High Dose PRAX-628 Achieves Complete Response in Phase 2a Study of Photo Paroxysmal Response

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In a small-scale study, treatment with PRAX-628 resulted in significant reduction in the number of generalized photo paroxysmal response events.

Marcio Souza, president and chief executive officer at Praxis

Marcio Souza

Praxis Precision Medicines recently announced positive topline data from its phase 2a proof of concept study assessing its investigational agent PRAX-628 patients with epilepsy who have photo paroxysmal response (PPR). Although the cohort was small in numbers, 100% of the patients in the 45 mg dosed group, the higher dose studied, achieved a complete response.1

The small-scale study featured 10 individuals who demonstrated PPR during screening who received either 15 mg or 45 mg of PRAX-628, or placebo. Patient electroencephalogram (EEG) signatures, an indicator of anti-seizure activity, were assessed at defined measurement points over a 24-hour period following treatment. After excluding 1 patient in the 45 mg cohort because of lack of eligibility, the remaining 3 patients all showed a complete response to treatment, defined as a reduction to 0 in the number of generalized PPR events.

A total of 6 patients were baselined in the 15 mg cohort, of whom 5 were evaluable. In this group, 4 (80%) achieved complete response while the remaining 1 showed partial response. Of note, 3 patients in the 15 mg cohort participated in the 45 mg cohort after a washout period of more than 100 day. In addition, 3 patients in the study were on background antiseizure medications.

"The strength and consistency of response across both study arms, combined with a continued positive tolerability and safety profile, build on our earlier conviction that PRAX-628 has the potential to be the first precision sodium channel modulator for focal epilepsy patients," Marcio Souza, president and chief executive officer at Praxis, said in a statement.1 "With such a clear response, we have advanced our planning of the focal epilepsy efficacy study for PRAX-628, expected to begin in the second half of 2024. We extend our thanks to the patients who participated in this PPR study."

READ MORE: NeuroVoices: Danielle Andrade, MD, MSc, FRCPC, on Challenges in the Transition from Pediatric to Adult Epilepsy Care

PRAX-628 a next-generation, functionally selective small molecule targeting the hyperexcitable state of sodium-channels in the brain, is being developed as an oral treatment for adult focal onset epilepsy. In a phase 1 study of healthy volunteers, the therapy was generally well tolerated all tested doses, with the most common treatment-related adverse events being fatigue, dizziness, somnolence, headache, disturbance in attention, and nausea.2

The study featured 40 healthy participants who were randomly assigned to PRAX-628 (n = 30) or placebo (n = 10). Single-ascending dose cohorts evaluated PRAX-628 doses ranging from 5 mg to 45 mg and multiple ascending dose cohorts evaluated PRAX-628 doses of 20 mg and 30 mg, with treatment resulting in more than 15-fold concentrations than the mouse Maximal Electroshock Seizure model (MES) EC50. Overall, there was no AEs that led to study drug withdrawal, as well as no serious AEs, clinically significant electrocardiogram findings, vital signs or neurological examinations.

At the 2023 American Academy of Neurology Annual Meeting, investigators presented in vivo data on the efficacy and tolerability of PRAX-628 using MES mouse models. Results showed that PRAX-628 (10 mg/kg) completely blocked evoked seizures (MES ED50: 0.67 mg/kg, brain EC50: 67.2 ng/g) without affecting spontaneous locomotor activity (TD50: 10.27 mg/kg; plasma TC50: 1123 ng/g; protective index [PI], 16.7). In contrast, standard of care carbamazepine and lamotrigine had PIs of 5-6x.3

REFERENCES
1. Praxis Precision Medicines reports positive results of PRAX-628 study evaluating photo paroxysmal response (PPR) achieving 100% response in treated patients. Praxis Precision Medicines. March 26, 2024. Accessed March 27, 2024. https://www.globenewswire.com/news-release/2024/03/26/2852195/0/en/Praxis-Precision-Medicines-Reports-Positive-Results-of-PRAX-628-Study-Evaluating-Photo-Paroxysmal-Response-PPR-Achieving-100-Response-in-Treated-Patients.html
2. Praxis Precision Medicines announces positive topline results from PRAX-628 phase 1 study enabling best-in-class profile. Praxis Precision Medicines. May 11, 2023. Accessed March 27, 2024. https://investors.praxismedicines.com/news-releases/news-release-details/praxis-precision-medicines-announces-positive-topline-results
3. Kahlig K, Eckert WA, Anderson L, Petrou S. PRAX-628 is a novel, well-tolerated, activity dependent sodium channel blocker with potent anticonvulsant activity. Presented at: 2023 AAN Annual Meeting; POSTER 4-012.
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