Safety of recombinant coagulation factors in treating hemophilia

ABSTRACT

Introduction: During the last decade, new FVIII/IX concentrates have been developed for the treatment of patients affected by hemophilia A/B. Significant progress has been achieved regarding their half-life, but the old issue of immunogenicity and new concerns about safety need to be addressed.

Areas covered: After the implementation of virucidal methods, both plasma-derived and recombinant clotting factor concentrates achieved a very safe profile. The development of anti-FVIII antibodies is the major adverse event of replacement therapy with both FVIII concentrates. Furthermore, the new extended half-life concentrates, protein fused or pegylated, raised some concerns about their side effects.

Expert Opinion: The treatment of hemophilia A with inhibitors by induction of immunotolerance and using by-passing concentrates, improved the quality of life of patients but did not allow them to have a life expectancy like that of patients without inhibitors. The new humanized monoclonal antibody (MAb) ACE910, mimicking FVIII function, seems to be able to reduce the bleedings of hemophilia A patients with inhibitors. The post-marketing surveillance will clarify if the adverse events observed during the phase III clinical trials and compassionate use were due to the association with a Prothrombin activated complex concentrate or to the prothrombotic effect of the drug itself.

KEYWORDS:

• Clotting factor concentrates
• viral safety
• immunogenicity
• Pegylation
• no-replacement therapy
• Hemophilia

Article highlights

• The development of alloantibodies anti-FVIII in 30–45% of hemophilia A patients during the first 50 Eds represents so far the most significant adverse event of replacement therapy

• Less frequent (2–3%) is the occurrence of anti-FIX alloantibodies in hemophilia B patients, complicated by occasionally severe anaphylactic reactions

• The preliminary reports of the ongoing post-marketing observational studies on immunogenicity of the new rFVIII EHL seem to confirm the epidemiology of rFVIII SHL, except probably for FVIII concentrates produced by HEK

• The randomized controlled study on the immunogenicity of pd-FVIII concentrates against rFVIII ones recognized the lower immune response in patients treated with the first ones.

• PEGylation of full-length or BDD FVIII concentrates improved significantly their half-life, about 1.5–1.6 that of the rFVIII SHL ones

• PEG of different molecular weights (10, 40, and 60 kDa) have been used and their specific toxicity and side effects are still under investigation

This box summarizes key points contained in the article.

Declaration of interest

M. Morfini declares that he acted as a paid consultant to Bayer, Baxter, Novo Nordisk, Pfizer Advisory Boards and received a fee as an invited speaker at CSL Behring Symposia, Biotest, Bayer, Kedrion, Novo Nordisk, SOBI and Octapharma. He has also received research grants from Bayer, Pfizer, and Baxter. The authors have no other 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.