--NG2-73, a Novel GABA(A) Partial Agonist, Rapidly Induced Sleep in a Transient Insomnia Study (Phase 2a)
NG2-73 is a partial GABA(A) agonist with preference for receptors containing the (alpha)3 subunit. Preclinical studies suggest that this compound has sedative hypnotic effects, supporting development as a potential treatment for insomnia.
This double-blind, placebo-controlled, randomized, multi-center study was designed to determine the effects of 1,3,10 and 20mg of NG2-73 compared to placebo on sleep onset as measured by Latency to Persistent Sleep (LPS) in healthy adults. The study design incorporated a single-night, polysomnography (PSG) model of transient insomnia using both first night sleep laboratory adaptation and "phase-advance" effects. Subjects were dosed in the sleep laboratory 2.5 hours prior to median habitual bedtime. "Lights off" and PSG recording started 30 minutes later. Safety was monitored by adverse event recording, physical exams, vital signs, electrocardiogram (ECG) and clinical laboratory tests. 369 healthy subjects aged 24-63 with no self-reported sleep disorders were enrolled.
LPS was statistically significantly reduced, compared to placebo, at all doses of NG2-73, and demonstrated a dose-response relationship. The mean times for LPS were 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, resp ectively. NG2-73 also had a statistically significant effect on Total Sleep Time and Sleep Efficiency at doses of 3mg and above. All doses had a statistically significant effect on "refreshing sleep," which was subjectively rated by study participants. NG2-73 was generally well tolerated, with adverse events (AEs) primarily reflecting an extension of the drug's sedative effects, including sedation, somnolence and dizziness. There were no drug-related, serious AEs or discontinuations, and no clinically important changes in safety labs, vital signs, or ECGs.
In this study, NG2-73 was shown to be a potent, well-tolerated, sedative hypnotic that significantly reduced time to onset of persistent sleep versus placebo at all doses tested.
--Exposure-Response Modeling of the GABA(A) receptor partial agonist NG2-73: An Approach for Determining Target Onset and Duration of Sleep Efficacy while Minimizing Next Morning Effects (Phase 1)
NG2-73, a GABA(A) partial agonist with preference for activation of (alpha)3 subunit receptors, represents a potential insomnia treatment with comparable efficacy and potentially fewer safety concerns relative to existing therapeutics. As with all therapeutics, determination of appropriate dose(s) and dosage formulation(s) is imperative to an efficient development program. To assist informed decision making, NG2-73 clinical development is being supported through intensive Exposure-Response (ER) modeling, in order to identify an optimal pharmacokinetic (PK) profile for sleep onset and maintenance while minimizing next morning effects.
Study 1, a Phase 1 crossover study where 19 subjects received single oral doses (1, 3, 5, 10 mg NG2-73, zolpidem 10 mg (Z10), and placebo), compared ER between NG2-73 doses and zolpidem. Plasma concentrations associated with half-maximal visual analog scale effects were approximately 13-fold greater for zolpidem vs. NG2-73. Maximal concentration (Cmax) for NG2-73 10 mg was approximately 6 -fold less than Z10. Altogether, ER indicated an approximate 4-5 mg oral NG2-73 dose would provide similar maximal response relative to Z10, which supported Study 2 dose selection. From digit symbol substitution test (DSST) modeling, next morning NG2-73 concentrations of less than 2 ng/mL were targeted to minimize residual effects.
Study 2, a Phase 2a parallel group study (placebo, 1, 3, 10 and 20 mg NG2-73) in healthy adults (N=369, PK in 133 subjects), evaluated NG2-73 sleep onset (latency to persistent sleep, LPS) relative to placebo. NG2-73 Cmax related to half-maximal LPS decrease was less than Cmax observed from NG2-73 1 mg. DSST ER modeling consistently supported the less than 2 ng/mL target to minimize next morning effects.
ER models guided doses and formulations for ongoing Phase 2b patient studies, which aim to confirm these relationships in patients, and establish the concentrations necessary for sleep maintenance. Model-based development using ER will continue supporting informed NG2-73 clinical development decisions.
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