In this issue of Blood, Mahlangu et al describe a well-designed and executed phase 3 multicenter study of a recombinant factor VIII (rFVIII) product fused with the Fc fragment of immunoglobulin G1 (IgG1) in 165 patients with severe hemophilia A.1
Hemarthrosis is the clinical hallmark of hemophilia and can lead to long-term musculoskeletal problems. Left untreated, joint hemorrhages can progress to chronic synovitis, with loss of cartilage, loss of joint space, and loss of joint function. In an attempt to prevent this vicious sequence of events, Nilsson et al, in Malmö, Sweden, began attempts at prophylaxis in the 1960s,2 and prophylaxis soon became the standard of care in Sweden. As more experience was gained, the Malmö group began regular prophylaxis at 1 to 1.5 years of age, before the onset of joint bleeds. FVIII (25-50 IU/kg/dose) was administered 3 times weekly or every other day.3 Such frequent dosing was needed, as the half-life of FVIII is only 8 to 12 hours. Many other centers in Europe and in North America began using prophylaxis in the early 1990s. However, cost was often a major issue because of the increased use of FVIII concentrates for prophylaxis compared with episodic treatment. Despite this, many subsequent studies documented the benefits of prophylaxis beginning at an early age, including far fewer bleeding episodes; much less joint damage than seen in children on episodic treatment; decreased disability, hospitalization, and time lost from school; and improved quality of life.4 However, such frequent intravenous dosing often necessitated the use of a central line (with its potential complications), and compliance with prophylaxis often decreased in teenagers and young adults.5
A longer-lasting FVIII was needed to reduce prophylactic injection frequency. Mahlangu et al demonstrate, in a phase 3 pivotal study, that a novel rFVIII Fc fusion product has a longer half-life than standard rFVIII, which resulted in a lower annualized bleeding rate when dosed prophylactically, 1 to 2 times weekly. Safety, efficacy, and pharmacokinetics were evaluated in 165 males with severe hemophilia A, aged ≥12 years. The rFVIII Fc fusion product was well tolerated and effective, and no subject developed an inhibitor to FVIII.1
Fc fusion technology uses a naturally occurring recycling pathway that delays the destruction of FVIII and cycles it back into the bloodstream, resulting in a longer circulating half-life. Fc fusion technology is also used in ≥7 US Food and Drug Administration–approved products for other chronic diseases, such as rheumatoid arthritis and platelet disorders. rFVIII Fc is a recombinant fusion protein composed of a single molecule of B-domain deleted rFVIII linked to the human IgG1 Fc domain. This technology has the potential to have a major impact on the worldwide use of prophylaxis for severe hemophilia, which could ultimately prevent bleeding episodes and their sequelae.
Although it would be even more beneficial to have a product with a longer half-life than rFVIII Fc, Mahlangu and colleagues note the obstacles in developing such a product. These center on the protective effects of von Willebrand factor (VWF) on circulating FVIII, with VWF protecting FVIII from proteolytic degradation and binding to FVIII clearance receptors. However, this beneficial interaction between VWF and FVIII also limits further extension of FVIII half-life beyond that of VWF (16-17 hours).1,6,7
At present, no longer-lasting FVIII or FIX products are yet licensed. Only Biogen Idec's rFVIII Fc and rFIX Fc are under regulatory review. Other pharmaceutical manufacturers are pursuing other methodologies, including glycopegylation,7 pegylation, and albumin fusion.
This is, indeed, an exciting time, with great promise for longer-acting FVIII and FIX products that could benefit persons with hemophilia around the globe.
Conflict-of-interest disclosure: The author declares no competing financial interests.