Source: European Medicines Agency (EU) Revision Year: 2025 Publisher: Sanofi Winthrop Industrie, 82 avenue Raspail, 94250 Gentilly, France
Pharmacotherapeutic group: Immunosuppressants, Interleukin inhibitors
ATC code: L04AC14
Sarilumab is a human monoclonal antibody (IgG1 subtype) that specifically binds to both soluble and membrane-bound IL-6 receptors (IL-6Rα), and inhibits IL-6-mediated signalling which involves ubiquitous signal-transducing glycoprotein 130 (gp130) and the Signal Transducer and Activator of Transcription-3 (STAT-3).
In functional human cell-based assays, sarilumab was able to block the IL-6 signalling pathway, measured as STAT-3 inhibition, only in the presence of IL-6.
IL-6 is a pleiotropic cytokine that stimulates diverse cellular responses such as proliferation, differentiation, survival, and apoptosis and can activate hepatocytes to release acute-phase proteins, including C-reactive protein (CRP) and serum amyloid A. Elevated levels of IL-6 are found in the synovial fluid of patients with rheumatoid arthritis (RA) and polyarticular juvenile idiopathic arthritis (pJIA) and play an important role in both the pathologic inflammation and joint destruction which are hallmarks of RA and pJIA. IL-6 is involved in diverse physiological processes such as migration and activation of T-cells, B-cells, monocytes, and osteoclasts leading to systemic inflammation, synovial inflammation, and bone erosion in patients with RA and pJIA.
The activity of sarilumab in reducing inflammation is associated with laboratory changes such as decrease in ANC and elevation in lipids (see section 4.4).
Following single-dose subcutaneous (SC) administration of sarilumab 200 mg and 150 mg in patients with RA rapid reduction of CRP levels was observed. Levels were reduced to normal as early as 4 days after treatment initiation. Following single-dose sarilumab administration, in patients with RA, ANC decreased to the nadir between 3 to 4 days and thereafter recovered towards baseline (see section 4.4). Treatment with sarilumab resulted in decreases in fibrinogen and serum amyloid A, and increases in haemoglobin and serum albumin. In patients with pJIA, decreases in CRP, erythrocyte sedimentation rate (ESR) and neutrophil count were observed after sarilumab administration.
Supportive efficacy and safety data were assessed in a multicentre, open-label, two-phase study in patients aged 2 to 17 years of age with polyarticular- juvenile idiopathic arthritis (pJIA) diagnosed according to American College Rheumatology (ACR) classification criteria who had an inadequate response to current therapy. This study was divided into a dose range finding portion and a confirmatory portion. Three doses were investigated in the 12-week core treatment phase of the dose range finding portion. Following the dose selection, patients were enrolled to receive the recommended dose [3 mg/kg every 2 weeks (q2w) in 42 patients weighing ≥30 kg (Group A) and 4 mg/kg q2w in 31 patients weighing ≥10 kg and <30 kg (Group B)]. A total of 101 patients were treated, including 73 patients who received the recommended dose regimen from baseline and 20 patients who had their dose switched to the recommended dose during the study.
The efficacy of sarilumab in paediatric patients with pJIA is based on pharmacokinetic (PK) extrapolation and the established efficacy of sarilumab in RA patients. The extrapolation is further supported by the efficacy evaluation that was conducted and based on JIA ACR 70 and 90 response rate, change from baseline for Juvenile Arthritis Disease Activity Score-27 (JADAS), and proportion of patients with clinical remission. Efficacy was assessed up to 48 weeks in the 73 patients that received the recommended dose from baseline.
Of these 73 patients, baseline mean disease duration and JADAS-27 were 2.48 years and 22.73, respectively. At baseline, 84.9% of patients had received at least one csDMARD (mainly MTX), 13.7% received systemic glucocorticoids, and 19.2% had prior treatment with biological DMARDs (mainly TNFi). The patients treated had subtypes of JIA that, at disease onset, included rheumatoid factor positive (17.8%), negative polyarticular JIA (65.8%), or extended oligoarticular JIA (16.4%).
JIA ACR responses were seen as early as Week 2. The proportion of patients with JIA ACR 70 response rate were 76.7% and 87.7% at Week 12 and Week 48, respectively, and JIA ACR 90 response rate were 42.5% and 69.9% at Week 12 and Week 48, respectively.
Change from baseline in JADAS-27 CRP was -17.46 at Week 12 and -20.75 at Week 48 for the patients on the recommended dose. At Week 48, 51.6% of patients on the recommended dose were in remission (inactive disease per Wallace criteria for 6 consecutive months).
The European Medicines Agency has deferred the obligation to submit the results of studies with Kevzara (sarilumab) in one or more subsets of the paediatric population in chronic idiopathic arthritis (including rheumatoid arthritis, spondylarthritis, psoriatic arthritis and juvenile idiopathic arthritis) (see section 4.2 for information on paediatric use).
The pharmacokinetics of sarilumab in pJIA patients was characterized by observed and population pharmacokinetic analysis which included 101 paediatric patients 2 to 17 years of age who were treated with repeated subcutaneous doses of sarilumab.
For 3 mg/kg sarilumab (patients with a body weight ≥30 kg) given every 2 weeks, the estimated mean (± SD) steady-state AUC, Cmin, and Cmax of sarilumab were 294 ± 148 mg.day/L, 9.84 ± 6.35 mg/L, and 29.2 ± 15.0 mg/L, respectively by population PK analysis.
For 4 mg/kg sarilumab (patients with a body weight 10 to <30 kg) given every 2 weeks, the estimated mean (± SD) steady-state AUC, Cmin, and Cmax of sarilumab were 375 ± 102 mg.day/L, 14.5 ± 8.56 mg/L, and 37.3 ± 8.10 mg/L, respectively by population PK analysis.
Consistent with RA adult patients, sarilumab is eliminated by parallel linear and non-linear pathways, in pJIA patients, these parallel elimination pathways result in an initial half-life of 5 to 7 days. Time to steady state was about 10 weeks longer compared to RA adult patients. Following subcutaneous administration at Week 48, accumulation ratio was approximately 5-fold based on the observed mean trough concentrations (11.6 mg/L and 14.2 mg/L) compared to single dose exposure (2.24 mg/L and 3.10 mg/L) for 3 and 4 mg/kg q2w, respectively. Steady state concentrations were within the range of exposures in adult RA patients following 200 mg every 2 weeks.
Non-clinical data reveal no special hazard for humans based on conventional studies of repeated-dose toxicity, carcinogenic risk assessment and toxicity to reproduction and development.
No long-term animal studies have been performed to establish the carcinogenicity potential of sarilumab. The weight of evidence for IL-6Rα inhibition mainly indicates anti-tumour effects mediated by multiple mechanisms predominantly involving STAT-3 inhibition. In vitro and in vivo studies with sarilumab using human tumour cell lines showed inhibition of STAT-3 activation and inhibition of tumour growth in human tumour xenograft animal models.
Fertility studies conducted in male and female mice using a murine surrogate antibody against mouse IL-6Rα showed no impairment of fertility.
In an enhanced pre-/postnatal developmental toxicity study, pregnant Cynomolgus monkeys were administered sarilumab once-weekly intravenously from early gestation to natural birth (approximately 21 weeks) Maternal exposure up to approximately 83 times the human exposure based on AUC after subcutaneous doses of 200 mg every 2 weeks, did not cause any maternal or embryo‑foetal effects. Sarilumab had no effect on maintenance of pregnancy or on the neonates evaluated up to 1 month after birth in body weight measurements, in parameters of functional or morphological development including skeletal evaluations, in immunophenotyping of peripheral blood lymphocytes, and in microscopic evaluations. Sarilumab was detected in the serum of neonates up to 1 month. The excretion of sarilumab in Cynomolgus monkey’s milk has not been studied.
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