Cardiome Pharma Corp. and its partner, Astellas Pharma US Inc., filed a new drug application seeking approval of RSD1235 for the acute conversion of atrial fibrillation.

The filing comes about six months after Vancouver, British Columbia-based Cardiome reported positive data from a second Phase III trial.

"It's the first time we've filed an NDA off a product that we've discovered ourselves," said Doug Janzen, the company's president and chief business officer. "This is our lead product. From our perspective, and certainly from the capital markets' perspective, the importance of this event is a big one."

The NDA is based on a five-year clinical development program and includes data from two pivotal trials, ACT 1 and ACT 3. Data from ACT 1 (Atrial Arrythmia Conversion Trial 1) were released in December 2004, showing that the intravenous form of RSD1235 converted 52 percent of patients with recent onset atrial fibrillation to normal heart rhythm, while placebo converted only 4 percent. The study, which included 237 patients, also showed the product was safe and well tolerated (See BioWorld Today, Dec. 21, 2004.)

Cardiome disclosed ACT 3 data last September. The trial showed that of the 170 patients with recent-onset atrial fibrillation, 52 percent of those receiving intravenous RSD1235 converted to normal heart rhythm, compared to 4 percent of placebo patients, basically mirroring the results of the ACT 1 study.

The company's stock climbed 22.8 percent, closing at $7.43, in December 2004, following results from the first pivotal trial, and it rose 14.2 percent, closing at $8.79, last September after results of ACT 3.

On Friday, the stock (NASDAQ:CRME) fell 29 cents to close at $12.70.

If RSD1235 reaches the market, it could bring Cardiome and Astellas between $300 million and $500 million in peak U.S. sales, Janzen said. The companies also are working in Phase II on an oral version of the product, which is about three years behind the intravenous form and slated for an NDA filing in 2009. The oral market, Janzen said, is between $1 billion and $3 billion.

"There's no labeled oral therapy right now," he told BioWorld Today.

Atrial fibrillation is an abnormal heart rhythm that affects the upper chambers of the heart and lowers its pumping capacity. It can cause breathlessness and fatigue and lead to an increased risk in stroke and congestive heart failure.

One major advantage to RSK1235 is that it has had no cases of drug-related "Torsades de Pointes," an arrhythmia side effect. "Historically, anti-arrhythmics have been limited in application because they harm patients. There's a pro-arrhythmia risk," Janzen said. "We have an asset that seems to be very efficacious and also very well tolerated. You don't see that from current therapies."

RSD1235 is the subject of another ongoing Phase III study, ACT II, which should have data available later this year. About three-quarters of the patients are enrolled in that trial, which is focused on those who have developed transient atrial fibrillation following cardiac surgery. A fourth study, ACT 4, began in October to test the drug in about 120 patients to provide supplemental safety data to the pivotal ACT 1 and ACT 3 trial results.

Cardiome started a Phase IIa pilot study of the oral version of the drug in December, and is enrolling 180 patients across 75 centers in the U.S., Canada and Europe.

The company partnered RSD1235 in October 2003 with Astellas, a Deerfield, Ill.-based subsidiary of Tokyo-based Astellas Pharma Inc. Astellas holds an exclusive license to develop and commercialize the intravenous formulation in North America and has been responsible for 75 percent of development costs.

Cardiome retains all rights to the intravenous formulation outside of Canada, the U.S. and Mexico, as well as worldwide rights to oral RSD1235 for the prevention of atrial fibrillation. It has no intention at this point to seek another partnership, Janzen said.

"They have strategic value to us to keep them unencumbered," he said, adding that "there's definitely interest in it," but that Cardiome is not ready to give up the rights.

FDA: Prestwick's Xenazine Approvable

Privately held Prestwick Pharmaceuticals Inc. received an approvable letter from the FDA for its treatment of chorea associated with Huntington's disease.

The Washington-based company must meet certain undisclosed conditions before obtaining final approval of Xenazine (tetrabenazine). The FDA has indicated to the company that it will discuss the NDA at a public meeting, for which a date has not been set, of the Peripheral and Central Nervous System Advisory Committee.

The product is a selective and reversible dopamine depletory that works by inhibiting vesicular monamine transporter 2. It is the first therapy for which an NDA has been filed in the U.S. to treat chorea associated with Huntington's disease, and it has orphan drug status and fast-track designation in the U.S.

It is approved in eight markets outside of the U.S. and is marketed by Prestwick in Canada as Nitoman.

Chorea is characterized by excessive, involuntary and repetitive movements that may involve the face, limbs or the entire body.