NG@-73 at Neuroscience 2007:
>>Program#/Poster#:
632.2/AAA17
Title:
III. Clinical trial data demonstrating sedative-hypnotic efficacy of the a3-subunit preferring GABAA receptor partial allosteric activator, NG2-73: Translational validity of pharmacokinetic/pharmacodynamic (PK/PD) relationships derived from preclinical studies
Location:
San Diego Convention Center: Halls B-H
Presentation Start/End Time:
Tuesday, Nov 06, 2007, 9:00 AM -10:00 AM
Authors:
*K. J. SPRENGER, L. ANEIRO, L. FUNG, Y. LIU, A. CHANGCHIT, L. RAJACHANDRAN, J. H. KEHNE, L. XIE;
Neurogen Corp., Branford, CT
NG2-73 is a partial allosteric activator at the benzodiazepine (BZD) site associated with GABAA receptor complexes, with greatest intrinsic activity at receptors containing a3-subunits1. NG2-73 shows sedative-like actions in animal models2 and, based on these and other data, this a3-subunit preferring GABAA receptor partial allosteric activator is proposed to be a unique treatment for sleep disorders differentiable from a1-subunit selective full allosteric activators such as zolpidem2. The present study summarizes early clinical data demonstrating efficacy of NG2-73 as a sedative-hypnotic agent and shows that preclinical studies have high validity and accuracy in predicting two key properties essential for a robust sedative-hypnotic: time to fall asleep and pharmacokinetics, particularly t½ and Tmax. Based on pharmacokinetic modeling and experimental data of t½ in rats (4.4 h), dogs (1.4 h), and monkey (0.5 h), the human plasma t½ after oral dosing was predicted to be approximately 0.6-1.3h. Furthermore, the Tmax was expected to be 1 h or less, based on physicochemical properties and Tmax measured in rat, dog, and chimpanzee. Predicted minimal efficacious concentration (MEC) in plasma, determined from a PK/PD experiment in rats at the time of sleep induction measured by behavioral observation, was 2.6 ng/mL2. Factoring in estimated protein binding in humans, the predicted MEC for sleep induction was 3.4 ng/mL and the dose to achieve the efficacious plasma concentration was < 1 mg. In a Phase 2 clinical trial using a transient insomnia model in healthy volunteers, 1 mg NG2-73 produced a statistically-significant reduction in Latency to Persistent Sleep relative to placebo (30.8 min vs 17.8 min, p < 0.01). The mean Cmax at this dose, measured in a subset of subjects at a second dosing, was 2.1 ± 0.83 ng/mL, the Tmax was 0.94 ± 0.45h and the t½ was 1.13 ± 0.40h. This short t½ may require that the compound be formulated with a different release rate to give optimal sleep onset and sleep maintenance effects. In summary, early clinical studies in humans confirmed preclinical predictions regarding t½ and sedative-hypnotic efficacy of orally-administered NG2-73. The close agreement between the predicted and actual MECs indicate that the ethologically-based animal model of sleep induction used has high translational value and that homologous mechanisms of sleep modulation by GABAA receptors exist across species. Overall, the data support the conclusion that NG2-73 represents a novel and effective approach for the treatment of insomnia.<<
I don't have time to look at this versus the PR. Any red flags? The stock has been in the crapper for weeks, and today as well. All time lows day after day, little new news. There is other preclinical data, and some aplindore stuff, too, I think. All is off embargo.
here's the abstract viewer:
sfn.abstractsonline.com
Just use "Neurogen" as the keyword and you should get everything. I'm on vacation, and busy with it, can't do much but check in from time to time.
Cheers, Tuck |
