Shares of Cardiome Pharma Corp. fell 20 percent after the company reported that the FDA declined to accept a new drug application filed by partner Astellas Pharma US Inc. for arrhythmia drug RSD1235.

The agency cited "inconsistencies and omissions in the database" in its refusal to accept the application, which was filed in late March seeking approval of the intravenously administered RSD1235 in acute conversion of atrial fibrillation. Once an NDA is filed, the FDA has 60 days to accept or reject the application for review. Rejections, however, are not common.

"We are chagrined to be associated with this kind of event," Bob Rieder, Cardiome's CEO, said during a conference call. But, while "disappointing," he added that the FDA's letter "does not in any way allude" to inadequacies in the data package.

"We believe it was much more of an execution error," he said, and following a meeting with Astellas and the FDA, "absolutely intend to refile the NDA."

Cardiome's shares (NASDAQ:CRME) lost $2.25 Wednesday to close at $9.03.

Rieder estimated that the companies should be able to file an amended application in the third quarter, which would delay potential approval a few months past the original Jan. 31, 2007, PDUFA date. It also postpones Cardiome's receipt of a $10 million milestone from Astellas, expected upon NDA acceptance.

The NDA was based on a five-year clinical program and included data from two pivotal trials. Results from 237-patient ACT 1 (Atrial Arrhythmia Conversion Trial 1) study showed that RSD1235 converted 52 percent of patients with recent onset atrial fibrillation to normal heart rhythm, compared to 4 percent in the placebo group. Data from the 170-patient ACT 3 trial nearly were identical. (See BioWorld Today, April 3, 2006.)

Once the FDA receives the application, "it appears that it's a matter of routine" for the FDA to audit selected patient data, and in conducting that audit found "inconsistencies between the submission document and the underlying locked data set, as well as omissions of data supporting the submission document," Rieder said.

He said it was too early to tell whether the problems could be attributed to corruption in the electronic filing format or to actual errors in document.

It's also too early to "point blame," Rieder added.

Astellas, a Deerfield, Ill.-based subsidiary of Tokyo-based Astellas Pharma Inc., was responsible for handling all regulatory submissions, though Cardiome did provide input and collected data for the ACT 1 trial.

Rieder maintained that "we have a lot of confidence and comfort in Astellas as our partner."

Vancouver, British Columbia-based Cardiome signed a deal in October 2003 with Fujisawa Healthcare Inc., which later became Astellas' U.S. subsidiary.

Under the terms, Astellas holds an exclusive license to develop and commercialize the intravenous formulation of RSD1235 in North America and has been responsible for 75 percent of the development costs. Cardiome would be entitled to potential royalties. (See BioWorld Today, Oct. 17, 2003.)

Outside of North America, Cardiome retains all rights to the product and also holds worldwide rights to an oral formulation of RSD1235 to prevent atrial fibrillation. The oral version is in Phase II and is estimated for an NDA filing in 2009.

To provide supplemental safety information to the pivotal trial data, Cardiome and Astellas are conducting ACT 2, a Phase III study in patients who have developed transient atrial fibrillations following cardiac surgery. That data should be available later this year. Another study, ACT 4, began enrolling patients in October to evaluate RSD1235 for additional safety data. So far, results from those trials are not being required for FDA approval.

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