• ENX-101 exhibited a favorable safety and pharmacokinetic profile in healthy volunteers
• ENX-101 was well tolerated following once-daily oral administration with no dose titration
• Translational biomarker data indicated target engagement consistent with anti-seizure activity
• Engrail plans to initiate the ENACT phase 2 trial in epilepsy
SAN DIEGO – June 7, 2022 – Engrail Therapeutics™ (Engrail) (the Company), a precision neuroscience company focused on the acquisition, development, and commercialization of transformational therapies, has announced positive results from a phase 1b clinical trial of ENX-101, a subtype-selective GABA-A positive allosteric modulator (PAM). The phase 1b clinical trial data were presented on June 6, 2022, at the 2022 Epilepsy Pipeline Conference in Santa Clara, California. Following these results and recent interaction with the US FDA that included alignment on the phase 2 development program, Engrail plans to initiate the ENACT Trial, an international multi-center phase 2 clinical trial to evaluate the efficacy and safety of ENX-101 in patients with focal epilepsy.
“We are excited to announce that repeated administration of ENX-101 showed a highly favorable safety and tolerability profile in healthy volunteers across a wide range of doses,” said Kimberly Vanover, Ph.D., chief scientific officer of Engrail Therapeutics. “Moreover, translational biomarker data provided strong evidence of target engagement by ENX-101 that we believe are predictive of positive clinical benefit in patients with epilepsy as well as other disorders of the central nervous system.”
ENX-101, administered orally once daily for ten days, was safe and well tolerated in healthy volunteers. There were no dose-related, clinically meaningful changes in vital signs, electrocardiograms, physical exams, or clinical laboratory values. Treatment-emergent adverse events (TEAEs) were generally mild and transient. There were no serious adverse events or severe adverse events reported. The most frequent TEAE associated with ENX-101 administration was mild and transient somnolence that occurred primarily during the first few days of dosing. ENX-101 exhibited predictable dose-related exposure with a half-life of approximately 20 hours.
ENX-101 exhibited activity across pharmacodynamic biomarkers confirming target engagement. Notably, ENX-101 decreased saccadic peak velocity, consistent with centrally acting GABA-A PAM pharmacology, and increased beta power of quantitative electroencephalogram (qEEG) recordings. ENX-101 exhibited little to no adverse effect on alertness, psychomotor function, or sustained attention with repeated administration. Additionally, ENX-101 did not show a sedative-like increase in qEEG delta power, rather, ENX-101 decreased delta power. Moreover, there was no evidence of tachyphylaxis to functional target engagement or tolerance to the central nervous system inhibitory effects of ENX-101 with repeated administration. Taken together, the data are consistent with a GABA-mediated pharmacodynamic profile that is distinct from sedative benzodiazepines and other non-selective GABA-A PAMs.
“The data generated to date with ENX-101 are highly encouraging. I look forward to seeing the translation of these results into outcomes in patients suffering from therapy resistant epilepsy – an inherently tough disease in need of better treatment options,” said Jacqueline French, M.D., professor of Neurology at NYU Langone Health’s Comprehensive Epilepsy Center.
Vikram Sudarsan, Ph.D., chief executive officer and president of Engrail added, “the positive ENX-101 phase 1b clinical results are just one of many important outcomes we expect to see from the organization over the coming years. We founded Engrail in 2019 with the aspiration of becoming a leading neuroscience company. Our stellar and experienced team has built a deep and differentiated pipeline spanning six unique programs, including two programs rapidly advancing to phase 2. We built this pipeline through thoughtful business development as well as internal drug discovery efforts and are now focused on advancing our entire portfolio.”
About the ENX-101-004 Phase 1b Trial
ENX-101-004 was a randomized, placebo-controlled multiple ascending dose trial conducted in healthy volunteers. ENX-101 or placebo was administered orally once daily in the morning for 10 days. Five cohorts (N=9; 6:3 active:placebo in each cohort) evaluated doses of 5, 10, 15, 25, and 50 mg ENX-101. The primary objective of the study was to evaluate the safety and tolerability of ENX-101 following repeated administration. Secondary objectives included the evaluation of the effects of ENX-101 on electrocardiogram (ECG) parameters, pharmacokinetic (PK) parameters, and a battery of pharmacodynamic biomarkers such as saccadic eye movement, quantitative electroencephalographic (qEEG) parameters, visual analog scales, and cognitive performance.
Following a Screening Period (Day -28 to Day -3), healthy volunteers meeting inclusion criteria were admitted to an inpatient clinical research center for a Baseline Period (Day -2 to Day -1). Study treatment was administered on Days 1 through 10 and participants were followed for an additional three days following the cessation of treatment and discharged on Day 13. The extensive biomarker battery was collected at Baseline and on Days 2 and 9. Safety and tolerability were assessed daily.
Targeting the gamma-aminobutyric acid A (GABA-A) receptor is a well-validated pharmacological approach for the treatment of epilepsy, anxiety, pain, and other centrally-mediated disorders. However, conventional, non-selective GABA-A modulators, such as benzodiazepines, have several liabilities limiting chronic use, primarily driven by GABA-A α1 subunit containing channels. ENX-101 is an investigational precision targeted GABA-A PAM that enhances neurotransmission in receptors containing α2, α3, and α5 subunits while blocking α1. This profile is thought to contribute to anti-seizure efficacy and a favorable safety profile while minimizing the undesirable effects associated with α1-mediated GABAergic neurotransmission. ENX-101 has been well-tolerated in clinical trials with once daily oral dosing and does not require dose titration.
About Engrail Therapeutics
Founded in 2019, Engrail is forging a new direction to reduce the enormous burden of diseases that impact the nervous system. At our core, we unite biological insights with clinically meaningful solutions to build and catalyze a diversified portfolio of transformative medicines. Harnessing our rigorous scientific approach to identify the most promising therapies, we leverage our flexible transaction model to advance assets with validated mechanisms and efficiently move them through development to commercialization. Our dedicated team is restless about ensuring our therapies ultimately reach patients with life-limiting diseases.
Engrail is supported by a long-term capital commitment from Pivotal Life Sciences. For more information, visit engrail.com.
Anil Vootkur, PharmD