Safety, Tolerability, and Efficacy of PLX-200 in Patients With CLN3

This is a phase 3, double-blind, placebo-controlled, dose-titration study to evaluate escalating weight-based dose levels of PLX-200, provided as a solution that contains 15 mg/mL PLX-200 and administered orally using a syringe, as needed, twice daily (BID), 30 minutes before breakfast and dinner. Participants will enter the Titration Period, during which the starting dose of PLX-200 or placebo will be based on patient weight. Each patient's dose will be titrated upward on a weekly basis during the Titration Period, until he or she reaches a maximally tolerated dose (MTD) or the Week 5 dose for their weight category. The patient will then enter the Maintenance Period at the final Titration Period dose for a maximum of 60 weeks. Safety, efficacy, and pharmacokinetics will be assessed periodically. Thereafter, all patients will have the opportunity to receive active treatment in an Open-Label Extension (OLE) for an additional 36 weeks.

Inclusion criteria

• Male and female participants between the ages of 6 and 18 years of age. Any deviations from this age range must be approved by the Medical Monitor and Sponsor prior to entry into study.
• Has a diagnosis of "classic" CLN3 disease as determined by age of symptom onset (i.e., 4 to 7 years) and genetic analysis for a defect in the CLN3 (battenin) transmembrane gene at study entry. If no genotype information is available, blood will be collected for the CLN3 gene analysis at the Screening visit.
• Participant must have mild-to-moderate CLN3 disease documented by a total in the 3-domain score of 5 to 7 for the aggregate of the motor, language, and vision domains of the Hamburg Scale and a score of at least 2 in 2 of these 3 domains.
• Participant must be able to independently walk for a distance of at least 20 feet (6 meters).
• Participant must be able to tolerate swallowing oral medication.
• Participants who are of childbearing potential (i.e., have begun menstruation) must have a negative serum pregnancy test at Baseline before receiving PLX-200. Nursing mothers are excluded from participation in this study.
• Participants' parents/guardians must agree to comply in good faith with the conditions of the study, including attending all required baseline and follow-up assessments.
• Participant parents and legal guardians must sign the informed consent form, and participants will provide assent, depending on local regulations and developmental status.

Exclusion criteria

• Participant has asymptomatic CLN3 disease, defined as no evidence of neurological signs or symptoms attributed to CLN3 disease such as seizures, ataxia, language delay, or other developmental delays. Similarly, outliers who progress much more slowly or quickly compared to the rest of the study population will be excluded from study at the discretion of the PI in consultation with the Medical Monitor (e.g., c.1A > C start codon mutation).
• Participant has clinically documented generalized motor status epilepticus within 4 weeks of the Baseline visit (treatment may be postponed after discussion with the Medical Monitor until seizures are adequately controlled).
• Participant has another inherited neurologic disease in addition to CLN3 disease.
• Participant has another neurological illness that may cause cognitive or motor decline.
• Participants with enteral feeding with NG tubing and any difficulty in oral administration and/or absorption of study drug will be excluded.
• Participant requires ventilation support, except for noninvasive support at night (e.g., Continuous Positive Airway Pressure [CPAP], Bilevel Positive Airway Pressure [BiPAP]).
• Participant has moderate or severe hepatic dysfunction defined as alanine aminotransferase, aspartate aminotransferase, or total bilirubin >3x upper limit of normal (ULN) except for participants with Gilbert syndrome. Participant has primary biliary cirrhosis.
• Participant has anemia (defined as hemoglobin <10 g/dL or hematocrit <30%).
• Participant has a baseline serum creatinine >2 mg/dL.
• Participant has gallbladder disease (e.g., cholelithiasis or cholecystitis).
• Participant has hypersensitivity to gemfibrozil.
• Participant is using or requires treatment with 1. HMG-CoA reductase inhibitors, 2. repaglinide (Prandin®), 3. dasabuvir (Exviera®), 4. selexipag (Uptravi®), or 5. pioglitazone (Actos®).
• Since the participant may take anticoagulants, increased frequency of INR monitoring is essential to avoid potential toxic effects with concurrent PLX-200 and anticoagulants (in particular with warfarin).
• Participant has a medical condition or personal circumstance that, in the opinion of the Investigator, might compromise the participant's or parent/guardian's ability to comply with the protocol requirements, or compromise the participant's wellbeing, safety, or the interpretability of the study data.
• Participant has received any investigational product or medical device within 30 days of the Baseline visit that, in the Investigator's judgment, would make the participant ineligible or confound results. All subjects who have had an investigational product or products in the form of stem cell or gene therapy are excluded, regardless of when the therapy had been initiated and/or discontinued.