"Safety and Tolerability in Early Phase I Studies of NG2-73, a Novel GABA(A) Sleep Agent"
NG2-73 is a GABA(A) receptor partial agonist which is alpha-3 subunit preferring. In vivo animal experiments suggest that NG2-73 will be a potent sedative hypnotic and may have an improved side effect profile compared to zolpidem, with respect to ethanol interaction and learning and memory at equipotent hypnotic doses.
The first-in-human studies included a single ascending dose and a five day multiple dose study in healthy subjects. The single ascending dose study started at 0.1 mg of NG2-73 and was planned to ascend to 100 mg of NG2-73 as a powder in a bottle formulation. The multiple ascending dose study was designed to test five days of once per day administration of 5, 10 and 20 mg tablets of NG2-73.
In the single ascending dose study, 48 subjects were enrolled (38 male and 10 female); all 48 subjects completed the study. Doses administered ranged from 0.1 to 60 mg. The 60 mg dose proved to be the maximum tolerated dose, as defined by the depth of sedation. The time to maximum concentration (Tmax) ranged from 0.33 to 3 hours and the half-life (T1/2) was 1.1 to 1.4 hours for all dosage groups. NG2-73 exhibited linear increases in maximum concentration (Cmax) and area under-the-curve (AUC, 0-inf) with increasing doses.
In the multiple ascending dose study, 32 subjec ts were enrolled (20 male and 12 female). Repeated daily dosing of NG2-73 did not result in accumulation and NG2-73 exhibited linear pharmacokinetics. The ability of NG2-73 to produce drowsiness and sleepiness was confirmed by the sedation assessment scores on the Stanford Sleepiness Scale and Visual Analog Scale in the multiple ascending dose study. In both studies the safety and tolerability of the compound were confirmed by the absence of serious adverse events, clinically significant laboratory findings, oxygen saturation level alterations, and electrocardiogram (ECG) abnormalities.
In these studies, NG2-73 was shown to be a novel sedative hypnotic which exhibited linear pharmacokinetics and was well tolerated up to 60 mg. This dosage is estimated to be 10- to 20-times the anticipated therapeutic dose.
Neurogen Corporation is a drug discovery and development company focusing on small molecule drugs to improve the lives of patients suffering from disorders with significant unmet medical need, including insomnia, obesity, pain, Parkinson's disease, restless legs syndrome (RLS), and depression. Neurogen conducts its research and development independently and, when advantageous, collaborates with world-class pharmaceutical companies to access additional resources and expertise.
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Elaine Grimsell Dodge, 203-315-4615