Washington Editor

BETHESDA, Md. - An FDA advisory panel unanimously agreed that Cephalon Inc.'s wake-promoting agent, Provigil, is effective in treating excessive sleepiness associated with sleep apnea. And in a 6-2 vote, the panel said Cephalon's data supported the claim that Provigil is effective in the treatment of excessive sleepiness in patients with shift-worker sleep disorder.

But in a 4-4 vote, the Peripheral and Central Nervous System Drugs Advisory Committee Thursday was split when asked if Cephalon had proved Provigil's effectiveness in treating excessive sleepiness associated with "disorders of sleep and wakefulness," and the panel voted 5-3 in favor of the drug's safety in such a broad indication. (In truth, one panel member split his safety vote, making the actual tally 4.5 to 3.5.)

Following the meeting, Frank Baldino, chairman and CEO of West Chester, Pa.-based Cephalon, expressed his pleasure at the meeting's outcome in a conference call.

Baldino expects an "action" letter from the FDA by Oct. 20, the company's Prescription Drug User Fee Act, or PDUFA, date (federal law requires FDA action within a certain period of time). He cautioned that he's not positive the letter will grant approval at that time - there might be additional questions - but he believes the new indications will be on the label sometime in early 2004.

The FDA makes the final decision on all drug approvals and is not bound by committee recommendations.

Provigil (modafinil) is approved in the U.S. and 20 other countries for excessive daytime sleepiness associated with narcolepsy. Cephalon, of West Chester, Pa., said Provigil benefits patients through its ability to promote daytime wakefulness without affecting nighttime sleep.

While that claim might be true and useful in narcolepsy patients, several panel members were concerned about marketing Provigil to a vast, diverse population of patients who could be treated under such a broad label.

Since Provigil is meant to keep people awake, Lois Krahn, panel member and chair, department of psychiatry and psychology at the Mayo Clinic in Scottsdale, Ariz., asked FDA representatives if they would be able to keep people from misusing the product as a means of skipping sleep completely.

Absolute control by the FDA is not possible, said Russell Katz, the FDA's director of the division of neuropharmacologic drug products. Labeling and education, though, are generally the agency's best weapons.

Cehalon sNDA Filled With Clinical Data

There were other aspects of the Provigil supplemental new drug application that bothered some of the eight panel members.

Specifically, the company's decision to support its label expansion with studies of patients affected by narcolepsy, sleep apnea and shift-worker sleep disorder. And, as pointed out by several panel members as well as the FDA, Provigil is meant to treat symptoms of these illnesses, i.e., sleepiness, rather than the underlying causes of the disorders.

Cephalon arrived at the panel meeting armed with positive data from six clinical trials conducted over the last decade. Studies included in the sNDA were:

Two pivotal Phase III studies in narcolepsy, referred to as study 301 and study 302, which were part of the original NDA and included 558 patients. Results demonstrated that Provigil provides relief from symptoms of excessive sleepiness associated with narcolepsy. According to the company, the trials showed a significant increase in sleep latency for Provigil-treated patients compared to placebo-treated patients (p<0.001, at 200 mg and 400 mg).

Studies 303 (pivotal) and 402 evaluated patients suffering from residual excessive sleepiness associated with obstructive sleep apnea/hypopnea syndrome (OSAHS) who were adequately treated with a continuous positive airway pressure device (CPAP). Study 303, a 12-week trial, compared 191 patients treated with Provigil to 100 patients treated with placebo. The company said there was a significant increase from baseline in sleep latency for Provigil-treated patients compared to the placebo group (p<0.0001). Results were similar in study 402, which evaluated 75 patients treated with Provigil and 80 patients in the placebo group. (See BioWorld Today, Oct. 10, 2001.)

Studies 305 (pivotal) and 306. Study 305 evaluated patients with chronic shift-worker sleep disorder (SWSD), while Study 306 assessed the quality of life of Provigil patients with excessive sleepiness (ES) associated with SWSD. The company said evaluations of efficacy in SWSD show that intermittent administration of Provigil provides improvement in measures of excessive sleepiness associated with chronic SWSD. (See BioWorld Today, Oct. 24, 2002.)

The most common adverse events associated with Provigil were nausea and headache.

Expanded Label Could Make Provigil A Blockbuster

Provigil was first approved in 1998 in the U.S. as an orphan drug for patients with narcolepsy. Cephalon's orphan status expires in 2006 and its patent expires in 2014. (See BioWorld Today, Dec. 29, 1998.)

Some reports indicate that 80 percent of Provigil's U.S. sales are off-label, and with FDA approval of the expanded label, Cephalon could hope for blockbuster status.

A research note by Bill Tanner, managing director of Leerink Swann & Co. in Boston, said Cephalon has experienced revenue growth from $72 million in 2000 to $196 million in 2002. Absent the label expansion, Tanner said the U.S. market opportunity could stagnate at about $300 million to $400 million annually.

"Formal label expansion for Provigil will likely be necessary for strong revenue growth in the out years," Tanner said. "Although development of generic competitor[s] has become visible, the Provigil franchise should have protection for the next few years. Performance of [Cephalon] shares will be keyed to Provigil label expansion, better-than-sector-average, top- and bottom-line growth and ability to demonstrate effective defenses against encroaching generic competition."

Going forward, Cephalon might seek an indication for attention deficit hyperactivity disorder (ADHD) in children.

The company said positive results from a well-controlled trial using Provigil with children and adolescents who suffer from ADHD showed that the drug significantly improved symptoms of the disease. The company intends to conduct larger clinical trials in that area.

Cephalon's stock (NASDAQ:CEPH) rose $1.23 Thursday to close at $46.90.

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