Gene Therapy for Children With CLN3 Batten Disease

Study Overview
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Brief Summary
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This is a phase 1/2, open-label, single dose, dose-escalation clinical trial to evaluate the safety and efficacy of AT-GTX-502 (previous NCH Code: scAAV9.P546.CLN3) delivered intrathecally into the lumbar spinal cord region of subjects with CLN3 Batten disease.

Detailed Description
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This is a phase 1/2, open-label, single-dose, dose-escalation study of AT-GTX-502 administered intrathecally into the lumbar spinal cord region of pediatric patients with CLN3 Batten disease. This study consists of a one-time injection of AT-GTX-502 with follow-up visits on Day 7, 14, 21, and 30, followed by every 3 months through 1 year post-dose, and then every 6 months through the fifth year. There are two Cohorts with a low dose and a high dose. The primary outcome for this clinical study is to evaluate safety. The co-primary objective is to determine the efficacy of AT-GTX-502 as measured by United Batten Disease Rating Scale (UBDRS) physical subscale. The secondary outcome measures include Pediatric Quality of Life (PedsQL) inventory, seizure subscale of the UBDRS and global impression subscale of the UBDRS. The exploratory outcome measures include visual impairment assessment, cognitive evaluations, Brain magnetic resonance imaging (MRI), electroencephalogram (EEG), electrocardiogram (ECG) and echocardiogram (ECHO). For more information about this study, please contact Amicus Therapeutics Patient Advocacy at clinicaltrials@amicusrx.com or +1 609-662-2000.

Official Title
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Phase I/IIa Gene Transfer Clinical Trial for Juvenile Neuronal Ceroid Lipofuscinosis, Delivering the CLN3 Gene by Self-Complementary AAV9

Conditions
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CLN3, Batten Disease

Intervention / Treatment
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* Genetic: Low dose AT-GTX-502
* Genetic: High dose AT-GTX-502


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Diagnosis of CLN3 Batten disease determined by genotype available at screening by a College of American Pathologists/Clinical Laboratory Improvement Amendments (CAP/CLIA)-certified laboratory (or a non-US laboratory with an equivalent national accreditation/certification) Aged ≥ 3 to < 11 years UBDRS physical impairment score of ≤ 7 Able to walk independently at least 50 feet Exclusion Criteria Presence of another inherited neurologic or metabolic disease, eg, other forms of Batten disease (also known as neuronal ceroid lipofuscinosis; NCL) or seizures unrelated to CLN3 Batten disease (subjects with febrile seizures may be eligible at the discretion of the investigator) Presence of another neurological illness that may have caused cognitive decline (eg, trauma, meningitis, hemorrhage) before screening Active viral infection (includes HIV or serology positive for hepatitis B or C) Subjects with 2 consecutive aminotransaminase liver tests > 3 times the upper limit of normal or > 1.5 times the upper limit of normal if taking valproic acid at Visit 1 (screening/baseline) Subjects with anti-AAV9 antibody titers > 1:400 as determined by ELISA (enzyme-linked immunosorbent assay) binding immunoassay Abnormal laboratory values considered clinically significant Presence of immunologic disease Has received stem cell or bone marrow transplantation Has received any form of organ transplant History of or current chemotherapy, radiotherapy, or other immunosuppression therapy within the past 30 days (corticosteroid treatment may be permitted at the discretion of the investigator) Current use of cannabinoids and any by-products Contraindications for intrathecal administration of the product or lumbar puncture (for collection of CSF), such as bleeding disorders or other medical conditions (eg, spina bifida, meningitis, or clotting abnormalities) Contraindications for MRI scans (eg, cardiac pacemaker, metal fragment or chip in the eye, aneurysm clip in the brain) Poorly controlled seizures - intractable epilepsy Episode of generalized motor status epilepticus within 4 weeks before the Gene Transfer visit History of corneal or intraocular surgery Severe infection (eg, upper respiratory tract infection, pneumonia, pyelonephritis, or meningitis) within 4 weeks before the Gene Transfer visit (Enrollment may be postponed.) Has received any investigational medication within 30 days before the infusion of study drug Has a medical condition or extenuating circumstance that, in the opinion of the investigator, might compromise the subject's ability to comply with the protocol required testing or procedures or compromise the subject's wellbeing, safety, or clinical interpretability Pregnancy at screening or Day 0. Any female subject judged by the investigator to be of childbearing potential will be tested for pregnancy. Family does not want to disclose subject's study participation with primary care physician and other medical providers

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 10 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: Single Treatment Group (AAV9-CLN3) - 2 Cohort Assignment (Low-dose, High-dose) Dose escalation in this study will begin with low-dose, determined to be the minimal efficacious dose as determined in non-clinical studies. Dose escalation to a high-dose (2x the minimally effective dose (MED) as evaluated in Cohort 1) will proceed as part of Cohort 2 of the study upon demonstration of safety of the low-dose in Cohort 1 of the study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: AT-GTX-502 Low-Dose<br>No more than 5 mL of 6 x 1013 vg AT-GTX-502 administered via intrathecal injection | Genetic: Low dose AT-GTX-502<br>* Subjects with diagnosis of CLN3 Batten disease will receive a single dose of AT-GTX-502 at low dose<br>|
| Experimental: Cohort 2: AT-GTX-502 High-Dose<br>No more than 10 mL of 1.2 x 1014 vg of AT-GTX-502 administered via intrathecal injection | Genetic: High dose AT-GTX-502<br>* Subjects with diagnosis of CLN3 Batten disease will receive a single dose of AT-GTX-502 at high dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety evaluation based on the development of dose-limiting toxicity (DLT). | The DLT is defined as any unanticipated AE that is considered related to AT-GTX-502 and is Common Terminology Criteria for Adverse Events Grade 3 or higher. | 36 Months | 
| Efficacy: Change in rating as determined using the Unified Batten Disease Rating Scale (UBDRS) rating scale. | The UBDRS is a clinical ratings instrument used specifically to assess motor, seizure, behavioral and functional capabilities. The Physical Assessment is a 20 item subscale that measures vision, speech, motor strength, gait, abnormal involuntary movements and balance. Each item has a score range of 0 to 4. The minimum score is 0 and the maximum score is 112. The items are summed up to obtain a total score.The higher the score, the more severe the disability and worse the outcome. | 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| QOL: Change in Quality of Life (QOL) as determined using the Pediatric Quality of Life (PedsQL™) scale. | The PedsQL is used to assess physical, emotional, social, and school functioning of pediatric subjects in ranging from 2 years to 18 years of age. | 36 months | 
| Seizures: Change is seizure subscore as determined using Seizure subscale of the UBDRS scale. | The UBDRS seizure subscale is used to assess seizure history, type, frequency, duration, and frequency of seizure-related injury. | 36 months | 
| Global impression: Change in disease severity using the UBDRS clinical global impression (CGI) subscale. | The clinical global impression subscale includes assessment of motor, seizure, behavioral and cognitive function in NCL subjects. | 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CLN3, Neuronal ceroid lipofuscinosis, NCL, Gene Transfer