Abstract Details

Title PRAX-562-102: A Phase 1 Trial Evaluating the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of PRAX-562 in Healthy Volunteers

Topic Child Neurology and Developmental Neurology

Presentation(s) P4 - Poster Session 4 (8:00 AM-9:00 AM)

Poster/Presentation
Number 4-011

Background

PRAX-562 is a next-generation sodium channel blocker with a unique profile expected to translate to a wider therapeutic window compared to current standard-of-care for severe DEE.

Objective

We report findings from a Phase 1 clinical trial characterizing the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of PRAX-562 in healthy adults.

Design/Methods

PRAX-562-102 was a randomized, placebo-controlled trial in healthy adults (18–55 years). Part A evaluated 90mg PRAX-562 over 28 days (QD) vs. placebo. Part B evaluated oxcarbazepine (OXC) in combination with 120mg PRAX-562 (QD) over 28 days vs. OXC alone. PD effects were examined on quantitative EEG (qEEG) and stimulated EEG (auditory steady state response, ASSR).

Results

48 participants were enrolled (Part A, n=18 PRAX-562, n=12 placebo; Part B, n=14 OXC+PRAX-562, n=4 OXC+placebo). PRAX-562 concentrations exceeded the EC₅₀ in the mouse maximal electroshock seizure (MES) model by 13-fold and was unaltered with OXC coadministration.

PRAX-562 was generally well tolerated in Part A. TEAEs were mostly mild or moderate (100% Part A; 96% Part B). Part B was stopped early after 5 participants receiving OXC+PRAX-562 developed TEAEs; one of whom experienced 3 study drug-related SAEs leading to study drug discontinuation.

Exposure-depended PD changes were observed on qEEG (all frequencies) and ASSR. 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), and in Part B participants receiving OXC+PRAX-562 vs. OXC alone on qEEG (Delta, P=0.012; Theta, P=0.018).

Conclusions

PRAX-562 was well tolerated in healthy adults at 90mg (Part A). Most AEs including SAEs in Part B were considered due to coadministration of projected supratherapeutic doses of PRAX-562 with OXC. Our PK and tolerability findings are consistent with a wide therapeutic window for PRAX-562, while PD findings indicate qEEG may be a sensitive translational biomarker of sodium channel blockade.

Authors/Disclosures
Brian Pfister PRESENTER	Dr. Pfister has received personal compensation for serving as an employee of PTC Therapeutics. Dr. Pfister has stock in PTC Therapeutics.
Rajeshwari Mahalingam, MD	Dr. Mahalingam has nothing to disclose.
Michael S. Oldham, MD, MPH	Dr. Oldham has received personal compensation for serving as an employee of Praxis Precision Medicines.
Corey Puryear, PhD (Praxis Precision Medicines)	Dr. Puryear has received personal compensation for serving as an employee of Praxis Precision Medicine. Dr. Puryear has stock in Praxis Precision Medicines.
	No disclosure on file
	No disclosure on file
	No disclosure on file
Henry Jacotin (Praxis)	No disclosure on file
	No disclosure on file
	No disclosure on file
Bernard M. Ravina, MD, MSCE (Voyager Therapeutics, Inc.)	Dr. Ravina has received personal compensation for serving as an employee of Praxis Precision Medicines. Dr. Ravina has stock in Praxis.
Marcio Souza	No disclosure on file
	No disclosure on file