Intermezzo 3.5 mg Achieves Greater Early Bioavailability Than Ambien 10 mg Despite 65% Lower Dose
BALTIMORE, June 11, 2008 /PRNewswire/ -- Data was presented today at the 22nd Annual Meeting of the Associated Professional Sleep Societies (APSS) demonstrating that within 20 minutes of administration, Intermezzo(R), an investigational low-dose, sublingual formulation of zolpidem, delivered overall bioavailability that was significantly greater than that produced by a swallowed Ambien(R) tablet containing a zolpidem dose that was nearly 3 times higher. Despite this higher initial bioavailability, zolpidem blood levels from sublingual 3.5 mg Intermezzo(R) were significantly lower four hours after administration than the levels produced by the 10 mg Ambien(R) dose. Transcept Pharmaceuticals is developing Intermezzo(R) for the treatment of insomnia characterized by middle-of-the-night (MOTN) awakenings with difficulty returning to sleep.
"One significant challenge in trying to help insomnia patients return to sleep after a middle-of-the-night awakening is that the most commonly prescribed bedtime medications are not designed to be taken as needed in the middle of the night without risking significant drowsiness the following day," said Thomas Roth, Ph.D., Chief of Sleep Medicine, Henry Ford Hospital Sleep Disorders and Research Center in Detroit and principal investigator in this study. "The only recourse to date for patients has been either to try to predict what nights they will awaken, or to take sleep medication every night at bedtime. Studies of Intermezzo(R) show promise in offering the first viable, 'use only when needed' option for treating awakenings in the middle of the night when they occur."
Intermezzo(R): Rapid bioavailability despite a lower dose
In the pharmacokinetic comparison study presented at APSS, 36 healthy subjects between the ages of 19 and 64 were randomized to receive either a 3.5 mg. Intermezzo(R) sublingual lozenge or a 10 mg. Ambien(R) tablet following an overnight fast. Bioavailability assessments began prior to dosing and continued for eight hours. Although Ambien(R) doses were approximately three times higher than those of Intermezzo(R), overall bioavailability at 5 minutes, 10 minutes and 20-minutes was significantly higher for Intermezzo 3.5 mg compared to Ambien(R) 10 mg. In a previous clinical sleep laboratory study, Intermezzo(R) 1.75 mg and 3.5 mg demonstrated a statistically significant improvement in latency to sleep onset vs. placebo; these are the lowest doses of zolpidem ever shown to be statistically effective vs. placebo in inducing sleep.
Another of the study's authors, Andrew Krystal, M.D., Associate Professor and Director of the Duke Clinic Sleep Laboratory, commented, "The Intermezzo(R) sublingual delivery system appears to markedly increase the early uptake of zolpidem. Combining early bioavailability with a low dose may offer patients who wake up in the middle of the night help in returning to sleep while potentially avoiding next day residual effects."
MOTN Awakenings: Redefining Insomnia
Middle-of-the-night (MOTN) or nocturnal awakenings have been reported to be one of the most common sleep problems, affecting approximately one-third of the adult population. According to a recent epidemiological study ("Nocturnal awakenings and comorbid disorders in the American general population" -- Journal of Psychiatric Research [in press], Maurice M. Ohayon, MD, DSc, PhD.), nocturnal awakenings are the most frequently reported insomnia symptom in the general population, with 35 percent of Americans experiencing awakenings at least three times per week and 23 percent waking up at least once every night. Ninety percent of the MOTN insomnia population report that their pattern of awakenings persists for at least six months and 50 percent report such insomnia problems lasting more than 5 years. Currently, there is no approved PRN ("use only when needed") treatment for MOTN insomnia.
"The prevalence and impact of nocturnal awakenings may require significant adjustments in how we define, diagnose and treat insomnia, which is currently approached in a one-size-fits-all fashion due to the limitations of available therapies," said Dr. Roth, who participated in a June 2008 APSS symposium convened to discuss the prevalence and consequences of nocturnal awakenings.
A Potential New Approach for Patients with Middle of the Night Awakenings
In a related APSS poster presentation, investigators described a study in which they sought to quantify the proportion of MOTN insomnia patients who would be suitable candidates for treatment with a rapidly effective and short-acting agent. Investigators monitored 654 patients participating in an insomnia clinical trial using an Interactive Voice Response System (IVRS) that patients called each night after a middle of the night awakening. This system tracked the time of awakenings and amount of bedtime remaining.
Of the original group, 300 met the study criteria and were verified to suffer from MOTN awakenings with difficulty returning to sleep. These patients experienced a weekly average of 5.2 such awakenings and more than 90 percent of these awakenings occurred with at least four hours of bedtime remaining.
"Nearly all patients in this study experienced frequent awakenings at a time of night when they had at least four hours of sleep remaining. Thus, they would be appropriate candidates for treatment with a rapid-acting, low-dose medication," said Russell Rosenberg, Ph.D., principal study author and Director, NeuroTrials Research and the Atlanta School of Sleep Medicine. "The study underscored the potential for Intermezzo(R) to be useful in a patient population such as this."
To date, zolpidem has been available in the United States as the active agent in Ambien(R) and Ambien CRTM, prescribed for adults at 10 mg and 12.5 mg doses respectively. These amounts are between three and four times the highest Intermezzo(R) dose available.
It is estimated that over 15 billion doses of zolpidem have been prescribed since its original approval by the FDA. Zolpidem has been shown to be safe and effective for the treatment of insomnia, but the high dose products available in the U.S. and elsewhere have been designed to produce 6 to 8 hours of sleep, and are thus unsuitable for "as needed" treatment of patients who awaken in the middle of the night and have fewer hours remaining before waking up in the morning.
Intermezzo(R) (zolpidem tartrate sublingual lozenge) employs Transcept Pharmaceuticals' proprietary Bimucoral(R) technology in a mint-flavored, sublingual lozenge formulated to dissolve under the tongue in approximately two minutes. This novel approach has been shown to accelerate the bioavailability of zolpidem, despite the substantially lower Intermezzo(R) dose vs. the doses employed with previously available forms of the drug.
About Transcept Pharmaceuticals
Transcept Pharmaceuticals, Inc. is a specialty pharmaceutical company deriving significant new patient benefits from proven CNS drugs. Transcept development projects leverage new understanding of CNS conditions to provide additional uses and enhanced clinical benefits for existing active agents. The lead Transcept product candidate, Intermezzo(R) (zolpidem tartrate sublingual lozenge), is a low dose formulation of zolpidem for the treatment of insomnia in patients who awaken in the middle of the night and have difficulty returning to sleep. Phase 3 clinical trials have been completed for Intermezzo(R) and Transcept plans to submit an NDA in the third quarter of 2008. Transcept is also developing TO-2060, a novel, fixed-dose combination of olanzapine and ondansetron for the treatment of dopamine associated psychiatric disorders. For further information, please visit the company's website at: http://www.transcept.com.
Contacts: The Ruth Group Transcept Pharmaceuticals, Inc. Investors / Media Michael Gill Stephanie Carrington / Jason Rando Director of Communications (646) 536-7017 / 7025 (510) 215-3575 firstname.lastname@example.org email@example.com
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Posted: June 2008