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Hemophilia has historically been undiagnosed and untreated. Effective treatment began in the 1960s, first with the discovery that cryoprecipitate was enriched in factor VIII, followed subsequently by plasma fractionation processes that led to purified factor VIII and factor IX from pooled plasma. This ushered in a great inflection point in treatment, allowing effective bleed treatment, prevention, and home-based care. Mortality was reduced, and reduced morbidity from joint disease was realized. However, purified factor VIII and IX concentrates required the pooling of up to 120,000 donors, resulting in widespread viral contamination of plasma-derived clotting factors. This tragic complication accelerated the development of recombinant DNA-produced clotting factors following the cloning of the genes for factor VIII and factor IX in the early 1980s. After the widespread adoption of recombinant FVIII, multiple manufacturers produced products with similar efficacy and safety profiles, with only slight variations in upstream and downstream manufacturing. This situation persisted through the first decade of the 2000s, as patent protection prevented others from entering the field. Incremental changes, such as gradually eliminating all human and animal protein from the entire production process, improved the overall safety profile, but the basic efficacy and dosing regimens remained unchanged.
As patents expired, the concept of “biobetters,” or bioengineered improved versions of factor VIII and factor IX, became the focus of pharma and biotech research. By 2014, the first of several extended half-life factor VIII and factor IX products reached the market, promising a decreased burden of treatment and equivalent or improved protection from bleeding on a less frequent dosing schedule. Effective technologies include molecular fusion of albumin or the Fc portion of immunoglobulin G to factor VIII or factor IX or PEGylation of the clotting factors. These products allow the maintenance of higher-equivalent levels of clotting factor activity, which should impact the natural history of hemophilia. The extended half-life class of products has barely had time to establish a market niche and is now being challenged by widely different classes of product utilizing technologies considered highly experimental just a few years ago. These products were the subject of scientific presentations at the International Society on Thrombosis and Haemostasis meetings in Berlin in the summer of 2017.
A bispecific antibody directed against factors IX, IXa, X, and Xa, which can mimic the function of factor VIIIa, has completed phase 3 clinical testing and is now under regulatory review. This product, emicizumab, dramatically decreases bleeding in subjects with and without neutralizing inhibitor antibodies against factor VIII. Therapies that target the coagulation inhibitors include a small interfering RNA to anti-thrombin and monoclonal antibodies to tissue factor pathway inhibitor. These molecules are in phase 1/2 testing and are designed to prevent or slow the shutting down of the clotting cascade, a process critically important in normal individuals, but which impedes hemostasis in individuals with hemophilia. In addition, these therapies are administered subcutaneously and have demonstrated efficacy in preventing breakthrough bleeding; thus, patients require only infrequent intravenous factor infusions.
Gene therapy represents an entirely new class of disruptive technology. As shown now for both factor VIII and factor IX, a single infusion using adeno-associated virus vectors results in normal or near-normal clotting factor levels in individuals with hemophilia A or B. Trough levels, breakthrough bleeding, and periodic infusions of replacement therapies all disappear if a severe hemophilia patient (<1% clotting activity) is converted to a mild (>5%) or normal (>50%) phenotype.
Why this cornucopia of technologies and activity in hemophilia? Some of it is explained by the appeal of easily and objectively measuring coagulation in the blood, a readily available tissue amenable to human testing. Some may be explained by technology in search of disease. And the final reason is that there remain unmet needs in hemophilia treatment. Whatever the reasons, the hemophilia worldwide marketplace is being fractured into multiple therapeutic modalities to better address these “simple” monogenic disorders.
Treatment of hemophilia is far from ideal. Prophylactic therapy to prevent bleeding episodes is the standard of care in the developed world. However, therapy requires frequent intravenous infusions, which are invasive and difficult in the very young as well as the elderly, who may have advanced hemophilic arthropathy and poor venous access. Prophylactic regimens are designed to produce peak corrective levels of factor VIII or factor IX, which then trend back to baseline (<1% in severe hemophilia) before the next dose is administered. Unfortunately, patients have breakthrough bleeding once activity levels return to the low single digits, depending on patient-specific factors (i.e., arthritic target joints) and physical activity levels; bleeding episodes are unpredictable. Continued breakthrough bleeding leads to progressive hemophilic arthropathy in multiple joints and tissues over many years, resulting in crippling and debilitation. Thus, improved therapies that can maintain higher troughs—or eliminate troughs entirely—and prevent breakthrough bleeding are important advances.
Hurdles remain before these diverse protein, RNA, and DNA technologies replace conventional and extended half-life clotting factors. Adverse events of thrombosis and thrombotic microangiopathy have been reported in the clinical trial programs, particularly when concomitant hemostatic factor therapies have been required for breakthrough bleeding, leading to risk mitigation guidance for the investigators. However, as these new therapies advance through phase 3 testing and application for licensure, they represent a series of scientifically complex choices that have not previously confronted health care providers and patients in the bleeding disorders community or in other disease areas, for that matter. These developments highlight the need for more in-depth training of the molecular pathways that underlie the mechanism of action of these new modalities and call for an organized approach for further education of health care provider and patient alike.