Hemophilia: Damoctocog alfa pegol for Children? Probably not yet.

After a long hiatus, I am back! Today, I’m doing a write up on extended half-life Factor VIII products.

On March 16, 2021, Hemophilia published the results of the PROTECT VIII Kids extension study, showing efficacy of Jivi^®️ (damoctocog alfa pegol, a PEGylated recombinant Factor VIII product) in previously treated children with severe Hemophilia A (Factor VIII activity <1%) age <12 (Mancuso et al., 2021; 10.1111/hae.14294). 73 patients were enrolled in the main and expansion study and 59 entered the extension study. Jivi^®️ was administered intravenously twice weekly (25-60 IU/kg), every 5 days (45-60 IU/kg), or every 7 days (60 IU/kg) according to clinical needs, for 0.4 to 5.9 years (median 5.0 years). 2 patients, both <6 years old, discontinued the trial for non-treatment-related reasons. Median annualized bleeding rate for total bleeds was 1.5 in children <6 years old and 1.9 in children 6-12 years old. Annualized bleeding rate improved with time, and median annualized bleeding rate was 0.0 for spontaneous bleeds in both age groups in the last year of the study. No patients developed anti-PEG or Factor VIII antibodies.

Currently, Jivi^®️ is licensed by the FDA to be used in the United States in people age 12 and older. (https://www.jivihcp.com/) The starting prophylactic (prevention of bleeds) dosing regimen is 30-40 IU/kg twice a week, which can be adjusted to 45-60 IU/kg every 5 days, and can be further adjusted (dose or frequency) according to bleeding episodes. Top-up doses are to be given for bleeding episodes (10-20 IU/kg every 24-48 hours to achieve Factor VIII activity 20-40%, 15-30 IU/kg every 24-48 hours to achieve Factor VIII activity 30-60% and 30-50 IU/kg every 8-24 hours to achieve Factor VIII activity 60-100% for minor, moderate and major bleeding respectively, until bleeding is resolved), as well as for perioperative management (beginning pre-operatively, at 15-30 IU/kg every 24 hours to achieve Factor VIII activity 30-60% for at least one day until healing is achieved for minor surgery, and 40-50 IU/kg every 12-24 hours to achieve Factor VIII activity 80-100% until healing is complete followed by a dose achieving 30-60% Factor VIII activity for a further 7 days for major surgery). (https://www.fda.gov/files/vaccines,%20blood%20%26%20biologics/published/Package-Insert-JIVI.pdf)

In children <12 years old, the PROTECT VIII Kids study (main and expansion phases, with 61 and 12 patients enrolled respectively) showed efficacy amongst the 61 patients who completed the study, with median annualized bleeding rate of 2.5 and 2.4 for children <6 years old in the main phase and the expansion phase respectively and 2.9 for children 6-12 years old, for all bleeds, and 0.0, 0.0 and 1.5 respectively for spontaneous bleeds. However, safety concerns were raised. 12 out of the 73 patients discontinued the trial – 1 for perceived inefficacy and 11 for hypersensitivity and/or inefficacy within the first four exposure days (4 moderate hypersensitivity, 1 hypersensitivity; 4 of these patients were <6 years old and 1 was 6-12 years old). All adverse events were transient and did not require intervention. Patients who discontinued the trial successfully resumed their previous Factor VIII product. 7 patients developed anti-BAY 94-9027 (pre-marketing name for Jivi^®️) antibodies, which were transient in all 7 patients, 3 patients developed anti-PEG IgE antibodies, which were transient in all 3 patients, and 4 developed anti-PEG IgM antibodies, which persisted in one of the patients. Anti-PEG IgE antibodies were not detected in any of the patients who developed hypersensitivity reactions. No factor VIII inhibitors were reported. (Santagostino et al., 2020; 10.1111/hae.13963) The safety concerns led to children under 12 years to be excluded from licensed use of Jivi^®️ by the FDA, stating a greater risk of hypersensitivity reactions as a reason. Since the publication of the results of the extension study, Bayer has not announced any plans for obtaining FDA approval for the use of Jivi^®️ in children under 12 years.

Other extended half-life Factor VIII products include Eloctate^®️ (efmoroctocogalfa, or rFVIII-Fc), licensed since 2014, (dosed at 50 IU/kg every 4 days for patients 12 years and older, and 50 IU/kg twice a week for patients under 12 years old, to adjust by 25-65 IU/kg at 3-5 day intervals according to response – from https://www.fda.gov/media/88746/download), Adynovate^®️ (rurioctocog alfa pegol), licensed by FDA since 2015, (dosed at 40-50 IU/kg twice a week for patients 12 years and older, and 55-70 IU/kg twice a week for patients under 12 years old – from https://www.fda.gov/files/vaccines,%20blood%20&%20biologics/published/Package-Insert—ADYNOVATE.pdf), Afstyla^®️ (lonoctocog alfa, or rFVIII-Sc), licensed since 2016, (dosed at 20-50 IU/kg 2 to 3 times a week for patients 12 years and older, and 30-50 IU/kg for patients under 12 years old – from https://www.fda.gov/media/98080/download), and Esperoct^®️, (turoctocog alfa pegol), licensed since 2019, (dosed at 50 IU/kg every 4 days for patients 12 years and older and 65 IU/kg twice a week for patients under 12 years old – from https://www.fda.gov/media/120351/download) which have been licensed for use for patients of all ages with Hemophilia A for routine prophylaxis (recommended doses given above), perioperative management and management of bleeding episodes (“on-demand” treatment) . Like Jivi^®️, Adynovate^®️ and Esperoct^®️ are composed of recombinant Factor VIII conjugated with polyethylene glycol (PEG) to extend their plasma half-life by protecting them from proteolytic enzymes. Eloctate^®️, however, is fused with the Fc domain (region) of IgG1, allowing it to utilize the neonatal Fc receptor pathway to delay lysosomal degradation and re-enter the circulation. Afstyla^®️, on the other hand, is composed of the heavy and light chains of Factor VIII covalently bound together forming a single chain, that has greater affinity to von Willebrand factor that other factor VIII products, which protects it from degradation by prolonging its association to its natural carrier protein that has a critical role in the initiation of the hemostatic process.

How do institutions, providers, patients and their parents choose between these products and standard half-life Factor VIII, and how useful can multiple Factor VIII products in the market be? For patients newly diagnosed with hemophilia, Jivi^®️, which has not been licensed for previously untreated patients, is unsuitable unless in the context of a clinical trial. Extended half-life products are potentially less immunogenic (Lieuw 2017; 10.2147/JBM.S103796). However, immune tolerance treatment schedules with these products are not widely available. In some patients, rapid clearance and hence shorter half-lives of Factor VIII may require shorter dosing intervals of extended half-life products, making the higher cost of these products compared to standard half-life products untenable. Finally, even with the availability of long-term (5 years, in the case of Jivi^®️) data, consequences to lifelong exposure to polyethylene glycol is unknown. (Wynn and Gumuscu 2016; 10.2147/JBM.S82457). Institutional and provider experience and funding patterns will undoubtedly be the deciding factors amid this plethora of choice for treatment of hemophilia.

Rocks of different shapes, sizes and colors. Alta Vista Trail, Paradise, Mount Rainier National Park, Washington, USA.

Further reading

Aledort L, Mannucci PM, Schramm W, Tarantino M. Factor VIII replacement is still the standard of care in haemophilia A. Blood Transfus. 2019 Nov;17(6):479-486. doi: 10.2450/2019.0211-19. Epub 2019 Dec 11.