A next-generation, precision-targeted GABAA positive allosteric modulator (PAM) for the treatment of generalized anxiety disorder (GAD)

The inhibitory neurotransmitter GABA is a central player in the regulation of anxiety, and modulation of the GABAA receptor is a well-validated approach for controlling GAD symptoms.1,2 Nonselective GABAA modulators, such as benzodiazepines, have robust anxiolytic efficacy but are limited to short-term use due to the risk of drug dependence and significant side effects such as sedation and cognitive and motor impairment — consequences largely mediated by activation of α1 subunit–containing GABAA receptors.2-5

ENX-102 is a GABAA α2,3,5 PAM that blocks α1; it is advancing into Phase 2 studies for the treatment of GAD.6

This profile is expected to facilitate sustained efficacy with chronic dosing and a favorable safety and tolerability profile that minimizes many of the risks and side effects associated with α1-mediated GABAergic transmission. The bioavailability and receptor occupancy of ENX-102 were engineered to deliver a best-in-class pharmacologic profile.6

ENX-102 has shown strong anxiolytic effects in a gold-standard preclinical model of GAD. In clinical studies, ENX-102 was well tolerated, with a pharmacokinetic profile supporting rapid onset of action and a predictable dose-related exposure with oral, once-daily dosing without the need for dose titration.6

No new treatments for GAD have been approved in over a decade7 ⁠— novel approaches that can provide sustained anxiolytic efficacy while limiting the risk of addiction or dependence open the door to better care

+ References and Abbreviations

GABA, gamma-aminobutyric acid; GAD, generalized anxiety disorder; PAM, positive allosteric modulator.

1. DeMartini J, et al. Ann Intern Med. 2019;170:ITC49 –ITC64. 2. Nuss P. Neuropsychiatr Dis Treat. 2015;11:165–175. 3. Babaev O, et al. Exp Mol Med. 2018;50:1–16. 4. Gomez AF, et al. Expert Opin Pharmacother. 2018;19:883-894. 5. Vinkers CH & Olivier B. Adv Pharmacol Sci. 2012;2012:416864. 6. Engrail Therapeutics. Data on file. 7. Garakani A, et al. Front Psychiatry. 2020;11:595584.