Gene Transfer Clinical Trial for Spinal Muscular Atrophy Type 1

Study Overview
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Brief Summary
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The purpose of this trial is to evaluate safety and efficacy of intravenous delivery of AVXS-101 as a treatment of spinal muscular atrophy Type 1 (SMN1).

Detailed Description
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The study will evaluate safety and efficacy of gene therapy in spinal muscular atrophy Type 1 (SMA1) patients. SMA is caused by low levels of the survival motor neuron (SMN) protein, and affects all muscles in the body. There is no effective treatment for SMA and current drug therapy has been unsuccessful in stabilizing or reversing this disease. Only supportive care is currently possible. Open-label, dose-escalation clinical trial of AVXS-101 injected intravenously through a peripheral limb vein. Short-term safety will be evaluated over a two year period. Patients will be tested at baseline and return for follow up visits on days 7, 14, 21, 30, followed by once every month through 12 months post dose, and then every three months through two (2) years post infusion. Unscheduled visits may occur if the PI determines that they are necessary. The primary analysis for efficacy will be assessed when all patients reach 13.6 months of age (a database lock will be performed at the time point at which all patients reach 13.6 months of age). A follow-up safety analysis will be completed at the time point at which the last patient reaches 24 months post-dose. Upon completion of the 2-year study period, patients will be monitored annually as per standard of care for up to 15 years.

Official Title
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Phase I Gene Transfer Clinical Trial for Spinal Muscular Atrophy Type 1 Delivering AVXS-101

Conditions
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Spinal Muscular Atrophy 1

Intervention / Treatment
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* Biological: AVXS-101


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Six or nine months of age and younger (depending on cohort) on day of vector infusion with Type 1 SMA 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 at birth up to 6 months of age. Hypotonia by clinical evaluation with delay in motor skills, poor head control, round shoulder posture and hypermobility of joints. Exclusion Criteria: Active viral infection (includes HIV or serology positive for hepatitis B or C) Use of invasive ventilatory support (tracheotomy with positive pressure)* or pulse oximetry <95% saturation. Patients may be put on non-invasive ventilator support (BiPAP) for less than 16 hours a day at the discretion of their physician or research staff. Concomitant illness that in the opinion of the PI creates unnecessary risks for gene transfer Concomitant use of any of the following drugs: drugs for treatment of myopathy or neuropathy, agents used to treat diabetes mellitus, or ongoing immunosuppressive therapy or immunosuppressive therapy within 3 months of starting the trial (e.g. corticosteroids, cyclosporine, tacrolimus, methotrexate, cyclophosphamide, intravenous immunoglobulin, rituximab) Patients with Anti-AAV9 antibody titers >1:50 as determined by ELISA binding immunoassay. Abnormal laboratory values considered clinically significant (GGT > 3XULN, bilirubin ≥ 3.0 mg/dL , creatinine ≥ 1.8 mg/dL, Hgb < 8 or > 18 g/Dl; WBC > 20,000 per cmm) Participation in a recent SMA treatment clinical trial that in the opinion of the PI creates unnecessary risks for gene transfer. Family does not want to disclose patient's study participation with primary care physician and other medical providers. Patient with signs of aspiration based on a swallowing test and unwilling to use an alternative method to oral feeding. Patients with a single base substitution in SMN2 (c.859G>C in exon 7) will be excluded based on predicted mild phenotype.

Ages Eligible for Study
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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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>6.7 X 10^13 vg/kg of AVXS-101 delivered one-time through a venous catheter inserted into a peripheral vein (n=3) | Biological: AVXS-101<br>* Self-complementary AAV9 carrying the SMN gene under the control of a hybrid CMV enhancer/chicken-β-actin promoter<br>* Other names: Zolgensma;|
| Experimental: Cohort 2<br>2.0 X 10^14 vg/kg of AVXS-101 delivered one-time through a venous catheter inserted into a peripheral vein (n=12) | Biological: AVXS-101<br>* Self-complementary AAV9 carrying the SMN gene under the control of a hybrid CMV enhancer/chicken-β-actin promoter<br>* Other names: Zolgensma;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants That Experienced One Grade III or Higher Unanticipated, Treatment-related Toxicity That Presents With Clinical Symptoms and Requires Medical Treatment |  | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced Permanent Ventilation or Death | Permanent ventilation was defined as the requirement of ≥ 16-hour respiratory assistance, including non-invasive ventilatory support, per day continuously for ≥ 2 weeks in the absence of an acute reversible illness, excluding perioperative ventilation. | Up to 13.6 months of age | 
| Percent Change From Baseline in Mean Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) Score | Score ranges from 0 to 64, where 64 is the maximum possible score. A higher score is indicative of higher/better motor function. CHOP-INTEND assessments were discontinued once patients achieved higher functioning status, so the number of available data points decreased over time. | Baseline to 24 months post-dose | 
| Number of Participants With Assessed Improvement in Motor Function | Improvement in motor function was determined by achievement of developmental milestones, specifically achievement of ability to sit unassisted for at least 30 seconds, determined by physical therapist and confirmed by an independent central video reviewer. Achievement of functional independent sitting was defined as the ability to maintain a sitting position independently for at least 30 seconds as confirmed per video evaluation by an expert central reviewer based on videos taken either at scheduled visits or provided by the parent/legal guardian. | 24 months post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SMN, Gene Transfer, Gene Therapy, Adeno-associated virus, Survival Motor Neuron, AAV9