose is appropriate. TRIAL REGISTRATION NUMBER: NCT01649765.

Subcutaneous golimumab for children with active polyarticular-course juvenile idiopathic arthritis: results of a multicentre, double-blind, randomised-withdrawal trial.

OBJECTIVE: This report aims to determine the safety, pharmacokinetics (PK) and efficacy of subcutaneous golimumab in active polyarticular-course juvenile idiopathic arthritis (polyJIA). METHODS: In this three-part randomised double-blinded placebo-controlled withdrawal trial, all patients received open-label golimumab (30 mg/m2 of body surface area; maximum: 50 mg/dose) every 4 weeks together with weekly methotrexate during Part 1 (weeks 0-16). Patients with at least 30% improvement per American College of Rheumatology Criteria for JIA (JIA ACR30) in Part 1 entered the double-blinded Part 2 (weeks 16-48) after 1:1 randomisation to continue golimumab or start placebo. In Part 3, golimumab was continued or could be restarted as in Part 1. The primary outcome was JIA flares in Part 2; secondary outcomes included JIA ACR50/70/90 responses, clinical remission, PK and safety. RESULTS: Among 173 patients with polyJIA enrolled, 89.0% (154/173) had a JIA ACR30 response and 79.2%/65.9%/36.4% demonstrated JIA ACR50/70/90 responses in Part 1. At week 48, the primary endpoint was not met as treatment groups had comparable JIA flare rates (golimumab vs placebo: 32/78=41% vs 36/76=47%; p=0.41), and rates of clinical remission were comparable (golimumab vs placebo: 10/78=12.8% vs 9/76=11.8%). Adverse event and serious adverse event rates were similar in the treatment groups during Part 2. Injection site reactions occurred with <1% of all injections. PK analysis confirmed adequate golimumab dosing for polyJIA. CONCLUSION: Although the primary endpoint was not met, golimumab resulted in rapid, clinically meaningful, improvement in children with active polyJIA. Golimumab was well tolerated, and no unexpected safety events occurred. CLINICAL TRIAL REGISTRATION: NCT01230827; Results.

Efficacy and safety of tocilizumab in patients with polyarticular-course juvenile idiopathic arthritis: results from a phase 3, randomised, double-blind withdrawal trial.

OBJECTIVE: To evaluate the interleukin-6 receptor inhibitor tocilizumab for the treatment of patients with polyarticular-course juvenile idiopathic arthritis (pcJIA). METHODS: This three-part, randomised, placebo-controlled, double-blind withdrawal study (NCT00988221) included patients who had active pcJIA for ≥6 months and inadequate responses to methotrexate. During part 1, patients received open-label tocilizumab every 4 weeks (8 or 10 mg/kg for body weight (BW) <30 kg; 8 mg/kg for BW ≥30 kg). At week 16, patients with ≥JIA-American College of Rheumatology (ACR) 30 improvement entered the 24-week, double-blind part 2 after randomisation 1:1 to placebo or tocilizumab (stratified by methotrexate and steroid background therapy) for evaluation of the primary end point: JIA flare, compared with week 16. Patients flaring or completing part 2 received open-label tocilizumab. RESULTS: In part 1, 188 patients received tocilizumab (<30 kg: 10 mg/kg (n=35) or 8 mg/kg (n=34); ≥30 kg: n=119). In part 2, 163 patients received tocilizumab (n=82) or placebo (n=81). JIA flare occurred in 48.1% of patients on placebo versus 25.6% continuing tocilizumab (difference in means adjusted for stratification: -0.21; 95% CI -0.35 to -0.08; p=0.0024). At the end of part 2, 64.6% and 45.1% of patients receiving tocilizumab had JIA-ACR70 and JIA-ACR90 responses, respectively. Rates/100 patient-years (PY) of adverse events (AEs) and serious AEs (SAEs) were 480 and 12.5, respectively; infections were the most common SAE (4.9/100 PY). CONCLUSIONS: Tocilizumab treatment results in significant improvement, maintained over time, of pcJIA signs and symptoms and has a safety profile consistent with that for adults with rheumatoid arthritis. TRIAL REGISTRATION NUMBER: NCT00988221.

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.

Subcutaneous Abatacept in Patients With Polyarticular-Course Juvenile Idiopathic Arthritis: Results From a Phase III Open-Label Study.

OBJECTIVE: To investigate the pharmacokinetics, effectiveness, and safety of subcutaneous (SC) abatacept treatment over 24 months in patients with polyarticular-course juvenile idiopathic arthritis (JIA). METHODS: In this phase III, open-label, international, multicenter, single-arm study, patients with polyarticular JIA (cohort 1, ages 6-17 years and cohort 2, ages 2-5 years) in whom treatment with ≥1 disease-modifying antirheumatic drug was unsuccessful received weight-tiered SC abatacept weekly: 10 to <25 kg (50 mg), 25 to <50 kg (87.5 mg), ≥50 kg (125 mg). Patients who had met the JIA-American College of Rheumatology 30% improvement criteria (achieved a JIA-ACR 30 response) at month 4 were given the option to continue SC abatacept to month 24. The primary end point was the abatacept steady-state serum trough concentration (Cminss ) in cohort 1 at month 4. Other outcome measures included JIA-ACR 30, 50, 70, 90, 100, and inactive disease status, the median Juvenile Arthritis Disease Activity Score in 71 joints using the C-reactive protein level (JADAS-71-CRP) over time, safety, and immunogenicity. RESULTS: The median abatacept Cminss at month 4 (primary end point) and at month 24 was above the target therapeutic exposure (10 µg/ml) in both cohorts. The percentage of patients who had achieved JIA-ACR 30, 50, 70, 90, or 100 responses or had inactive disease responses at month 4 (intent-to-treat population) was 83.2%, 72.8%, 52.6%, 28.3%, 14.5%, and 30.1%, respectively, in cohort 1 (n = 173) and 89.1%, 84.8%, 73.9%, 58.7%, 41.3%, and 50.0%, respectively, in cohort 2 (n = 46); the responses were maintained to month 24. The median (interquartile range) JADAS-71-CRP improved from baseline to month 4: cohort 1, from 21.0 (13.5, 30.3) to 4.6 (2.1, 9.4); cohort 2, from 18.1 (14.0, 23.1) to 2.1 (0.3, 4.4). Improvements were sustained to month 24, at which time 27 of 173 patients (cohort 1) and 11 of 22 patients (cohort 2) had achieved JADAS-71-CRP remission. No unexpected adverse events were reported; 4 of 172 patients (2.3%) in cohort 1 and 4 of 46 (8.7%) in cohort 2 developed anti-abatacept antibodies, with no clinical effects. CONCLUSION: Weight-stratified SC abatacept yielded target therapeutic exposures across age and weight groups, was well tolerated, and improved polyarticular JIA symptoms over 24 months.