Phase III infliximab for primary treatment of Kawasaki disease IND 11046 6/27/200

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DESCRIPTION (provided by applicant): Kawasaki disease (KD, OMIM 300530) is a self-limited vasculitis that is the leading cause of acquired heart disease in children in the U.S. and Japan (Taubert et al. 1991). There are approximately 126,000 affected children in the U.S. (4,200 children/year x 30 years), thus meeting the FDA criterion for an orphan disease (Holman et al. 2003). While most children will respond to intravenous immunoglobulin (IVIG) (Newburger et al. 1991), approximately 10-20% will have persistent or recrudescent fever, will require additional therapy, and will be at increased risk of developing coronary artery abnormalities (Burns et al. 1998; Tremoulet et al. 2008). Hyper-activation of the immune system, which targets coronary as well as other muscular arteries, is a central feature of KD. Levels of the pro-inflammatory cytokine tumor necrosis factor a (TNFa) are elevated during acute KD and levels are highest in children in whom coronary artery aneurysms subsequently develop (Furukawa et al. 1994). The applicant postulates that infliximab, a synthetic monoclonal antibody that binds with high affinity to TNFa, might benefit patients with acute KD. Therefore, an investigator-initiated, company-sponsored (Centocor), multicenter, randomized, prospective trial was performed of second IVIG infusion versus infliximab in 24 children with acute KD who had persistent fever following initial treatment with IVIG (Burns et al., submitted). Primary outcome measures were infliximab safety, tolerability, and pharmacokinetics. Infliximab was well-tolerated with no adverse events related to infusions. However, several subjects in both arms of the study developed coronary artery abnormalities. Therefore, they postulate that earlier blockade of TNFa by the addition of infliximab to standard primary therapy will improve coronary artery outcome for these children. The applicant propose to test this hypothesis in a randomized, double-blind, placebo-controlled, multicenter Phase 3 trial of infliximab plus standard therapy vs. placebo plus standard therapy for the primary treatment of acute KD. The primary outcome measure of the study will be the larger of the z scores for the right and the left anterior descending coronary arteries at week 2 after randomization. The secondary outcome measures will be change in markers of inflammation, duration of fever, duration of hospitalization, and cost. Patient genotype for the functional polymorphism in inositol 1,4,5-triphosphate 3-kinase C (ITPKC) that affects T-cell activation and for the TNFa -308A allele that affects TNFa levels will be correlated with response to therapy (Quasney et al. 2001; Onouchi et al. 2008). If the addition of infliximab to primary therapy of KD shows benefit, the applicant will seek licensing for the use of infliximab in KD patients. FDA funding is essential to carry out this study as too few patients in the U.S. would benefit from this therapy to make this new indication economically attractive to the manufacturer (Centocor).