Evaluation of Safety and Efficacy of Gene Therapy Drug in the Treatment of Spinal Muscular Atrophy (SMA) Type 1 Patients

Study Overview
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Brief Summary
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The study will evaluate safety and efficacy of intrathecal delivery of GC101 gene therapy drug as a treatment of spinal muscular atrophy Type 1 (SMA 1) patients.

Detailed Description
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The purpose of this trial is to evaluate safety and efficacy of gene therapy drug GC101 in SMA 1 patients. Open-label, dose-escalation clinical trial of GC101 will be conducted in multiple centers in China. GC101 will be administrated intrathecally. Short-term safety will be evaluated in 52 weeks and enter long-term follow-up study of 5 years at will. Patients will be tested at baseline and followed up on various time points. The primary analysis for efficacy will be assessed when all patients reach 18 months of age on the motor milestone of sit unassisted for at least 10 seconds.

Official Title
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A Multi-center, Open Label, Single-arm, Dose Ascending Clinical Trial for Evaluation of Safety and Efficacy of Gene Therapy Drug GC101 in the Treatment of Spinal Muscular Atrophy (SMA) Type 1 Patients

Conditions
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Spinal Muscular Atrophy

Intervention / Treatment
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* Genetic: GC101


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Six months of age and younger on day of vector infusion with Type 1 SAM as defined by the following features: Diagnosis of SMA based on gene mutation analysis with bi-allelic SMN1 mutations (deletion or point mutations) and 2 copies of SMN2; Onset of disease before 6 months of age The patient's legal guardian(s) must be able to understand the purpose and risks of the study and voluntarily provide signed and dated informed consent prior to any study-related procedures being performed. Exclusion Criteria: Patient who has participated in a previous gene therapy research trials; Patient who has received Nusinersen and Risdiplam treatment; Patient who has AAV9 neutralizing antibody titer ≥1:200; Patient who requires non-invasive ventilatory support averaging≥16 hours/day; Patient with a point mutation in SMN2 (c.859G>C); Patient who requires non-invasive ventilatory support averaging≥16 hours/day at screening; Patient who use invasive ventilatory support or pulse oximetry < 95% saturation while awake and calm at screening; Patient who is positive for human immunodeficiency virus (HIV) antibody, hepatitis B surface antigen, hepatitis C antibody, or treponema pallidum antibody; Abnormal laboratory values considered clinically significant, including gamma-glutamyl transferase(GGT), Aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin > 3x upper limit of normal (ULN), Hemoglobin (Hgb)< 110 or >150 g/L, platelet <183x10^9/L or 614x10^9/L; Class IV patient based on Modified Ross Heart Failure Classification for Children; Patient with a history of glucocorticoid allergy; Contraindication that would interfere with the lumbar puncture procedures; Presence of an untreated active infection requiring systemic antiviral therapy at any time during the screening period; Vaccination less than 2 weeks before infusion of vector; Patient who has any concurrent clinically significant major disease or any other condition that, in the opinion of the Investigator, makes the subject unsuitable for participation in the study. Note: Other protocol defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 0 Months
Maximum Age: 6 Months

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low dosage group<br>2.4x10^14 vg/person of GC101 delivered one-time intrathecally (n=3) | Genetic: GC101<br>* Self-complementary AAV9 carrying a codon-optimized SMN coding sequence(coSMN1) driven by CMV enhancer and chicken β-actin promoter<br>|
| Experimental: High dosage group<br>4.8x10^14 vg/person of GC101 delivered one-time intrathecally (n=3) | Genetic: GC101<br>* Self-complementary AAV9 carrying a codon-optimized SMN coding sequence(coSMN1) driven by CMV enhancer and chicken β-actin promoter<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] | Frequency of treatment-related adverse events (AEs), serious adverse events (SAEs), and changes from baseline in relevant clinical laboratory tests | when patient reaches 18 months of age | 
| Proportion of patients treated with GC101 who achieve motor milestone of sit unassisted for at least 10 seconds at 18 months of age |  | when patient reaches 18 months of age | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ability to thrive | Ability to thrive is defined as the following at 18 months of age: does not receive nutrition through mechanical support or other non-oral method; maintains weight | when patient reaches 18 months of age | 
| Changes from baseline Children's hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) score | CHOP INTEND score ranges from 0 to 64 with higher scores indicating higher motor function | when patient reaches 18 months of age | 
| Proportion of event-free survival patients |  | when patient reaches 14 months of age | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 1