Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of PLX-200 in Pediatric Patients (Master Protocol)

This is an open-label, proof-of-concept, Phase 2 basket trial evaluating the safety, tolerability, and clinical activity of PLX-200 in pediatric participants with lysosomal storage disorders (LSDs) including CLN2, CLN3, Sandhoff disease, and Krabbe disease. Participants will receive PLX-200 oral solution twice daily (BID) for approximately 101 weeks, comprising of a 5-week Titration Period and 96-week Maintenance Period. Clinical activity will be evaluated using synthetic control comparisons. Dosing strategies and study durations for all other indications will be defined in their respective ISAs.

Inclusion criteria

• Male or female participants aged 2 to 15 years at the time of informed consent. Any deviations must be approved in advance by the Medical Monitor and Sponsor.
• Genetically confirmed diagnosis of one of the four LSDs included in this study: CLN2, CLN3, Sandhoff disease or Krabbe disease. Diagnosis must be supported by all of the following:

• Age of symptom onset consistent with the targeted subtype,
• Relevant clinical manifestations, and
• Documented genotype at Screening or prior to enrollment. If no genotype is available at Screening, blood samples will be collected for genetic analysis as part of study procedures.
• Written informed consent must be obtained from the participant's parent(s) or legal guardian(s). Assent must also be obtained from the participant, when applicable, in accordance with local regulations and the participant's developmental status.
• Parent(s) or legal guardian(s) must demonstrate willingness and ability to comply with the protocol, including adherence to all required baseline, treatment, and follow-up assessments.

Exclusion criteria

• The participant has a known inherited neurologic disease other than the targeted lysosomal storage disorder subtype.
• The participant has a neurological illness unrelated to the study indication that may independently cause cognitive or motor decline.
• The participant requires ventilatory support, except for noninvasive support during sleep (e.g., Continuous Positive Airway Pressure [CPAP], Bilevel Positive Airway Pressure [BiPAP]).
• The participant has moderate or severe hepatic dysfunction, defined as alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin greater than 3 times the upper limit of normal (ULN), except in cases of Gilbert syndrome. The participant has a diagnosis of primary biliary cirrhosis.
• The participant has clinically significant anemia
• The participant has a body surface area (BSA)-adjusted eGFR <90 mL/min/1.73m2 at Screening or baseline.
• The participant has a history or current diagnosis of gallbladder disease (e.g., cholelithiasis or cholecystitis).
• The participant has a known hypersensitivity to gemfibrozil or any component of the study drug.
• The participant is currently using, or is expected to require during the study, any of the following medications which are contraindicated with PLX-200:

• HMG-CoA reductase inhibitors
• Repaglinide (Prandin®)
• Dasabuvir (Exviera®)
• Selexipag (Uptravi®)
• Pioglitazone (Actos®)
• Fibrate medication (e.g., gemfibrozil, fenofibrate). Participants must not have received gemfibrozil or other fibrates for at least 2 weeks or five half-lives, whichever is shorter, before Visit 2 (Day 1). They may not receive gemfibrozil or other fibrates during the study
• Participants receiving Zavesca® (miglustat) or any other prohibited therapies must be willing to discontinue these therapies, complete a washout period (2 weeks or five half-lives, whichever is shorter) prior to Visit 2 (Day 1), and refrain from receiving them while they are participating in the study. If participants were previously on Brineura®, they must complete a 3-month washout period prior to Visit 2 (Day 1) and refrain from receiving it while they are participating in the study.
• The participant has a medical condition or personal circumstance that, in the opinion of the Investigator or Sponsor, could compromise safety, protocol compliance, or the interpretability of study data.
• The participant has received any investigational product or medical device within 30 days prior to the baseline visit that could confound study results or pose additional risk. All participants who have previously received stem cell or gene therapy are excluded regardless of timing.
• The participant receives systemic anticoagulant therapy (e.g., warfarin) and is unable or unwilling to comply with increased frequency of INR monitoring during study participation. Note: Participants may be eligible if receiving anticoagulants (e.g., warfarin) provided that INR can be monitored with increased frequency and dose adjustments are implemented to maintain therapeutic range and avoid bleeding complications.
• The participant has uncontrolled seizures, defined as ≥4 generalized tonic-clonic seizures per month or a recent episode of status epilepticus.
• The participant has severe central nervous system abnormalities (e.g., hydrocephalus, intracranial shunt).
• The participant has a history of clinically significant arrhythmia or QTc prolongation at Screening or baseline.
• The participant is pregnant or breastfeeding or is a female showing signs of pubertal development (e.g., Tanner Stage ≥2) who is unable or unwilling to undergo pregnancy testing at Screening or baseline. All such determinations must involve consultation with the Medical Monitor and follow the procedures outlined in each ISA.