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A Blood Coagulation Factor IX Variant that Functions Independently of Factor VIII Mitigates the Hemophilia A Phenotype in Patient Plasma

V.J. Strijbis1, L.G. Romano2, K.L. Cheung1, Y.P. Liu3, A.C. McCreary3, F.W. Leebeek2, M.H. Bos1

1Div. of Thrombosis and Hemostasis, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, Netherlands, 2Dept. of Hematology, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, Netherlands, 3uniQure Biopharma B.V., Amsterdam, Netherlands

Abstract Number: OC 48.1

Meeting: ISTH 2021 Congress

Theme: Hemophilia and Rare Bleeding Disorders » Novel Biotherapeutics in Hemophilia

Background: Previously, factor (F)IX-FIAV has been generated that functions independently of the cofactor VIIIa and ameliorates the hemophilia A (HA) phenotype in vitro/vivo [Quade-Lyssy et al. J.Thromb.Haemost. 2014].

Aims: Efficacy and potency assessment of purified recombinant FIX-FIAV in mild, moderate, and severe HA patient plasma using thrombin generation (TG) and intrinsic clotting activity (aPTT) analyses.

Methods: Plasma was obtained from 21 HA patients (>18yrs; seven/phenotype) and analyzed for FVIII/FIX levels, FVIII mutation, Bethesda Units, and aPTT. Plasma was spiked with FIX-FIAV and the FXIa-triggered TG lag-time and aPTT were quantified in terms of FVIII-like activity using a FVIII calibration for each patient plasma. This study was approved by the local medical ethics committee, and patients provided written informed consent.

Results: Supplementation of patient plasma with FIX-FIAV demonstrated a dose-dependent improvement in TG parameters and aPTT (Fig.1). For severe HA, a linear response in TG lag-time and aPTT was observed with a maximum at ~400-600% FIX-FIAV added, solely resulting from FIX-FIAV’s FVIII-independent activity. A higher potency was observed in moderate/mild HA plasma with a maximal effect at ~200-250% FIX-FIAV, which is in line with the residual FVIII activity in moderate/mild HA and demonstrates the contribution of the cofactor-dependent FIX-FIAV activity. Importantly, addition of an inhibitory anti-FVIII antibody to moderate/mild HA patient plasma resulted in a FIX-FIAV response similar to severe HA, confirming the cofactor-independent activity of FIX-FIAV. Efficacy assessment using the TG lag-time revealed that 100% (5 µg/ml) FIX-FIAV mitigated the HA phenotype from severe to moderate (<0.01% → 5±4% FVIII-like activity), from moderate to mild (4±2% → 13±5% FVIII-like activity), and from mild to normal (17±13% → 34±12% FVIII-like activity) (Fig.2).
Representative reference curves of the % FVIII activity over % FIX-FIAV supplementation in severe, moderate, or mild HA patient plasma. Dotted lines represent 1, 5, or 40% FVIII activity. The FVIII activity was quantified using a FVIII calibration of the TG lag-time for each patient plasma.Phenotype improvement determined as FVIII activity at 100% (5 µg/ml) FIX-FIAV addition to severe, moderate, or mild HA patient plasma. Dotted lines represent 1, 5, or 40% FVIII activity. The FVIII activity was quantified using a FVIII calibration of the TG lag-time for each patient plasma.

Conclusions: FIX-FIAV is capable of increasing the FVIII-like activity and coagulation activity in HA patient plasma, thereby mitigating the HA phenotype. Hence, FIX-FIAV could serve as a potential treatment for HA.

To cite this abstract in AMA style:

Strijbis VJ, Romano LG, Cheung KL, Liu YP, McCreary AC, Leebeek FW, Bos MH. A Blood Coagulation Factor IX Variant that Functions Independently of Factor VIII Mitigates the Hemophilia A Phenotype in Patient Plasma [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/a-blood-coagulation-factor-ix-variant-that-functions-independently-of-factor-viii-mitigates-the-hemophilia-a-phenotype-in-patient-plasma/. Accessed July 1, 2022.

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