PB0672 - Safety and pharmacokinetics of a subcutaneous recombinant FVIII (OCTA101) in adult patients with severe haemophilia A

Background: Regular, prophylactic intravenous FVIII is the standard of care for severe haemophilia A, but can be challenging for some patients. Subcutaneous FVIII administration could provide an alternative treatment option without the complications associated with venous access.

Aims: This phase I/II study (NCT04046848) assessed the safety, pharmacokinetics (PK), and bioavailability of subcutaneous OCTA101, a recombinant FVIII with a recombinant von Willebrand factor fragment dimer.

Methods: Previously treated (≥150 exposure days to FVIII) male patients (≥18 years) with severe haemophilia A were eligible for this single-centre, prospective, open-label, dose-escalation study. Patients in the dose-escalation cohorts received a single injection of OCTA101 for PK assessment followed by 3-month daily prophylaxis, with assessment by an independent Data Monitoring Committee (DMC) before the next higher dose. Primary outcome measures included FVIII and VWF fragment PK, dose-linearity, adverse events (AEs), dose-limiting toxicities, thromboembolic events, local injection site reactions, and FVIII inhibitor formation.

Results: Twenty patients were enrolled in the PK part of the study. Half-life and recovery were as expected from pre-clinical studies, and trough plasma FVIII levels ≥10% were achieved. Two patients developed inhibitory antibodies to OCTA101, and the trial was put on hold during discussion with the DMC. The trial resumed with an amended protocol, including a lower dose and integration of additional safety steps, and ten patients started OCTA101 treatment. Another two patients subsequently developed inhibitors while on daily prophylaxis. In accordance with the amended protocol and in agreement with the DMC, the study was immediately terminated. Other than the development of FVIII inhibitors, no serious treatment-related AEs were reported.

Conclusion(s): The occurrence of inhibitors despite dose reduction suggests that their development may be related to the subcutaneous route of administration. Similarly, development of another subcutaneous recombinant FVIII product (turoctocog alfa pegol) was terminated due to antibody development in previously treated patients.