Emapalumab in patients with macrophage activation syndrome

Emapalumab, an interferon gamma (IFNγ)-blocking monoclonal antibody, has shown efficacy and safety in patients with macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (SJIA)

MAS is a rare, systemic life-threatening disorder characterised by uncontrolled hyperinflammation which may develop on a background of rheumatic diseases such as SJIA. It is classified as a secondary form of hemophagocytic lymphohistiocytosis (HLH) and is caused by excessive activation and expansion of T cells and macrophages. In recent years, evidence has shown uncontrolled overproduction of IFNγ as a major driver of hyperinflammation and hypercytokinaemia in diseases such as MAS and HLH. Emapalumab is a monoclonal antibody that binds to and neutralises interferon gamma (IFNγ).

Dr Fabrizio De Benedetti et al. (Ospedale Pediatrico Bambino Gesù, Italy) initiated a pilot study which aimed to assess the pharmacokinetics, efficacy, and safety of intravenous emapalumab in patients with MAS, and to confirm the proposed dose regimen. A total of 6 patients who had MAS, confirmed or high presumption of SJIA, and inadequate response to high-dose intravenous glucocorticoids were included in the study. Five of them were female, the median age was 11 years with range 2-25 years. Prior to emapalumab, all patients failed methylprednisolone pulse therapy. Four patients received concomitantly either cyclosporine A (n=2) and/or cyclosporine A and anakinra (n=2), a human IL-1-receptor antagonist. All subjects received an initial intravenous emapalumab dose of 6 mg/kg. Treatment was continued at 3 mg/kg twice weekly, for a total of ≤4 weeks, depending on achieved response rate. Serum concentrations of emapalumab, as well as IFNγ-induced chemokine CXCL9 and sIL2R, were measured. Efficacy was defined as a complete response by week 8; absence of MAS signs and white blood cells and platelets counts above lower limit of normal; lactate dehydrogenase (LDH)/AST/ALT below 1.5x upper limit of normal, fibrinogen >100 mg/dL, and ferritin decreased by ≥80% or to <2,000 ng/mL, whichever was lower).

The trial showed that treatment with emapalumab led to rapid neutralisation of IFNγ and that a complete response was reached in all patients by week 8. All patients weaned from glucocorticoids. A cytomegalovirus reactivation was reported as a serious event possibly related to emapalumab, but resolved completely with treatment. It was concluded that emapalumab treatment was effective and safe in controlling MAS. Thus, translational therapeutics in the MAS arena is pointing towards a key role for IFNγ in addition to other studies showing key roles for IL-18 and possibly IL-1, which is helping to elucidate the immunopathogenetic basis for these diseases.

1. De Benedetti, F. et al. Abstract OP0204. EULAR 2019

Posted on 4 September 201915 February 2024