Tapering Canakinumab Monotherapy in Patients With Systemic Juvenile Idiopathic Arthritis in Clinical Remission: Results From a Phase IIIb/IV Open‐Label, Randomized Study

Abstract

Objective To evaluate the efficacy and safety of 2 canakinumab monotherapy tapering regimens in order to maintain complete clinical remission in children with systemic juvenile idiopathic arthritis (JIA). Methods The study was designed as a 2‐part phase IIIb/IV open‐label, randomized trial. In the first part, patients received 4 mg/kg of canakinumab subcutaneously every 4 weeks and discontinued glucocorticoids and/or methotrexate as appropriate. Patients in whom clinical remission was achieved (inactive disease for at least 24 weeks) with canakinumab monotherapy were entered into the second part of the trial, in which they were randomized 1:1 into 1 of 2 treatment arms. In arm 1, the dose of canakinumab was reduced from 4 mg/kg to 2 mg/kg and then to 1 mg/kg, followed by discontinuation. In arm 2, the 4 mg/kg dose interval was prolonged from every 4 weeks, to every 8 weeks, and then to every 12 weeks, followed by discontinuation. In both arms, canakinumab exposure could be reduced provided systemic JIA remained in clinical remission for 24 weeks with each step. The primary objective was to assess whether >40% of randomized patients in either arm maintained clinical remission of systemic JIA for 24 weeks in the first part of the study. Results In part 1 of the study, 182 patients were enrolled, with 75 of those patients randomized before entering part 2 of the trial. Among the 75 randomized patients, clinical remission was maintained for 24 weeks in 27 (71%) of 38 patients in arm 1 (2 mg/kg every 4 weeks) and 31 (84%) of 37 patients in arm 2 (4 mg/kg every 8 weeks) (P ≤ 0.0001 for arm 1 versus arm 2 among those meeting the 40% threshold). Overall, 25 (33%) of 75 patients discontinued canakinumab, and clinical remission was maintained for at least 24 weeks in all 25 of these patients. No new safety signals were identified. Conclusion Reduction of canakinumab exposure may be feasible in patients who have achieved clinical remission of systemic JIA, but consistent interleukin‐1 inhibition appears necessary to maintain this response.

Interleukin-1 Blockade in Polygenic Autoinflammatory Disorders: Where Are We now?

“…( Ruperto et al, 2018 ). Quartier et al (2020) tried to resolve a question, whether dose tapering, interval prolongation or discontinuation of canakinumab may have any impact on the duration of clinical remission (no joints with active arthritis; no fever due to sJIA; no rash, serositis, splenomegaly, hepatomegaly nor generalized lymphadenopathy attributable to sJIA; normal CRP serum levels Physician Global Assessment- PGA ≤10 mm). At week 24, 71% of patients with a reduced dose to 2 mg/kg every 4 weeks and 84% of patients with a prolonged interval to 8 weeks maintained clinical remission, and further reduction of the dose or interval prolongation was feasible without disease flares in the majority of the them.…”

“…However, only 33% of thepatients discontinued canakinumab and remained in remission. ( Quartier et al, 2020 ). In a recently published trial, Brunner et al (2020) compared the treatment efficacy of canakinumab in patients with or without fever at treatment initiation.…”

Efficacy And Safety of Canakinumab As A Second-Line Biologic After Tocilizumab Treatment Failure in Children With Systemic Juvenile Idiopathic Arthritis: A Single-Center Cohort Study Using Routinely Collected Health Data

“…This single-center retrospective cohort study evaluated treatment outcomes in children with sJIA who switched from tocilizumab to canakinumab. Data were collected for participants enrolled in one of two clinical trials at the study center, CACZ885G2301E1 (G2301; NCT00891046) and CACZ885G2306 (G2306; NCT02296424) [11], in addition to those who switched treatment in routine clinical practice.…”

“…In these cases, the e cacy of IL-1 inhibitors can be expected as it can be considered as a therapy for 'biologically naïve' patients. The development of antibodies to canakinumab in such patients is unlikely as no anti-drug neutralizing antibodies were detected [11,37]. Finally, tocilizumab does not affect the concentration of IL-1β [30], i.e., does not have an indirect effect on the key mechanism of sJIA pathogenesis.…”

Similar Clinical Outcomes in Patients with Systemic Juvenile Idiopathic Arthritis and Adult-Onset Still’s Disease Treated with Canakinumab: Bayesian and Population Model-Based Analyses

“…Canakinumab has been shown to be effective at achieving rapid and sustained efficacy in multiple sJIA clinical trials [6][7][8][9]. However, the limited number of randomized controlled studies conducted in patients with AOSD makes drawing definitive conclusions on the efficacy of IL-1 inhibition in AOSD challenging [4,5].…”