With cancer, heart disease, AIDS, hepatitis C and inflammatory devils such as rheumatoid arthritis tormenting the world populace, hardly anybody's losing sleep over insomnia.
But most of those afflicted with the condition would pay dearly for a drug that would help them get shut-eye. About 85 million people in the U.S. suffer from sleep disorders, and the pharmaceutical information company IMS Health says the market in this country for prescription sleep products is almost $1 billion annually, and growing at a rate of about 30 percent per year.
Analyst Michael King with Robertson Stephens said Ambien (zolpidem), the amnesia drug marketed by Sanofi-Synthelabo SA, "will do close to $1 billion [in sales] this year. Clearly, with a product with a better profile, you can go even higher than that."
In happy agreement was Henry Pan, chief scientific officer of Neurocrine Biosciences Inc., which last week took the wraps off a Phase III program with its insomnia drug that will include eight trials and about 3,500 patients.
Although the company knew at the end of its Phase II investigations that the next step would be large, officials noted that last week's was the first public disclosure of the program's formidable size.
"This is a huge market with so many different patients with different types of insomnia," Pan said. "We all have some form of insomnia in our lives, but no single patient has one type of insomnia," Pan added, distinguishing chronic insomnia from transient insomnia, and separating the insomnia that bothers adults from the condition as it appears in elderly patients.
"That by itself there tells you [Neurocrine's Phase III effort] won't be a small program," he said, vowing that it will "definitely cover the spectrum" of insomnia types not served by two treatments available now: Ambien, and Wyeth-Ayerst Laboratories Inc.'s Sonata (zaleplon).
Neurocrine's drug, NBI-34060, belongs to a new class called non-benzodiazepines, acting on the GABA-A receptor to promote sleep, and the company has two versions of it. One is for immediate release (IR), and one for modified release (MR).
"The IR and MR formulations are two different programs," and the patients can't cross over, Pan said. "Safety you can cross, but not efficacy. The dose is different, and so is the target population."
MR would be used for sleep maintenance a market that, analysts note, is hardly well-enough served and IR for those who wake in the middle of the night, Pan said. For the latter indication, only Sonata has a label, but it's believed to have a shorter term of action than Neurocrine's drug. Ambien's term of action is longer, but must be taken before bed.
"In order to understand the possible differences between our drugs and other drugs on the market, we need to understand the pharmacokinetics," Pan said. With the existing drugs, "for a person who takes [them] before bedtime, by the time the patient wakes up, there's still a lot of it left in his circulation," which can mean hangover-like side effects, he said.
Ambien, for example, "is a good drug, but it certainly has a longer half-life than our drug three hours, three and a half hours, which means it takes about 15 hours to clear from the body," Pan told BioWorld Financial Watch. "Our compound has about a one-and-a-half-hour half-life, which means it will be cleared between five and seven-and-a-half hours for most patients."
IR allows for dosing when needed. "What [other] drug can patients take in the middle of the night? This, they can take at 2 a.m.," Pan said. "Those patients who only have problems with sleep induction, and occasional problems [that require dosing] in the middle of the night, will benefit from out IR formulation."
As for MR, "even though it reaches peak plasma levels a little later, by the time the patient gets up there will be very little left," he said. The available drugs all boast reduced latency to persistent sleep, but staying asleep is what troubles many insomniacs and that's what may give MR an edge, since it seems not only to benefit total sleep time but also reduces waking.
Perhaps even worse than the long half-life of currently available drugs is that they can be prescribed only for seven to 10 days at a time, with a maximum of 35 days. Neurocrine is seeking a label for much longer treatment.
That's one reason why Neurocrine's studies won't be completed until the end of next year, with a new drug application filing expected toward the end of 2003.
"It's not just to broaden the use, but increase the duration of treatment way beyond seven to 20 days," Pan said, adding that Neurocrine wants the FDA to let doctors prescribe its drug for "six months, if not beyond six months for up to one year."
The company has a "very broad Phase IIIb program and Phase IV, to further define the profile of our drug," he said. "What happens to shift workers, and individuals who travel across time zones? Are there ways we can help them sleep better in a hotel room?"
Also on the near horizon is Sepracor Inc.'s drug Estorra (esopiclone, formerly known as zoplicone, licensed by Sepracor from Rhone-Poulenc Rorer SA [now Aventis SA] in 1999) for chronic and transient insomnia. The product has completed three pivotal studies and 19 clinical trials with about 2,000 patients. The company is preparing a new drug application.
In a quarterly report last year, Sepracor said it and FDA officials took part in a pre-NDA meeting in October, "at which there was discussion concerning the completeness of the data package."
Pan acknowledged that Sepracor is working on a single isomer of esoplicone. King told BioWorld Financial Watch "there are rumors that Sanofi has another molecule, like a 'son of Ambien,' but it's very hush-hush. It's GABA-ergic, but supposedly in the clinic for something else. We're monitoring it. I haven't heard anything yet."
Because of the flexibility in Neurocrine's two forms, King said, he's sold on that company's approach as opposed to any of the others.
"You would have modified release with the [label] claim for chronic insomnia, and immediate release for transient insomnia, so you would tailor your therapy to the kind of condition you've got," he said.
Middle-of-the-night dosing is important, King added. Although Sonata can be taken that way, "they never marketed it effectively. I don't think Wyeth knows what it's got, frankly. And then [Sonata] has the hangover effect."
Neurocrine has more going for it, he said, most notably the CRF receptor program in anxiety and depression, and farther back in the pipeline the oral GnRH antagonists, with potential application in prostate cancer and endometriosis.
But the news of the moment involves insomnia. Neurocrine's twin drug seems ideal for what ails non-sleepers, targeting all varieties and even enabling doctors to prescribe both versions, if needed, for the same patient.
Said King: "This is the classic 'right drug at the right time.'"