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Hemophilia

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Adynovate

Adynovate® (rurioctocog alfa pegol),1 previously known as BAX 855,2 is a recombinant antihemophilic factor VIII (FVIII) developed by Baxter International. It is approved for on-demand, perioperative, or prophylactic treatment and for the control of bleeding in children and adults with hemophilia A.

Adynovate Synthesis

Adynovate is synthesized by covalently attaching polyethylene glycol (PEG) to Advate®, which is an unmodified, full-length recombinant FVIII produced in the Chinese Hamster Ovary (CHO) cell line. Advate is approved for the treatment of hemophilia A. The addition of PEG to Advate reduces its binding to the physiological FVIII clearance receptor called LDL receptor-related protein 1 (LRP1), which mediates the hepatic clearance of FVIII. As a result, Adynovate remains longer in the circulation The mean half-life of Adynovate in humans has been shown to be 18 hours, which is approximately 1.5 times that of Advate. Because of its prolonged half-life in plasma, Adynovate needs to be injected only twice a week when used for prophylaxis.3

Get full prescribing information for Adynovate at MPR

Clinical Studies

A phase 1 study4 (NCT01599819)5 compared the safety and pharmacokinetics of Adynovate with those of Advate in 19 patients with severe hemophilia A. This was followed by a pivotal phase 2/3 study (NCT01736475)6 in which the safety, efficacy, and pharmacokinetics of Adynovate administered twice weekly as a prophylactic or on-demand therapy were evaluated in 137 patients (aged 12-65 years) with previously treated severe hemophilia A. The studies showed that the mean half-life of Adynovate was 1.4 to 1.5 times longer than that of Advate. Adynovate was found to be effective as a prophylactic treatment, with a median annualized bleeding rate (ABR) of 1.9 and no episodes of bleeding in 39.6% of patients. Adynovate was also effective as an on-demand treatment; 95.9% of episodes of bleeding were treated with 1 to 2 infusions.

A prospective, uncontrolled, multicenter phase 3 trial7 (NCT02210091)8 conducted in 66 children younger than 12 years with previously treated hemophilia A evaluated the safety, efficacy, and pharmacokinetics of Adynovate when used as a prophylactic treatment. In this study, Adynovate was administered twice weekly over 6 months. The pediatric study showed an extended half-life of Adynovate, approximately 1.3 to 1.5 times longer than that of Advate. The mean ABR was 3.04, due mainly to injury-related bleeds. During the 6-month period of prophylactic treatment, 38% of patients did not experience any bleeding. Hemostatic efficacy was excellent or good in 90% of bleeds, and most episodes of bleeding (approximately 83%) were successfully treated with a single infusion. FVIII inhibitors did not develop in any patient.

Another single-arm, multicenter phase 3 study9 (NCT01913405)10 demonstrated the safety and efficacy of Adynovate when used perioperatively in 21 previously treated patients (aged 16-61 years) with severe hemophilia A; the patients underwent 21 major and 5 minor surgeries. Overall, Adynovate was well tolerated and effective for perioperative use in patients with hemophilia, with blood loss similar to that observed in patients without hemophilia. No deaths or treatment-related serious adverse events were observed.

Warning and Precautions

The use of Adynovate may result in hypersensitivity reactions, including anaphylaxis. In such cases, Adynovate must be discontinued and appropriate treatment administered.

The administration of Adynovate may also lead to the production of neutralizing antibodies against factor VIII (inhibitors). If bleeding is not controlled or plasma FVIII levels do not rise as expected, an assay should be performed to determine the level of FVIII inhibitory antibodies.1  

References

  1. Adynovate. Prescribing information. Shire. Revised June 2021. Accessed January 1, 2022.
  2. Turecek PL, Bossard MJ, Graninger M, et al. BAX 855, a PEGylated rFVIII product with prolonged half-life. Development, functional and structural characterisation. Hamostaseologie. 2012;32(suppl 1):S29-S38.
  3. Adynovi. Committee for medicinal products for human use (CHMP). Assessment report. European Medicines Agency. Accessed January 1, 2022.
  4. Konkle BA, Stasyshyn O, Chowdary P, et al. Pegylated, full-length, recombinant factor VIII for prophylactic and on-demand treatment of severe hemophilia A. Blood. 2015;126(9):1078-1085. doi:10.1182/blood-2015-03-630897
  5. BAX 855 dose-escalation safety study. ClinicalTrials.gov. NCT01599819. Accessed January 1, 2022.
  6. Study investigating a PEGylated recombinant factor VIII (BAX 855) for hemophilia A (PROLONG-ATE Study). ClinicalTrials.gov. NCT01736475. Accessed January 1, 2022.
  7. Mullins ES, Stasyshyn O, Alvarez-Román MT, et al. Extended half-life pegylated, full-length recombinant factor VIII for prophylaxis in children with severe haemophilia A. Haemophilia. 2017;23(2):238-246. doi:10.1111/hae.13119
  8. BAX 855 pediatric study. ClinicalTrials.gov. NCT02210091. Accessed January 1, 2022.
  9. Gruppo R, López-Fernández MF, Wynn TT, Engl W, Sharkhawy M, Tangada S. Perioperative haemostasis with full-length, PEGylated, recombinant factor VIII with extended half-life (rurioctocog alfa pegol) in patients with haemophilia A: Final results of a multicentre, single-arm phase III trial. Haemophilia. 2019;25(5):773-781. doi:10.1111/hae.13807
  10. Phase 3 efficacy and safety study of BAX 855 in severe hemophilia A patients undergoing surgical procedures. ClinicalTrials.gov. NCT01913405. Accessed January 1, 2022.

Reviewed by Harshi Dhingra, MD, on 1/2/2022.

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