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A 24-month open-label study of canakinumab in neonatal-onset multisystem inflammatory disease.

ABSTRACT: OBJECTIVE:To study efficacy and safety of escalating doses of canakinumab, a fully human anti-IL-1? monoclonal antibody in the severe cryopyrin-associated periodic syndrome, neonatal-onset multisystem inflammatory disease (NOMID). METHODS:6 patients were enrolled in this 24-month, open-label phase I/II study. All underwent anakinra withdrawal. The initial subcutaneous canakinumab dose was 150?mg (or 2?mg/kg in patients ?40?kg) or 300?mg (or 4?mg/kg) with escalation up to 600?mg (or 8?mg/kg) every 4?weeks. Full remission was remission of patient-reported clinical components and measures of systemic inflammation and CNS inflammation. Hearing, vision and safety were assessed. Primary endpoint was full remission at month 6. RESULTS:All patients flared after anakinra withdrawal, and symptoms and serum inflammatory markers improved with canakinumab. All patients required dose escalation to the maximum dose. At month 6, none had full remission, although 4/6 achieved inflammatory remission, based on disease activity diary scores and normal C-reactive proteins. None had CNS remission; 5/6 due to persistent CNS leucocytosis. At the last study visit, 5/6 patients achieved inflammatory remission and 4/6 had continued CNS leucocytosis. Visual acuity and field were stable in all patients, progressive hearing loss occurred in 1/10 ears. Adverse events (AEs) were rare. One serious AE (abscess due to a methicillin-resistant Staphylococcus aureus infection) occurred. CONCLUSIONS:Canakinumab at the studied doses improves symptoms and serum inflammatory features of NOMID, although low-grade CNS leukocytosis in four patients and headaches in one additional patient persisted. Whether further dose intensifications are beneficial in these cases remains to be assessed. CLINICALTRIALSGOV IDENTIFIER:NCT00770601.

SUBMITTER: Sibley CH

PROVIDER: S-EPMC4258169 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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A 24-month open-label study of canakinumab in neonatal-onset multisystem inflammatory disease.

Sibley Cailin H CH Chioato Andrea A Felix Sandra S Colin Laurence L Chakraborty Abhijit A Plass Nikki N Rodriguez-Smith Jackeline J Brewer Carmen C King Kelly K Zalewski Christopher C Kim H Jeffrey HJ Bishop Rachel R Abrams Ken K Stone Deborah D Chapelle Dawn D Kost Bahar B Snyder Christopher C Butman John A JA Wesley Robert R Goldbach-Mansky Raphaela R

Annals of the rheumatic diseases 20140606 9

<h4>Objective</h4>To study efficacy and safety of escalating doses of canakinumab, a fully human anti-IL-1β monoclonal antibody in the severe cryopyrin-associated periodic syndrome, neonatal-onset multisystem inflammatory disease (NOMID).<h4>Methods</h4>6 patients were enrolled in this 24-month, open-label phase I/II study. All underwent anakinra withdrawal. The initial subcutaneous canakinumab dose was 150 mg (or 2 mg/kg in patients ≤40 kg) or 300 mg (or 4 mg/kg) with escalation up to 600 mg (o ...[more]

PMID: 24906637

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Project description:OBJECTIVE:To evaluate proinflammatory cytokines and leukocyte subpopulations in the cerebrospinal fluid (CSF) and blood of patients with neonatal-onset multisystem inflammatory disease (NOMID) after treatment, and to compare inflammatory cytokines in the CSF and blood in 6 patients treated with 2 interleukin-1 (IL-1) blockers-anakinra and canakinumab. METHODS:During routine follow-up visits between December 2011 and October 2013, we immunophenotyped the CSF of 17 pediatric NOMID patients who were treated with anakinra, and analyzed CSF cytokine levels in samples obtained at baseline and at 3-5-year follow-up visits and compared them to samples from healthy controls. RESULTS:CSF levels of IL-6, interferon-?-inducible 10-kd protein (IP-10/CXCL10), and IL-18 and monocyte and granulocyte counts significantly decreased with anakinra treatment but did not normalize to levels in the controls, even in patients fulfilling criteria for clinical remission. CSF IL-6 and IL-18 levels significantly correlated with measures of blood-brain barrier function, specifically CSF protein (r?=?0.75 and r?=?0.81, respectively) and albumin quotient (r?=?0.79 and r?=?0.68, respectively). When patients were treated with canakinumab versus anakinra, median CSF white blood cell counts and IL-6 levels were significantly higher with canakinumab treatment (10.2 cells/mm3 versus 3.7 cells/mm3 and 150.7 pg/ml versus 28.5 pg/ml, respectively) despite similar serum cytokine levels. CONCLUSION:CSF leukocyte subpopulations and cytokine levels significantly improve with optimized IL-1 blocking treatment, but do not normalize. The correlation of CSF IL-6, IP-10/CXCL10, and IL-18 levels with clinical laboratory measures of inflammation and blood-brain barrier function suggests that they may have a role as biomarkers in central nervous system (CNS) inflammation. The difference in inhibition of CSF biomarkers between 2 IL-1 blocking agents, anakinra and canakinumab, suggests differences in efficacy in the intrathecal compartment, with anakinra being more effective. Our data indicate that intrathecal immune responses shape CNS inflammation and should be assessed in addition to blood markers.

Dataset Information

A 24-month open-label study of canakinumab in neonatal-onset multisystem inflammatory disease.

Publications

A 24-month open-label study of canakinumab in neonatal-onset multisystem inflammatory disease.

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