Clinical Pearls & Morning Reports
Hemophilia A is characterized by spontaneous or traumatic bleeding caused by deficient coagulation factor VIII activity. The current standard of care for persons with hemophilia A with a severe bleeding phenotype is prophylactic intravenous infusions of factor VIII two to three times weekly; however, exposure to factor VIII concentrates is associated with the development of neutralizing anti–factor VIII alloantibodies (inhibitors), which render replacement factor VIII ineffective, in approximately 30% of patients with hemophilia A. The phase 3 HAVEN 1 trial assessed the efficacy, safety, and pharmacokinetics of once-weekly subcutaneous emicizumab prophylaxis in patients with hemophilia A with inhibitors. Read the new Original Article.
Q. What therapies are currently available to treat hemophilia A in patients with inhibitors?
A. Inhibitors result in substantial medical complications and decreased health-related quality of life. Treatments for hemophilia A in patients with a high titer of inhibitors (≥5 Bethesda units per milliliter) include eradication with induction of immune tolerance and episodic or prophylactic treatment with bypassing agents (recombinant activated factor VII [factor VIIa] or activated prothrombin complex concentrate). The efficacy of bypassing agents remains suboptimal, and both options involve frequent intravenous infusions that depend on adequate venous access; thus, more effective and less burdensome treatments are needed.
Q. What is emicizumab?
A. Emicizumab is a recombinant, humanized, bispecific monoclonal antibody that bridges activated factor IX and factor X to restore the function of missing activated factor VIII, which is needed for effective hemostasis. Owing to its unique structure, emicizumab is not expected to be affected by existing factor VIII inhibitors or to induce new development of such inhibitors.
A: In the HAVEN 1 trial, once-weekly emicizumab prophylaxis that was administered subcutaneously in patients with hemophilia A with inhibitors was associated with a bleeding rate that was 87% lower than the rate with no prophylaxis. These findings were supported by substantially lower rates of other bleeding-related end points (events of spontaneous bleeding, joint bleeding, and target-joint bleeding as well as all bleeding events) with emicizumab prophylaxis than with no prophylaxis. A total of 63% of the participants who were randomly assigned to receive emicizumab prophylaxis had zero bleeding events during the trial. Only 1 of the 18 participants (6%) who were assigned to no prophylaxis had zero bleeding events. These positive outcomes confirm previously reported results of a phase 1 study. No participants tested positive for antidrug antibodies; however, two participants had pharmacokinetic profiles with declining exposure to emicizumab that were potentially indicative of antidrug antibodies.
A: Thrombotic microangiopathy or thrombosis occurred only in patients who received high cumulative doses of activated prothrombin complex concentrate for breakthrough bleeding while receiving emicizumab prophylaxis; thus, the usefulness of this bypassing agent may be limited in patients who have bleeding events while receiving emicizumab prophylaxis. The 5 participants who had thrombotic microangiopathy or thrombosis did so after treatment with activated prothrombin complex concentrate that averaged more than 100 U per kilogram daily for more than 1 day. No events occurred after the use of activated prothrombin complex for 1 day, after treatment with recombinant factor VIIa alone (even at high doses), or with emicizumab prophylaxis alone.