Somaxon Presents Pharmacological Data on Doxepin at the 21st European College of Neuropsychopharmacology Congress

Business Wire, Sept 2, 2008

Study confirms doxepin, the active ingredient in Silenor[R] for the treatment of insomnia, as a potent and specific histamine antagonist

SAN DIEGO -- Somaxon Pharmaceuticals, Inc. (Nasdaq:SOMX), a specialty pharmaceutical company focused on the in-licensing and development of proprietary product candidates for the treatment of diseases and disorders in the fields of psychiatry and neurology, today announced that data from a pharmacological profiling study relating to doxepin, the active ingredient in the company's product candidate Silenor for the treatment of insomnia, were presented yesterday at the 21st European College of Neuropsychopharmacology (ECNP) Congress.

The data presented at the ECNP Congress are from a study that examined the in vitro pharmacological profile of doxepin. The study evaluated the relative affinity and functional activity of doxepin at various central nervous system (CNS) targets known to play a role in its overall pharmacological profile.

The results demonstrate that doxepin has high affinity for and potent antagonistic activity at the human H1 histamine receptor, which is thought to be a primary mediator of the sleep-wake cycle. In addition, doxepin was shown to have lower or little affinity for a number of other CNS binding sites.

It is hypothesized that at the point in the circadian cycle during which the release of histamine and wakefulness are both naturally reduced, blocking the H1 receptor can further reduce wakefulness and promote the initiation and maintenance of sleep. The high potency of doxepin as an H1 antagonist represents the likely mechanism for its sleep-promoting effects and provides a potential explanation for its efficacy in humans at oral doses of 1 mg, 3 mg and 6 mg, the doses evaluated in the company's clinical trials of Silenor for the treatment of insomnia. In addition, the relative selectivity of doxepin for H1 as compared to a number of other neuropharmacological sites may account for the low incidence in such clinical trials of adverse events that have been associated with higher doses (25 mg to 50 mg) of doxepin.

"When the dose of doxepin is lowered to the 1-6 mg range, the clinical profile appears to be consistent with that of a selective H1 antagonist," said Philip Jochelson, M.D., Somaxon's Senior Vice President and Chief Medical Officer. "We believe that this selectivity may explain the clinical efficacy and safety profile of Silenor observed in our clinical development program for the treatment of insomnia. Specifically, in our controlled clinical trials of the 1 mg, 3 mg and 6 mg doses of doxepin contained in Silenor, improvements were demonstrated in measures of sleep onset, sleep maintenance and prevention of early awakenings, with no anticholinergic effects and no clinically meaningful next-day residual effects."

Somaxon's clinical trials for Silenor also demonstrated a low dropout rate and no evidence of amnesia, complex sleep behaviors, hallucinations, tolerance or withdrawal effects.

A summary of the poster presentation delivered at the ECNP annual meeting is as follows:

In Vitro Pharmacological Profile of Doxepin, a Sleep-Promoting Histamine H1 Antagonist

The study evaluated the affinity of doxepin at CNS targets known to play a role in its overall pharmacological profile. Functional assays were performed at selected sites of interest. Three comparison agents with established use in insomnia (trazodone, diphenhydramine and doxylamine) were also evaluated.

Doxepin was found to have high affinity and potency as an antagonist at the H1 receptor. Doxepin had measurable affinity for various adrenergic, muscarinic and serotonergic sites, but these affinities were substantially lower than for the H1 receptor.

Trazodone, an antidepressant frequently prescribed off-label for the treatment of insomnia, had low affinity for the H1 site. The antihistaminergic sleep aids diphenhydramine and doxylamine had relatively high affinity for the H1 site, but bound to muscarinic sites as well. Doxepin's superior margin of selectivity for H1 versus muscarinic M1 receptors may help explain the reduced incidence of anticholinergic side effects observed with Silenor compared with that of over-the-counter antihistamines used in insomnia, which typically contain diphenhydramine or doxylamine.

About Silenor

Silenor is a low-dose (1 mg, 3 mg and 6 mg) oral tablet formulation of doxepin hydrochloride that is patent protected for use in insomnia. Doxepin has been prescribed for more than 35 years for the treatment of depression and anxiety at dosages typically ranging from 75 mg to 300 mg per day. At these higher doses used for these indications, doxepin is known to have a range of undesirable side effects, including anticholinergic and next-day residual effects. However, based upon the controlled clinical trials of Silenor completed by Somaxon, the company believes that Silenor will be well tolerated by patients. In addition, the FDA has indicated that it will recommend that Silenor not be scheduled as a controlled substance.