Hemophilia

Hemophilia A is a blood disorder resulting from the deficiency or dysfunction of coagulation factor VIII (FVIII). The disease predominantly affects males since it is consequent to mutations in the F8 gene on the X chromosome.¹ Patients with hemophilia A present with bleeding symptoms associated with the level of factor deficiency in the plasma, and the disease can therefore be mild, moderate, or severe.^1,2 These patients have prolonged bleeding because the blood flow from a wound is not halted easily.¹

Hemophilia treatment has greatly progressed from whole blood transfusions with low clinical efficacy to the use of freeze-dried plasma concentrates of coagulation factors and recombinant therapy.^2,3 

Advate^® (octocog alfa; antihemophilic factor [recombinant]) is a recombinant antihemophilic factor indicated for use in adults and children with hemophilia A that was developed by Shire (now acquired by Takeda Pharmaceuticals).^4,5 Advate is designed to replace FVIII to allow the control and prevention of bleeding, and it is used as routine prophylaxis to reduce the number of bleeding episodes and assist in perioperative management.⁴

Mechanism of Action and Usage of Advate

Advate is a synthesized and purified glycoprotein formulated as a sterile and nonpyrogenic white powder. It is prepared in a single-use vial containing 250 to 40,000 IU and is administered as an intravenous injection after reconstitution. Both the dose and duration of treatment are dependent on the severity of FVIII deficiency.⁴

Contraindications to the use of Advate include life-threatening hypersensitivity reactions to any constituent of the formulation, which may include anaphylaxis.⁴ The development of inhibitors that neutralize the infused FVIII may also occur.³ Common adverse reactions include fever, headache, cough, arthralgia, vomiting, upper respiratory tract infection, limb injury, nasal congestion, and diarrhea.⁴

Get detailed prescribing information on Advate at MPR

Advate in Clinical Studies

The use of Advate for preventing and treating bleeds has been evaluated through a pivotal clinical trial. Safety, efficacy, immunogenicity, and pharmacokinetics were evaluated in an open-label, double-blinded, randomized, cross-over trial that included 111 previously treated patients (PTPs) with hemophilia A.⁶

In this trial, Advate was routinely administered prophylactically and on-demand when bleeding episodes occurred in 108 patients, and it was compared to a different formulation, Recombinate™. Efficacy was evaluated using a scale based on the quality of hemostasis that Advate allowed patients to obtain. The pharmacokinetic profile was assessed at the start and end of treatment.⁶

Exposure to Advate in this trial lasted for at least 75 days. There were 510 bleeding events reported, 93% of which were managed with one or 2 drug infusions. In addition, 86% of the events received an “Excellent” or “Good” rating for Advate efficacy. Adherence to treatment was deemed important, as results from the trial revealed that lower rates of compliance led to higher bleeding rates.⁶

The efficacy, safety, immunogenicity, and pharmacokinetics of Advate was also investigated in 53 PTPs under the age of 6 years in an open-label, multicenter, prospective, uncontrolled study. A total of 7980 Advate infusions were performed over a median of 156 exposure days. There were 354 reported bleeding episodes. Of these episodes, 90.1% were managed with 1 to 2 Advate infusions and 93.8% received an “Excellent” or “Good” rating for Advate efficacy.⁷

As surgery is often necessary to address hemophilia complications following continuous bleeding into joints and muscles, the efficacy and safety of Advate in perioperative management was investigated in a different trial.³ This was a multicenter, prospective, open-label, uncontrolled study performed in PTPs who were undergoing surgical procedures. In this study, 65 procedures performed in 58 patients were analyzed.⁸ Patients were administered a loading dose of Advate before surgery and received replacement therapy during the surgery. In the postoperative phase, Advate was also prescribed for hemostasis control. Reported intra- and postoperative hemostatic efficacies were rated “Excellent” or “Good” in 100% of the procedures. No serious adverse events or inhibitor development were noted during the study.⁸

References

1. Hemophilia A. National Organization for Rare Disorders (NORD). Accessed December 7, 2021.

2. Mannucci PM. Hemophilia therapy: the future has begun. Haematologica. 2020;105(3):545-553. doi:10.3324/haematol.2019.232132

3. Shapiro AD. Anti-hemophilic factor (recombinant), plasma/albumin-free method (octocog-alpha; Advate) in the management of hemophilia A. Vasc Health Risk Manag. 2007;3(5):555-565.

4. Advate. Package insert. Baxalta US Inc.; 2018. Accessed December 7, 2021.

5. Takeda completes acquisition of Shire, becoming a global, values-based, R&D-driven biopharmaceutical leader. News release. Takeda; January 8, 2019.

6. Tarantino MD, Collins PW, Hay CRM, et al.; RAHF-PFM Clinical Study Group. Clinical evaluation of an advanced category antihaemophilic factor prepared using a plasma/albumin-free method: pharmacokinetics, efficacy, and safety in previously treated patients with haemophilia A. Haemophilia. 2004;10(5):428-437. doi:10.1111/j.1365-2516.2004.00932.x

7. Blanchette VS, Shapiro AD, Liesner RJ, et al.; rAHF-PFM Clinical Study Group. Plasma and albumin-free recombinant factor VIII: pharmacokinetics, efficacy and safety in previously treated pediatric patients. J Thromb Haemost. 2008;6(8):1319-1326. doi:10.1111/j.1538-7836.2008.03032.x

8. Négrier C, Shapiro A, Berntorp E, et al. Surgical evaluation of a recombinant factor VIII prepared using a plasma/albumin-free method: efficacy and safety of Advate in previously treated patients. Thromb Haemost. 2008;100(2):217-223.

Reviewed by Kyle Habet, MD, on 12/26/2021.

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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.