Several new therapies for hemophilia have emerged in recent years. These strategies range from extended half-life (EHL) 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.
The half-lives of FVIII and FIX in plasma are 10–12 hours and 16–18 hours, respectively5. For prophylaxis, patients with severe disease need to be injected with standard half-life (SHL) replacement therapy two to three times per week to minimize spontaneous bleeds by maintaining a factor level >1%. EHL–rFIX products have successfully decreased infusion frequency from twice weekly to every 10–14 days using fusion to Fc–IgG1 or albumin or PEGylation technologies; however, EHL–rFVIII products have only decreased infusions from about three to about two times per week. All licensed EHL products recommend tailoringthe dose to the individual patient’s pharmacokinetic response.
Hence, for each individual patient, a particular product may not offer significant half-life extension and therefore may be less effective from a cost and convenience standpoint.
Whether the EHL products alter the immunogenicity profile of rFVIII products and might be safer than pdFVIII–VWF products is an unanswered question. There is only one reported caseof inhibitor development to date for EHL products. The available data suggest that the immune profile of EHL products is similar to, if not better than, SHL recombinant products. There are no data available comparing recombinant EHL with plasma-derived factors. Preliminary data also suggest that EHL products may fare better for ITI, both for those who fail with rFVIII and as first-line therapy.
Novel technologies aimed at promoting hemostasis in patients with hemophilia without replacing the deficient factor are currently in clinical development. These include FVIII mimicsand agents that obstruct the function of natural anti-coagulants, such as antithrombin (AT), tissue factor pathway inhibitor (TFPI), and activated protein C (APC).
The hemostatic effect of non-factor therapies (NFTs) is impervious to inhibitors. NFTs can also be administered subcutaneously at weekly to monthly frequencies, which is appealing compared to frequent intravenous administrations of standard factor products, though injection site adverse events have these new treatments will be integrated into clinical practice depends on the resolution of several ongoing debates.
Thrombotic complications are rare (<10 per 100,000 infusions) but are a well-recognized risk, especially when combined with other hemostatic therapies such as rFVIIa The risk of thrombotic complications due to unregulated hemostasis is not unique to emicizumab. Though no thrombotic adverse events were observed in the phase I studies, elevated D-dimer levels, a marker of pathological coagulation, were noted in several study participants receiving NFTs targeting ATand TFPI. Recently, a phase II study evaluating fitusiran was temporarily suspended after a fatal thrombotic complication.
Decades of collective effort on the use of adeno-associated virus (AAV) as a vector for hemophilia have culminated with recent successes in long-term expression of therapeutic FVIII and FIX levels, amelioration of the disease phenotype, and reduction or even discontinuation of factor replacement. AAV is a single-stranded DNA, non-pathogenic, replication defective virus from the parvovirus family.Data from clinical studies show that capsid-mediated immune responses occur with all serotypes in a vector dose-dependent manner. The onset and dose dependence varies among distinct serotypes. As for any other novel therapy for hemophilia, there are concernsregarding the risk of inhibitor formation. To date, the presenceor history of inhibitors and minimal exposure to factorconcentrates are exclusion criteria in all of these studies.
These new therapies will likely transform hemophilia care, providing more efficacious and convenient management options and possibly curative therapies. However, it is imperative that the excitement over the considerable potential of these drugs to help undertreated patients does not obscure early safety concerns such as potential pathological PEG accumulation, thrombotic complications in NFTs, and irreversible supraphysiological factor levels after gene therapy.
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F1000Res. 2018 Apr
<h3>Emerging therapies for hemophilia: controversies and unanswered questions</h3>
Arruda VR, Doshi BS, Samelson-Jones BJ.