Reaction to Xyrem's "Approvable" Status

Minneapolis, MN - July 4, 2001

On Tuesday, July 3rd, Orphan Medical announced that the company had received an "Approvable Letter" from the Food and Drug Administration (FDA) regarding Xyrem®. The drug has been under priority review by the FDA for the treatment of cataplexy in persons with narcolepsy.

The FDA indicates that Xyrem is approvable, pending resolution of some final issues. The company will meet with the FDA as soon as possible to clarify the issues and begin work to meet the FDA's requirements, in order to obtain final approval to market Xyrem.

A Brief History

The road to approval of Xyrem has not been easy. In 1994, the FDA approached Orphan Medical to develop the drug now known as Xyrem. Because the patient population to be helped was so small, major pharmaceutical companies were not interested in the drug. By 1998, clinical trials were showing positive results.

However, since Xyrem's active ingredient is GHB (gamma hydroxybutyrate), there has been active public opposition to the use of the drug, as GHB is also known as the "date-rape" drug. GHB slows down the central nervous system. As with other depressants, like alcohol, a moderate dose can produce a feeling of relaxation. But large doses of GHB, especially when mixed with alcohol, can bring on coma and death. After some debate, Congress banned GHB, putting it in the same category as heroin. That law, however, did approve the scheduling of Xyrem as a potential treatment for narcolepsy. (More information on the early development of Xyrem)

In October of 2000, a New Drug Application (NDA) was submitted for the approval of Xyrem. Initial research results were favorable and the FDA granted Priority Review status to the NDA. Based on the original grant of Priority Review status, a decision on Xyrem had been expected in April of this year, but a March Advisory Committee meeting was rescheduled to early June to seek clarification of some data.

At the June meeting of the Peripheral and Central Nervous System Drugs Advisory Committee, committee members reviewed safety and efficacy data presented by Orphan Medical and conducted a public hearing for comments from interested parties. Xyrem® was then recommended for approval by the Committee.

Upon further review by the FDA, Xyrem was given "Approvable" status, with final approval to come after the issues outlined in the FDA letter of July 2nd are resolved.

Company Reaction

John Bullion, Orphan Medical CEO, told financial analysts that the additional requirements posed by the FDA are not major issues and that the company hopes to meet those requirements no later than the end of the year. The company's first priority is to meet with the FDA on these issues, to be sure that they are clearly defined and well understood.

Regarding the FDA's concern about the Good Manufacturing Practices (GMP) of Xyrem's manufacturer (currently under a warning letter from the FDA for products not related to Xyrem), Mr. Bullion pointed out that the manufacturer in question is a very large, well-established pharmaceutical maker who provides many products to the medical industry. The unnamed manufacturer is scheduled to meet with the FDA regarding the GMP issues this month, and Orphan expects that the pre-approval inspection of manufacturing facilities for Xyrem will take place as soon as the GMP issues are resolved.

Bullion also indicated that working out final product labeling and minor changes to the company's proposed risk-management program would not be difficult to accomplish.

Orphan's Medical Director and Chief Operating Officer, William Houghton, M.D., pointed out that the request for additional safety updates of on-going clinical trials was routine and occurs whenever there is a extension in the FDA timeline.

Perhaps the only surprise in the FDA requirements, said Mr. Bullion, was the requirement to conduct a clinical trial in patients with respiratory problems, such as Obstructive Sleep Apnea (OSA) and Chronic Obstructive Pulmonary Disease (COPD). This trial is to review the pharmacological impact of Xyrem on patients who have respiratory issues, but who do not have narcolepsy.

Dr. Houghton indicated that while the details of the trial would need to be discussed with the FDA, he anticipated a small trial of 30-40 patients, whose night-time oxygen and CO2 levels would be monitored following their use of a sleeping pill, a standard dose of Xyrem, and a standard dose of Xyrem combined with a stimulant. The logistics of finding a center to undertake the study, getting approval of the Institutional Review Board for that center, agreeing on the final protocol of the study and finding the patient population to be studied are not insurmountable, but they will take some time to accomplish.

Once that study is complete, the submission of new data gives the FDA an additional six month review period, but Dr. Houghton indicated that the nature of this trial would not likely require a lengthy review period.

Comments from the Sleep Community

Robert Cloud is Executive Director of the Narcolepsy Network, the patient support organization for persons with narcolepsy. He has actively followed the progress of the Xyrem trials and told TalkAboutSleep.com that "Speaking for Narcolepsy Network, we are very pleased that the FDA has approved the safety and efficacy data resulting from Orphan Medical's clinical trials these past years, and apparently recognizes the immense benefit this will bring to narcolepsy patients with cataplexy."

Commenting on the additional requirements outlined in the Approvable Letter, Cloud said "We understand that the additional issues the FDA wishes to resolve before granting final approval are common in the drug approval process, particularly when studying a drug which is subject to unlawful abuse by others. The concerns relating to final drug labeling, and refining the risk management program do not present serious difficulties. The same is true regarding the requirement that the drug manufacturer under go a new pre-approval inspection by the FDA regarding manufacturing practices."

"However, the FDA's requirement for a new clinical trial to measure the safety of Xyrem for patients with respiratory diseases is new, and was not previously required by the FDA," Cloud indicated. "I understand Orphan intends to promptly respond to this requirement, will design the trial in accord with FDA requirements, and hopes to complete it within the next several months. Accordingly, the several months required for final approval do not appear unreasonable. We are encouraged that final approval appears quite possible before the end of the year."

Robert Cloud is also a narcolepsy patient. He has been using Xyrem, always under FDA approved protocol, for 19 years, and believes he was the first American to use the product.

"I have found it to be extremely effective and safe in controlling of my substantial cataplexy and other REM symptoms associated with narcolepsy," Cloud stated. "I have never changed the dosage, noted side-effects, experienced tolerance or any withdrawal effects. The medication is as effective today as it was 19 years ago."

Cloud sees the light at the end of the tunnel, expecting Xyrem to become available early next year and perhaps sooner. "My hope is that all narcolepsy patients with cataplexy will soon be able to enjoy the very dramatic relief that I have experienced, so as to allow such patients to continue functioning as responsible family members, and able to resume their employment and civic responsibilities."

Sharon L. Merritt, RN, MSN, EdD, is Associate Professor and Director of the Center for Narcolepsy Research in the College of Nursing at the University of Illinois at Chicago. Reacting to the FDA announcement, she takes a cautious approach.

"Xyrem will be another compound available to treat cataplexy. I see it being used for people who cannot tolerate the antidepressants or do not receive adequate control from these traditional compounds. My understanding is that some people have achieved control of their cataplexy when other compounds were not effective. I do not think Xyrem will be for everyone, as are none of the other current compounds. Because none of the current medications are equally effective in everyone, I use the expression "what works for me." All medications have to be carefully titrated to the symptom experiences and circumstances of the particular individual."

Dr. Merritt has some concerns about the possible impact of the drug. "Because of the stuporous effects it has on night time sleep, I would tend to advise people who live (and sleep) alone not to try this compound."

"However," she said, "health care professionals have to be aware of the quality of life of people with narcolepsy -- for some individuals with narcolepsy, control of cataplexy could mean the difference between living a fairly normal life versus being confined to the home environment."

In a statement issued by the National Sleep Foundation (NSF), Richard L. Gelula, NSF's executive director, looked to future availability of Xyrem. "We hope that the availability of this new drug will foster faster diagnosis and more appropriate treatment for the thousands of Americans suffering from the debilitating and disabling effects of narcolepsy," Gelula said. He points out that no medications specifically indicated for the treatment of cataplexy are available to people with narcolepsy. "Current treatment options for cataplexy include medications with undesirable side effects," he said.

Gelula also noted that the onset of these disorders often occurs in people in their developmental years, from the mid-teens to the mid-twenties, before completion of psychological and emotional development, education, and a career path. Effective treatment of narcolepsy at this stage of life can help people maintain optimal life and career choices.