FDA Approves Emicizumab-kxwh for Hemophilia A

In November 2017, the FDA approved emicizumab-kxwh (Hemlibra, Genentech) for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients with hemophilia A with factor VIII inhibitors. Replacement of factor VIII with plasma-derived or recombinant factor VIII products can prevent bleeding episodes in Hemophilia A patients.

However, inhibitory antibodies to factor VIII may develop during treatment.¹ These inhibitors bind factor VIII and prevent its ability to participate in the coagulation cascade, leading to a bleeding risk and increased morbidity.¹ Emicizumab-kxwh is a bispecific monoclonal antibody that brings together factors IXa and X to restore the function of the missing activated factor VIII and the blood clotting process.^2,3

Efficacy

Approval of emicizumab-kxwh was based on data from HAVEN 1, a multicenter open-label single-arm randomized phase 3 clinical trial of 109 adult and adolescent males with hemophilia A with factor VIII inhibitors who had previously received treatment with bypassing agents.^3,4 Patients were randomized 2:1 to weekly emicizumab-kxwh prophylaxis (3 mg/kg administered subcutaneously once weekly for the first 4 weeks followed by 1.5 mg/kg once weekly) or no prophylaxis.⁴

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For patients receiving prophylaxis, the annualized bleeding rate (ABR) requiring treatment with coagulation factors was 2.9 compared with 23.3 for patients not receiving prophylaxis, corresponding to an 87% ABR reduction (p<0.0001). In addition, patients receiving prophylaxis reported improvements in hemophilia-related symptoms and physical functioning.

Safety

The most common adverse reactions (≥ 10%) were injection site reactions (19%), headache (15%), and arthralgia (10%).³ Injection site reactions were reported as mild to moderate intensity and 88% resolved without treatment.⁴

The product labeling includes a boxed warning about thrombotic microangiopathy and thromboembolism. If activated prothrombin complex concentrate (aPCC) is coadministered, the patient should be monitored for the development of thrombotic microangiopathy and thrombotic events; aPCC should be discontinued if symptoms occur.³ The decision to resume emicizumab-kxwh following complete resolution of thrombotic microangiopathy should be based on clinical judgment.

Emicizumab-kxwh can interfere with some laboratory coagulation tests, including activated partial thromboplastin time (aPTT), Bethesda assays (clotting-based) for factor VIII inhibitor titers, aPTT-based activated protein C resistance (APC-R), activated clotting time (ACT), and one-stage aPTT-based single-factor assays.³

No contraindications with emicizumab-kxwh are known to exist. Insufficient information exists on the risks of emicizumab-kxwh on the fetus.³ Females of child-bearing potential should be advised to use effective contraception during treatment.

Dosing and Cost

The recommended dose of emicizumab-kxwh is 3 mg/kg administered subcutaneously once weekly for the first 4 weeks followed by 1.5 mg/kg once weekly.³ If a dose is missed, administer the dose as soon as possible before the day of the next scheduled dose, and then resume usual weekly dosing. The medication is supplied as 30 mg/mL, 60 mg/0.4 mL, 105 mg/0.7 mL, and 150 mg/mL injections. The average wholesale price is not yet available.

References

1. Kempton CL, White II GC. How we treat a hemophilia A patient with a factor VIII inhibitor. Blood. 2009 Jan;113(1):11-17.

2. Emicizumab-kxwh. Lexi-Drugs. Lexicomp. Wolters Kluwer Heath, Inc. Riverwoods, IL. Available at: http://online.lexi.com. Accessed November 20, 2017.

3. Hemlibra (emicizumab-kxwh) Package insert. San Francisco, CA: Genentech, Inc.; November 2017.

4. Oldenburg J, Mahlangu JN, Kim B, et al. Emicizumab prophylaxis in hemophilia A with inhibitors. N Engl J Med, 2017; 377: 809-818. doi: 10.1056/NEJMoa1703068