Op0204 emapalumab, an Interferon Gamma (Ifn-Y)-Blocking Monoclonal Antibody, in Patients With Macrophage Activation Syndrome (Mas) Complicating Systemic Juvenile Idiopathic Arthritis (Sjia)

Abstract

BackgroundMAS is a severe complication of rheumatic diseases, most frequently sJIA, caused by excessive activation and expansion of T cells and macrophages. It is characterized by fever, hepatosplenomegaly, liver dysfunction, cytopenias, coagulation abnormalities and hyperferritinemia, possibly progressing to multiple organ failure and death. MAS is categorized as a secondary form of HLH. A vast body of evidence points to uncontrolled overproduction of IFNγ as a major driver of hyperinflammation and hypercytokinemia in MAS and HLH. Emapalumab has been shown to effectively control disease activity in patients with primary HLH.ObjectivesTo assess the pharmacokinetics (PK), efficacy and safety of intravenous (IV) emapalumab in patients with MAS and confirm the proposed dose regimen.MethodsThis is a pilot open-label single arm international study (NCT03311854). Patients had to have MAS (defined according to the 2016 ACR/EULAR classification criteria), on a background of confirmed, or high presumption of, sJIA, and inadequate response to high-dose IV glucocorticoids. Emapalumab initial dose was 6 mg/kg and treatment was continued at 3 mg/kg, twice weekly for a total of 4 weeks or less upon achievement of complete response. Serum concentrations of emapalumab, IFNγ-induced chemokine CXCL9 and sIL2R were measured. Safety assessments included adverse events (AEs) and laboratory abnormalities. Efficacy was defined as complete response by week 8, i.e. absence of MAS clinical signs plus white blood cell and platelet counts above lower limit of normal, LDH, AST/ALT<1.5 x upper limit of normal, fibrinogen >100 mg/dL, and ferritin decreased by ≥80% or to <2000 ng/mL, whichever was lower. Twin protocols are in place to recruit 5 patients each in Europe and North America (trial not started yet). We report data on the 6 patients recruited in the European protocol.ResultsSix patients (5 females, median age 11 years, range: 2-25 years) received emapalumab according to the prescribed dose regimen. Treatment duration ranged from 3 (2 patients) to 4 weeks. Prior to emapalumab, all patients failed methylprednisolone pulses, in 2 patients plus cyclosporine A (CsA) and in 2 patients plus CsA and anakinra. The achieved emapalumab concentrations led to rapid neutralization of IFNγ as indicated by CXCL9 levels and subsequent deactivation of T cells as indicated by sIL2R levels. In all patients, complete response was achieved by week 8, in 4 patients by end of treatment (Table). Systemic glucorticoids were weaned in all patients. Emapalumab infusions were well tolerated and none of the patients discontinued emapalumab. A CMV reactivation was reported by investigator as a serious event possibly related to emapalumab, but resolved completely with treatment.ConclusionEmapalumab administration with the tested dosing regimen led to rapid neutralization of IFNγ as shown by normalization of CXCL9, associated with evidence of decreased T cell activation. In all patients, emapalumab treatment was effective in controlling MAS with a favourable safety pr...

The interferon-gamma pathway is selectively up-regulated in the liver of patients with secondary hemophagocytic lymphohistiocytosis

“…Our findings may also have therapeutic relevance. Indeed, the growing body of evidence pointing to IFNγ as a therapeutic target in primary and secondary HLH, led to clinical trials with emapalumab, an IFNγ neutralizing antibody, in patients with primary HLH or with MAS during sJIA [26, 27]. It is therefore conceivable to hypothesize that IFNγ may be a valuable target also in patients with HLH with prominent/restricted involvement of a single organ.…”

Proceedings from the 2nd Next Gen Therapies for Systemic Juvenile Idiopathic Arthritis and Macrophage Activation Syndrome symposium held on October 3-4, 2019

“…Emapalumab is an anti-IFNγ antibody that has been approved by the FDA for patients with primary hemophagocytic lymphohistiocytosis (HLH). The preliminary results of the ongoing phase II trial of emapalumab in MAS/SJIA showed complete response in all of the 9 patients enrolled, all of whom had previously failed conventional therapies [34].…”

Macrophage Activation Syndrome and Secondary Hemophagocytic Lymphohistiocytosis in Childhood Inflammatory Disorders: Diagnosis and Management

“…There is also an ongoing phase II trial evaluating emapalumab for MAS complicating sJIA. An abstract presented at the 2019 European League Against Rheumatism (EULAR) meeting showed that a complete clinical response was achieved in all six patients enrolled in the study to date [138]. While the final results of these two trials are not yet published, there is a case report in the literature describing successful use of emapalumab in the setting of EBV-associated HLH [139].…”