New directions to develop therapies for people with hemophilia

ABSTRACT

Introduction

The past few decades have seen a tremendous advancement in the management of hemophilia. Whether it is improved methods to attenuate critical viruses, recombinant bioengineering with decreased immunogenicity, extended half-life replacement therapies to mitigate the burden of repeated infusion treatments, novel nonreplacement products to avoid the drawback of inhibitor development with its attractive subcutaneous administration and then the introduction of gene therapy, the management has trodden a long way.

Areas covered

This expert review describes the progress in the treatment of hemophilia over the years. We discuss, in detail, the past and current therapies, their benefits, drawbacks, along with relevant studies leading to approval, efficacy and safety profile, ongoing trials, and future prospects.

Expert opinion

The technological advances in the treatment of hemophilia with convenient modes of administration and innovative modalities offer a chance for a normal existence of the patients living with this disease. However, it is imperative for clinicians to be aware of the potential adverse effects and the need for further studies to establish causality or chance association of these events with novel agents. Thus, it is crucial for clinicians to engage patients and their families in informed decision-making and tailor individual concerns and necessities.

KEYWORDS:

• Hemophilia
• replacement factor VIII
• replacement factor IX
• extended halflife factor VIII
• extended halflife factor IX
• gene therapy
• inhibitor

Article highlights

• Factor replacement products once the mainstay of hemophilia treatment, however newer products are now available with easier modes of administration, decreased immunogenicity and increased efficacy.

• Recombinant bioengineering with the development of extended half-life replacement therapies are available to diminish the frequency of administration and improved compliance.

• Emicizumab is considered by many to be another standard of care agent for bleed prophylaxis in patients with hemophilia A.

• Subcutaneous administration of some these new therapies makes it further attractive for prophylaxis in patients with poor venous access and studies are underway to develop subcutaneous and even oral replacement therapies.

• The most striking of newer development is gene therapy that involves the introduction of either a wild-type or a modified factor gene with greater activity or longer half-life and establishing continuous endogenous expression of factor VIII or factor IX.

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.

Abbreviations

HA Hemophilia A HB Hemophilia B FVIII Factor VIII and FIX Factor IX TFPI Tissue Factor Pathway Inhibitor SHL Standard half-life EHL Extended half life; IV intravenous; SQ subcutaneous PEG polyethylene glycol FDA Food and Drug Administration ABR annualized bleeding rates vWF Von Willebrand factor AAV adeno-associated virus dL deciliter IU international units aPCC activated prothrombin concentrate PUPs previously untreated patients PTPs previously treated patients

Additional information

Funding

The paper was not funded.