Recombinant B‐domain‐deleted porcine sequence factor VIII (r‐pFVIII) for the treatment of bleeding in patients with congenital haemophilia A and inhibitors

Abstract

Introduction: Development of inhibitors to human FVIII (hFVIII) significantly complicates the control of bleeding events in patients with haemophilia A. Aim: This prospective, multicentre, open-label, non-comparative, Phase II study evaluated the haemostatic activity of a recombinant B-domain-deleted porcine FVIII (r-pFVIII), in the treatment of non-life/non-limb-threatening bleeding in individuals with haemophilia A and FVIII inhibitors. Methods: Acute bleeding episodes in patients with pFVIII inhibitor titres <0.8 BU mL À1 were treated with 50 U kg À1 body weight r-pFVIII. Those with pFVIII inhibitor titres of >0.8 BU mL À1 received an initial calculated r-pFVIII loading dose followed by 50 U kg À1 treatment dose. Treatment continued at 6-hourly intervals until bleeding was determined, controlled or till a maximum of eight doses was reached. Results: All 25 bleeding episodes in nine patients (mean age: 23.7 years; range: 14-34 years) were controlled successfully with eight or fewer injections of r-pFVIII. The median time from bleeding onset to the administration of r-pFVIII was 5.7 h (range: 1.5-20.0 h). Twenty of the bleeding episodes (80%) were controlled with one treatment dose of r-pFVIII (with or without a loading dose, median dose: 200.8 U kg À1; range: 50-576 U kg À1) regardless of pFVIII level. r-pFVIII was well tolerated and no treatment-emergent serious adverse events were considered by the investigator to be related to r-pFVIII administration. Conclusion: The results suggest that FVIII replacement therapy with r-pFVIII could be a viable alternative to bypassing agents for the treatment of bleeding episodes in individuals with haemophilia A and FVIII inhibitors.

Inhibitors in haemophilia A and B: Management of bleeds, inhibitor eradication and strategies for difficult‐to‐treat patients

“…A new FVIII agent for replacement therapy, recombinant B‐domain deleted porcine FVIII (OBI‐1), demonstrated efficacy and safety for the treatment of bleeding episodes in patients with acquired haemophilia A in phase II/III studies and in patients with congenital haemophilia A in a phase II study . A recombinant fusion protein linking rFVIIa with albumin (rVIIa‐FP), a new bypassing agent in clinical development with extended half‐life, showed good tolerability in 40 healthy males in a phase I study …”

Continuous infusion of recombinant porcine factor VIII for neurosurgical management of intracranial haemorrhage in a patient with severe haemophilia A with factor VIII inhibitor

“…However, even a low level of titre inhibitor would likely reduce the pFVIII half-life, plus the risk was high for a de novo or anamnestic rise in porcine FVIII inhibitor titre. 7 Thus, we elected to proceed with r-pFVIII by CI and closely monitor the patient with FVIII:C and TEG. Because the stability of reconstituted r-pFVIII in CI systems 6 was unknown, each bag was infused over a short time interval.…”

“…In vitro cross-reactivity of the FVIII inhibitor to porcine FVIII has been well described for patients with congenital and acquired HA, [7][8][9][10] with higher levels of titre inhibitors having a higher degree of cross-reactivity; however, the clinical impact of this cross-reactivity has not been well studied. The de novo development or anamnestic rise in porcine inhibitor titre generally occurs after 8 exposure days.…”

Requirements to participate in haemophilia clinical trials

“…Many of the recently completed clinical trials in haemophilia have focused on products with improved pharmacokinetics and/or alternative route of administration . Clinical trials which do not improve one or more of the product characteristics are likely to have a poor trial uptake and delayed completion.…”

“…Many of these novel therapy programs have reached or completed the human intervention phase of their evaluations. The clinical studies include the next generation of factor replacement therapies, non‐factor replacement therapies and adeno‐associated virus gene therapies . The traditional sites where most clinical trials in haemophilia studies are conducted have been the well‐resourced centres with experienced clinical trialists guided by a functional regulatory and ethical framework.…”