By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
The FDA has approved a once-weekly recombinant factor VIII therapy for adults and children who have been diagnosed with hemophilia A with congenital factor VIII deficiency. The molecule, formerly known as efanesoctocog alfa, is modified by recombinant technology, resulting in decoupling factor VIII from the von Willebrand factor (VWF) and extending its elimination half-life. The FDA granted fast-track and orphan drug designations. It is marketed as Altuviiio.
INDICATIONS
Antihemophilic factor (recombinant) extended half-life factor VIII (EHL rFVIII) can be prescribed to adults and children with hemophilia A (congenital factor VIII deficiency) for routine prophylaxis to reduce the frequency of bleeding episodes, on-demand treatment and control of bleeding episodes, and perioperative bleeding management.1
DOSAGE
For routine prophylaxis, administer 50 IU/kg once weekly. For on-demand treatment and control of bleeding episodes, administer a single dose 50 IU/kg. Additional doses may be considered based on the type of bleeding.1 For perioperative management, administer a single dose of 50 IU/kg pre-operatively and 30 IU/kg or 50 IU/kg after two to three days for minor surgery (e.g., tooth extraction). Administer 30 IU/kg or 50 IU/kg every two to three days as clinically needed for major surgery (e.g., intracranial, intraabdominal, joint replacement, or complicated dental procedures). EHL rFVIII is available in measurements of 250 IU, 500 IU, 750 IU, 1,000 IU, 2,000 IU, 3,000 IU, or 4,000 IU, each as a single-dose lyophilized powder.
POTENTIAL ADVANTAGES
EHL rFVIII decouples FVIII from VWF; thus, Altuviiio is not limited to the 16-hour half-life of VWF. Instead, the drug circulates independently and carries a mean half-life of 42.5 hours, permitting once-weekly dosing.2
POTENTIAL DISADVANTAGES
Formation of neutralizing antibodies (inhibitors) are possible, although they have not been reported in clinical trials.1,3 Hypersensitivity reactions may occur. The most common adverse reactions include headache (21%) and arthralgia (16%).
COMMENTS
The efficacy of EHL rVIII was evaluated in two open-label studies that included previously treated subjects with severe hemophilia A. This was defined as less than 1% endogenous FVIII activity or a documented genetic mutation consistent with severe hemophilia A. Study 1 included adults and adolescents age 12 years and older. Study 2 included children younger than age 12 years.1,3 For routine prophylaxis, subjects (n = 133) were enrolled in a 12-month observational pre-study, followed by weekly prophylaxis with 50 IU/kg for a total of 52 weeks. The primary endpoint was the mean annualized bleeding rate (ABR). The mean ABR, with at least 26 weeks of exposure, decreased from 2.96 (95% CI, 2.00-4.37) to 0.69 (95% CI, 0.5-1.0), showing statistical superiority.1,3
Researchers included 26 subjects in the on-demand study involving a 12-month prestudy, 26 weeks on-demand with EHL rFVIII, and weekly prophylaxis for 26 weeks. ABR was 21.4 (95% CI, 18.8-24.4) in the on-demand treatment period and 0.7 (95% CI, 0.3-1.5) in the prophylaxis period.1 In study 2, an ongoing routine prophylaxis in pediatric subjects with at least 26 weeks of exposure, the mean ABR was 0.5 (95% CI, 0.2-1.3).1
CLINICAL IMPLICATIONS
Hemophilia A is an X-linked congenital bleeding disorder, resulting in deficiency of functional FVIII, which leads to bleeding episodes.4 The standard of care is primary prophylaxis with infusions of FVIII, either plasma-derived or recombinant. Most of these require daily dosing. Antihemophilic factor (recombinant) single-chain (Afstyla) can be dosed twice weekly. Antihemophilic factor (recombinant) fc fusion protein (Eloctate) can be dosed every four days. EHL rFVIII is a new option that maintains high, sustained FVIII levels for most of the one-week dosing interval.4,5 The manufacturer has not yet announced cost information, but it is expected to be comparable to Eloctate, which starts at $625,000/year for the lowest dose.6
REFERENCES
1. Bioverativ Therapeutics Inc. Altuviiio prescribing information. February 2023.
2. Demers M, Aleman MM, Kistanova E, et al. Efanesoctocog alfa elicits functional clot formation that is indistinguishable to that of recombinant factor VIII. J Thromb Haemost 2022;20:1674-1683.
3. von Drygalski A, Chowdary P, Kulkarni R, et al. Efanesoctocog alfa prophylaxis for patients with severe hemophilia A. N Engl J Med 2023;388:310-318.
4. U.S. Food & Drug Administration. Summary basis for regulatory action. Altuviiio. Feb. 21, 2023.
5. National Hemophilia Society. FDA approves Altuviiio for hemophilia A patients. Feb. 24, 2023.
6. Jamison A. FDA approves revolutionary (and expensive) hemophilia A drug. OneDigital. March 23, 2023.
Altuviiio can be prescribed to adults and children with hemophilia A (congenital factor VIII deficiency) for routine prophylaxis to reduce the frequency of bleeding episodes, on-demand treatment and control of bleeding episodes, and perioperative bleeding management.
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