Mod-5014, a Long-Acting FVIIa-CTP, Proposing a Novel Prophylactic Treatment Supporting Less Frequent Subcutaneous or Intravenous Injections with a Similar Mechanism of Action to rFVIIa: Proof-of-Concept in Hemophilic Animal Models

Introduction:

OPKO Biologics is a clinical-stage public company developing bio-better long-acting versions of existing therapeutic proteins, utilizing a technology termed CTP. The technology involves fusion of the C-terminal peptide of hCG to a target protein. The aim of this work was to comprehensively assess the feasibility of intravenous (IV) or subcutaneous (SC) administration of FVIIa-CTP (MOD-5014) utilizing the most relevant in vivo pre-clinical models, and to characterize the FVIIa-CTP mechanism of action in preparation for an on-going clinical study.

Methods:

FVII-CTP was expressed in CHO cells, purified and activated utilizing a CTP-specific purification process. FVIIa-CTP's pharmacokinetics (PK), pharmacodynamics (PD), long-term hemostatic effect and safety parameters were extensively characterized following SC and IV administration in transient FVII-/- rats and FVIII-/- mice. In addition, the long-term hemostatic effect of FVIIa-CTP was evaluated following a bleeding challenge and compared to commercial rFVIIa. Finally, interaction with co-factors, activity, and the off-target effect of FVIIa-CTP was comprehensively characterized.

Results:

The studies demonstrated that FVIIa-CTP provides long-term exposure (AUC) and half-life that are significantly superior to those of rFVIIa, and consistent with the prolonged half-life of FVIIa-CTP (at an average of 3- and 5-fold, respectively) when compared to IV or SC administration of FVIIa. In addition, a 30% increase in bioavailability was observed relative to commercial FVIIa. A profound improvement in clotting parameters and survival rate following TVT, as well as a reduction of bleeding duration and intensity in tail-clip studies were obtained for both routes of administration for up to 48 hours. Moreover, the safety profile of FVIIa-CTP was further confirmed.

Conclusion:

Attachments of CTP to FVIIa led to a pronounced enhancement of PK and PD, increased exposure as reflected by AUC, elevated half-life, and improved recovery in mice, rats and pigs following SC and IV administration. FVIIa-CTP injection resulted in an improved bioavailability that translated to a marked in vivo hemostatic effect. Our data suggest that CTP-fused FVIIa can potentially provide a novel approach for IV or SC prophylactic treatment of hemophilic patients (both pediatric and adult), with the major benefit of significant improvement in quality of life.