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

Anxiety disorders, like GAD, have become a major public health concern. In fact, the United States Preventive Task Force (USPTSF) now recommends routine screening for anxiety disorders in all adults under 65 years of age.1

Over 5.4 million Americans are currently receiving treatment for GAD, but based on claims data, >60% of them are not well managed on first- or second-line therapies, like SSRIs and SNRIs.2 Patients with ongoing GAD symptoms are susceptible to comorbid conditions, relapse, and poor treatment adherence.3 Even those who respond to treatment may not experience improvements in anxiety for months due to long dose titration periods.4,5

The inhibitory neurotransmitter GABA has a central role in regulating anxiety, and modulation of the GABAA receptor is a well-validated approach for controlling GAD symptoms.6,7 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, including sedation and cognitive and motor impairment. These consequences are largely mediated by activation of α1 subunit–containing GABAA receptors.7-10

ENX-102 is a GABAA α2,3,5 PAM that blocks α111

ENX-102 is expected to facilitate sustained efficacy with chronic dosing and favorable safety and tolerability to minimize 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.11

ENX-102 has shown strong anxiolytic effects in the gold-standard preclinical model of GAD. In clinical studies, ENX-102 was well tolerated, with pharmacokinetics that support rapid onset of action and a predictable dose-related exposure with oral, once-daily dosing without the need for dose titration.11

The efficacy and safety of ENX-102 as a monotherapy treatment for patients with GAD is being evaluated in a multi-center phase 2 study (the ENCalm study).

For more information on the ENCalm study, please click here: https://clinicaltrials.gov/study/NCT05749055

No new treatments for GAD have been approved in over a decade5 ⁠— 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; SNRI, selective norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor.

1. US Preventive Services Task Force. JAMA. 2023;329(24):2163–2170. 2. IQVIA Generalized Anxiety Disorder Claims Analysis. 2021. Data on file. 3. Tomsai J, et al. J Psychiatr Res. 2019;119:33–47. 4. Locke AB, et al. Am Fam Physician 2015;91:617–624. 5. Garakani A, et al. Front Psychiatry. 2020;11:595584. 6. DeMartini J, et al. Ann Intern Med. 2019;170:ITC49 –ITC64. 7. Nuss P. Neuropsychiatr Dis Treat. 2015;11:165–175. 8. Babaev O, et al. Exp Mol Med. 2018;50:1–16. 9. Gomez AF, et al. Expert Opin Pharmacother. 2018;19:883-894. 10. Vinkers CH & Olivier B. Adv Pharmacol Sci. 2012;2012:416864. 11. Engrail Therapeutics. Data on file.