OC 43.2 - CAY001, a synthetic short-chain polyphosphate (polyP) complexed with silica nanoparticle (SNP), has pro-hemostatic activities as assessed by in vitro and ex vivo studies

Background: Platelet-length polyP is a cofactor of Factor (F) V, FXI and thrombin. CAY001 is a synthetic biomimetic of platelet-length polyP complexed with SNP. The polyP-SNP complex facilitates intravenous (IV) delivery of polyP as a potential pro-hemostatic therapeutic for serious or life-threatening bleeding. In this study, the coagulation activity of CAY001 was characterized by thrombin generation assay (TGA) in human pooled normal plasma (hPNP), thromboelastography (TEG) in hPNP and in rat whole blood (rWB) following IV administration of CAY001.

Aims: To characterize the pro-hemostatic potential of CAY001 by in vitro and ex vivo coagulation assays.

Methods: CAY001 and SNP were synthesized as ready-to-use research batches.
TGA was performed in hPNP in a 96-well fluorogenic assay format. The reaction was initiated by adding CaCl2/phospholipid in citrated hPNP with CAY001 or SNP (0–0.5 mg/mL). TGA parameters were derived from relative fluorescence unit (RFU)-over-time profiles and its first-order derivative (RFU/min).
TEG was performed using TEG5000 (Haemonetics Corp). The reactions were initiated by adding CaCl2 in hPNP (in vitro) with CAY001 or SNP (0–0.8 mg/mL) or rWB (ex vivo) drawn at t=0, 0.75, 3.0 and 6.0-hour following IV administration of CAY001 (10 mg/kg) or saline.

Results: In hPNP, CAY001accelerated thrombin generation (time-to-peak) by 12- and 6-fold compared to control and SNP at the same concentration, respectively, without increase of total thrombin (Figure 1). Similarly, CAY001 improved all the TEG-parameters (R, K, α and MA) in a concentration-dependent manner.
The effect of CAY001 on ex vivo TEG in rWB were observable at 0.75-hour, peaked at 3-hour and had some effect remaining at 6-hour following IV administration (Figure 2).

Conclusion(s): The results demonstrate that CAY001 accelerates coagulation activity and is a potential pro-hemostatic therapeutic for serious or life-threatening bleeding.