PRAX-562-102: A Phase 1 Trial Evaluating the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of PRAX-562 in Healthy Volunteers
Rajeshwari Mahalingam1, Michael Oldham1, Prashant Bansal1, Balaji Sriram1, Dharit Patel1, Henry Jacotin1, Marjie Hard1, Million Arefayene1, Bernard Ravina1
1Praxis Precision Medicines
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.
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.
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.