Clinical Trial to Assess the Safety and Efficacy of EXG001-307 in Patients with Spinal Muscular Atrophy Type 1

The purpose of this trial is to evaluate safety and efficacy of intravenous delivery of EXG001-307 as a treatment of spinal muscular atrophy Type 1 (SMN1).

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 EXG001-307 injected intravenously through a peripheral limb vein. Short-term safety will be evaluated over a 1.5 year period. Patients will be tested at baseline and return for follow up visits on days 14, 21, 30, followed by once every month through 12 months post dose, and then every three months through a year and a half 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 18 months of age (a database lock will be performed at the time point at which all patients reach 18 months of age). A follow-up safety analysis will be completed at the time point at which the last patient reaches 18 months of age after post-dose.

Upon completion of the 1.5-year study period, patients will be monitored annually as per standard of care for up to 5 years.

Eligibility Criteria:
Inclusion Criteria:

1. SMA was diagnosed by a bilaterally allelic SMN1 mutation (deletion or point mutation) gene with 2 copies of the SMN2 gene.
2. On the day of dosing, the subject ' s age did not exceed postnatal Day 180.
3. The clinical history and signs were consistent with type 1 SMA manifestations, i.e. hypotonia, delayed motor function development, poor head control, round shoulder posture, and joint hypermobility.
4. The subject's legal guardian understands the purpose, possible risks and interests of the study, agrees to participate in the study, completes all study procedures, tests and visits, and voluntarily signs the informed consent form.
5. During the study, the subject's legal guardian was willing to perform standard treatment requirements such as nasogastric feeding, noninvasive mechanical ventilation, and expectoration machine as recommended by the investigator.

Exclusion Criteria:

1. Gestational age at birth was less than 35 weeks (245 days).
2. At screening, the subject had an oxygen saturation \< 96% while awake or sleeping and did not receive any supplemental oxygen or respiratory support.
3. Requirement of invasive ventilation or tracheotomy, or current use of noninvasive ventilatory support for an average of ≥ 16 hours/day.
4. Weighed below the 3rd percentile by age according to the WHO Child Growth Criteria (WHO 2009).
5. Before administration, if the subject has not received or delayed vaccination according to the current month-old national vaccination plan, it will significantly affect the safety of the subject as assessed by the investigator and the medical manager of the project team;
6. Active viral infections (including HIV, COVID-19, hepatitis B or C seropositivity, torch virus, Epstein-Barr virus, and syphilis).
7. Serious non-respiratory disease within 2 weeks prior to screening.
8. Upper respiratory tract infection or lower respiratory tract infection within 4 weeks prior to screening.
9. Current presence of other severe infections or diseases.
10. Known cardiac disease or ECG abnormalities that are clinically significant.
11. Known hypersensitivity to prednisolone, other glucocorticoids, or its excipients.
12. Immunosuppressive therapy (eg, cyclosporine, tacrolimus, methotrexate, cyclophosphamide, rituximab) other than protocol-required prophylaxis within 3 months prior to dosing.
13. Immunomodulatory drugs (eg, thymosin, interferon, etc.) are being used to treat myopathy, neuritis, diabetes mellitus (eg, immunosuppressants, glucocorticoids, insulin).
14. Anti-AAV9 antibody titer \> 1: 50 (as determined by ECL). If the potential subject has an anti-AAV9 antibody titer \> 1: 50, it can be retested during the screening period. If the anti-AAV9 antibody titer is ≤ 1: 50 at the retest, the subject may continue to participate in the screening.
15. Clinically significant abnormal laboratory values (GGT, ALT, and AST \> 2.5 × ULN, bilirubin ≥ 3.0 mg/dL, creatinine ≥ 1.0 mg/dL, hemoglobin \< 8 or \> 18 g/dL; white blood cell count \> 20,000/cm3; platelet count \< 100,000/cm3).
16. Prior use of other SMA therapeutic agents (e.g., nosinasenat, rispolam, and Zolgensma, etc.) or participated in clinical studies with other SMA therapeutic agents (including but not limited to the above 3 drugs).
17. Major surgery is expected during study treatment.
18. Other circumstances that, in the judgment of the investigator, are not suitable for participation in this study.