Wyeth-Ayerst is awaiting the production of commercial quantities of its antihemophilic factor ReFacto for introduction into the U.S. market.

A launch is planned in the third quarter when an adequate supply of the recombinant antihemophilic factor will be on hand to ensure continued availability, the company indicated.

ReFacto was approved March 6 for the control and prevention of bleeding in patients with hemophilia.

Developed by Wyeth-Ayerst's Genetics Institute, ReFacto is being manufactured under contract by Pharmacia & Upjohn at its production facility in Stockholm, Sweden.

Genetics Institute committed to using "U.S. licensed plasma in the manufacture of cell culture human serum albumin" for production of the product, the approval letter states.

P&U sold the development and commercialization rights for ReFacto in August 1997, but retained manufacturing rights.

Approval for ReFacto followed expiration of orphan exclusivity for Bayer's Kogenate Feb. 25. A shortage of Kogenate in 1998 almost caused FDA to overturn that product's orphan exclusivity and would have allowed ReFacto to be approved earlier. The BLA for ReFacto was filed Feb. 2, 1998.

One point of differentiation for ReFacto from other Factor VIII products may be that it is albumin-free. While human serum albumin is used in the cell culture production of ReFacto, labeling states that the product "contains no preservative or added human components in the final formation." ReFacto contains trace amounts of mouse and hamster proteins.

"Our recombinant technology and human serum albumin-free formulation offers the potential to reduce the risk of viral contamination for hemophilia A patients," the company said.

ReFacto is indicated for "the control and prevention of hemorrhagic episodes and for surgical prophylaxis in patients with hemophilia A (congenital factor VIII deficiency or classic hemophilia)."

The agent is also indicated for "short-term routine prophylaxis to reduce the frequency of spontaneous bleeding episodes." Labeling adds that "the effect of regular routine prophylaxis on long-term morbidity and mortality is unknown."

ReFacto is the only hemophilia A therapy approved for short-term routine prophylaxis. There are approximately 17,000 people in the U.S. with hemophilia A, Wyeth said.

Among its Phase IV commitments for postmarketing studies, Wyeth will provide FDA with a detailed protocol for a randomized trial utilizing two regimens (short-term and pre-surgical) for prophylaxis of hemophilia A and submit a report containing data and analyses on the feasibility of such a trial.

FDA said in its approval letter that "if you elect not to undertake" such a trial, "you will make your assessment available to the public including the power analysis based on your pharmacokinetic/ pharmacodynamic model."

"The clinical trial experience with routine prophylaxis...is limited," the labeling notes. Short-term routine prophylaxis was studied in uncontrolled clinical trials.

"Investigators exercised their own discretion in deciding when and in whom prophylaxis was to be initiated and terminated," labeling states.

In December 1998, FDA's Blood Products Advisory Committee expressed concern over the potential for dosing errors with ReFacto, especially without supervision by a physician experienced in the treatment of hemophilia (¹ Also see "GI's ReFacto May Use Standard One-Stage Assay With Dose Adjustments" - Pink Sheet, 14 December, 1998.).

Labeling states that "the one stage factor VIII clotting assay gave results which were approximately 50% of the values obtained with the chromogenic assay." ReFacto "is labeled on the basis of the chromogenic assay. The available clinical trial data suggest either the one-stage clotting assay or the chromogenic assay may be used to help follow patients clinically."

Patients treated with ReFacto experienced typical injectable protein adverse events, including headache, fever, chills, flushing, nausea, vomiting, lethargy and manifestations of allergic reactions, labeling states.

Wyeth ReFacto Launch Set For Third Quarter; Awaiting Adequate Supply

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