OP0147 KAWAKINRA: A PHASE IIA MULTICENTER TRIAL TO ASSESS THE EFFICACY, AND SAFETY OF ANAKINRA IN PATIENTS WITH INTRAVENOUS IMMUNOGLOBULIN-RESISTANT KAWASAKI DISEASE
Authors: Isabelle Koné-Paut, Stephanie Tellier, Virginie Lambert, Corinne Guitton, Alexandre Belot, Perrine Dusser, Linda Rossi-Semerano, Isabelle Marie, Gregory Allain, Helene Agostini, Celine Piedvache
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> The development of more potent therapeutic approaches of KD is an urgent need because intravenous immunoglobulin (IVIg) treatment is not effective in 20% of patients, increasing the risk of coronary dilatations/aneurysms. The combination of genetic and transcriptomic data revealed the key role of interleukin-1 (IL-1) signaling in KD vasculitis and mouse model of KD has shown that anakinra (IL1RA: IL-1R1receptor antagonist) could prevent the development of vascular aneurysms. <h3>Objectives</h3> To assess as primary objective, the efficacy of anakinra in patients with KD who fail to respond to at least one infusion of 2g/kg of IVIg. To assess its safety and tolerability and its effect on disease activity, systemic inflammation and coronary lesions. <h3>Methods</h3> A 45-day, phase IIa proof of concept study open labeled with anakinra dose escalation, with a target of at least 12 patients completing the study Eligible patients had KD according to the AHA criteria, duration of fever ≤ 14 days, and were ≥ 3 months and 5 Kg. They had persistent (or relapsing) fever (≥38°C) within 48h of the last IVIG infusion, had not received other alternative treatment including steroids, and had no others exclusion criteria. After informed consent, they received a starting dose of 2mg/kg<i> (patients &lt;10kg and/or &lt;8 months: 4mg/kg)</i> of anakinra, which could be increased every 24h of 2mg/kg until a maximum of 6mg/kg<i> (patients &lt;10kg and/or &lt;8 months: 8mg/kg)</i>, in case of persistent fever. Anakinra treatment duration was 15 days. Outcome measures were fever, KD symptoms, blood inflammation and cardiac echography. Total study duration was 45 days. <b>Clinical trials: NCT02390596</b>. The study is supported by a grant from the French ministry of health, APHP, national PHRC 2014. IRB approval was obtained and all patients (parents) gave informed consent. <h3>Results</h3> 18 patients were screened and 16 were included and 13 have completed the study. Anakinra was started in 16 patients (14 boys, 2 girls) at a median age 2 years (3 months to 6 years) and at a median of 9.5 days after the onset of fever. 4 patients escaped early for SAE, and 1 had sJIA final diagnosis. The maximum dose of anakinra was 6mg/kg in 6 patients, 4mg/kg in 6, and 2mg/kg in 4. Mean PGA decreased from 7.80 (4-10) to 1.2 (0-3) at D14. Median temperature was 37.6°C (36.7-39.7) at day 3 and 37.2°C at D7 (36.7- 37.9)). Median CRP was 135mg/L at screening and decreased to 9.5 mg/L at D7. 8/14 evaluated patients had coronary dilatation (Z score max ≥2.5mm) at inclusion, 5/14 at D14 and 3/14 at D45. 3/14 patients who increased Z score at D14 decreased it at J45. We observed 3 severe adverse events (SAE) where treatment was discontinued: anakinra overdose, MAS in a patient evolving to sJIA and increase of coronary dilatation. Others AE included cytolytic hepatitis (2 patients), hypereosinophilia (1), injection site reaction (1) and pancreatitis (1) without treatment discontinuation. <h3>Conclusion</h3> We have realized the first experimental study assessing IL-1 blockade in severe refractory KD. 15 days-duration of anakinra treatment, given early in the course of IVIG-resistant KD, was rapidly effective on KD symptoms, biologic inflammation and coronary dilatations in almost all patients, with a good tolerability. This study calls for further investigation of IL1 blockade in KD <h3> Disclosure of Interests</h3> Isabelle Koné-Paut Grant/research support from: SOBI has supported drug product (anakinra) for the presented study, Consultant for: SOBI, Novartis, Pfizer, Abbvie, UCB, CHUGAI, ROCHE, stephanie tellier: None declared, virginie Lambert: None declared, Corinne Guitton: None declared, alexandre belot: None declared, Perrine Dusser: None declared, Linda Rossi-Semerano Grant/research support from: Roche, Isabelle Marie: None declared, gregory allain: None declared, helene agostini: None declared, celine piedvache: None declared&nbsp;