Long-term efficacy and safety of subcutaneous tocilizumab in clinical trials of polyarticular or systemic juvenile idiopathic arthritis

Abstract

Objective: To investigate the safety and efficacy of subcutaneous tocilizumab (SC-TCZ) treatment in a long-term extension (LTE) of clinical trials in polyarticular or systemic juvenile idiopathic arthritis (pJIA or sJIA).

Methods: Patients with pJIA or sJIA from two open-label, 52-week phase 1b core trials of SC-TCZ who had adequate response per investigator assessment entered the LTE and continued SC-TCZ treatment according to body weight-based dosing regimens until commercial availability or up to 5 years. Pharmacokinetics, pharmacodynamics, and efficacy were assessed for up to 3 years, and safety for up to 5 years in the LTE.

Results: Forty-four patients with pJIA and 38 patients with sJIA entered the LTE. Tocilizumab trough concentrations were maintained within the range expected to provide clinical benefit (mean values: pJIA, ∼10 μg/ml; sJIA, ∼75 μg/ml over 3 years). Pharmacodynamic parameters (interleukin-6, soluble interleukin-6 receptor, erythrocyte sedimentation rate, C-reactive protein) were maintained throughout the LTE at levels achieved in the core trials. Inactive disease per American College of Rheumatology provisional criteria was reported for 90% (17/19) and 53% (8/15) of patients with pJIA and 91% (10/11) and 92% (12/13) of patients with sJIA in the <30 and ≥30 kg body weight groups, respectively. Serious adverse events in the LTE were reported in six patients with pJIA (13.6%; five serious infections) and five patients with sJIA (13.2%; one serious infection).

Conclusion: Patients with pJIA or sJIA experienced long-term disease control with SC-TCZ treatment. Long-term safety was consistent with the known tocilizumab safety profile.

Clinical trial registration: clinicaltrials.gov, NCT02165345.

Keywords: autoinflammatory conditions; biologic therapies; clinical trial; interleukin-6; juvenile idiopathic arthritis; long-term extension; paediatric/juvenile rheumatology; pharmacology; pharmacovigilance; tocilizumab.

Figure 1.

Patient disposition in the LTE study. Per protocol, patient participation in the study continued until tocilizumab became commercially available in a country or region or for a maximum of 5 years. Some patients with sJIA weighing <30 kg changed their dosing regimen from Q10D to Q2W following planned interim analysis. AE: adverse event; BW: body weight; LTE: long-term extension; OL: open-label; pJIA: polyarticular juvenile idiopathic arthritis; Q10D: every 10 days; Q2W: every 2 weeks; Q3W: every 3 weeks; QW: weekly; SC: subcutaneous; sJIA: systemic juvenile idiopathic arthritis; TCZ: tocilizumab

Figure 2.

Tocilizumab trough concentrations among (A) patients with pJIA and (B) patients with sJIA (pharmacokinetic population). Data are shown as individual TCZ C_trough results (open circles) collected in the core trials (for patients who transitioned to the LTE) or in the LTE. C_trough: trough concentration; LTE: long-term extension; pJIA: polyarticular juvenile idiopathic arthritis; Q10D: every 10 days; Q2W: every 2 weeks; Q3W: every 3 weeks; QW: weekly; sJIA: systemic juvenile idiopathic arthritis; TCZ: tocilizumab

Figure 3.

sIL-6R (A, B), IL-6 (C, D), and ESR (E, F) in the LTE (intention-to-treat population). BL is the last observation before initiation of study treatment in the LTE. Patients without BL assessment were excluded. The 75th percentile for interleukin-6 in patients with sJIA at week 144 is not shown because it is outside the limits of the graph (value = 322.0 pg/ml). BL: baseline; ESR: erythrocyte sedimentation rate; IQR: interquartile range; LTE: long-term extension; pJIA: polyarticular juvenile idiopathic arthritis; Q10D: every 10 days; Q2W: every 2 weeks; Q3W: every 3 weeks; QW: weekly, SC: subcutaneous; sIL-6R: soluble interleukin-6 receptor; sJIA: systemic juvenile idiopathic arthritis; TCZ: tocilizumab

Figure 4.

JADAS-71 (A, B), inactive disease (C, D), and clinical remission (E, F) (LTE intention-to-treat population). Horizontal lines connecting bars indicate the trend over time. Last observation carried forward was applied to JADAS-71 components that were missing. ^aInactive disease was defined according to Wallace criteria as no presence of active joints; absence of uveitis; no fever, rash, serositis, splenomegaly, hepatomegaly, or generalized lymphadenopathy attributable to pJIA or sJIA; erythrocyte sedimentation rate <20 mm/h; physician global visual analogue scale score ≤10 mm; and duration of morning stiffness ≤15 minutes. ^bClinical remission was defined as inactive disease for a minimum of 6 continuous months irrespective of disease-modifying antirheumatic drug, nonsteroidal anti-inflammatory drug, or glucocorticoid use. EOS: end of study efficacy assessment (week 156 for pJIA, week 152 for sJIA); JADAS-71: Juvenile Arthritis Disease Activity Score on 71 joints (maximum value = 71); n/N: number of patients meeting criteria/total number of patients with assessment; LTE: long-term extension; pJIA: polyarticular juvenile idiopathic arthritis; Q10D: every 10 days; Q2W: every 2 weeks; Q3W: every 3 weeks; QW: weekly; sJIA: systemic juvenile idiopathic arthritis; TCZ: tocilizumab