Evaluation of PRAX-628 Efficacy and Safety in Adults with Focal Onset or Primary Generalized Tonic-Clonic Seizures: An Open-Label Clinical Trial

Trial ID: 2024-517061-16-01
Protocol: PRAX-628-212
Sponsor: Praxis Precision Medicines Inc.

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Diseases & Conditions

Generalised tonic-clonic seizure Partial seizures

Objectives

The primary objective of this clinical trial is to evaluate the **efficacy** of PRAX-628 on seizure frequency in adults with **focal onset seizures** (FOS) or **primary generalized tonic-clonic seizures** (PGTCS) who are currently taking anti-seizure medications (ASMs). This objective is clinically relevant as it aims to determine the potential of PRAX-628 to reduce seizure frequency, which is a critical factor in improving the quality of life for patients with these types of seizures.

Secondary objectives include:

Evaluating the efficacy of PRAX-628 on seizure frequency in adults with FOS or PGTCS currently taking ASMs.
Assessing the safety and tolerability of PRAX-628 in the same patient population. These objectives are important for understanding the overall benefit-risk profile of PRAX-628, ensuring that it is not only effective but also safe and well-tolerated by patients.

Participants

The clinical trial involves a total of **15 participants** diagnosed with **focal onset seizures** or **primary generalized tonic-clonic seizures**. The study population includes both male and female adults aged between 18 and 75 years. Participants are required to have a stable health status, specifically with stable doses of allowable antiseizure medications (ASMs) for at least four weeks prior to the screening period. The selection criteria necessitate that participants have a history of at least two countable focal onset seizures per month or one countable generalized tonic-clonic seizure per month in the three months preceding the screening. Additionally, participants must maintain a seizure diary with a minimum completion rate of 80% during the four-week screening period. The trial does not include any vulnerable populations, and the selection process ensures that participants have no progressive causes of epilepsy as confirmed by prior imaging studies. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy and safety of **PRAX-628** in adult patients diagnosed with focal onset seizures or primary generalized tonic-clonic seizures. This is a Phase 2, open-label trial, which means that both the researchers and participants are aware of the treatment being administered. The trial aims to assess the impact of **PRAX-628** on seizure frequency in adults who are currently on stable doses of anti-seizure medications (ASMs). The trial is expected to commence recruitment on December 15, 2024, and conclude by October 16, 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age between 18 and 75 years, a confirmed diagnosis of the specified seizure types, and a stable ASM regimen. The screening period will also involve the completion of a seizure diary to establish baseline seizure frequency. Following the screening, eligible participants will enter the treatment period, during which they will receive **PRAX-628** orally in capsule form, with a maximum daily dose of 30 mg and a total dose not exceeding 150 mg over the treatment period. The treatment period will last up to 8 weeks.

Throughout the trial, participants will attend follow-up visits to monitor the primary endpoint, which is the median percent change in monthly seizure frequency from the screening period to the treatment period. Secondary endpoints include the time to reach the same or higher number of monthly seizures, the impact on patient and clinician global impression scales, and the incidence of treatment-emergent adverse events (TEAEs). Vital signs, clinical laboratory results, ECG parameters, and suicidality will also be assessed. The end-of-study visit will occur after the treatment period to evaluate the overall outcomes and safety of the intervention.

Participant involvement is expected to last approximately 12 weeks, including the screening and treatment periods. Conditions that may lead to early termination from the study include non-compliance with the study protocol, the occurrence of severe adverse events, or withdrawal of consent by the participant. The trial is conducted in accordance with International Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, ensuring the integrity and reliability of the data collected.

Treatment

The clinical trial involves the administration of **PRAX-628**, an investigational medication developed by Praxis Precision Medicines Inc. **PRAX-628** is formulated as a **capsule** and is intended for oral administration. The active substance, also named **PRAX-628**, is of chemical origin. The trial protocol specifies a maximum daily dose of 30 mg, with a total maximum dose of 150 mg over the course of the treatment period. The treatment duration is set at a maximum of 8 weeks. The medication is not a pediatric formulation and is not classified as an orphan drug. The primary objective of the trial is to evaluate the efficacy of **PRAX-628** in reducing seizure frequency in adult patients with focal onset or primary generalized tonic-clonic seizures who are currently taking anti-seizure medications (ASMs).

In addition to the experimental treatment, participants will continue their standard-of-care therapy, which includes their current regimen of ASMs. The trial does not involve the use of a placebo or comparator treatment. Compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the prescribed regimen. Participants' seizure frequency and any adverse events will be closely monitored to assess the safety and efficacy of **PRAX-628**. The trial is designed to provide comprehensive data on the potential benefits and risks associated with the use of **PRAX-628** in the specified patient population.

Efficacy

The efficacy of PRAX-628 in adult patients with **focal onset seizures** (FOS) or **primary generalized tonic-clonic seizures** (PGTCS) will be assessed through a series of primary and secondary endpoints. The primary endpoint is the median percent change in monthly (28 days) seizure frequency from the Screening/Observation Period to the Treatment Period. This will provide a quantitative measure of the drug's impact on seizure reduction.

Secondary endpoints include the number of days after the first administration of PRAX-628 to reach the same number or higher of monthly seizures, the impact on Patient Global Impression of Severity (PGI-S) and Clinical Global Impression of Severity (CGI-S), and the incidence and severity of treatment-emergent adverse events (TEAEs), including discontinuation due to TEAEs. Additional secondary measures involve changes in vital signs, clinical laboratory results, ECG parameters, and suicidality as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS). The proportion of participants experiencing a ≥50% reduction in monthly seizure frequency (Responder Rate) and those achieving seizure freedom (100% reduction) will also be evaluated.

Data collection will occur at specified intervals throughout the trial, with efficacy assessments being conducted from the Screening/Observation Period through the Treatment Period. The trial is designed to ensure comprehensive evaluation of PRAX-628's efficacy in reducing seizure frequency and improving patient outcomes in the specified population.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Participant and caregiver (if applicable), is willing to sign an informed consent document in accordance with International Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, indicating that they understand the purpose of the clinical trial; understands, and can perform, complete, and comply with all the procedures and assessments that are required during the clinical trial, including the seizure diary and contraception, and is willing to participate in the clinical trial.
Aged ≥18 to ≤75 years of age at the time of Screening.
A diagnosis of focal onset, seizures or idiopathic generalized tonic clonic seizures according to the International League Against Epilepsy [ILAE] Classification of Epilepsy (Fisher et al 2017).
Prior to enrollment, evidence by computed tomography (CT) or magnetic resonance imaging (MRI) in the past that has ruled out a progressive cause of epilepsy.
Participant must have been receiving stable doses of allowable ASMs (a minimum of 1 and a maximum of 3 ASMs). ASM treatment must be stable for at least four weeks prior to the Screening/Observation Period (Visit 1).
Participant and/or caregiver (if applicable) self-reports at least 2 countable focal onset seizures per month for focal onset patients, or 1 countable generalized tonic-clonic seizure per month in the 3 months immediately prior to the Screening/Observation Period for PGTCS patients. (Note: Countable focal seizures are defined as 1. Focal aware seizures with observable signs; 2. Focal seizures with impaired awareness; and 3. Focal seizures to bilateral tonic-clonic seizures. 4. Primary Generalized tonic-clonic seizures)
Participant records at least 2 countable seizures during the Screening/Observation Period for focal onset patients, or 1 countable primary generalized tonic-clonic seizure during the Screening/Observation Period for PGTCS patients.
The participant’s seizure diary must be completed a minimum of approximately 80% of all days during the 4-week Screening/Observation Period.

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Exclusion Criteria

History of pseudo or psychogenic seizures, or cluster seizures only, within the 12-month period preceding study entry where the individual seizures cannot be counted, or an episode of convulsive status epilepticus requiring hospitalization and intubation in the 12 months prior to Screening.
Seizures secondary to illicit drug or alcohol use, ongoing infection, neoplasia, demyelinating disease, or central nervous system disease deemed progressive, metabolic illness, or progressive degenerative disease, progressive structural lesion or encephalopathy.
Planned epilepsy surgery during the course of the clinical trial.
History of neurosurgery for seizures <1 year prior to enrollment, or radiosurgery <2 years prior to enrollment.
Schizophrenia and obsessive-compulsive disorder, or other serious mental health disorders. Uncontrolled unipolar major depression where changes in pharmacotherapy are needed or anticipated during the study.
Active suicidal plan/intent in the past 6 months, or a history of suicide attempt in the last 2 years, or more than 1 lifetime suicide attempt.
Has any significant ongoing disease, disorder, laboratory abnormalities, alcohol or drug abuse or dependence, environmental factor, or ongoing or history of any psychiatric, medical, or surgical condition that in the judgement of the investigator in consultation with the medical monitor and/or sponsor designee, might jeopardize the participant’s safety or interfere with the absorption, distribution, metabolism or excretion of PRAX-628; or impact the clinical trial objectives; or interfere with the participation in the clinical trial.
Participants with a history of malignancy, myeloproliferative or lymphoproliferative disorders within the past 5 years are excluded. Exceptions:1) Participants with completely excised non-melanoma skin cancer (such as basal cell carcinoma or squamous cell carcinoma) or cervical carcinoma in situ are permitted at any time, 2) Participants with a history of other malignancies deemed cured by adequate treatment are also permitted at any time.
Has any of the following: persistently abnormal test results at Screening: a serum total bilirubin value >1.5×upper limit of normal (ULN); a serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value >3×ULN. As an exception, participants that present with elevated bilirubin in the absence of elevations in ALT or AST that fits the pattern of Gilbert’s syndrome may be enrolled after discussion with the medical monitor and/or sponsor designee if their conjugated bilirubin is below the ULN.
Subjects who are vulnerable including: subjects who are institutionalized, lack decisional capacity or are employees or dependent on the sponsor, investigator or trial site.”.
History of cardiac disease(s)/cardiac conduction disorders/or cardiac structural abnormality(ies) (e.g., atrial or ventricular septal defects, valvular heart disease, coarctation of the aorta, left bundle branch block, arrhythmias, Brugada syndrome, congenital heart disease, familial short QT syndrome, presence/history of long QT syndrome or QT interval corrected with the Fridericia formula (QTcF) >450 msec, or hypertrophic obstructive cardiomyopathy) or family history of sudden death or ventricular arrhythmias, including idiopathic ventricular fibrillation (non-clinically significant patent foramen ovale (PFO) is not considered exclusionary).
Is pregnant or breastfeeding at the time of Screening, or has a positive serum pregnancy test at Screening or is planning to become pregnant during the clinical trial or within 14 days of the last study drug dose
Has received any other experimental or investigational drug, device or other therapy within 30 days or 5 half-lives (whichever is longer) prior to Screening, or any prior use of gene therapy.
Vigabatrin: Use in the last 5 years without stable visual fields tested twice over the 12 months after the last dose of vigabatrin.
Felbamate: If used as a concomitant ASM, patients must be on felbamate for at least 2 years, with a stable dose for 2 months prior to Screening. If a patient received felbamate in the past, it must have been discontinued 2 months prior to Screening.
Participant is receiving a prohibited medications as per the prohibited concomitant medications section (Appendix 4).
History of allergies or a severe reaction to an ASM(s), including dermatological (e.g., Stevens-Johnson syndrome), hematological, or organ toxicity reactions.