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November 16, 2017

https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761083s000lbl.pdf

On November 16, 2017, the Food and Drug Administration approved emicizumab-kxwh (HEMLIBRA®, Genentech, Inc.) for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients with hemophilia A (congenital factor VIII deficiency) with factor VIII inhibitors.

Approval was based on data from two clinical trials—an adult and adolescent trial (HAVEN 1) and a pediatric trial (HAVEN 2). HAVEN 1 (NCT02622321) was a randomized, multicenter, open-label, phase 3 trial in 109 adult and adolescent males (aged 12 to 75 years and >40 kg) with hemophilia A with FVIII inhibitors who previously received either episodic (on-demand) or prophylactic treatment with bypassing agents. Patients on prior episodic treatment were randomized 2:1 to weekly emicizumab-kxwh prophylaxis (3 mg/kg once weekly for the first 4 weeks followed by 1.5 mg/kg once weekly, thereafter) or no prophylaxis. Patients randomized to no prophylaxis could switch to emicizumab-kxwh prophylaxis after 24 weeks. For patients receiving emicizumab-kxwh prophylaxis, the annualized bleeding rate (ABR) requiring treatment with coagulation factors was 2.9 (95% CI; 1.7, 5.0) compared with 23.3 (95% CI: 12.3, 43.9) for patients not receiving prophylaxis corresponding to an 87% ABR reduction (95% CI: 72.3%, 94.3%), p<0.0001. In addition, improvements in patient-reported hemophilia-related symptoms and physical functioning in patients receiving emicizumab-kxwh prophylaxis were observed.

HAVEN 2 (NCT02795767) was a single-arm, multicenter, open-label, clinical trial in pediatric males (age < 12 years, or 12-17 years who weigh <40 kg) with hemophilia A with FVIII inhibitors. Patients received emicizumab-kxwh prophylaxis at the dose and schedule described above. In 23 patients evaluated at the interim analysis, ABR for treated bleeds was 0.2 (95% CI: 0.1, 0.6). ABR for all bleeds was 2.9 (95% CI: 1.8, 4.9).

The most common adverse reactions (occurring in ≥ 10% of patients taking emicizumab-kxwh) are injection site reactions, headache, and arthralgia. Cases of thrombotic microangiopathy and thrombotic events were reported when on average a cumulative amount of >100 U/kg/24 hours of activated prothrombin complex concentrate (aPCC) was administered for 24 hours or more to patients receiving emicizumab-kxwh prophylaxis. The prescribing information contains a boxed warning to monitor for thrombotic microangiopathy and thrombotic events when aPCC is administered. If symptoms occur, aPCC should be discontinued and emicizumab-kxwh should be suspended.

The recommended dose of emicizumab-kxwh is 3 mg/kg by subcutaneous injection once weekly for the first 4 weeks, followed by 1.5 mg/kg once weekly.

Full prescribing information is available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761083s000lbl.pdf

Emicizumab-kxwh was approved 3.3 months prior to the assigned regulatory action date. FDA granted Priority Review, Breakthrough Therapy designation, and Orphan Drug designation for this indication. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

 


Pharmacist's Applications to Practice

Emicizumab-kxwh (Hemlibra) for Routine Prophylaxis in Patients with Hemophilia A with Factor VIII Inhibitors

Authors: Payal Kakadiya, PharmD BCPS
PGY-2 Internal Medicine Pharmacy Resident
VCU Health
Richmond, VA

Cady Noda, PharmD BCPS
Pediatric Hematology/Oncology Clinical Pharmacist
VCU Health
Richmond, VA

What is the potential role for emicizumab-kxwh in the treatment of hemophilia A with factor VIII (FVIII) inhibitors?1,2,3

  • The U.S. Food and Drug Administration (FDA) granted emicizumab-kxwh approval as an orphan drug and breakthrough therapy on November 16, 2017, for the prevention or reduction in frequency of bleeding episodes in adult and pediatric patients with hemophilia A with factor VIII inhibitors.
  • The approval was granted by the FDA based on data from two trials:
    • HAVEN I (N = 109) was a phase 3 randomized multicenter open-label trial conducted to evaluate the efficacy, study, and pharmacokinetics of once-weekly emicizumab-kxwh prophylaxis compared to no prophylaxis for a duration of 24 weeks in patients who were 12 years of age and older with hemophilia A with inhibitors.
      • The primary end point, annualized bleeding rate, was significantly reduced by 87% (2.9 vs. 23.3 events, risk ratio = .13; p < .001) in those receiving emicizumab-kxwh, compared to placebo.
        • The annualized bleeding rate was defined as the difference in the rate of treated bleeding events over a period of at least 24 weeks between those receiving prophylaxis versus no prophylaxis.
      • The results of using emicizumab-kxwh also showed a statistically significant reduction of 79% (95% confidence interval [CI]: 51.4–91.1; p = .0003) of annual treated bleeds in a cohort of 24 patients who had previously received prophylaxis with a bypassing agent.
      • Overall, emicizumab-kxwh prophylaxis showed a reduction in all bleeds (80%, p < .0001), treated spontaneous bleeds (92%, p < .0001), and treated joint bleeds (89%, p < .005).
      • The results showed improvement in the Physical Health Score in the Hemophilia-Specific Quality of Life Index at the end of 24 weeks for patients receiving emicizumab-kxwh compared to the placebo group.
      • Common adverse events reported in the emicizumab-kxwh group included injection-site reaction (15%), headache (12%), upper respiratory tract infection (9%), fatigue (6%), and arthralgia (6%).
    • HAVEN II is an ongoing single-arm multicenter open-label study including children younger than 12 years of age with hemophilia A with FVIII inhibitors (N = 23) to evaluate the efficacy, safety, and pharmacokinetics of once-weekly emicizumab-kxwh prophylaxis. The interim analysis was conducted after 12 weeks of treatment.
      • Nearly 87% (95% CI: 66.4–97.2) of patients who received emicizumab-kxwh for prophylaxis reported zero bleeding events.
      • In the intrapatient analysis of 13 patients, the annualized bleeding rate was 0.2 (95% CI: 0.1–0.8) in patients on emicizumab-kxwh prophylaxis compared to 17.2 (95% CI: 12.4–23.8) in patients on previous treatment with bypassing agents as prophylaxis or on demand.
  • Emicizumab-kxwh is currently the only bispecific factor IXa- and factor X-directed monoclonal antibody designed to bridge factor IXa and factor X to restore function of missing factor VIII.
    • Other products that can be used in the setting of high-titer inhibitors are the bypassing agents, which include factor VII products, fresh frozen plasma, cryoprecipitate, and desmopressin.
    • Bypassing agents are often used during severe, spontaneous bleeds or when a patient’s baseline factor activity is unknown. However, they are only a temporary solution because they have short half-lives and need to be redosed quite frequently.

What role can the pharmacist play in the management of patients on emicizumab-kxwh? 4

  • Patients are given a loading dose followed by a maintenance dose via subcutaneous injection.
    • Loading: 3 mg/kg once weekly for 4 weeks
    • Maintenance: 1.5 mg/kg once weekly
      • The HAVEN 1 protocol allowed for a dose increase to 3 mg/kg once weekly in those who experience 2 or more spontaneous and clinically significant bleeds after the loading dose and a minimum of 24 weeks of treatment on 1.5 mg/kg injections.  Notably, the FDA label does not include this dosing.
  • If a dose is missed, it should be administered as soon as possible before the next scheduled dose, and then the usual weekly schedule should be resumed.
  • Pharmacists can help in educating patients about the subcutaneous self-injection technique because the medication is approved for self-injection in patients over the age of 7 years.
    • Sites of self-injection include thighs or abdomen. The upper outer arm should be used only if the patient has a caregiver to administer the injection.
  • Subcutaneous injections can result in injection-site reactions. To ease these reactions, apply pressure after administration of the injection and, if bruising occurs, apply an ice pack to the site of the injection.
  • Emicizumab-kxwh comes with a black-box warning for thrombotic microangiopathy and thrombotic events when used concomitantly with activated prothrombin complex concentrate (aPCC) doses of greater than 100 U/kg/24 hr.
    • Pharmacists can play a role in checking for administration of aPCC within the previous 24 hours before the administration of emicizumab-kxwh.
  • Genentech offers two options for financial assistance to help patients afford emicizumab-kxwh,

Clinical Pearls1-4

  • Emicizumab-kxwh is not expected to induce the new development of inhibitors or be affected by existing factor VIII inhibitors.
  • Unused vials should be stored in the refrigerator at a temperature of 2–8 °C and protected from light.
    • Unopened vials may be stored in or out of refrigeration at temperatures less than 30 °C for up to 7 days.
  • Emicizumab-kxwh can interfere with the activated clotting time, activated partial thromboplastin time, Bethesda assays for factor VIII inhibitor titers, and activated protein C resistance test.
  • Emicizumab-kxwh is indicated for patients with hemophilia A with high-titer inhibitors (5 Bethesda units or greater) and is not recommended for hemophilia A patients without inhibitors at this time.

References

  1. Emicizumab-kxwh. U.S. Food and Drug Administration: FDA News Release. November 16, 2017. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm585567.htm. Accessed January 21, 2018.
  2. Oldenburg J, Mahlangu JN, Kim B, et al. Emicizumab prophylaxis in hemophilia A with inhibitors. N Engl J Med. 2017;377(9): 809-818
  3. U.S. National Library of Medicine. clinicaltrials.gov. A study of emicizumab administered subcutaneously in pediatric participants with hemophilia A and factor VIII inhibitors (HAVEN 2). June 10, 2016. https://clinicaltrials.gov/ct2/show/NCT02795767. Accessed January 21, 2018.
  4. Hemlibra (emicizumab-kxwh) [package insert]. San Francisco, CA: Genentech, Inc.; November 2017.
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