The key ingredient in Silenor is doxepin, a tricyclic compound that has been used extensively for the treatment of depressive and anxiety disorders for about thirty years. A histamine-1 (H1) specific antagonist, Silenor has long been observed to have sedative effects and improve disrupted sleep patterns: Benadryl (diphenhydramine), an OTC allergy medicine, is an antihistamine commonly prescribed as an off-label sleep aid, but unlike low-dose doxepin, has several unwanted side effects including dry eye, dry mouth and excessive next day drowsiness. Somaxon's NDA for Silenor - low dose (3 mg and 6 mg), oral tablet formulation of doxepin - includes the data from four Phase 3 clinical trials.
BNET: Before we begin, could you clarify for BNET Pharma readers the difference between objective and subjective interpretation of clinical data in sleep studies?
Rich Pascoe: When measuring the efficacy of drugs for insomnia, the FDA looks for submitted trial data to include clinical endpoints that measure both objective and subjective outcomes, as each assesses different sides of a patient's sleep experience: (i) an agreed upon objective standard for measuring sleep is a polysomnography (PSG), a parametric tool which records physical and physiological processes, such as brain, eye movement, and breathing functions, during observed sleep periods in a lab setting; and (ii) the subjective component involves having the patient fill-out an accepted instrument, such as a sleep diary (self-rated questionnaire, assessing sleep quality - from perceived sleep quality and duration to daytime function) typically over a 1-month time interval.
BNET: Given the higher likelihood of observer bias with subjective global scoring, why even weight sleep diaries as efficacy endpoints?
RP: They are important for two reasons. First, they do provide important information about a respective drug's efficacy from the patient's point of view, and secondly, the FDA requires that subjective endpoints be measured and reported as approval criteria for a sedative hypnotic.
BNET: This is the second time the FDA has expressed doubts with the efficacy data in Silenor's NDA. Care to comment?
RP: The (first) Complete Response Letter received from the FDA on February 25 indicated that regulators did not find sufficient evidence to support the inclusion of "sleep onset" in the indication labeling - nor did the 1-mg dose show sufficient efficacy to warrant approval of that dosing strength. That said, clinical trials in adults and elderly patients with either transient insomnia or primary sleep maintenance insomnia did demonstrate statistically significant improvements compared to placebo in a range of primary and secondary endpoints, from wake after sleep onset (WASO) to subjective Total Sleep Time (sTST) throughout four-week treatment periods. Moreover, the primary endpoints in all of our placebo controlled clinical trials were met with statistical significance.
BNET: What about the recent Response Letter (received on December 7) in which the agency singled out a supposed "lack of robustness in the sustained sleep maintenance effects" measured subjectively in adult patients with primary insomnia?
RP: In April we hired independent third party statisticians to perform statistical analyses of Silenor's clinical data relating to the sustained durability of subjective sleep-maintenance efficacy in adults. Their principal conclusion was that the data contained in the NDA did demonstrate sustained subjective efficacy in the adult population and that the drug effect wasn't lost over the treatment period of 30 days.
It is important to note that Silenor has previously demonstrated efficacy in subjective sleep maintenance: a four-week elderly outpatient trial [SP-509] of Silenor 6 mg demonstrated no loss of drug effect relative to placebo and clinically significant improvements in Silenor-treated patients in the self-reported sleep maintenance endpoint.
BNET: I know that the FDA no longer stands on semantics like "approved" and "rejected" applications. Nonetheless, after two "do not pass go" Complete Response Letters and a declarative that no further clinical trials with Silenor were necessary - what else can one suppose is on regulators' minds - except diplomatically waiting for your company to voluntarily withdraw its NDA?
RP: Working with the FDA is a process. We believe Silenor has an important differentiated product profile and we are committed to working with the FDA to seek approval for Silenor and commercialize the product.