Abstracts

Rationale: Developmental and epileptic encephalopathies (DEEs) are devastating neurological disorders presenting in infancy and early childhood, characterized by severe and frequent seizures, developmental delay, intellectual disability, and other comorbidities. Poor prognosis, increased risk of early death, and limited treatment options constitute a significant burden for affected patients and caregivers. _x000D_ _x000D_ Gain-of-function pathogenic variants in voltage-gated sodium channel (NaV) genes cause several severe DEEs. These mutations can increase persistent sodium current (persistent INa), leading to neuronal hyperexcitability and seizures. PRAX-562 is a next-generation NaV blocker in clinical development with demonstrated potency and preference for persistent INa as well as limited effects on peak INa. We hypothesize this unique profile may translate to improved tolerability over standard-of-care treatments for DEEs. _x000D_ _x000D_ Here we report preliminary findings from a first-in-human clinical trial evaluating safety, tolerability, and pharmacokinetics (PK) of single and multiple ascending doses of PRAX-562, as well as the effect of food on PK of a single dose in healthy adults. _x000D_
Methods: PRAX-562-101 was a 3-part Phase 1 trial in healthy participants aged 18-55 years. Parts A and B were randomized, placebo-controlled and evaluated the effects of single (2.5-150 mg) and multiple (30-120 mg, 14 days QD) ascending oral doses of PRAX-562, respectively. Part C was an open-label, randomized, crossover design evaluating the PK of a single oral dose (90 mg) in fasted and fed states. In Parts A (n=64) and B (n=32), participants were randomized 3:1 to PRAX-562 or placebo (n=8/cohort). In Part C (n=16), participants were randomized 1:1 to one of two treatment sequences receiving PRAX-562 in the fed (following a high-fat/high-calorie meal) or fasted (≥10 h after the last, and 4h before the next, meal) state. 

Results: 112 participants were enrolled across the trial (n=88 PRAX-562, n=24 placebo). PRAX-562 was well-tolerated with no clinically significant safety findings in vital signs, clinical laboratory results, physical exams, ECGs, or C-SSRS data. TEAEs were mild (>92%); the most common being catheter-site related, headache and dizziness. _x000D_ _x000D_ Exposure increased dose proportionally over the evaluated dose range. PRAX-562 rapidly appeared in plasma with time to observed maximum concentration (tmax) between 2 and 3h, and detectable levels over a dose interval. Administration of a 90-mg dose in the fed state resulted in a slight increase in Cmax (9%), delay in tmax (4 vs. 2.5 h), and a modest increase in AUC (14%) compared to fasted state. _x000D_
Conclusions: PRAX-562 was well tolerated in healthy participants at single doses up to 150 mg (fasted) in Part A, at multiple doses of up to 120 mg QD for 14 days (fasted) in Part B, and at a single dose of 90 mg in the fed and fasted states in Part C. Our findings further suggest that PRAX-562 can be administered without regard for food. 

Funding: Praxis Precision Medicines