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Review
. 2018 Apr 24:7:F1000 Faculty Rev-489.
doi: 10.12688/f1000research.12491.1. eCollection 2018.

Emerging therapies for hemophilia: controversies and unanswered questions

Valder R Arruda  1   2   3 , Bhavya S Doshi  1 , Benjamin J Samelson-Jones  1   2
Affiliations
Review

Emerging therapies for hemophilia: controversies and unanswered questions

Valder R Arruda et al. F1000Res. .

Abstract

Several new therapies for hemophilia have emerged in recent years. These strategies range from extended half-life factor replacement products and non-factor options with improved pharmacokinetic profiles to gene therapy aiming for phenotypic cure. While these products have the potential to change hemophilia care dramatically, several challenges and questions remain regarding broader applicability, long-term safety, and which option to pursue for each patient. Here, we review these emerging therapies with a focus on controversies and unanswered questions in each category.

Keywords: EHL; NFT; gene therapy; hemophilia.

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Conflict of interest statement

Competing interests: BSJ is an investigator on AAV gene therapy clinical trials for hemophilia sponsored by Spark Therapeutics. VRA and BSD declare that they have no competing interests.No competing interests were disclosed.No competing interests were disclosed.No competing interests were disclosed.No competing interests were disclosed.

Figures

Figure 1.
Figure 1.. Mechanism of action of hemophilia therapies.
Factor X (FX) can be activated to FXa either via FIXa–FVIIIa complex or the tissue factor (TF) factor–FVIIa complex. FXa and FVa activate prothrombin (FII) to thrombin (FIIa) in order to generate a fibrin clot. Natural anti-coagulants targeted by non-factor therapeutics are represented in red. Protein-based therapeutics are represented in purple, nucleotide-based therapeutics are represented in blue, and antibody-based therapeutics are represented in green. Fitusiran decreases the production of antithrombin (AT), decreasing its inhibition of FIXa, FXa, and FIIa. Concizumab and anti-protein C serine protease inhibitors (serpins) block tissue factor pathway inhibitor (TFPI) from inhibiting FXa and TF–FVIIa complex or protein C from inhibiting FVIIIa and FVa, respectively. Emicizumab is a FVIIa mimic that brings together FIXa and FX to generate FXa. Factor-based therapies include adeno-associated virus (AAV)-based liver-directed gene therapy, which results in endogenous factor production, and exogenously given factor therapeutics given intravenously. APC, activated protein C; EHL, extended half-life.
See this image and copyright information in PMC

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