FDA approves first recombinant von Willebrand factor to treat bleeding episodes

December 8, 2015

The U.S. Food and Drug Administration approved orphan drug Vonvendi, von Willebrand factor (Recombinant), for use in adults 18 years of age and older who have von Willebrand disease (VWD).

Vonvendi is the first FDA-approved recombinant von Willebrand factor, and is approved for the on-demand (as needed) treatment and control of bleeding episodes in adults diagnosed with VWD.

DESCRIPTION

VONVENDI is a purified recombinant von Willebrand factor (rVWF) expressed in Chinese Hamster Ovary (CHO) cells.

VONVENDI is produced and formulated without the addition of any exogenous raw materials of human or animal origin in the cell culture, purification, or formulation of the final product.

The only proteins present in the final container product other than rVWF are trace quantities of mouse immunoglobulin (IgG, from the immunoaffinity purification), host cell (i.e., CHO) protein, rFurin (used to further process rVWF), and recombinant factor VIII (rFVIII).

Von Willebrand factor is a large multimeric glycoprotein that is normally found in plasma, and stored as ultra-large multimers in alpha-granules of platelets and intracellular organelles known as Weibel-Palade bodies, prior to secretion into the blood.

Once the VWF is released to the blood stream and in contact with ADAMTS13 a (proteolytic enzyme in blood), it is cleaved to smaller sizes that can be detected with SDS agarose gels as multimer bands, representing the various species of VWF within the circulation. VONVENDI is rVWF that contains ultra-large multimers in addition to all of the multimers found in plasma as it is not exposed to proteolysis by ADAMTS13 during the manufacturing process.

CLINICAL PHARMACOLOGY

Mechanism of Action

In VWD patients, VONVENDI acts

  • 1) to promote hemostasis by mediating platelet adhesion to damaged vascular sub-endothelial matrix (e.g. collagen) and platelet aggregation, and
  • 2) as a carrier protein for factor VIII, protecting it from rapid proteolysis. The adhesive activity of VWF depends on the size of its multimers, with large multimers being the most effective in supporting interactions with collagen and platelet receptors.

The binding capacity and affinity of VONVENDI to factor VIII in plasma is comparable to that of endogenous VWF, allowing for VONVENDI to reduce factor VIII clearance.

Safety and Efficacy

The safety and efficacy of Vonvendi were evaluated in two clinical trials of 69 adult participants with VWD. These trials demonstrated that Vonvendi was safe and effective for the on-demand treatment and control of bleeding episodes from a variety of different sites in the body. No safety concerns were identified in the trials. The most common adverse reaction observed was generalized pruritus (itching).

DOSAGE AND ADMINISTRATION

For intravenous use after reconstitution only.

  • For each bleeding episode, administer the first dose of VONVENDI with an approved recombinant (non-von Willebrand factor containing) factor VIII if factor VIII baseline levels are below 40% or are unknown.
  • Initial dose is 40 to 80 international units (IU) per kg body weight. Adjust the dosage based on the extent and location of bleeding

vwf

  • If recombinant factor VIII is required, give recombinant factor VIII within 10 minutes of completing VONVENDI infusion at a ratio of 1.3:1 (i.e., 30% more VONVENDI than recombinant factor VIII, based on the approximate mean recoveries of 1.5 and 2 IU/dL for VONVENDI and recombinant factor VIII, respectively). Consult the package insert for the specific factor VIII product for dosing recommendations.Administer VONVENDI within 3 hours after reconstitution.

DOSAGE FORMS AND STRENGTHS

VONVENDI is available as a lyophilized powder in single-use vials containing nominally 650 or 1300 international units VWF:RCo.

CONTRAINDICATIONS

Do not use in patients who have had life-threatening hypersensitivity reactions to VONVENDI or its components (mannitol, trehalose, sodium chloride, histidine, Tris, calcium chloride, polysorbate 80, and hamster or mouse proteins).

WARNINGS AND PRECAUTIONS

Thromboembolic reactions can occur, particularly in patients with risk factors for thrombosis. Monitor for early signs of thrombosis. In patients requiring frequent doses of VONVENDI with recombinant factor VIII, monitor plasma levels of factor VIII activity because an excessive rise in factor VIII levels can increase the risk for thromboembolic events.

Hypersensitivity reactions, including anaphylaxis, may occur. Discontinue VONVENDI if hypersensitivity symptoms occur and administer appropriate emergency treatment. Inhibitors to von Willebrand factor and/or factor VIII can occur. If the expected plasma levels of VWF activity (VWF:RCo) are not attained, or if bleeding is not controlled with an appropriate dose, perform an appropriate assay to determine if an anti-VWF or anti-FVIII inhibitors are present.

ADVERSE REACTIONS

The most common adverse reaction observed (≥2% of subjects) was generalized pruritus.

The FDA granted Vonvendi orphan product designation for these uses. Orphan product designation is given to drugs intended to treat rare diseases in order to promote their development.

Vonvendi is manufactured by Baxalta U.S., Inc., based in Westlake Village, California.

Reference:

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