Background/Purpose:

Based on the growing evidence that IFNg plays a pivotal role in HLH, NI-0501, an anti-IFNg monoclonal antibody, is being developed as the first targeted treatment of HLH. Since a dose-finding study could not be performed in this fragile population, an innovative, individualized-dosing approach is being investigated in a pilot study, with the objective of achieving, as quickly as possible, a complete IFNg neutralization. 

Methods:

The pilot study foresees the recruitment of 10 pediatric patients receiving NI-0501 either as first or second line HLH treatment. The NI-0501 dose required for reaching and maintaining, for a defined period of time, complete IFNg neutralization depends on the amounts of cytokine produced in various body compartments.

On the basis of calculated neutralizing NI-0501 concentrations, NI-0501 PK parameters in healthy volunteers and PK information from use of recombinant IFNg in humans, we predicted, by means of PK modelling and simulation, the dose neutralizing existing and de novo IFNg production over 3 days. The initial interval between NI-0501 infusions was 3 days. Guided by close PK monitoring, modifications of NI-0501 dose or frequency of administration were allowed. 

Results:

A dose of 1 mg/kg achieved the desired NI-0501 concentration in the 7 patients enrolled thus far in the study. NI-0501 elimination kinetics was linear at high concentrations and appeared non-linear, due to target mediated drug disposition, at lower drug concentrations. After reaching steady state, up to a 7-day administration frequency could be applied. Kinetics was not affected by the numerous therapeutic interventions (blood transfusions, hemofiltration or hemodialysis, bone marrow transplantation). IFNg neutralization in serum was confirmed ex vivo via the use of STAT-1 bio-assays and in vivo through down-modulation of IFNg-inducible proteins, such as CXCL9 and CXCL10.

Conclusion:

The adequacy of the originally planned dosing regimen was demonstrated in all patients enrolled to date in the pilot study. NI-0501 treatment has shown to be effective in improving or even abrogating all relevant clinical and laboratory features of HLH such as fever, splenomegaly, cytopenia, hyperferritinemia, hypofibrinogenemia, and also CNS disease. All infusions were well tolerated and no safety concerns emerged.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/innovative-approach-for-the-identification-of-an-appropriate-dose-regimen-of-a-targeted-treatment-ni-0501-an-anti-interferon-gamma-ifng-antibody-in-patients-with-hemophagocytic-lymphohistiocytosi/