Nearly two years after the company filed its new drug application, Orphan Medical Inc. said after the markets closed Wednesday it won FDA approval for Xyrem, designed to treat cataplexy associated with narcolepsy.

Xyrem has generated controversy on its road to approval because of its active ingredient, gamma hydroxybutyrate (GHB), sometimes referred to as the "date-rape drug."

"I am very pleased that we received written approval from the FDA to market Xyrem, or sodium oxybate oral solution, for the treatment of cataplexy associated with narcolepsy," Orphan Medical CEO John Bullion said Thursday in a conference call. "Xyrem is the first and only treatment approved for cataplexy."

Orphan submitted its NDA in October 2000. In June 2001, members of the Peripheral and Central Nervous System Advisory Committee, in a 6-3 vote, said the drug in a 9-mg dose was effective in treating cataplexy. In July, the FDA sent Orphan an approvable letter, but required the company to address several issues. (See BioWorld Today, July 5, 2001, and June 7, 2001.)

"The NDA process alone has felt like eight years," Bullion said in the call.

The company, he said, conducted two trials that proved the drug is efficacious in the indication of cataplexy, even though Bullion admits that researchers don't fully understand its mechanism of action or why it works.

Still, Orphan's pivotal Phase II trial, which was randomized, double-blinded and placebo-controlled, showed that Xyrem was highly statistically significant in demonstrating that it reduced the median number of cataplexy attacks by 69 percent at the 9-mg dose, Bullion said.

Of the approximately 140,000 people who have narcolepsy, about 60 percent to 90 percent experience cataplexy - or sudden loss of muscle control - associated with narcolepsy. Many individuals who experience cataplexy have been prescribed stimulants such as Ritalin and Dexedrine to address excessive daytime sleepiness, Bullion told BioWorld Today.

The drug, an oral solution, is taken at bedtime, followed by another dose two-and-a-half to four hours after bedtime. However, Bullion said, since patients with narcolepsy experience frequent sleep disruptions, the requirement to wake up to take another dose during the night is not a drawback.

Although there were reports of respiratory difficulties during the trials, Bullion said they weren't enough to prevent approval. Orphan Medical will examine that issue in a Phase IV trial of Xyrem in individuals with compromised respiratory systems.

"Xyrem does not appear to act as a respiratory depressant across the board," Bullion said. "We have yet to work out with the FDA what the [Phase IV] will look like and how it will be structured."

Xyrem's active ingredient, GHB, Bullion pointed out, is "a known drug of abuse." GHB has been known to cause adverse events related to the central nervous system, the company said, such as seizures, respiratory depression, decreases in the level of consciousness, and even instances of coma and death.

Because Xyrem is a Schedule III controlled substance, its distribution is governed by the FDA's Subpart H regulations. To address concerns that Xyrem could fall into the hands of individuals who might abuse the drug, Orphan Medical has designed a distribution process with a number of controls.

"We will be using a single pharmacy to distribute the product to patients," Bullion said. "The drug will go directly from the manufacturer to a single-source pharmacy."

The pharmacy will validate the prescribing doctor and contact the patients, and the doctor and patients will be entered into a registry. The drug will be shipped directly to the patient, who also will confirm delivery, Bullion said.

"It is a direct-distribution system that obviously keeps the points of distribution to a minimum," he said.

The drug's launch is planned for the early part of the fourth quarter. To market the drug, Orphan Medical decided to build an internal sales force of about 35 individuals, rather than turn to a contracted sales force, as originally planned, something the company was able to do because of its $14.1 million financing in December and the strength of its management team, Bullion said. (See BioWorld Today, Dec. 11, 2001.)

The market for Xyrem is expected to be about $100 million annually, Bullion said. And Orphan Medical's plan is to add excessive daytime sleepiness to the indication for which it is approved. The company is continuing Phase III trials in excessive daytime sleepiness. With that added indication, Bullion estimated the market for the drug to be $200 million.

Orphan Medical plans to seek approval in excessive daytime sleepiness in mid-2003, Bullion said.

Prior to the approval of Xyrem, Orphan Medical had six FDA-approved products that generated revenues of $11 million in 2001, Bullion said.

Orphan Medical's stock (NASDAQ:ORPH) rose 42 cents Thursday to close at $10.17.