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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT04637282
Recruitment Status : Not yet recruiting
First Posted : November 19, 2020
Last Update Posted : December 4, 2020
Information provided by (Responsible Party):
Polaryx Therapeutics, Inc.

Brief Summary:
The purpose of this study is to evaluate the safety and efficacy of multiple doses of PLX-200 in subjects with CLN3 disease.

Condition or disease Intervention/treatment Phase
Juvenile Neuronal Ceroid Lipofuscinosis Drug: PLX-200 Phase 2

Detailed Description:
This is a phase 2, open-label, within-subject, 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 or through a gastric/jejunostomy tube 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 will be based on participant weight. Participants will receive the total daily dose in 2 equal doses approximately 12 hours apart. Each participant'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. After a participant reaches his or her MTD or the Week 5 dose is administered, he or she will complete the Titration Period at that dose and enter the Maintenance Period, during which the participant will receive the dose at which he or she completed the Titration Period. Safety, efficacy, and pharmacokinetics will be assessed periodically. The Maintenance Period will be dosing of PLX-200 for up to 144 weeks.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: Open-label, non-comparator, within subject, dose-titration trial
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Safety, Tolerability, and Efficacy Study of PLX-200 in Participants With Mild-to-Moderate Juvenile Neuronal Ceroid Lipofuscinosis (CLN3) Disease
Estimated Study Start Date : February 1, 2021
Estimated Primary Completion Date : February 1, 2023
Estimated Study Completion Date : August 1, 2024

Arm Intervention/treatment
This is an open-label, non-comparator, non-randomized study of PLX-200 in patients with CLN3 disease.
Drug: PLX-200
15 mg/mL oral PLX-200 solution administered twice daily

Primary Outcome Measures :
  1. Efficacy of PLX-200 in CLN3 as assessed by the mean rate of increase in the Physical domain sub-score of the Unified Batten Disease Rating Scale (UBDRS) clinical rating scale compared with that of the natural history data. [ Time Frame: 149 weeks ]
    The rate of increase in the Physical Domain sub-score of the UBDRS clinical rating scale will be calculated as the change from Baseline to the last assessment, divided by the length of follow-up (treatment period). Descriptive statistics of the rate of increase will be provided in the PLX-200 and historical cohorts. The scale is from 0 (normal physical assessment) to 104 (severe physical impairment).

  2. Number of patients with treatment-related adverse events, as assessed by CTCAE v5.0, abnormal laboratory results, and abnormal cardiovascular and/or abdominal findings. [ Time Frame: 149 weeks ]
    The aggregate of clinical chemistries, hematology, urinalysis, electrocardiogram readings, abdominal ultrasound findings, and tabulation of the number and severity of adverse events will be compared with baseline values throughout the study to evaluate the safety and tolerability of PLX-200 at escalating oral doses in children with CLN3 disease.

Secondary Outcome Measures :
  1. Efficacy of PLX in each of the domains of the Unified Batten Disease Rating Scale (UBDRS) including seizure, behavioral, and functional capabilities. [ Time Frame: 149 weeks ]
    To evaluate the efficacy of PLX-200 using the individual domain scores of the Unified Batten Disease Rating Scale: seizure, behavioral, and functional capabilities, compared with the Batten Disease Registry at the University of Rochester (BDR-UR) periodically throughout the study period. The seizure domain is a series of items with a maximal total score of 54 (the higher the score, the more severe the disease). The behavioral domain is a series of items with a maximal total score of 56 (the higher the score, the more severe the disease). The capabilities domain is a series of items with a maximal total score of 28 (the higher the score, the more severe the disease).

  2. Evaluate the Clinical Global Impression (CGI) scale of symptoms [ Time Frame: 149 weeks ]
    To evaluate the Clinical Global Impression (CGI) scale of symptom severity and change from baseline periodically throughout the study. The scale is from the Unified Batten Disease Rating Scale where each domain (seizures, cognitive function, behavior, mood, motor, and overall) is ranked 0 (normal function) to 5 (severe impairment) with a minimum score of 0 and maximum score of 30.

  3. Evaluate the efficacy of PLX-200 using quality of life (QoL) assessments, namely the PedsQL Generic Core Scales and the PedsQL Family Impact Module where the higher score reflects better outcomes. [ Time Frame: 149 weeks ]
    To evaluate the efficacy of PLX-200 using Quality of Life assessments in the pediatric populations utilizing the PedsQL™ Generic Core Scales Version 4.0 and PedsQL™ Family Impact Module Version 2.0. These scales consist of 23 items applicable for pediatric populations with acute and chronic health conditions, encompassing physical function (8 items), emotional functioning (5 items), social functioning (5 items), and school functioning (if applicable; 5 items). The PedsQL Family Impact module is similarly constructed involving the child and parent(s). Items are reverse-scored and linearly transformed to a 0 to 100 scale (0 = 100, 1 = 75, 2 = 50,3 = 25, and 4 = 0), so that higher scores indicate better HRQOL. Scale Scores are computed as the sum of the items divided by the number of items answered (this accounts for missing data). To summarize, a higher score in each of the individual items and total score reflect a healthier child.

  4. PLX-200 pharmacokinetics (PK) will be evaluated through periodic blood draws during the trial. PLX-200 levels will be determined to estimate area under the curve, maximal concentration, time to maximal concentration, half-life, and dosing interval. [ Time Frame: 12 weeks ]
    To evaluate PLX-200 plasma concentrations in blood collected from participants during the Titration and Maintenance Periods for PK analyses, namely Cmax (maximal PLX-200 concentration) and Tmax (time to Cmax), elimination half-life (t1/2), area under the plasma concentration-time curve (AUC), and the dosing interval.

Information from the National Library of Medicine

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Ages Eligible for Study:   5 Years to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Male and female participants between the ages of 5 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.
  2. 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 Baseline visit.
  3. Participant must have a mild-to-moderate CLN3 disease documented by the UBDRS. Participants are included with a Baseline UBDRS ≤ 15 for Physical Assessment. Participant must be able to independently walk for a distance of at least 20 feet (6 meters).
  4. Participant must be able to tolerate swallowing oral medication or have a gastric/jejunostomy tube for drug administration.
  5. 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.
  6. 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.
  7. Participants' parents and legal guardians must sign the informed consent form, and participants will provide assent, depending on local regulations and developmental status.

Exclusion Criteria:

  1. 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.
  2. 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).
  3. Participant has another inherited neurologic disease in addition to CLN3 disease.
  4. Participant has another neurological illness that may cause cognitive or motor decline.
  5. Participant requires ventilation support, except for noninvasive support at night (e.g., Continuous Positive Airway Pressure [CPAP], Bilevel Positive Airway Pressure [BiPAP]).
  6. 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.
  7. Participant has anemia (defined as hemoglobin <10 g/dL or hematocrit <30%).
  8. Participant has a baseline serum creatinine >2 mg/dL.
  9. Participant has gallbladder disease (e.g., cholelithiasis or cholecystitis).
  10. Participant has hypersensitivity to gemfibrozil.
  11. Participant is using or requires treatment with 1. HMG-CoA reductase inhibitors, 2. repaglinide (Prandin®), 3. dasabuvir (Exviera®), 5. pioglitazone (Actos®) or 4. selexipag (Uptravi®). 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).
  12. 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT04637282

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Contact: David R Luke, PharmD 8606085296
Contact: Hahn-Jun Lee, PhD 2017241786

Sponsors and Collaborators
Polaryx Therapeutics, Inc.
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Study Chair: Hahn-Jun Lee, PhD Polaryx Therapeutics
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Responsible Party: Polaryx Therapeutics, Inc. Identifier: NCT04637282    
Other Study ID Numbers: PLX-200-002
First Posted: November 19, 2020    Key Record Dates
Last Update Posted: December 4, 2020
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: None planned.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Polaryx Therapeutics, Inc.:
Batten disease
Additional relevant MeSH terms:
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Neuronal Ceroid-Lipofuscinoses
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Nervous System Diseases
Genetic Diseases, Inborn
Lipid Metabolism, Inborn Errors
Metabolism, Inborn Errors
Lipid Metabolism Disorders
Metabolic Diseases