Efficacy and safety of emapalumab in macrophage activation syndrome

Abstract

Objectives: Macrophage activation syndrome (MAS) is a severe, life-threatening complication of systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease (AOSD). The objective of this study was to confirm the adequacy of an emapalumab dosing regimen in relation to interferon-γ (IFNγ) activity by assessing efficacy and safety. The efficacy outcome was MAS remission by week 8, based on clinical and laboratory criteria.

Methods: We studied emapalumab, a human anti-IFNγ antibody, administered with background glucocorticoids, in a prospective single-arm trial involving patients who had MAS secondary to sJIA or AOSD and had previously failed high-dose glucocorticoids, with or without anakinra and/or ciclosporin. The study foresaw 4-week treatment that could be shortened or prolonged based on investigator's assessment of response. Patients entered a long-term (12 months) follow-up study.

Results: Fourteen patients received emapalumab. All patients completed the trial, entered the long-term follow-up and were alive at the end of follow-up. The investigated dosing regimen, based on an initial loading dose followed by maintenance doses, was appropriate, as shown by rapid neutralisation of IFNγ activity, demonstrated by a prompt decrease in serum C-X-C motif chemokine ligand 9 (CXCL9) levels. By week 8, MAS remission was achieved in 13 of the 14 patients at a median time of 25 days. Viral infections and positive viral tests were observed.

Conclusions: Neutralisation of IFNγ with emapalumab was efficacious in inducing remission of MAS secondary to sJIA or AOSD in patients who had failed high-dose glucocorticoids. Screening for viral infections should be performed, particularly for cytomegalovirus.

Trial registration number: NCT02069899 and NCT03311854.

Keywords: Still's disease, adult-onset; arthritis, juvenile; biological therapy; inflammation; therapeutics.

Figure 1

Pharmacokinetic (emapalumab* (A)) and pharmacodynamic (CXCL9† (B), total IFNγ‡ (C) and sIL-2R§ (D)) parameters in patients with MAS treated with emapalumab. *Serum emapalumab concentrations in patients treated with emapalumab (initial dose of 6 mg/kg, followed by intended maintenance dosing of 3 mg/kg every 3 days until day 15, and twice weekly until day 28). †Serum concentrations of CXCL9, a biomarker of IFNγ activity, being, at baseline, 4–362 times the 95th percentile of healthy volunteers (271 pg/mL), indicated by the horizontal dotted line. ‡Total IFNγ (free and emapalumab-bound) that reflects IFNγ production, ranging, at day 3, from normal to 12 times the 95th percentile of healthy volunteers receiving emapalumab (2084 pg/mL) indicated by the horizontal dotted line. §Serum sIL-2R, a biomarker of T cell activation, being, at baseline, 1.6–20 times the 95th percentile of healthy volunteers (1071 pg/mL, unpublished data) indicated by the horizontal dotted line. CXCL9, C-X-C motif chemokine ligand 9; IFNγ, interferon-γ; MAS, macrophage activation syndrome; sIL-2R, soluble interleukin-2 receptor.

Figure 2

Time to MAS remission*. *Time to MAS remission defined as resolution of clinical signs and symptoms according to the investigator (visual analogue scale ≤1/10) (online supplemental table S2) and resolution of the abnormalities of MAS laboratory parameters: white blood cell and platelet count above lower limit of normal, LDH below 1.5 times ULN, alanine aminotransferase/aspartate aminotransferase below 1.5 times ULN, fibrinogen >100 mg/dL and ferritin levels decreased by at least 80% or below 2000 ng/mL, whichever was lower. The continuous line represents the proportion of patients with MAS remission, the dotted line represents the 95% CI. The cross indicates the censored patient. LDH, lactate dehydrogenase; MAS, macrophage activation syndrome; ULN, upper limit of normal.

Figure 3

Changes in ferritin* (A), aspartate aminotransferase† (B), platelets (C) and LDH‡ (D) levels over time. *Panel A insert shows in detail changes from baseline to week 4 for patients with baseline levels of ferritin <50 000 ng/mL. †Panel B insert shows in detail changes from baseline to week 4 for patients with baseline levels of aspartate aminotransferase below 300 U/L. ‡Panel D insert shows in detail changes from baseline to week 4 for patients with baseline levels of LDH below 2500 U/L. LDH, lactate dehydrogenase.

Figure 4

Changes in glucocorticoid dose* over time†. *The dose of glucocorticoids is shown as average daily dose in each week of the study, starting from the week preceding emapalumab treatment (week −1). The dose is shown in mg/kg of prednisone equivalent. †Weeks are defined starting form week −1 (from day −6 to day 0), followed by week 1 (form day 1 to day 7); week 2 (from day 8 to day 14); week 3 (from day 15 to day 21); up to week 8 (from day 50 to day 56).