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

Abstract

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.

Keywords: immunology - inflammation; immunology - monoclonal antibodies; paediatrics - children; pharmacodynamics - modelling and simulation; pharmacodynamics - pharmacokinetics-pharmacodynamics.

FIGURE 1

Schematic representation of (A) the overall PK‐PD‐efficacy/safety analysis strategy for emapalumab in patients with HLH and (B) PK‐PD‐disease interactions between IFNγ, emapalumab, CXCL9 and HLH disease activity. Note: In patients with HLH, the endogenous production of IFNγ (red) is exacerbated and leads to high circulating concentrations of free IFNγ. After administration, emapalumab (blue) binds reversibly to IFNγ, reducing its free concentration, and leads to the formation of an IFNγ‐emapalumab complex (violet), which is in equilibrium with the free moieties. To confirm the neutralisation of IFNγ by emapalumab, the decrease in serum concentration of CXCL9 (orange), a chemokine almost exclusively produced through the activation of the IFNγ receptor, is monitored. As such, CXCL9 can be considered as a biomarker of free IFNγ activity, hence the pharmacological activity of emapalumab in neutralising IFNγ. The decrease in free IFNγ is expected to improve disease status, which can be monitored by parameters such as sIL2R and ferritin (black). These parameters are included in the panel of HLH diagnostic criteria and considered as components of response to HLH treatments. All components described above (ie, free IFNγ, free emapalumab, IFNγ‐emapalumab complex, CXCL9, sIL2R and ferritin) have their own intrinsic clearance and their concentrations correspond to an equilibrium between production and elimination. Furthermore, for emapalumab, the formation of the complex with IFNγ corresponds to an additional clearance proportional to the IFNγ production. This phenomenon is known as TMDD. In patients with HLH receiving emapalumab, serum concentrations of free emapalumab (before drug administration), total IFNγ (ie, free IFNγ + IFNγ‐emapalumab complex) and CXCL9 have been measured. When free emapalumab is in excess, total IFNγ concentration at equilibrium can be considered as proportional to the IFNγ production and changes in total IFNγ concentration indicate proportional changes in IFNγ production. CL, clearance; CXCL9, chemokine (C‐X‐C motif) ligand 9; IFNγ, interferon γ; HLH, haemophagocytic lymphohistiocytosis; PD, pharmacodynamic; PK, pharmacokinetic; Pop, population; sIL2R, soluble interleukin‐2 receptor; TMDD, target mediated drug disposition

FIGURE 2

Total IFNγ concentrations in patients with HLH up to the last dose of emapalumab or HSCT in studies NI‐0501‐04/‐05. Note: The maximum administered dose of emapalumab is given in blue above the x axis. Concentrations before day 3 were omitted as steady state was not yet reached. IDN numbers are arbitrary designations to allow comparisons between figures. Patient 1 was erroneously administered one dose of emapalumab 5 mg/kg, but otherwise received 1 mg/kg during the entire treatment period. HLH, haemophagocytic lymphohistiocytosis; HSCT, haematopoietic stem cell transplant; IFNγ, interferon γ; IDN, identifier

FIGURE 3

Estimated apparent total clearance of emapalumab versus total IFNγ concentrations in patients with primary HLH participating in studies NI‐0501‐04/‐05 or having received emapalumab in compassionate use. Note: The dots are individual predicted clearances in patients. The green line is the population predicted clearance. The orange dotted line is the clearance in healthy subjects. HLH, haemophagocytic lymphohistiocytosis; IFNγ, interferon γ

FIGURE 4

Total CXCL9 concentrations in patients with primary HLH up to the last dose of emapalumab or HSCT in patients with primary HLH participating in the NI‐0501‐04 study. Note: Red dots indicate CXCL9 levels at study entry. Blue dots indicate levels at end of treatment of study NI‐0501‐04. Black dots indicate values in between study entry and last emapalumab dose. The horizontal dotted line indicates the 95th percentile of CXCL9 levels in healthy subjects. IDN numbers are arbitrary designations to allow comparisons between figures. CXCL9, chemokine (C‐X‐C motif) ligand 9; HLH, haemophagocytic lymphohistiocytosis; HSCT, haematopoietic stem cell transplant; IDN, identifier

FIGURE 5

Log‐scale comparison of changes in baseline CXCL9 and laboratory parameters in patients with primary HLH administered emapalumab in studies NI‐0501‐04/‐05 who had abnormal ferritin levels, sIL2Rα levels, D‐dimer levels, platelet counts, neutrophil counts or fibrinogen levels at baseline. Note: Values are percent of baseline. Green dots indicate improvement in a parameter. Black dots indicate no change or worsening in CXCL9 or laboratory parameter. CXCL9, chemokine (C‐X‐C motif) ligand 9; HLH, haemophagocytic lymphohistiocytosis; SD, study day; sIL2‐RA, soluble interleukin‐2 receptor α

FIGURE 6

Predicted risk of severe AEs as a function of the log₁₀‐transformed AUCτ of emapalumab. Note: The orange area represents the 95% CIs. The black dots represent the actual observed severe AEs throughout treatment with emapalumab (0 = no severe AE and 1 = severe AE) with their corresponding AUCτ. AE, adverse event; AUCτ, area under the curve to over a dosing interval; CI, confidence interval