PRAX-562-102: A Phase 1 Trial Evaluating the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of PRAX-562 in Healthy Volunteers (P4-9.011)

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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. Disclosure: Dr. Mahalingam has nothing to disclose. Dr. Oldham has received personal compensation for serving as an employee of 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. Dr. Bansal has received personal compensation for serving as an employee of Praxis precision medicines . Dr. Bansal has stock in Praxis Precision medicines . Dr. Sriram has received personal compensation for serving as an employee of Praxis Precision Medicines. Dr. Sriram has stock in Praxis Precision Medicines. Dr. Sriram has stock in Biogen Inc. Dr. Patel has received personal compensation for serving as an employee of Praxis Precision Medicines, Inc.. Dr. Patel has received personal compensation for serving as an employee of Noven Pharmaceuticals. Dr. Patel has stock in Praxis Precision Medicines, Inc.. Dr. Jacotin has received personal compensation for serving as an employee of Praxis Precision Medicines. Dr. Jacotin has received personal compensation for serving as an employee of Takeda. Dr. Jacotin has stock in Takeda. Dr. Jacotin has stock in Certara. Dr. Jacotin has stock in Clover Health. Dr. Jacotin has stock in Coinbase. Marjie Hard has nothing to disclose. Dr. Arefayene has nothing to disclose. Dr. Ravina has received personal compensation for serving as an employee of Praxis Precision Medicines. Dr. Ravina has stock in Praxis. Dr. Souza has received personal compensation for serving as an employee of Praxis Precision Medicines. Dr. Souza has stock in Praxis Precision Medicines. Steven Petrou has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Praxis Precision Medicines. Steven Petrou has stock in Praxis Precision Medicines. The institution of Steven Petrou has received research support from Praxis Precision Medicines. The institution of Steven Petrou has received research support from Medical Research Future Fund. Steven Petrou has received intellectual property interests from a discovery or technology relating to health care. Steven Petrou has received intellectual property interests from a discovery or technology relating to health care.

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