Hemophilia

Jivi^® (antihemophilic factor [recombinant], PEGylated-aucl) is a replacement therapy based on a recombinant DNA-derived factor VIII (FVIII) with an extended half-life, and it is indicated for previously treated adults and adolescents with hemophilia A who are at least 12 years of age.¹ Hemophilia A is an X-linked congenital blood disorder caused by the lack or deficiency of FVIII, a clotting protein.² People with hemophilia A have longer bleeds compared to other people. These bleeds occur into joints and muscles, and their severity depends on the level of FVIII in the blood. Approximately 60% of hemophilia A cases are of severe disease, with an FVIII level lower than 1%, 15% of hemophilia A cases are of moderate disease, with an FVIII levels of 1-5%, and 25% of hemophilia A cases are of mild disease, with an FVIII levels of 6-30%.² Treatment of this disease is mainly directed toward the replacement of missing FVIII so that normal hemostasis can be achieved.²

Jivi was developed by Bayer and is currently approved in the United States, Europe, Japan, and Canada for routine prophylaxis to reduce the frequency of bleeding episodes in patients with hemophilia A, as well as for on-demand treatment and control of bleeding episodes and perioperative management.^1,3 Approval by the US Food and Drug Administration (FDA) was granted in 2018. This medication is not recommended for previously untreated patients or for patients under 12 years of age due to an increased risk of hypersensitivity reactions to the active substance, polyethylene glycol (PEG), mouse or hamster proteins.¹

Mechanism of Action and Usage of Jivi

One of the challenges concerning replacement therapy in hemophilia A is the development of products with extended half-lives that can reduce the frequent dosing that is typically needed. One method of increasing the lifetime of FVIII is the development of recombinant products by conjugating the clotting factor to albumin or the human immunoglobulin Fc. A different approach is the attachment of FVIII to a polyethylene glycol (PEG) moiety. These PEG molecules protect FVIII from plasma removal and therefore increase its half-life.³ Jivi is a PEGylated recombinant FVIII product produced by recombinant DNA technology that is formulated as a recombinant B-domain deleted human coagulation FVIII conjugated with a 60 kDa PEG moiety.^1,3 This PEGylated factor temporarily replaces the missing FVIII in patients with hemophilia A since the site-specific PEGylation reduces binding to the natural clearance receptors of FVIII. The terminal half-life of the product is therefore extended.^1,3 The longer half-life of Jivi allows for less frequent dosing and consequently may promote adherence to treatment in prophylactic regimens.⁴

The most common side effects of Jivi in previously treated patients are headache, cough, nausea, and fever.¹

Get full prescribing information for Jivi at MPR

Jivi in Clinical Trials

An initial phase 1 trial focused on addressing the safety and efficacy of Jivi (BAY 94-9027) was performed (NCT01184820). The study enrolled 14 participants aged 21–58 years with no history of FVIII inhibitors, ≥ 150 days of exposure to FVIII, and FVIII of < 1%, and reported a well-tolerated therapy with a half-life of approximately 19 hours.⁵

Following this phase 1 trial, a phase 2/3 study called PROTECT VIII was designed (NCT01580293). This was an open-label and partially randomized trial that included 132 participants aged 12 to 65 years with severe hemophilia A. Patients had a previous exposure to FVIII of more than 150 days. One of the goals of the study was to determine the safety and efficacy of Jivi when used on-demand and as prophylactic treatment. The primary efficacy outcome was the annualized bleeding rate (ABR).⁶ The results of the study showed that Jivi was effective in preventing bleeding through 3 individualized dose regimens. Two or fewer infusions of Jivi per week controlled 90.6% of the bleeding episodes reported during the trial, and the development of inhibitors that could reduce the efficacy of Jivi was not observed.⁶ The PROTECT VIII trial also allowed researchers to evaluate the efficacy and safety of Jivi during surgery.⁷ The primary outcome of this part of the study was the investigator or surgeon assessment of hemostasis during surgery. Data concerning 26 major surgeries were analyzed, and the results showed that Jivi was effective and well tolerated.⁷

The long-term efficacy and safety of prophylactic treatment with Jivi was also reported through the PROTECT VIII study. This open-label extension study enrolled previously treated patients who completed the PROTECT VIII main study and reported the efficacy of the treatment. During this extension trial, 20.6% of participants did not experience any bleeds.⁸

An additional extension study to determine the long-term safety and efficacy of Jivi in children with severe hemophilia A has been performed (NCT01775618). In the PROTECT VIII kids study, the participants enrolled were previously treated patients under the age of 12 years.⁹ Thirty-nine patients who had previously completed the main or expansion PROTECT VIII studies completed this new extension trial. The total ABR was improved in this extension study compared to that reported in the main trial. The median spontaneous ABR in the last 12 months of the study was reported as 0.0. No inhibitor development was observed.⁹

A postmarketing investigation is currently ongoing (NCT04085458) that will allow investigators to gain more insight into the safety and effectiveness of Jivi. In addition, an observational study, HEM-POWR, has been designed to evaluate the efficacy and safety of Jivi treatment in real-world settings (NCT03932201). This trial is currently recruiting, and at least 200 previously treated patients are expected to be enrolled.¹⁰

References

1. Jivi. Prescribing information. Bayer; 2018. Accessed December 29, 2021.

2. Hemophilia A. National Hemophilia Foundation. Accessed December 29, 2021.

3. Paik J, Deeks ED. Damoctocog alfa pegol: a review in haemophilia A. Drugs. 2019;79(10):1147-1156. doi:10.1007/s40265-019-01152-7

4. Reding MT, Pabinger I, Lalezari S, Santagostino E, Mancuso ME. Target joint resolution in patients with haemophilia A receiving long-term prophylaxis with BAY 94-9027. Haemophilia. 2020;26(4):e201-e204. doi:10.1111/hae.13982

5. Coyle TE, Reding MT, Lin JC, Michaels LA, Shah A, Powell J. Phase I study of BAY 94-9027, a PEGylated B-domain-deleted recombinant factor VIII with an extended half-life, in subjects with hemophilia A. J Thromb Haemost. 2014;12(4):488-496. doi:10.1111/jth.12506

6. Reding MT, Ng HJ, Poulsen LH, et al. Safety and efficacy of BAY 94-9027, a prolonged-half-life factor VIII. J Thromb Haemost. 2017;15(3):411-419. doi:10.1111/jth.13597

7. Santagostino E, Lalezari S, Reding MT, et al. Safety and efficacy of BAY 94-9027, an extended-half-life factor VIII, during surgery in patients with severe hemophilia A: results of the PROTECT VIII clinical trial. Thromb Res. 2019;183:13-19. doi:10.1016/j.thromres.2019.08.023

8. Lalezari S, Reding MT, Pabinger I, et al. BAY 94-9027 prophylaxis is efficacious and well tolerated for up to >5 years with extended dosing intervals: PROTECT VIII extension interim results. Haemophilia. 2019;25(6):1011-1019. doi:10.1111/hae.13853

9. Mancuso ME, Biss T, Fischer K, et al. PROTECT VIII kids extension study: long-term safety and efficacy of BAY 94-9027 (damoctocog alfa pegol) in children with severe haemophilia A. Haemophilia. 2021;27(3):434-444. doi:10.1111/hae.14294

10. Sanabria M, Álvarez Román MT, Castaman G, et al. Design of the HEM-POWR study: a prospective, observational study of real-world treatment with damoctocog alfa pegol in patients with haemophilia A. BMJ Open. 2021;11(9):e044997. doi:10.1136/bmjopen-2020-044997

Reviewed by Debjyoti Talukdar, MD, on 1/31/2022.

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Diana Diez Gaspar, PharmD, PhD

Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.