By Kim Coghill
BETHESDA, Md. ¿ Members of the Peripheral and Central Nervous System Advisory Committee on Wednesday appeared concerned about introducing to the market a drug that contains the controversial active ingredient, gamma hydroxybutyrate, sometime referred to as the ¿date-rape drug.¿
The committee reviewed and discussed the data surrounding trials and labeling of Xyrem, Orphan Medical Inc.¿s oral solution for the treatment of narcolepsy and its symptoms. Following the meeting, Claudia Kawas, chair of the committee and professor of neurology at the University of California, said Orphan Medical¿s next step is to work with the FDA.
The committee, in a 6-3 vote, said the drug in a 9-mg dose was effective in treating cataplexy. Committee members did not endorse the drug, however, as a treatment for excessive daytime sleepiness. Members were split on the drug¿s safety.
The development of Xyrem has sparked some controversy because of its use of gamma hydroxybutyrate, or GHB, a tasteless, colorless controlled substance that can be lethal if improperly used.
Xyrem (sodium oxybate) has been granted orphan status to treat cataplexy, the sudden loss of muscle control, a symtom of narcolepsy. The drug is designed to work by consolidating the fragmented sleep patterns characteristic of narcolepsy into a more normal sleep pattern. Narcolepsy is a chronic neurologial disorder affecting between 100,000 and 125,000 Americans, whose main symtoms are excessive daytime sleepiness and cataplexy.
Ernest Andberg, an analyst with Miller Johnson Steichen Kinnard in Minneapolis, said Xyrem likely would generate $50 million to $100 million in sales for Minneapolis-based Orphan Medical. Provigil, an approved Cephalon Inc. product, treats daytime sleepiness associated with narcolepsy. Andberg said, however, that there is nothing on the market to address narcolepsy or cataplexy.
During a 90-minute public comment period, the advisory committee heard from about a dozen people, half who had positive experiences with Xyrem and supported recommended approval. The others requested further research after telling horror stories of mostly teen-age death related to abuse of GHB.
Even so, Orphan Medical has a plan to control Xyrem.
Patti Engel, vice president of marketing and sales for Orphan Medical, said the company has developed a draft plan for distribution that limits manufacturing and distribution centers to one plant each. The drug will be dispersed through a courier system, doctors will not be provided with samples and pharmacies will not stock the medicine.
Furthermore, patients will be educated about the potential dangers of overdosing as well as the legal and/or criminal responsibilities related to giving or selling Xyrem to others, she said.
Orphan Medial in October was granted priority review status for Xyrem and in March was prepared to go before the advisory committee.
However, just prior to the meeting, the advisory committee meeting was canceled due to questions surrounding some data. The move caused Orphan Medical¿s stock to drop 29.5 percent to close at $9.375, down $3.937. Trading on the stock was held Wednesday at $12.37. (See BioWorld Today, March 5, 2000.)
Xyrem was effective in two pivotal Phase II clinical studies. The results of a 136-patient, placebo-controlled, double-blind study showed that patients receiving the high dose of Xyrem (9 grams) experienced 68.6 percent fewer attacks than placebo patients. After completion of that study, 118 patients agreed to continue on Xyrem. The study investigators established the effective dose for each individual patient and monitored excessive daytime sleepiness. The 9-gram dose of the drug markedly reduced daytime sleepiness ¿ some patients even obtained levels of sleepiness considered normal. (See BioWorld Today, Jan. 20, 2000.)
Orphan introduced positive data Wednesday from an open-label clinical trial that demonstrated an overall improvement in both the quality and integration of sleep for narcolepsy patients being treated with Xyrem, as well as a reduction in daytime sleepiness. The trial was conducted over 14 weeks with 21 individuals with narcolepsy.
Narcolepsy patients typically do not sleep effectively at night and cannot maintain effective wakefulness during the day. Narcolepsy may be caused by abnormalities in an area of the brain called the hypothalamus, and can have social, emotional and economic impact.
Orphan Medial is conducting a Phase IIIb controlled trial designed to assess the efficacy of Xyrem in treating excessive daytime sleepiness related to narcolepsy. Patient enrollment is under way and the clinical portion of the trial is expected to be completed by the end of the year.
Aside from Xyrem, Orphan Medical is developing other products, including busulfan IV formulation (Busulfex), which has received orphan drug designation from the European Agency for the Evaluation of Medicinal Products (EMEA) for use as conditioning treatment prior to hematopoietic progenitor cell transplantation. Another product, Antizol (fomepizole) Injection, has received priority review status from the Therapeutics Products Programme in Canada for the upcoming efficacy supplemental for the additional indication of methanol poisoning. Antizol is the first FDA-approved antidote for confirmed or suspected ethylene glycol poisoning.