The study met all 3 of its primary end points of change from baseline in mean sleep latency on the Maintenance of Wakefulness test, Clinical Global Impression Improvement, and weekly cataplexy attacks within the 6-, 7.5-, and 9-g groups. Kushida, MD, PhD, director, Stanford Center for Human Sleep Research, randomly assigned 222 patients with narcolepsy type 1 or type 2, all aged 16 years or older, to receive uptitration doses of 4.5 g, 6 g, 7.5 g, and 9 g of FT218 or placebo over the course of a 3-week screening period, a 13-week treatment period, and a 1-week follow-up period. The new drug application (NDA) was supported by data from the phase 3 REST-ON study (NCT02720744), which was held under a special protocol assessment agreement with the FDA.
1 Previously, the therapy was known as FT218. (See also postscript remarks).The FDA has granted tentative approval to Avadel Pharmaceuticals’ extended-release oral suspension formulation of sodium oxybate, marketed as Lumryz, for the treatment of excessive daytime sleepiness (EDS) or cataplexy in adults with narcolepsy. It may thus be possible to develop new pharmacological compounds that specifically target abnormal symptoms in narcolepsy, but do not disturb physiological sleep/wake cycles. Studies in canine narcolepsy also suggest that mechanisms and brain sites for triggering cataplexy are not identical to those regulating REM sleep. Pharmacological studies have shown that blockade of norepinephrine uptake mediates the anticataplectic effect of currently prescribed antidepressants, while blockade of dopamine uptake and/or stimulation of dopamine release mediates the awake-promoting effect of CNS stimulants. Experiments using canine narcolepsy have demonstrated that increased cholinergic and decreased monoaminergic transmission are likely to be at the basis of the pathophysiology of the disorder. The canine model is an invaluable resource for studying the pharmacological and physiological control of EDS and cataplexy. These compounds disturb nocturnal sleep in many patients, and tolerance may develop as a result of continuous treatment. These treatments are purely symptomatic and induce numerous side effects. Human narcolepsy is currently treated with central nervous system (CNS) stimulants for EDS and antidepressants for cataplexy and abnormal REM sleep. Positional cloning of this gene is in progress, and a human homologue of this gene, or a gene with a functional relationship to canarc-1, might be involved in some human cases. A highly-penetrant single autosomal recessive gene, canarc-1, is involved in the transmission of narcolepsy in Doberman pinschers and Labrador retrievers. Both sporadic and familial cases are also observed in this animal species. Narcolepsy was reported to exist in canines in the early 1970s. In addition, environmental factors are involved in disease predisposition most monozygotic twins pairs reported in the literature are discordant for narcolepsy. Genetic transmission is, however, likely to be polygenic in most cases, and genetic factors other than HLA-DQ are also likely to be implicated. The disorder is tightly associated with the specific human leukocyte antigen (HLA) allele, DQB1*0602. Although most cases occur sporadically, familial clustering may be observed the risk of a first-degree relative of a narcoleptic developing narcolepsy is 10-40 times higher than in the general population. It is a frequently-occurring but under-diagnosed condition that affects 0.02 to 0.18% of the general population in various countries.
Narcolepsy is a disabling sleep disorder characterized by excessive daytime somnolence (EDS), cataplexy and REM sleep-related abnormalities.
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