FDA approves recombinant antihemophilic factor for hemophilia A

November 13, 2015

The U.S. Food and Drug Administration approved Adynovate, Antihemophilic Factor (Recombinant), PEGylated for use in adults and adolescents, aged 12 years and older, who have Hemophilia A. Adynovate is modified to last longer in the blood and potentially require less frequent injections than unmodified Antihemophilic Factor when used to reduce the frequency of bleeding.

Hemophilia A is an inherited, sex-linked, blood-clotting disorder that primarily affects males, which is caused by defects found in the Factor VIII gene.

According to the Centers for Disease Control and Prevention, Hemophilia A affects one in every 5,000 male births in the United States. Patients with hemophilia A may experience repeated episodes of serious bleeding, primarily into the joints, which can be severely damaged as a result.

DESCRIPTION

ADYNOVATE, Antihemophilic Factor (Recombinant), PEGylated, is formulated as a sterile, non-pyrogenic, white to off-white lyophilized powder for reconstitution for intravenous injection. Each vial of ADYNOVATE is labeled with the actual factor VIII activity in IU determined using one stage clotting assay, using a reference material calibrated against a World Health Organization (WHO) International Standard for factor VIII concentrates. One IU, as defined by the WHO standard for blood coagulation factor VIII, human, is approximately equal to the level of factor VIII activity found in 1 mL of fresh pooled human plasma.

ADYNOVATE is a recombinant full-length human coagulation factor VIII(2,332 amino acids with a molecular weight (MW) of 280 kDa) covalently conjugated with one or more molecules of polyethylene glycol (MW 20 kDa).

The therapeutic activity of ADYNOVATE is derived from its parent drug substance, ADVATE [Antihemophilic Factor (Recombinant)], which is produced by recombinant DNA technology from the CHO cell line.

ADVATE is purified from the culture medium using a series of chromatography columns. The purification process includes an immunoaffinity chromatography step in which a monoclonal antibody directed against factor VIII is employed to selectively isolate the factor VIII from the medium. The production process includes a dedicated, viral inactivation solvent-detergent treatment step. The ADVATE molecule is then covalently conjugated with the polyethylene glycol, which mainly targets lysine residues. The cell culture, pegylation, purification process and formulation used in the manufacture of ADYNOVATE do not use additives of human or animal origins.

CLINICAL PHARMACOLOGY

Mechanism of Action

ADYNOVATE, a PEGylated form of recombinant antihemophilic factor (ADVATE), temporarily replaces the missing coagulation factor VIII needed for effective hemostasis in congenital hemophilia A patients. ADYNOVATE exhibits an extended terminal half-life through pegylation of the parent molecule, ADVATE, which reduces binding to the physiological factor VIII clearance receptor (LRP1).

Safety and Efficacy

The safety and efficacy of Adynovate were evaluated in a clinical trial of 137 adults and adolescents aged 12 years and older, which compared the recommended routine prophylactic (preventative) treatment regimen to on-demand therapy. The trial demonstrated that Adynovate was effective in reducing the number of bleeding episodes during routine care. Additionally, Adynovate was effective in treating and controlling bleeding episodes. No safety concerns were identified during the trial.

INDICATIONS AND USAGE

ADYNOVATE, Antihemophilic Factor (Recombinant), PEGylated, is a human antihemophilic factor indicated in adolescent and adult patients (12 years and older) with hemophilia A (congenital factor VIII deficiency) for:

  • On-demand treatment and control of bleeding episodes
  • Routine prophylaxis to reduce the frequency of bleeding episodes
  • ADYNOVATE is not indicated for the treatment of von Willebrand disease.

DOSAGE AND ADMINISTRATION

For intravenous use after reconstitution only

One unit per kilogram body weight will raise the factor VIII level by 2% international units per deciliter (IU per dL). Each vial of ADYNOVATE is labeled with the actual amount of recombinant factor VIII present in IU.

adynovate

On-demand treatment and control of bleeding episodes:

  • Estimated Increment of factor VIII (IU/dL or % of normal) = [Total Dose (IU)/body weight (kg)] x 2 (IU/dL per IU/kg)
  • Dose (IU) = Body Weight (kg) x Desired factor VIII Rise (IU/dL or % of Normal) x 0.5 (IU/kg per IU/dL)
  • Routine prophylaxis: Administer 40-50 IU per kg body weight 2 times a week.

CONTRAINDICATIONS

Do not use in patients who have had prior anaphylactic reaction to ADYNOVATE, the parent molecule (ADVATE), mouse or hamster protein, or excipients of ADYNOVATE.

WARNINGS and PRECAUTIONS

  • Hypersensitivity reactions, including anaphylaxis, are possible. Should symptoms occur, discontinue treatment with ADYNOVATE and administer appropriate treatment.
  •  Development of factor VIII neutralizing antibodies (inhibitors) may occur. If expected plasma factor VIII activity levels are not attained, or if bleeding is not controlled with an appropriate dose, perform an assay that measures factor VIII inhibitor concentration.

ADVERSE REACTIONS

Common adverse reactions reported in ≥1% of subjects in the clinical studies were headache and nausea.

Adynovate is manufactured by Baxalta US Inc., based in Westlake Village, California.

Reference:

FDA News