The New Therapeutic Renaissance for Patients with Rare Bleeding Disorders

TODAY, THE ROUGHLY 15,000 persons with hemophilia A who require factor replacement are presented with a smörgåsbord of products from which they and their physicians can choose. Six conventional and two extended half-life recombinant factor VIII products are available, as well as four high-purity plasma-based factor VIII concentrates. Three additional extended half-life factor VIII products have completed clinical testing and may soon join the crowd. While persons with hemophilia B number only about one-quarter that of the hemophilia A population, they and their providers can select from three conventional recombinant factor IX products, one extended half-life product (with two others awaiting U.S. Food and Drug Administration [FDA] approval), and three high-purity plasma-based factor IX concentrates.

For decades, manufacturers focused their energies and resources on developing treatments for these two predominant hereditary bleeding disorders. But more recently, the industry at last turned its attention — and in particular its expertise in recombinant proteins process development — to design therapeutics targeting much rarer hereditary and acquired coagulation disorders. The result is five new factor replacement therapies approved and introduced over the last five years that are specifically indicated to treat congenital factor X deficiency, factor XIII deficiency, acquired hemophilia A and the subset of patients with von Willebrand disease who require factor replacement therapy.

COAGADEX for Congenital Factor X Deficiency

Originally named Stuart-Prower factor after the names of the first two adults diagnosed in the 1950s, clotting factor X is the initial enzyme in the common pathway of thrombus formation. Activation of factor X to factor Xa occurs both through the intrinsic and extrinsic clotting cascades. Once formed, factor Xa mediates conversion of prothrombin to thrombin, which in turn activates fibrinogen to form a fibrin clot.

Inherited factor X deficiency is an autosomal recessive disorder; thus, heterozygous individuals with one defective gene encoding factor X are usually asymptomatic. As it requires inheritance of a defective gene from both parents, factor X deficiency is among the rarest of all congenital bleeding disorders, affecting an estimated one individual per 500,000 to 1 million.¹ Not unlike other hereditary bleeding disorders, factor X deficiency can vary from mild to severe. Hemorrhagic symptoms variously include easy bruising, soft-tissue bleeds, disabling hemarthroses, recurrent epistaxis and menorrhagia. Trauma-associated hemorrhage in more severely affected patients can lead to death.

Historically, clinicians have relied on fresh frozen plasma (FFP) or prothrombin complex concentrates to treat hemorrhages in patients with factor X deficiency. While FFP can be effective for bleeding control in persons with milder forms of the disease, its low factor X content limits its utility in more severely affected individuals. Further, factor X titers vary from one unit of FFP to the next and are not measured, forcing the clinician to dose empirically with a product that is not without potential adverse effects, including fluid volume overload and acute transfusion reactions. Use of prothrombin complex concentrates presents a significant risk of thromboembolic events.

In October, a novel high-purity human factor X concentrate produced by Bio Products Laboratory (BPL) — COAGADEX — was approved for on-demand treatment and control of bleeding episodes in adults and children aged 12 years and older with hereditary factor X deficiency. Available in 250 IU or 500 IU dosages, the product is also indicated for perioperative management of bleeding in patients with a mild form of the disease. In a multicenter, open-label clinical trial of 16 subjects with moderate to severe hereditary factor X deficiency, COAGADEX was rated excellent (91 percent) or good (7 percent) in 98 percent of bleeding episodes, more than 80 percent of which required only a single 25 IU/kg infusion.

COAGADEX also appears to be effective for the treatment of acquired factor X deficiency associated with systemic light-chain amyloidosis.² In these fragile patients, both unpredictable kinetics of infused factor X and a much more rapid decline in plasma levels require frequent monitoring of factor X levels and typically higher and/or more frequent dosing to reach target thresholds similar to patients with inherited factor X deficiency (10 to 15 IU/mL). The standardized content of factor X in COAGADEX makes it possible to monitor the hemostatic response and tailor treatment to the patient’s individual needs.

Corifact and TRETTEN for Congenital Factor XIII Deficiency

When activated by thrombin at the site of vascular injury, circulating factor XIII performs an essential function at the very end of the coagulation cascade: It promotes cross-linking of fibrin and protects the clot against fibrinolysis; for this reason, it is also sometimes referred to as “fibrin stabilizing factor.” Cross-linked fibrin provides tensile strength to the primary hemostatic platelet plug. Up to 30 percent of patients without prophylactic coverage sustain a spontaneous intracranial hemorrhage, the leading cause of mortality. Other symptoms may include nose and mouth bleeds, muscle bleeds and delayed bleeding after surgery. Inherited in an autosomal recessive fashion — defective genes must be inherited from both parents — it occurs once in every three to five million live births, making it the rarest of all factor deficiencies.

Factor XIII is present in FFP and cryoprecipitate, but their use is accompanied by a number of serious limitations that may include 1) potential for fluid overload due to the need to transfuse high volumes to supply enough factor XIII, 2) risk of allergic reactions and transfusion-related acute lung injury (TRALI),3 a leading cause of transfusion-related mortality, and 3) risk of exposure to infectious agents.4 In addition, the natural variability in factor XIII content from one unit of plasma to the next complicates the clinician’s effort to adjust dosing to maintain plasma factor XIII in a therapeutic range.

The solution developed by CSL Behring was to purify factor XIII from pooled plasma, using precipitation followed by adsorption and ion exchange chromatography steps. Corifact, approved by FDA in February 2011, is indicated both for routine prophylaxis and for perioperative management of surgical bleeding in patients with congenital factor XIII deficiency. Remarkably, thanks to an unusually prolonged mean circulating half-life (between six and seven days), Corifact can be dosed prophylactically every 28 days to maintain a protective trough level of 5 percent to 20 percent of normal factor XIII activity.

In December 2013, less than three years after the introduction of Corifact, FDA approved Novo Nordisk’s TRETTEN, a recombinant version of the factor XIII A-subunit. Ninety-five percent of patients with factor XIII deficiency have the A-subunit deficiency, while just 5 percent have the B-subunit form. TRETTEN is specifically indicated for routine prophylaxis of bleeding in patients with A-subunit deficiency. Similar to Corifact, TRETTEN has about a seven-day half-life and can be dosed once monthly to achieve a target trough level of factor XIII at or above 10 percent. Thus for the 95 percent of patients with the A-subunit form of factor XIII deficiency, there are two very good prophylactic treatment options to prevent serious or life-threatening bleeds.

OBIZUR for Acquired Hemophilia A

For reasons that are not well-understood, typically older adults with no personal or family history of bleeding spontaneously develop IgG autoantibodies — “inhibitors” — that neutralize the procoagulant function of their own normal factor VIII. About half have a malignancy, autoimmune disorder, active infection or other possible underlying condition; the remaining half of cases are idiopathic. The result of this functional deficiency of factor VIII is a bleeding disorder that can range from mild superficial bruising to life-threatening hemorrhage. Based on a European patient registry,⁵ hemophilia A is believed to occur in about 500 U.S.patients each year.

Prior to its withdrawal from the market in 2004 due to detection of parvovirus, a porcine factor VIII product purified from the plasma of pigs (Hyate:C) was available to treat acquired hemophilia A. Its efficacy lay in the fact that the inhibitor against human factor VIII tends not to cross-react with porcine factor VIII, allowing the porcine clotting protein to remain in the circulation and perform the same enzymatic functions as endogenous human factor VIII.

Animal studies of a novel recombinant analogue of porcine factor VIII developed by Baxalta — OBIZUR — demonstrated that it has similar pharmacokinetics as Hyate:C and is similarly well-tolerated.6 In a prospective, open-label clinical trial, all 28 subjects with acquired hemophilia A who received OBIZUR had a positive response to treatment at 24 hours after a median of three doses to manage the initial bleeding episode.7 While about one-quarter developed anti-porcine factor VIII antibodies, no safety concerns were identified in the trial.

Prior to approval of OBIZUR in 2014, hematologists relied on Novo Nordisk’s recombinant activated human factor VIIa product (NovoSeven RT) as first-line therapy. NovoSeven RT acts as a bypassing agent, circumventing the inhibition of factor VIII by targeting a different part of the coagulation cascade. As no validated laboratory test is available to monitor the efficacy of bypassing agents, response to NovoSeven RT must be assessed by clinical observation.8 Response to OBIZUR can be monitored by subjective clinical assessments in combination with achieved objective factor VIII levels.⁹ Clearly, OBIZUR provides hematologists with a helpful new treatment option in managing bleeding episodes in adults with acquired hemophilia A.

VONVENDI for von Willebrand Disease

Named after the Norwegian physician who first characterized the familial bleeding disorder caused by its deficiency, von Willebrand factor (VWF) is a large glycoprotein stored as ultra-large multimers released from platelets into the bloodstream, where it is cleaved by a proteolytic enzyme (ADAMTS13) to smaller multimers. Once circulating in the plasma, VWF acts to promote hemostasis by mediating platelet adhesion to damaged vascular sub-endothelial matrix and platelet aggregation, and serves as a carrier protein for factor VIII to protect it against rapid proteolysis.

Historically, plasma-derived factor VIII preparations rich in VWF have been used to treat spontaneous or trauma-induced bleeding events in patients with severe von Willebrand disease (VWD), or in patients with mild to moderate VWD that does not respond to desmopressin. Because factor VIII is being co-administered with the VWF, clinicians are instructed to carefully monitor trough factor VIII levels to avoid excessive accumulation of the clotting protein. Particularly with repeated dosing, the factor VIII that accompanies VWF in plasma-derived preparations could result in a supraphysiologic level of factor VIII and an associated increased risk of a thromboembolic event.

This same warning applies for Baxalta’s newly approved VONVENDI (von Willebrand factor [recombinant]).¹⁰ The binding capacity and affinity of VONVENDI to factor VIII is comparable to endogenous VWF, thus enabling VONVENDI to reduce the rate of factor VIII clearance. But VONVENDI may be advantageous in certain clinical circumstances: With the same administered dose of VWF measured in VWF:Ristocetin Cofactor (VWF:RCo) international units (IU) as a plasma-based product in patients with a baseline factor VIII level already sufficient to assure hemostasis, the absence of factor VIII in VONVENDI translates into a lesser likelihood of an excessive surge in the level of circulating factor VIII.

VONVENDI can be administered either with or without recombinant factor VIII as appropriate to achieve target plasma levels of greater than 0.6 IU/mL (60 percent) of VWF:RCo and greater than 0.4 IU/mL (40%) of factor VIII:C. In a pivotal clinical study, all bleeding episodes treated with VONVENDI alone or in combination with Baxalta’s ADVATE recombinant factor VIII were controlled with an efficacy rating of excellent (96.9 percent) or good (3.1 percent).¹⁰

More Products on the Way

Other innovative new products are well along in the research and development pipeline. A recombinant form of ADAMTS13 is now being investigated for use as replacement therapy in patients with thrombotic thrombocytopenic purpura. Novel extended half-life versions of factor VIIa currently in development may enable clinicians to more effectively treat patients with congenital factor VII deficiency and prevent bleeding episodes in hemophilia A and B patients with inhibitors.

As it has since the first commercially produced factor VIII concentrate introduced in 1968 instantly transformed the lives of American hemophilia A patients, innovation continues to be the life-blood of this industry.