A Phase 1 Trial Evaluating the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of PRAX-562 in Healthy Volunteers
Abstract number :
2.478
Submission category :
7. Anti-seizure Medications / 7B. Clinical Trials
Year :
2022
Submission ID :
2232932
Source :
www.aesnet.org
Presentation date :
12/4/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:28 AM
Authors :
Balaji Sriram, PhD – Praxis Precision Medicines; Rajeshwari Mahalingam, MBBS – Praxis Precision Medicines; Michael Oldham, MD, MPH – Praxis Precision Medicines; Corey Puryear - Praxis Precision Medicines; Prashant Bansal, PhD – Praxis Precision Medicines; Dharit Patel, MPH – Praxis Precision Medicines; Henry Jacotin, MD – Praxis Precision Medicines; Marjie Hard, PhD – Praxis Precision Medicines; Million Arefayene, PhD – Praxis Precision Medicines; Bernard Ravina, MD – Praxis Precision Medicines
This is a Late-Breaking abstract.
Rationale: Gain-of-function pathogenic variants in voltage-gated sodium channel (Nav) genes can increase persistent sodium current (persistent INa) leading to neuronal hyperexcitability and seizures observed in severe developmental and epileptic encephalopathies (DEEs). PRAX-562 is a next-generation NaV blocker with demonstrated potency and preference for persistent INa as well as limited effects on peak INa. This unique profile is expected to translate to a wider therapeutic window compared to current standard-of-care. Here we report findings from PRAX-562-102, a Phase 1 clinical trial characterizing the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of PRAX-562 in healthy adults.
Methods: PRAX-562-102 was a 2-part randomized, placebo-controlled Phase 1 trial in healthy participants aged 18-55 years. Part A evaluated the effects of 90mg PRAX-562 over 28 days (QD) vs. placebo. Part B evaluated the effects of oxcarbazepine (OXC) in combination with 120mg PRAX-562 (QD) vs. OXC alone over 28 days. PD effects were examined on quantitative EEG (qEEG) and stimulated EEG using auditory steady state response (ASSR).
Results: A total of 48 participants were enrolled (Part A, n=18 PRAX-562, n=12 placebo; Part B, n=14 0XC+PRAX-562, n=4 OXC+placebo). PRAX-562 exposure resulted in concentrations that exceeded the EC50 in the mouse maximal electroshock seizure (MES) model by 13-fold (based on Day 28 mean concentration), and was unaltered with OXC coadministration. PRAX-562 did not appear to alter the PK of OXC or its primary metabolite. _x000D_
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There were no clinically significant safety findings in vital signs, clinical laboratory results, physical exams, ECGs, or C-SSRS. TEAEs were mostly mild or moderate (100% Part A; 96% Part B). One Part B participant experienced 3 study drug related SAEs leading to study drug discontinuation. Part B was stopped early after 5 participants receiving OXC+PRAX-562 (including the participant with SAEs) developed TEAEs. _x000D_
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PD biomarker changes observed on qEEG and ASSR were exposure dependent, with the former observed across all spectral frequencies. Statistically significant differences between placebo and PRAX-562 were observed in Part A on qEEG (Delta, P=0.0013; Theta, P< 0.0001) and ASSR (phase-locking-factor, P=0.028; Evoked power, P=0.016). Statistically significant differences were observed in Part B participants receiving OXC+PRAX-562 vs. OXC alone on qEEG (Delta, P=0.012; Theta, P=0.018), but not ASSR. _x000D_
Anti-seizure Medications