Pharmacokinetic and safety considerations when switching from standard to extended half-life clotting factor concentrates in hemophilia

ABSTRACT

Introduction: Plenty of new FVIII/IX concentrates have been developed and entered the market of hemophilia treatment. Others are going to end the long/demanding procedures for approval. Changes of the FVIII molecule (single chain), pegylation of B-domain deleted FVIII, and fusion with Fc succeeded to improve the FVIII half-life, about 4 hours. Pegylation and fusion with albumin or Fc of rFIX caused a substantial increase of half-life, approximately 3–4 times that of FIX standard concentrates.

Area covered: Extended Half-life concentrates may allow a longer time interval between the prophylaxis bolus, a feature very well accepted by young patients. Also, adherence of adolescents can be improved by these new, less demanding, concentrates. The immunogenicity of these new molecules is so far under post-marketing evaluation. The incidence of neutralizing antibodies is very low in previously treated patients, but the data on previously untreated patients are not yet assessed. The cost of some Extended Half-Life concentrates is higher than that of standard ones, and some concerns have been raised about the cost for public or private health care institutions.

Expert opinion: An accurate evaluation of patients’ needs, individual pharmacokinetics, and cost/effectiveness might allow a more appropriate usage of these new and expensive concentrates.

KEYWORDS:

• Extended half-life concentrates
• hemophilia A & B
• factor VIII inhibitors
• pharmacokinetics
• pharmaco-economic issues

Article highlights

• New rFVIII and rFIX molecules are now available for the treatment of hemophilia A and B, all characterized by an extended Half-life.

• The new PEGylated rFVIII concentrates, most of them B-domain deleted, show a small but significant improvement of their Half-life, of the order of 1.43-1.53 fold. Due to the cardinal role of Von Willebrand factor it is impossible to extend the Half-life of FVIII by more than 4-5 hours. This limitation is also evident with rFVIIIFc, whose recycling is due to its uptake by hepatocytes, but which associates with VWF in Kupfer’s cells and macrophages [44]. Recently, a new single chain B-domain deleted rFVIII Fc-VWF-XTEN concentrates showed a 37 hrs half-life in an animal model [72], confirming the promise of an EHL rFVIII product if the VWF association can be accommodated.

• Significant successes were achieved in the production of new rFIX concentrates by pegylation or by fusion of the molecule with albumin or the crystallizable fragment of Ig. The new rFIX EHL concentrates are characterized by a half-life which is 3-5 times that of the SHL products.

• The improvement in half-life will enhance significantly patient adherence to prophylaxis.

• Concerns and uncertainties around the new EHL products include immunogenicity in PUPs, long-term prevention of adherence of and the cost of these new molecules.

• The availability of new therapies detached from replacement therapy may affect the interest of patients in switching from rFVIII/IX SHL to EHL concentrates.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.