Emapalumab in Children with Primary Hemophagocytic Lymphohistiocytosis.

BACKGROUND: Primary hemophagocytic lymphohistiocytosis is a rare syndrome characterized by immune dysregulation and hyperinflammation. It typically manifests in infancy and is associated with high mortality. METHODS: We investigated the efficacy and safety of emapalumab (a human anti-interferon-γ antibody), administered with dexamethasone, in an open-label, single-group, phase 2-3 study involving patients who had received conventional therapy before enrollment (previously treated patients) and previously untreated patients who were 18 years of age or younger and had primary hemophagocytic lymphohistiocytosis. The patients could enter a long-term follow-up study until 1 year after allogeneic hematopoietic stem-cell transplantation or until 1 year after the last dose of emapalumab, if transplantation was not performed. The planned 8-week treatment period could be shortened or extended if needed according to the timing of transplantation. The primary efficacy end point was the overall response, which was assessed in the previously treated patients according to objective clinical and laboratory criteria. RESULTS: At the cutoff date of July 20, 2017, a total of 34 patients (27 previously treated patients and 7 previously untreated patients) had received emapalumab; 26 patients completed the study. A total of 63% of the previously treated patients and 65% of the patients who received an emapalumab infusion had a response; these percentages were significantly higher than the prespecified null hypothesis of 40% (P = 0.02 and P = 0.005, respectively). In the previously treated group, 70% of the patients were able to proceed to transplantation, as were 65% of the patients who received emapalumab. At the last observation, 74% of the previously treated patients and 71% of the patients who received emapalumab were alive. Emapalumab was not associated with any organ toxicity. Severe infections developed in 10 patients during emapalumab treatment. Emapalumab was discontinued in 1 patient because of disseminated histoplasmosis. CONCLUSIONS: Emapalumab was an efficacious targeted therapy for patients with primary hemophagocytic lymphohistiocytosis. (Funded by NovImmune and the European Commission; NI-0501-04 and NI-0501-05 ClinicalTrials.gov numbers, NCT01818492 and NCT02069899.).

Efficacy and safety of emapalumab in macrophage activation syndrome.

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.

Emapalumab in primary haemophagocytic lymphohistiocytosis and the pathogenic role of interferon gamma: A pharmacometric model-based approach.

AIM: Primary haemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening, hyperinflammatory syndrome generally occurring in early childhood. The monoclonal antibody emapalumab binds and neutralises interferon γ (IFNγ). This study aimed to determine an emapalumab dosing regimen when traditional dose-finding approaches are not applicable, using pharmacokinetic-pharmacodynamic analyses to further clarify HLH pathogenesis and confirm IFNγ neutralisation as the relevant therapeutic target in pHLH. METHODS: Initial emapalumab dosing (1 mg/kg) for pHLH patients participating in a pivotal multicentre, open-label, single-arm, phase 2/3 study was based on anticipated IFNγ levels and allometrically scaled pharmacokinetic parameters estimated in healthy volunteers. Emapalumab dosing was adjusted based on estimated IFNγ-mediated clearance and HLH clinical and laboratory criteria. Frequent dosing and emapalumab dose adaptation were used to account for highly variable IFNγ levels and potential target-mediated drug disposition. RESULTS: High inter- and intra-individual variability in IFNγ production (assessed by total IFNγ levels, range: 102 -106  pg/mL) was observed in pHLH patients. Administering emapalumab reduced IFNγ activity, resulting in significant improvements in clinical and laboratory parameters and a reduced risk of adverse events, mainly related to pHLH. Modelled outcomes supported dose titration starting from 1 mg/kg, with possible increases to 3, 6 or 10 mg/kg based on re-evaluation of parameters of disease activity every 3 days. CONCLUSIONS: The variable and unanticipated extremely high IFNγ concentrations in patients with pHLH are reflected in parameters of disease activity. Improved outcomes can be achieved by neutralising IFNγ using frequent emapalumab dosing and dose adaptation guided by clinical and laboratory observations.

Role of interferon-γ in immune-mediated graft failure after allogeneic hematopoietic stem cell transplantation.

Pathophysiology of graft failure (GF) occurring after allogeneic hematopoietic stem cell transplantation (HSCT) still remains elusive. We measured serum levels of several different cytokines/chemokines in 15 children experiencing GF, comparing their values with those of 15 controls who had sustained donor cell engraftment. Already at day +3 after transplantation, patients developing GF had serum levels of interferon (IFN)-γ and CXCL9 (a chemokine specifically induced by IFNγ) significantly higher than those of controls (8859±7502 vs. 0 pg/mL, P=0.03, and 1514.0±773 vs. 233.6±50.1 pg/mlL, P=0.0006, respectively). The role played by IFNγ in HSCT-related GF was further supported by the observation that a rat anti-mouse IFNγ-neutralizing monoclonal antibody promotes donor cell engraftment in Ifngr1-/-mice receiving an allograft. In comparison to controls, analysis of bone marrow-infiltrating T lymphocytes in patients experiencing GF documented a predominance of effector memory CD8+ cells, which showed markers of activation (overexpression of CD95 and downregulation of CD127) and exhaustion (CD57, CD279, CD223 and CD366). Finally, we obtained successful donor engraftment in 2 out of 3 children with primary hemophagocytic lymphohistiocytosis who, after experiencing GF, were re-transplanted from the same HLA-haploidentical donor under the compassionate use coverage of emapalumab, an anti-IFNγ monoclonal antibody recently approved by the US Food and Drug Administration for treatment of patients with primary hemophagocytic lymphohistiocytosis. Altogether, these results suggest that the IFNγ pathway plays a major role in GF occurring after HSCT. Increased serum levels of IFNγ and CXCL9 represent potential biomarkers useful for early diagnosis of GF and provide the rationale for exploring the therapeutic/preventive role of targeted neutralization of IFNγ.