A next-generation, precision-targeted GABAA positive allosteric modulator (PAM) for the treatment of focal (partial-onset) seizures

Seizures are typically provoked by uncontrolled excitatory neurotransmission.1 GABA, the primary inhibitory neurotransmitter in the brain, acts as a counterbalance to excitatory neurotransmission.2 Nonselective GABAA receptor modulators like benzodiazepines are highly effective in controlling seizures, but long-term use is generally limited by a rapid loss of efficacy and significant side effects, including sedation, cognitive impairment, and motor impairment. These undesirable effects largely result from activation of α1 subunit–containing GABAA receptors.3

ENX-101 enhances neurotransmission through GABAA receptors
α2, α3, or α5 subunits while blocking α1.4

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-101 were engineered to deliver a best-in-class pharmacologic profile. It may also be used synergistically with other antiseizure medications.4

In clinical studies, ENX-101 was well-tolerated with once-daily, oral dosing without a need for dose titration and demonstrated evidence of persistent target engagement predictive of antiseizure efficacy. The Phase 2 study (ENACT) is designed to assess ENX-101 for the treatment of focal seizures.4

Drug-resistant seizures are inherently difficult to manage5 — new treatment approaches with enhanced efficacy and improved tolerability may improve patient outcomes

+ References and Abbreviations

GABA, gamma-aminobutyric acid; PAM, positive allosteric modulator.

1. Righes Marafiga J, et al. Epilepsy Behav. 2021;121:106935. 2. Fu X, et al. Epilepsy. Brisbane (AU): Exon Publications. Online first 2022 Feb 25. 3. Vinkers CH & Olivier B. Adv Pharmacol Sci. 2012;2012:416864. 4. Engrail Therapeutics. Data on file. 5. Laxer KD, et al. Epilepsy Behav. 2014;37:59-70.