Overview
This is a Phase 1/2, open-label, multiple-dose, dose-escalating study to evaluate the safety, tolerability, and plasma and cerebrospinal fluid (CSF) concentrations of GTX-102 in pediatric patients with Angelman syndrome. Approximately 20 patients (male and female) 4 and 17 years of age with a genetically confirmed diagnosis of full maternal UBE3A gene deletion (within 15q11.2-q13 region) will be enrolled.
Description
This is a Phase 1/2, open-label, multiple-dose, dose-escalating study to evaluate the safety, tolerability, and plasma and CSF concentrations of GTX-102 in pediatric patients with AS.
The study includes screening, baseline, treatment, and safety follow-up periods. Eligible patients who meet all of the inclusion criteria and none of the exclusion criteria and who successfully complete all screening and baseline assessments will be assigned to one of 5 sequential dose cohorts. GTX-102 will be administered by intrathecal (IT) injection via lumbar puncture (LP) at Baseline followed by 3 subsequent IT injections on study Days 30, 58 and 86. The procedure for IT administration of GTX-102 will performed by a clinician with experience in LP and anesthetic care will be directed by experienced anesthesiologists with a focus on patient safety and comfort. The total duration of study for each patient is anticipated to be approximately 6 months. An open-label extension (OLE) study will be conducted under a separate protocol where patients can receive continued treatment with GTX-102.
Eligibility
Inclusion Criteria:
- Signed informed consent from parent(s) or legal guardian(s)
- Documented genetic confirmation of full maternal UBE3A gene deletion causing AS (e.g. DNA methylation testing with either a chromosomal microarray or FISH) in the region of 15q11.2-q13 including class I, II or III).
- Age 4 to 17 years at screening
- Stable seizure control (defined as clinically stable with no changes in antiepileptic medications over the prior 1 month before screening visit, other than weight associated dose adjustments)
- Platelet count, prothrombin time (PT) / international normalized ratio (INR) and partial thromboplastin time (PTT) within normal limits
- Normal renal function with serum creatinine and spot urine protein within normal limits
- Normal hepatic function with total bilirubin, aspartate aminotransferase (AST),alanine aminotransferase (ALT) and alkaline phosphatase within normal limits
- Willing and able to comply with scheduled visits, drug administration plan, laboratory tests, study restrictions, and all study procedures LP.
- Able to tolerate the anesthetic regimen required for LP procedure
Exclusion Criteria:
- Any change in medications (excluding antiepileptic drugs) or diet intended to treat symptoms of AS (e.g. sleeping aids, supplements, ketogenic or low-glycemic index diet, other) over the prior 3 months before screening.
- Inability to ambulate independently or with an assistive device or caregiver hand-hold
- Any bleeding or platelet disorder
- Any clinically significant (CS) cardiovascular, endocrine, hepatic, renal, pulmonary, gastrointestinal, neurologic, malignant, metabolic, psychiatric, or other condition that, in the judgment of the Investigator, will pose a safety risk, will make the patient unsuitable for participation in, and/or unable to complete the study procedures.
- Any laboratory abnormality, that, in the Investigator's opinion, could adversely affect the safety of the patient, make it unlikely that the course of treatment or follow up would be completed, or impair the assessment of study result
- Any active infection
- Bone, spine, bleeding, or other disorder that exposes the patient to risk of injury or unsuccessful lumbar puncture
- Drugs that increase the risk of bleeding (e.g. heparin, low molecular weight heparin, platelet inhibitors).
- Use of any investigational oligonucleotide in the past 6 months
- Any prior use of gene therapy
- Use of any investigational drugs in the past 6 months
- Any medical condition that would require intubation for the anesthesia procedure