Abstract Number: PB1146
Meeting: ISTH 2020 Congress
Theme: Hemophilia and Rare Bleeding Disorders » Novel Biotherapeutics in Hemophilia
Background: Dalcinonacog alfa (DalcA) is a full-length recombinant FIX with 3 amino acid substitutions that confer the product with increased specific activity, enhanced FVIIIa binding and reduced inhibition by antithrombin. Labelled potencies do not always reflect the full therapeutic potential as factor assays may not take into account the full functionality of FIX variants. Thrombin generation tests could be employed to provide a better understanding of the dynamic functionality of DalcA in plasma.
Aims: To compare thrombin generation profiles of DalcA with recombinant (RB) and plasma derived (PD) FIX products in FIX immunodepleted plasma.
Methods: Thrombin generation profiles (Thrombinoscope, Stago) of DalcA (Catalyst Biosciences), RB (Benefix, Pfizer) and PD (14/148, NIBSC) were compared at 3 concentrations: 0.01, 0.05 and 0.3 International Unit (IU)/ml, based on labelled potency, using 3 different stimuli: high tissue factor (TF) (~1pM), low TF (~0.1pM) and FXIa (6.5 mIU FXIa/ml + 0.05pM TF), each containing phospholipid (4µM).
Results: Different thrombin generation profiles were seen when using the 3 triggers (figure 1) and peak thrombin values are presented in table 1. Lagtimes were shortest using high TF and longest with low TF. In all cases FXIa generated more thrombin than the other 2 triggers. The Endogenous Thrombin Potential followed a similar trend. FXIa was a more sensitive trigger especially for DalcA. On average, when compared at the same IU, DalcA had a shorter lagtime and was able to generate 10-300% more thrombin than RB and PD. RB was more active than PD using high TF and low TF but similar when FXIa was used.
Conclusions: On the same IU basis, DalcA had higher thrombin generation potential than RB and PD FIX and this may be due to the modifications in DalcA which enhance its binding to FVIIIa and reduced its inhibition by antithrombin. This may translate to better efficacy in vivo.
| DalcA 0.3 IU/ml | DalcA 0.05 IU/ml | DalcA 0.01 IU/ml | RB 0.3 IU/ml | RB 0.05 IU/ml | RB 0.01 IU/ml | PD 0.3 IU/ml | PD 0.05 IU/ml | PD 0.01 IU/ml | |
| High Tissue Factor (nM Thrombin) | 103.3 | 21.7 | 2.7 | 89.4 | 20.0 | 2.6 | 58.0 | 11.3 | 1.5 |
| Standard deviation (SD) | 2.82 | 1.16 | 1.25 | 4.85 | 0.77 | 0.94 | 2.40 | 1.10 | 0.86 |
| n | 4 | 4 | 4 | 4 | 4 | 4 | 4 | 4 | 4 |
| Low Tissue Factor (nM Thrombin) | 96 | 23.8 | 7.2 | 64.6 | 13.2 | 3.9 | 33.5 | 7.3 | 3.4 |
| Standard deviation (SD) | 2.80 | 1.80 | 1.84 | 2.03 | 1.45 | 0.24 | 2.93 | 1.18 | – |
| n | 4 | 4 | 4 | 4 | 4 | 3 | 4 | 4 | 1 |
| FXIa + very low Tissue factor (nM Thrombin) | 232.1 | 89.1 | 22.6 | 193.5 | 48.4 | 7.5 | 218.8 | 58.9 | 9.8 |
| Standard deviation (SD) | 9.3 | 11.9 | 4.76 | 18.27 | 10.11 | 2.25 | 25.89 | 12.07 | 3.56 |
| n | 4 | 4 | 4 | 4 | 4 | 4 | 4 | 4 | 4 |
[Table 1: Average peak thrombin (blank subtracted) + SD for the 3 FIX samples, at all concentrations tested, using 3 different triggers.]
[Figure 1: Representative thrombin generation curves for recombinant (RB), plasma derived (PD), dalcinonacog alfa (DalcA) at 0.3 IU/ml with 3 triggers]
To cite this abstract in AMA style:
Williams S, Gray E. Thrombin Generation Potential of Modified FIX: Dalcinonacog Alfa [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/thrombin-generation-potential-of-modified-fix-dalcinonacog-alfa/. Accessed September 29, 2023.« Back to ISTH 2020 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/thrombin-generation-potential-of-modified-fix-dalcinonacog-alfa/