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Submission to the FDA’s Regarding Hypersomnias

Submission to the FDA’s Regarding Hypersomnias

On September 24, 2013, the US Food and Drug Administration (FDA) held a public meeting to solicit information on the impact of narcolepsy on affected individuals’ daily lives and the effect of currently available medication on their disease symptoms.

A summary of that meeting, “The Voice of the Patient Report—Narcolepsy,” is available on the FDA’s web site. After the meeting, the FDA asked for additional input as part of its Patient-Focused Drug Development Initiative. This initiative is designed to ensure that the FDA pays proper attention to developing drugs for conditions that affect Americans. On behalf of the Hypersomnia Foundation, Drs. David Rye and Lynn-Marie Trotti from Emory University submitted the following letter to the FDA highlighting the need for additional attention to, and clear unmet needs among patients with, hypersomnia but not classic Type 1 narcolepsy.

RE:  FDA  DOCKET# –  2013-N-0815

We are clinician scientists board certified both in Sleep Medicine and Neurology with a combined 30 years of clinical experience that includes a particular focus on narcolepsy and related disorders collectively referred to as the “central hypersomnias”.  We are well published in the area and regularly participate in the annual patient conferences of the Narcolepsy Network.  We join with our patients in thanking you for your effort to reach out for input regarding the disease state(s) and especially the unmet needs of the patients who we treat. Having viewed the webcast of the recent September 24th public meeting on narcolepsy patient-focused drug development, we would like to add our voice to those of others.

Excessive daytime sleepiness remains common and the socioeconomic burden to the individual, family, and society is large.  Unfortunately, while routine sleep laboratory testing for genuine narcolepsy with cataplexy is sensitive, it is becoming clear that it is highly nonspecific.  The electrodiagnostic criteria for narcolepsy, for example, are satisfied by 2.5-4.0% of the general population 1,2, and even higher proportions of patients with comorbid sleep apnea, Parkinson’s disease, and end-stage renal disease.  Narcolepsy with cataplexy is caused by loss of the wake-promoting excitatory peptide hypocretin and manifests as discontinuous wake and sleep, abrupt transitions from wake to sleep, restorative naps, and the overt expression/experience of dream sleep phenomena such as cataplexy. What it is not associated with is hypersomnia – i.e., a condition characterized by abnormally long or frequent periods, or abnormal depth, of sleep.  Narcolepsy with cataplexy affects 1 in 2,000-4,000 individuals, and is the prototypical sleep disorder which medical students and physicians are first introduced to, and how they learn sleep biology.  There is therefore a deep rooted propensity to approach and treat any complaint of sleepiness as a loss-of function problem.  Conventional psychostimulants, newer wake promoting agents, and drugs in development to treat the excessive daytime sleepiness of “narcolepsy” are purposefully targeted to restore wake by way of enhancing neural pathways downstream from hypocretin.   In summary, a perfect storm is brewing for the overdiagnosis of “narcolepsy” and a real potential for the over prescribing of medications for its treatment.

With this background, we were not at all surprised to hear a number of presumed “narcolepsy” patients (and others at your April patient conference on Chronic Fatigue Syndrome) speak about the unmet clinical need that hypersomnia represents.  Despite feeling physically awake, we have heard innumerable stories of persistent cognitive problems and “brain fog” from hypersomnic patients prescribed conventional psychostimulants or wake promoting agents. Compelled by clinical intuition that these patients were not suffering from any loss in function (and finally brave enough to challenge a conventional wisdom that had even influenced our personal practice preferences for at least a decade), our team has recently shown, that a majority of patients suffering from hypersomnia do so because of an apparent gain in function in inhibitory GABAA receptor signaling due to a peptidergic somnogen3.  In this instance sleep is long, continuous, and unrefreshing, and followed by a transitional state of impaired consciousness termed “sleep drunkenness”.   Such a prolonged state of stupor that follows upon sleep has never been operationalized and its neural substrates remain ill-defined.  Thus, diagnostic means to differentiate the symptom of hypersomnia as part of, or distinct from, diagnoses such as narcolepsy without cataplexy, idiopathic hypersomnia, long sleeper syndrome, and depression and even chronic fatigue syndrome, and rational and effective treatments, have not been forthcoming.  The benzodiazepine antagonist flumazenil, which has little-to-no wake promoting actions in non-sleepy controls, reverses GABA enhancement in vitro, and normalized vigilance in seven of seven hypersomnic patients 3. Our serendipitous discovery that the macrolide antibiotic clarithromycin is also an antagonist at GABAA receptors, provided a rationale for its successful use in the central hypersomnias, where sustained improvements in vigilance were observed with off-label use 4, as well as in a double-blind, placebo-controlled, cross-over trial in 20 patients 5.

In summary, our experience in evaluating and treating nearly 500 patients with central hypersomnia would suggest that there is a well-defined group of genuine, hypocretin deficient, non-hypersomnic patients with narcolepsy who generally do quite well with the existing approved treatments.  The same can not be said of hypersomnics.   The prevalence remains ill-defined, but we are confident that it is greater than “rare” as stated in review articles and texts (we estimate a prevalence of at least ~ 1:800).  And, hypersomnia can be extraordinarily disabling.  In one-third of patients with hypersomnia, the magnitude of enhancement of GABA’s sleep-inducing effects is equivalent to: a) 5 mg of Versed®; b) a blood alcohol content of 0.10; and c) the psychomotor slowing that emerges after 30 hours of continuous wakefulness3.  We feel for these patients.  They are not simply “seized by sleep” as the narcoleptic with cataplexy, they are literally and figuratively consumed and transformed by it.  Many whom we have evaluated and treated are refractory to conventional wake promoting agents or experience intolerable side effects.  Strategies aimed at inhibiting sleep as opposed to promoting wake would appear more rational in that they would be targeted closer to the underlying pathophysiology.  In our hands such an approach to treatment continues to demonstrate remarkable and truly life altering results.

We hope that our perspective better informs the FDA in their future assessments of treatments being developed for narcolepsy versus hypersomnia.  Our ultimate desire is a more efficient means to diagnosis so that more rational and effective treatments can be instituted sooner, more knowledgeable about the risk-benefit ratios and cost.

References:

1.   Singh, M., Drake, C. L. & Roth, T. (2006). The prevalence of multiple sleep-onset REM periods in a population-based sample. Sleep 29, 890-5.

2.  Mignot, E., Lin, L., Finn, L., Lopes, C., Pluff, K., Sundstrom, M. L. & Young, T. (2006). Correlates of sleep-onset REM periods during the Multiple Sleep Latency Test in community adults.[see comment]. Brain129, 1609-23.

3.   Rye, D. B., Bliwise, D. L., Parker, K., Trotti, L. M., Saini, P., Fairley, J., Freeman, A., Garcia, P. S., Owens, M. J., Ritchie, J. C. & Jenkins, A. (2012). Modulation of vigilance in the primary hypersomnias by endogenous enhancement of GABAA receptors. Science Translational Medicine4, 161ra151.

4.   Trotti, L., Stout, A., Saini, P., Freeman, A., Jenkins, A., Garcia, P. & Rye, D. (2012).  Clarithromycin reduces sleepiness and improves vigilance in patients with central nervous system hypersomnias. Sleep35, A278.

5.   Trotti, L., Saini, S., Freeman, A., Bliwise, D., Jenkins, A., Garcia, P. & Rye, D. (2013). Clarithromycin for the treatment of hypersomnia: A randomized, double-blind, placebo-controlled, crossover trial. Sleep36, A248.



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