American Society of Hematology

Case Study: Emerging Therapies in Hemophilia

A 27-year-old man with a history of severe hemophilia A presents for follow-up after a recent hospitalization for a bleeding episode in his knee. His hospitalization was complicated by the presence of a high-titer factor VIII inhibitory antibody measured at 13 Bethesda units (BU), prompting the use of recombinant factor VIIa to control his bleeding.

On examination, his titer remains elevated at 9 BU. Options to best control further bleeding episodes are being considered, including initiation of immune tolerance induction (ITI) to eliminate his inhibitor.The patient asks if there are newer therapies that are on the horizon to prevent bleeding in hemophilia A. Data from the recently published phase III HAVEN 1 Trial report that patients with hemophilia A treated with weekly emicizumab prophylaxis, compared to no prophylaxis, had a lower rate of annualized bleeding events.

What is the mechanism of action of emicizumab?

  1. A bispecific monoclonal antibody binding activated factor IX and factor X
  2. Monoclonal antibody that blocks the tissue factor pathway inhibitor (TFPI)
  3. Monoclonal antibody that inhibits anti-thrombin III by a linked small interference RNA
  4. Recombinant fusion protein that binds activated factor IX and factor X

Answer: A

Emicizumab (answer A) is a bispecific monoclonal antibody binding factor X and activated factor IX, effectively restoring the function of the missing factor VIII. The HAVEN 1 Trial was a phase III open-label, multicenter trial primarily assessing annualized bleeding rates with use of weekly prophylactic emicizumab versus no prophylaxis in hemophilia A patients who were previously receiving episodic factor VIII bypassing agents. At 24 weeks, annualized bleeding rate in the emicizumab prophylaxis group was 2.9 events compared to 23.3 events in the no prophylaxis group( p<0.001). This represents an 87 percent decrease in annualized bleeding rates with use of emicizumab. Quality of life scores were also significantly higher in the emicizumab group. However, approximately 47 percent of subjects on emicizumab prophylaxis required activated prothrombin complex concentrate (aPCC) and/or recombinant factor VIIa.

Conicizumab (answer B) is a monoclonal antibody that blocks TFPI. TFPI helps regulate initiation of thrombin generation and has three separate domains that bind to tissue factor-factor VIIa, bind and inhibit factor Xa, and interact with protein S, respectively. Conicizumab interferes with factor Xa binding domain, and patients are currently being enrolled in a phase II trial.

Fitusiran is an investigational small RNA interference (RNAi) agent that targets antithrombin messenger RNA to improve thrombin generation and promote hemostasis in patients with hemophilia. It is not a monoclonal antibody (answer C). In a phase I dose escalation trial, once-monthly subcutaneous fitusiran injections resulted in increased thrombin generation. Of note, the population studied did not have inhibitory antibodies. Fitusiran resulted in decreased bleeding episodes and appeared to be well tolerated. Further enrollment of subjects onto this study has been put on hold due to the death of a subject, related to cerebral sinus venous thrombosis.

Recombinant factor VIII Fc fusion protein (answer D) has a half-life that is 1.5 times longer than standard recombinant factor VIII (18.8 hours vs. 11 hours). The efficacy of recombinant factor VIII Fc fusion protein was demonstrated in two phase III studies: A-LONG in adults and Kids A-LONG in children. It is dosed prophylactically one to two times a week, with 30 percent of patients in the trial achieving a five-day dosing interval.1-6

Case study submitted by Gemlyn George, MD, and Arun K Singavi, MD, of Medical College of Wisconsin, Milwaukee, WI.


  1. Arruda VR, Doshi BS, Samelson-Jones BJ. Novel approaches to hemophilia therapy: successes and challenges. Blood. 2017;doi: 10.1182/blood-2017-08-742312. [Epub ahead of print].
  2. Chowdary P, Lethagen S, Friedrich U, et al. Safety and pharmacokinetics of anti-TFPI antibody (concizumab) in healthy volunteers and patients with hemophilia: a randomized first human dose trial. J Thromb Haemost. 2015;13:743-754.
  3. Mahlangu J, Powell JS, Ragni MV, et al. Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A. Blood. 2014;123:317-325.
  4. Nolan B, Mahlangu J, Perry D, et al. Long-term safety and efficacy of recombinant factor VIII Fc fusion protein (rFVIIIFc) in subjects with hemophilia A. Haemophilia. 2016;22:72-80.
  5. Oldenburg J, Mahlangu JN, Kim B, et al. Emicizumab Prophylaxis in Hemophilia A with Inhibitors. N Engl J Med. 2017;377:809-818.
  6. Pasi KJ, Rangarajan S, Georgiev P, et al. Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy. N Engl J Med. 2017;377:819-828.
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