By Kim Coghill

Washington Editor

Orphan Medical Inc. received an approvable letter from the FDA for Xyrem (sodium oxybate) in the treatment of cataplexy related to narcolepsy.

In the letter the FDA said Orphan Medical, of Minneapolis, must address several issues prior to approval, including a safety update for ongoing clinical trials and an additional acute exposure trial in respiratory-compromised patients.

¿We need to meet with the FDA to clarify exactly what they require,¿ William Houghton, Orphan Medical¿s chief medical officer and chief operating officer, told BioWorld Today. ¿They did stress to us that the contents of the letter were negotiable to a point, so we really need to meet with them to clarify what time lines are required.¿

Houghton wasn¿t willing to speculate as to when Xyrem would be launched, but did say Orphan Medical expects to complete the FDA¿s requirements by the end of the year.

¿The clear point here is that the road map is laid out and we obviously are going to talk to the FDA and see what modifications we can make to get this thing approved,¿ John Bullion, Orphan Medical¿s CEO, said.

With the exception of Provigil, an approved Cephalon Inc. drug that treats daytime sleepiness associated with narcolepsy, there are no similar drugs on the market.

Xyrem has come under close scrutiny by the FDA because it contains the controversial active ingredient gamma hydroxybutyrate, sometimes called the ¿date-rape drug.¿ Gamma hydroxybutyrate, or GHB, is a tasteless, colorless controlled substance that can be lethal if improperly used.

In a 6-3 vote a month ago, the Peripheral and Central Nervous System Advisory Committee said a 9-mg dose of Xyrem is effective in treating cataplexy, a sudden loss of muscle control. The committee was split on the safety of Xyrem, and was not asked by the FDA to vote on whether Xyrem should receive approval. (See BioWorld Today, June 7, 2001.)

Orphan Medical initially had requested use of Xyrem in the treatment of narcolepsy and its symptoms.

Narcolepsy is a chronic neurological disorder affecting between 100,000 and 125,000 Americans whose main symptoms are excessive daytime sleepiness and cataplexy. Narcolepsy may be caused by abnormalities in an area of the brain called the hypothalamus, and can have a social, emotional and economic impact. Xyrem, which has been granted orphan status to treat cataplexy, is designed to work by consolidating the fragmented sleep patterns characteristic of narcolepsy into a more normal sleep pattern.

¿Cataplexy is the indication that we expected to receive approval on,¿ Houghton said. ¿We had pushed the envelope a little. It is important to note that we have an ongoing study with daytime sleepiness as the primary efficacy measure. It was always our plan to go back with a supplemental submission for daytime sleepiness as a primary indication.¿

The ongoing Phase IIIb controlled trial Houghton is referring to is expected to be complete by mid-2002 and submitted to the FDA by the end of 2002.

Because of possible dangers associated with Xyrem if it became accessible to the general population, the FDA is requiring additional labeling guidelines as well as minor modifications to Orphan Medical¿s risk-management program.

The company has developed a draft plan for distribution that limits manufacturing and distribution centers to one plant each. The company also proposes dispersing Xyrem through a courier system rather than stocking pharmacies.

The FDA granted Xyrem priority-review status in October and the company was prepared to go before an advisory committee in March. However, just prior to the scheduled date, the meeting was canceled due to questions surrounding some data.

The move caused Orphan Medical¿s stock (NASDAQ:ORPH) to drop 29.5 percent to close at $9.375, down $3.937. In the last year, the stock has traded between $18.375 and $6.375. It closed Tuesday at $11.10, up 11 cents.

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