Xyrem - A Promising Treatment for Narcolepsy?

This month has been busy for Orphan Medical. On October 2nd the company filed a New Drug Application (NDA) for Xyrem, a drug for the treatment of symptoms of narcolepsy. On October 17th, the company announced that the FDA had granted priority review status to the application. This commits the FDA to act on the application within six months of the submission of the NDA. If the Food and Drug Administration approves the NDA, Xyrem may become available to patients in mid-to-late 2001.

Xyrem has been developed as a potential treatment for narcolepsy. Narcolepsy is a chronic neurological disorder affecting an estimated 100,000 to 125,000 Americans, whose main symptoms are excessive daytime sleepiness and cataplexy. Cataplexy is a debilitating symptom characterized by loss of muscle control in response to strong emotional reactions such as laughter, anger, or surprise. In its most severe form, cataplexy can cause a person to collapse during waking hours. Various studies indicate that 60,000 to 75,000 narcolepsy patients suffer from cataplexy, and among these patients, up to 60% use prescribed pharmaceuticals in an attempt to control their cataplexy.

While the New Drug Application is being reviewed, Orphan continues to do research on this new drug. Two additional clinical trials, begun in the second squarter, have been completed and final reports are being generated. The first was a double-blind, well-controlled trial conducted at 20 sites with a primary endpoint confirming long-term efficacy of Xyrem in reducing cataplexy attacks. The second trial was an open-label, twenty-five patient trial to assess dose-related effects of Xyrem on brain wave activity during sleep as measured by polysomnograms to further define clinical pharmacology. A third clinical trial, which the FDA has previously indicated is not required for the Company's NDA submission, continues to move forward toward completion late in 2001. This trial is a Phase III(b) controlled clinical trial assessing the efficacy of Xyrem for treating excessive daytime sleepiness (EDS) related to narcolepsy as its primary endpoint.

Dr. Jed Black, director of the Stanford Sleep Disorders Center, answers our questions about Xyrem in a brief interview.

Is Xyrem Dangerous?

Like many drugs, Xyrem has both proponents and opponents. A recent Business Week article (October 23,2000) referred to Xyrem as a Jekyll and Hyde drug. While the drug seems to provide amazing results to narcolepsy patients, its main ingredient is gamma hydroxybutyric acid or GHB, which has been called a "date-rape drug." GHB is relatively easy to make, and instructions on how to make it can be found on the Internet.

Because it is colorless, it is easy to add GHB to someone's drink. Since it is known for its ability to create a sexual high and euphoria on the dance floor, it has become a regular on the rave scene. However, GHB slows down the central nervous system, and when taken in large doses (especially if combined with alcohol) it can lead to coma or even death. More than 1600 emergency room visits and over 60 deaths have been attributed to GHB in the last decade in the US.

Because of this, GHB has developed a lethal reputation, leading the Drug Enforcement Agency to seek to classify it as a Schedule One substance, just like heroin and LSD. After intense lobbying by Orphan Medical, the Narcolepsy Network, the National Sleep Foundation and the National Organization of Rare Diseases (NORD) a compromise was reached. In February 2000, President Clinton signed the Date Rape Prohibition Act of 2000, categorizing GHB as a dangerous drug with no medical benefits, but granting Orphan Medical an exemption to pursue research and market the drug for narcolepsy if approved by the FDA.

Orphan now faces a battle at the state level to insure that the drug will be available to narcoleptics, since the states can set stricter standards than the federal government. Also at tissue is how to control the distribution of the drug so that it is only used for narcoleptic patients.

Narcolepsy Patients Say Xyrem Helps Them Live a More Normal Life

Patients involved in the clinical trials for Xyrem, or otherwise taking GHB for their symptoms are adamant that the drug is safe and that it works to make their lives more normal. They are hopeful that the drug will become available as soon as possible.

"Xyrem has made an incredible difference in my life. In addition to adequately curbing my cataplexy it has virtually eliminated my sleep paralysis and Hypnagogic Hallucinations while also helping lessen my EDS due to the better quality sleep I am able to get at night. Xyrem has allowed me to not only discontinue my previous cataplexy medications of anti-depressants but I have also been able to significantly decrease my stimulant usage because of the better night time sleep." Those are the words of one patient, who prefers to remain anonymous.

Another patient, D.S., talks at length about his experience with GHB, and his similar results: (Editor's note: these comments have been edited slightly)

"Before I began treatment with GHB my symptoms had progressed to the point where I would absolutely not be able to remain awake numerous times throughout the day and night. Before I lost my job, I was falling asleep at work as many as 6 times a day. In a work environment where under pressure to perform and therefore fighting against sleep attacks with all my will, microsleeps would occur by the dozen."

"My Cataplexy was severe, invariably resulting in full collapse with the slightest trigger emotion. Even practicing rigorous emotional control it would not be unusual for me to have six episodes a day. To not practice this emotional control would result in many dozens of episodes a day. "

"Sleep Paralysis was a nightly occurrence and also occurred during naps at other times, both voluntary ones and involuntary ones. Hypnogogic and Hypnopompic Hallucinations were a common occurrence for me, as was Automatic Behavior."

"As for the impact the GHB has had on the above symptomology, daytime sleepiness became less immediately, I awoke from my first dose of GHB with the feeling of being refreshed from my sleep for the first time in almost a decade. Cataplexy was noticeably improved in the first few days as well. "

"Sleep Paralysis, which for me has been lifelong, completely disappeared in the first month along with the Hypnogogic and Hypnopompic Hallucinations, Cataplexy continued to become less and less and after 6 months disappeared completely. For the first time in over a decade I could freely allow myself to feel and express the full range of emotions without the slightest hint of Cataplexy rearing its ugly head."

"Excessive daytime sleepiness has not responded as successfully to GHB as my other symptoms, but the improvement is an order of magnitude above any relief I achieved from the standard treatments of stimulants combined with various antidepressants. "

"Over all, if I were to estimate that the standard pharmacology provided me with a 5 per cent improvement in my condition, then GHB gives me better than fifty per cent improvement for Excessive Daytime Sleepiness and the complete elimination of all other symptoms except Automatic Behavior. The improvement is that dramatic."

A third patient, Sharon, had these comments on her experience with Xyrem: "I had been taking Effexor for my severe cataplexy for over 5 years when I joined a Xyrem trial in September 1999. Effexor by itself had eliminated my cataplexy and had moderately improved my daytime sleepiness, but I was concerned about the long-term use of antidepressants. For me, the greatest benefit of Xyrem has been that it greatly improves my nighttime sleep, which in turn, further reduces my sleepiness during the day. I had a sleep study while taking Xyrem, and was pleasantly surprised at the results: my sleep architecture was normal! Whereas my first sleep study strongly supported a narcolepsy diagnosis, the results of the sleep study on Xyrem showed no evidence of an underlying sleep disorder!"

"Xyrem alone left me with some residual cataplexy, so I've chosen to combine Xyrem with Effexor. The primary benefits of adding Xyrem to my daily medications are 1) the consolidation of my nighttime sleep, 2) a further reduction in daytime sleepiness, and 3) an increase in the amount of deep sleep. Since the body's healing and restorative processes occur only during deep sleep (stages 3 and 4), Xyrem has got to produce additional benefits over the long term."

Xyrem Looks Promising

The impact of Xyrem on narcolepsy symptoms promises a tremendous improvement in the daily lives of narcolepsy patients, especially those who must cope with numerous cataplexy attacks. While obstacles still remain, Orphan Medical and thousands of narcolepsy patients are hopeful that this promising new drug will be approved soon. TalkAboutSleep will continue to follow this story and bring you updates as they occur