"Effects of NG2-73 on Sleep Onset, Quality and Next Day Function in a Transient Insomnia Study" (Phase 2a)
NG2-73 is a partial agonist with preference for GABA(A) receptors containing the alpha-3 subunit. This mechanism of action may provide an important alternative to existing therapeutics for insomnia.
This double-blind, placebo-controlled, multi-center, randomized trial evaluated the efficacy of four dose groups of NG2-73 versus placebo in reducing Latency to Persistent Sleep (LPS) in healthy adults in a sleep laboratory, single-night, polysomnographic model of transient insomnia. This model of transient insomnia used both first night adaptation and "phase-advance" to create insomnia in healthy subjects. Subjects completed questionnaires assessing sleep effects, sleep quality, and next day functioning. Safety was monitored as per usual practice. Three hundred and sixty nine adults, aged 24 - 63, with no self-reported sleep disorders, were enrolled.
LPS was significantly reduced, compared to placebo, at all doses of NG2-73, in a dose-dependent manner with mean LPS of 30.8 minutes for the placebo group, and 17.8, 10.6, 7.8, and 6.6 minutes for the 1, 3, 10, and 20 mg NG2-73 groups, respectively. Subjective sleep latency (sSL) was significantly reduced compared to placebo at all doses. All four NG2-73 treatment groups reported that their sl eep had been significantly more refreshing than did the placebo group. At 1, 3, and 10mg, subjects felt alert and more than 87% of subjects considered their ability to concentrate as "very good" or "excellent" the morning following dosing, which was similar to the placebo group.
In this study, NG2-73 was generally well tolerated with adverse events (e.g. somnolence) attributable to the pharmacological action of the drug. There were no deaths, or drug-related serious adverse events or discontinuations, and no clinically important changes in safety laboratory reports, vital signs or electrocardiograms (ECGs).
In this study, NG2-73 was shown to be a potent sedative hypnotic which significantly reduced LPS at all doses tested, which was supported by subjective responses indicating rapid sSL. Most subjects expressed good concentration, alertness, and feeling refreshed the next morning. In this study, NG2-73 was also generally well-tolerated.
"Pharmacokinetic-Pharmacodynamic Effects of NG2-73, a Novel GABA(A) Agonist, and Zolpidem" (Phase 1)
NG2-73 is a GABA(A) receptor partial agonist which has preference for the alpha-3 subunit. In vivo animal experiments suggest that NG2-73 will have an improved side effect profile compared to zolpidem based on ethanol interaction and on assessments of learning and memory at equipotent hypnotic doses. The objectives of this study were to evaluate the relationship of dose, plasma concentration, and time to the pharmacokinetics (PK) and pharmacodynamics (PD) of NG2-73 at doses of 1, 3, 5, and 10 mg and zolpidem 10 mg versus placebo in healthy subjects.
This was a single-center, randomized, double-blind, placebo-controlled, six-way crossover study of single oral doses of NG2-73 administered to 19 healthy volunteers. Safety and tolerability were assessed, and kinetic-dynamic relationships were determined using plasma concentrations and multiple measures of PD including a visual analog scale of sedation (V AS), posturography (a method of quantifying balance), digit symbol substitution test (DSST), electroencephalogram beta frequency band (EBFB), and psychomotor vigilance testing (PVT).
In the primary analysis, NG2-73 had a statistically significant effect on sedation compared with placebo, and as measured by the Observer and the Subject VAS, there was a dose-response relationship. Similar effects were seen with the EBFB, DSST, PVT and posturography. Zolpidem 10 mg had effects that appeared similar to a dose between 3 mg and 5 mg of NG2-73. The duration of action of NG2-73 in the VAS ranged from approximately 1.5 hours for the 1 mg dose to approximately 6 hours with the 10mg dose. Zolpidem had a duration of action of approximately 6 hours. NG2-73 was well tolerated with no serious adverse events or withdrawals due to adverse events.
In this study, NG2-73 was shown to be a novel, potent, well tolerated, effective sedative hypnotic, with dose-dependent sedation lasting between 1.5 and 6 hours. There was consistency of effect across all PD measures.
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