In a move that could significantly expand the market potential for Xyrem, Orphan Medical Inc. submitted a supplemental new drug application for the oral solution to help reduce excessive daytime sleepiness (EDS) and improve fragmented nighttime sleep.

The product was approved in July 2002 to treat cataplexy, a sudden loss of muscle tone and a debilitating symptom of narcolepsy. That market has brought the Minneapolis-based company about $10.5 million to $11 million in U.S. sales during 2004, but the potential at peak is about $50 million. (See BioWorld Today, July 19, 2002.)

An expansion of the Xyrem label to include improvement in other primary symptoms of narcolepsy could mean a quintupling of the sales potential to an estimated $275 million annually, said Tim McGrath, Orphan Medical's vice president and chief financial officer.

"It raises the market potential and certainly provides us with the opportunity to market for the expanded indication beyond cataplexy associated with narcolepsy," he told BioWorld Today.

A decision from the FDA is expected in 10 months.

The sNDA is based on two Phase IIIb studies in EDS, and positive data relating to the treatment of other narcolepsy symptoms. A double-blind, placebo-controlled, randomized trial known as SXB-15 assessed 228 patients over eight weeks in 48 sleep centers in North America and Europe. Trial results demonstrated statistically significant improvement in Epworth Sleepiness Scale scores at the 6- and 9-gram daily doses. A second trial, called Exceeds, evaluated the improvement of EDS associated with narcolepsy when Xyrem was used alone or with Provigil (modafinil, Cephalon Inc.). That trial showed that the combined use of the drugs showed a greater response than either agent alone. Provigil was approved in 1998 to treat narcolepsy.

"The trials show that there's additional improvement in the symptoms when Xyrem is added to their medication base," McGrath said. "Xyrem improves cataplexy as much as 90 percent and symptoms associated with daytime sleepiness significantly, as well."

The most common dose-related adverse events observed in clinical trials were nausea, dizziness, headache, vomiting, somnolence and enuresis.

Xyrem (sodium oxybate) is the first and only approved treatment for cataplexy, and there are no treatments that cover all of the primary symptoms of narcolepsy. Before Xyrem was introduced, physicians prescribed antidepressants to treat cataplexy, stimulant medications for EDS, and sedative-hypnotic drugs for disrupted nighttime sleep.

Narcolepsy affects between 100,000 and 140,000 Americans, and about 50,000 of them receive some sort of treatment for their symptoms. An estimated 60 percent to 90 percent of those patients suffer from cataplexy, while they all suffer from EDS.

John Bullion, Orphan Medical's CEO, said the market could grow substantially above the $275 million amount the company is targeting. He said the assumption is that only about half of narcolepsy patients are diagnosed.

In October 2003, Orphan Medical licensed the European sales and marketing rights for Xyrem to Celltech Pharmaceuticals, a unit of Celltech Group plc, of Slough, UK (later bought by UCB Pharma). Terms included a $2.5 million up-front payment to Orphan Medical, $13 million in product development and sales-related milestones, as well as royalties. The rights are for the use of Xyrem in narcolepsy, but Celltech could negotiate in the future for the license to cover additional indications.

A marketing authorization application to market Xyrem in the European Union is pending, and a decision is expected by the end of the second quarter, McGrath said.

The sNDA filing closes out the development program for narcolepsy, but Orphan Medical continues to develop Xyrem for fibromyalgia. The company expects results from a proof-of-principle trial this summer. It also is studying Xyrem in other indications, which are not yet disclosed.

"We have estimated that the market for fibromyalgia exceeds $1 billion," McGrath said.

He confirmed that the company had a strategy from the start of gaining approval for the smaller cataplexy market with the goal of expanding Xyrem into other, more prosperous indications.

The Phase II fibromyalgia study completed enrollment in December of 150 patients who will complete a three-month trial with an eight-week active-treatment period. It will assess the impact of Xyrem on fibromyalgia and the sleep disturbance that usually accompanies it.

Sales of Xyrem account for about half of the $21 million in product revenues Orphan Medical expects to post for 2004. The rest comes from the company's other two products, Antizol (fomepizole) injection for ethylene glycol or methanol poisoning, and Cystadane (betaine anhydrous for oral solution) for homocystinuria

Orphan Medical's stock (NASDAQ:ORPH) dropped 8 cents on Tuesday to close at $8.62.