Session Type: ACR Poster Session C
Session Time: 9:00AM-11:00AM
Background/Purpose: Data from an animal model of MAS and the observed high IFNγ and IFNγ-related chemokines (CXCL9, CXCL10) levels in MAS/sJIA patients have prompted the design of a study to investigate the therapeutic role of IFNγ neutralization in patients with this disease. An ongoing study in primary HLH (pHLH) shows promising efficacy and favourable safety of NI-0501, an anti-IFNγ antibody, in the control of HLH, known to be driven by high production of IFNγ. PK and PD data of NI-0501 obtained from the ongoing clinical trial in pHLH have been used to define the NI-0501 dosing strategy to be used to investigate the role of IFNγ neutralization in MAS/sJIA patients.
Methods: In active HLH the measurable circulating IFNγ levels do not account for the total amount of the cytokine present in the body. Following the administration of NI-0501 in pHLH patients, the measurement of “total IFNγ”, namely free and bound to NI-0501, is used as a surrogate for IFNγ production, revealing the high production of this cytokine, despite the relatively low “free IFNγ” levels at baseline in blood. Extrapolations from these data allowed the estimation of IFNγ production in MAS/sJIA patients, based on the levels of IFNγ-related chemokines present at baseline.
Results: The measurement of total IFNγ levels in pHLH revealed that the IFNγ concentration to be neutralized by NI-0501 was several hundreds fold higher compared to what indicated by the baseline free IFNγ level (median IFNγ at baseline <50 pg/ml; at peak 17’858 pg/ml). Total IFNγ at 48 hours post NI-0501 administration tightly correlates with IFNγ-related chemokine levels (CXCL9: r=0.6264, p=0.0008; CXCL10: r=0.6931, p=0.0001), suggesting that CXCL9 and CXCL10 concentrations are excellent markers of the presence of biologically active IFNγ. The amount of IFNγ produced in MAS/sJIA patients was then indirectly estimated on the basis of the total IFNγ concentration in pHLH patients with comparable levels of CXCL9 and CXCL10 following the administration of NI-0501. This information, coupled with modelling and simulation techniques, has allowed to i) determine the NI-0501 dose expected to neutralize rapidly the total amount of IFNγ in the majority of MAS/sJIA patients, ii) identify an appropriate frequency of NI-0501 administration to avoid unnecessary drug accumulation.
Conclusion: The methodology applied allowed a precise determination of the dosing strategy to be tested in the future trial, significantly reducing the risk of exposing patients to non-therapeutic NI-0501 doses.
To cite this abstract in AMA style:Jacqmin P, de Graaf K, Ballabio M, Nelson R, Johnson Z, Ferlin W, Lapeyre G, De Benedetti F, de Min C. Innovative Use of PK and PD to Guide Dose Selection for a Monoclonal Antibody Aimed at Neutralizing the High IFNγ Activity Present in Patients with Macrophage Activation Syndrome (MAS) [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/innovative-use-of-pk-and-pd-to-guide-dose-selection-for-a-monoclonal-antibody-aimed-at-neutralizing-the-high-ifn%ce%b3-activity-present-in-patients-with-macrophage-activation-syndrome-mas/. Accessed November 27, 2020.
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