Editor

With a Phase III program in full swing for its insomnia drug Indiplon (formerly NBI-34060), Neurocrine Biosciences Inc. unveiled full Phase II data for the first time during the meeting of the Associated Professional Sleep Societies earlier this month in Chicago.

A yawner it wasn't. Others in the race for sleep medicines - such as Sepracor Inc. and Cephalon Inc. - also offered abstracts and results, providing enough material to keep attendees from lapsing into the arms of Morpheus for the five-day event.

The insomnia market is sizable. In the U.S., sleep products, excluding off-label use of central nervous system agents not indicated for the condition, sold about $1.4 billion in 2002, and the prescription sleep agent demand has grown at a rate of almost 25 percent for the past two years, according to IMS Health.

Available now are such treatments as the popular Ambien (zolpidem), marketed by Sanofi-Synthelabo SA, and Sonata (zaleplon), from Wyeth-Ayerst Laboratories Inc.

Sonata has "had some issues with potency," Phil Nadeau, analyst with SG Cowen Securities, told BioWorld Financial Watch, and NBI's drug Indiplon has been touted by the company as likely to serve those types of sleep disorders not covered by existing therapies. (See BioWorld Financial Watch, March 25, 2002.)

"Ambien is a good drug but it doesn't have the label we're looking for," said Paul Hawran, vice president and chief financial officer for NBI. "We're looking for long-term use."

Indiplon belongs to a new class called nonbenzodiazepines, acting like other drugs on the GABA-A receptor to promote sleep, and the company has an immediate-release (IR) version plus one for modified release (MR), data from both of which were highlighted at the APSS meeting.

The MR formulation would be used for sleep maintenance and IR targets those who wake in the middle of the night. Although Sonata is labeled for middle-of-the-night waking, Indiplon is expected to last longer. Ambien's term of efficacy is longer than Sonata's, NBI said, but must be taken before bed - which can mean a greater chance of hangover-like side effects, since it takes about 15 hours to clear from the body.

"It's absolutely critical" to deal with hangover effects, Hawran said. "A lot of drugs can put you out. Valium can put you out. The problem there is that its half-life will keep you drowsy or drugged for upwards of 24 hours."

Indiplon, partnered with Pfizer Inc., clears between five hours and 7.5 hours for most patients, NBI has noted, which means a patient could take the IR drug as late in the sleep cycle as 2 a.m., if needed. The MR drug tends to reach peak plasma levels later, but is still mostly gone upon waking, and seems to reduce waking as well as adding to the total sleep time.

A particularly troublesome aspect of the available drugs, as Hawran pointed out, is that they are prescribed only for seven to 10 days at a stretch, and for a maximum of 35 days. NBI is trying to get around that with Indiplon, too, although Hawran allowed that "Ambien is probably off label used for longer" than seven to 10 days.

Cowen's consultants said the same, Nadeau noted. They said the longer-term Ambien use is so prevalent that the longer label for Indiplon would be only an "incremental positive," while not getting such a label would be no disaster, Nadeau said.

The population most afflicted by insomnia - the elderly - proved likely to benefit from Indiplon in a Phase II study that was among those detailed during the APSS meeting. A 60-patient trial compared four doses of Indiplon-MR against placebo in subjects with at least a three-month history of difficulty maintaining sleep.

Mean sleep efficiency, which is the percentage of time the patient is asleep while in bed, was 74 percent for placebo; 75.9 percent for 10 mg of Indiplon; 80 percent for 20 mg; 81.3 percent for 30 mg; and 81 percent for 35 mg, adding up to a highly statistically significant score (p<0.0001) for the three higher doses.

The change in sleep efficiency came about as a result of the decrease in resistance in latency to persistent sleep (LPS) for all dose levels and a decrease in waking after sleep onset (WASO) - the amount of time the patient spends awake in bed after initially falling asleep - for the three higher doses.

With placebo, the LPS value was 26 minutes. For Indiplon, the value was 17.6 minutes at the 10 mg dose; 11.2 minutes at 20 mg; 11 minutes at 30 mg; and 9.9 minutes at 35 mg. As for waking after sleep onset, the placebo value was 103.2 minutes, as compared with 102.1 minutes, 87.3 minutes, 81.9 minutes and 83 minutes on the respective Indiplon doses.

There was no significant hangover effect in any of the doses. At 20 mg, the dose NBI has taken into Phase III trials, there were neither next-day residual effects nor an increase in adverse events compared to placebo. NBI has said it expects to complete the studies and file a new drug application around the end of this year.

Some Phase III data have been trickling out, Hawran told BioWorld Financial Watch, but the major results are expected October and November.

"You're going to be seeing [more data on] the MR formulation coming out," he said. "A lot of people are interested in that."

At the sleep meeting NBI also offered results with Indiplon-IR in 42 elderly patients given one of three doses for two nights in a row. With efficacy measured by polysomnography, there were significant improvements in latency to persistent sleep, along with subjective total sleep time and sleep quality as compared to placebo - again with none of the hangover effects that can bedevil insomnia drugs.

Enter Estorra (eszopiclone), the Sepracor drug, the NDA for which was accepted April 1. The first Phase III data were presented last month and the company offered more at the APSS meeting. Efficacy seems high; experts consulted by Cowen believe Estorra and Indiplon are "the only two drugs in development with the potential to keep patients asleep throughout the night," according to a research report.

Though Sepracor has insisted Estorra carries no hangover side effects, a Cowen report said some investors and physicians are still skeptical. Data disclosed at the APSS meeting showed no hangover, but "some physicians were questioning whether the measures were taken at the correct time," the Cowen report said.

"The tests were taken 9.5 hours after lights out, and some physicians wondered whether there would have been appreciable hangover had the measures been taken an hour earlier, a time perhaps more representative of when a normal person gets out of bed," the report said.

Hawran said there is "a standard time when you measure. Ours has always been 8.5 hours after you take the drug," and no hangover effects were seen. Another potential drawback of Estorra found by Cowen: 34 percent of patients in the most recently reported trial didn't like the taste.

"Our consultants didn't seem to think taste mattered at all, but hangover was more of a split issue," Nadeau said, adding that Cowen's experts believe hangover problems with Estorra, should they appear, "won't be anything fatal to the compound."

Results with Estorra have been compelling, and the drug is seen as a likely head-to-head competitor with Indiplon. Investors knew all six Phase III trials with Estorra have come up positive, but of particular interest to Cowen at the sleep meeting were new data from a six-week study in 308 chronic-insomnia patients testing Estorra. The patients were given a nighttime dose of placebo, 2 mg of the drug or 3 mg for 44 days in a row.

Efficacy was measured by polysomnography and morning questionnaires, and next-day residual effects evaluated between nine and 9.5 hours after lights out. Estorra proved, as in other trials, effective at helping patients start sleeping and stay asleep, with no evidence of "rebound insomnia" or insomnia worse than baseline levels once treatment was discontinued.

"It is interesting to note," Cowen said in the report, "that the patients in [this trial] were much better at maintaining sleep than those in Indiplon's Phase II trials (baseline WASO in Estorra's trial was 44 minutes, while Indiplon-MR's Phase II was 103 minutes), and therefore it is difficult to directly compare the ability of the two agents to help patients sleep throughout the night."

Hardly to be ignored at the APSS meeting - and customarily a major player - was Cephalon, with its approved narcolepsy drug Provigil (modafinil). The company put forth 11 abstracts and two symposia, as well as hosting a cocktail party, but already had declared all Phase III trials in shift-work wakefulness and sleep apnea were positive, and Cephalon has submitted a supplemental NDA to expand the Provigil label beyond narcolepsy.

The insomnia market, Cowen's sleep physicians said, is huge, with the condition affecting approximately one-third to one-half of American adults, only 9 percent to 17 percent of whom are using any treatment. Consultants were impressed with Indiplon and Estorra, noting the former's two versions - and added to the growing sentiment a vote of confidence for Provigil against daytime sleepiness.

Still, they said Indiplon and Estorra's most likely first use will be in patients who are refractory to market leader Ambien, with its strong efficacy and faithful users.

"Between Indiplon or Estorra, our consultants are unsure which will capture the role of second-choice therapy," said a Cowen report. "Although Indiplon's two formulations will be attractive to some doctors (such as sleep specialists), our consultants think that some primary care physicians may not like the added complexity, and therefore might shy away from Indiplon toward Estorra."

Hawran, though, said NBI has done many marketing studies that found the dual formulation "seems to be the choice among doctors, certainly among sleep specialists. We think Indiplon will be first line."

Nadeau agreed Indiplon likely will take the spot - eventually.

"It will take them a little while to unseat Ambien," which faces another problem in that it is destined for generic competition, he said.

There's room for everybody, Nadeau added.

"If you look at the sales of Ambien over time, it was only a moderately growing product until Sonata was launched in the U.S.," he said. Sonata's availability served to raise the awareness of insomnia drugs. Sales of Ambien soared.

"You can see the same thing happening once Pfizer and Sepracor get into the sleep market," Nadeau said, noting that many insomniacs still "don't know there's something out there that will work."