Three months after reporting positive Phase III results on recombinant human thrombin, ZymoGenetics Inc. submitted a biologics license application to the FDA for use of the product to control bleeding during surgery.

"It's the first BLA filing that the company has put forward, so it's a big deal for us," said Douglas Williams, the Seattle-based company's executive vice president and chief scientific officer. "This was a homegrown opportunity that developed in our own research group, and we ran all of the clinical trials in-house."

ZymoGenetics also developed the manufacturing process for the product before transferring it to contract manufacturers. RhThrombin has been in clinical trials for more than five years.

The BLA is based on a successful Phase III trial that followed a randomized, blinded Phase II program in four surgical indications. The FDA "was comfortable with a single Phase III study," Williams told BioWorld Today.

If marketed, rhThrombin could cannibalize the currently used bovine-derived thrombin product, which is associated with the development of antibodies that might cross-react with human blood proteins and could be related to serious bleeding complications.

"We think it will replace bovine-thrombin fairly quickly," Williams said, adding that all of the company's market research indicate that surgeons would rather use recombinant proteins over those derived from a cow.

Bristol, Tenn.-based King Pharmaceuticals Inc.'s bovine product, Thrombin-JMI, earned sales of $220.6 million in 2005, and ZymoGenetics' officials have said it's likely they would price rhThrombin at a premium to plasma- and bovine-derived products. Williams estimates a 10-month FDA review process, meaning rhThrombin could be launched toward the end of 2007. The company intends to hire about 50 sales representatives closer to the launch.

"This is a situation where a fairly small number of sales reps should be able to attack the key accounts," he said.

Outside the U.S., ZymoGenetics will seek a partner.

"Our hope is the package that we put together to file with the FDA would be sufficient to gain approval in other territories," Williams said.

Pivotal Phase III data showed rhThrombin met its primary endpoint. Treatment with the therapy and bovine thrombin resulted in a comparable incidence of hemostasis at 10 minutes in four settings tested: spinal surgery, liver resection, peripheral artery bypass and arteriovenous graft construction. It also did well with a secondary endpoint that tested for the formation of antibodies against the products. Antibody response was 1.5 percent in rhThrombin-treated patients vs. 22 percent in those treated with the bovine thrombin product (p<0.0001). The trial included 411 surgical patients. The trial began in October 2005. (See BioWorld Today, Oct. 28, 2005, and Sept. 7, 2006.)

Although the clinical work was conducted in four surgery settings, ZymoGenetics is seeking approval to use rhThrombin more broadly in a variety of surgeries. Today, thrombin is used in more than 1 million surgeries each year in the U.S.

For a company that was founded in 1981 and operated as a wholly owned subsidiary of Bagsvaerd, Denmark-based Novo Nordisk A/S until its spinout in 2001, the BLA represents its most significant milestone to date, Williams said.

"It's a heck of a nice way to end the year," he added. "Our clinical team did a terrific job accruing a 400-patient study in eight months."

As the company awaits an FDA decision on rhThrombin, it will focus on its other endeavors, including a Phase II study of a spray applicator for thrombin, which could lead to a label expansion for the product. ZymoGenetics also is conducting a Phase II trial in rheumatoid arthritis for atacicept in collaboration with Geneva-based Serono SA; it is studying interleukin-21 in a Phase I/II program for renal-cell cancer, melanoma and lymphoma; it recently filed an investigational new drug application for interferon-lambda-1, which should move into the clinic in 2007 for hepatitis C virus.

ZymoGenetics has been public since 2002. Its shares (NASDAQ:ZGEN) fell 31 cents Monday to close at $16.26.

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