Safety and Efficacy Evaluation of GC101 Gene Therapy Via Intrathecal (IT) Injectionin the Treatment of Patients With Type 2 Spinal Muscular Atrophy (SMA) - Phase III

A Multicenter, Randomized, Open-Label, Standard-of-Care-Controlled, Phase III Clinical Trial to Evaluate the Safety and Efficacy of Intrathecal (IT) Injection of GC101 Adeno-Associated Virus Injection in the Treatment of Patients With Type 2 Spinal Muscular Atrophy (SMA)

This trial employs a multicenter, randomized, open-label, standard-of-care-controlled design and plans to enroll 50 patients with Type 2 SMA aged 2 to 12 years who have previously received nusinersen. The primary objective of the trial is to evaluate the efficacy of GC101 in treating Type 2 SMA. The secondary objectives are to assess the efficacy, safety, and pharmacokinetic (PK) profile of GC101 in treating Type 2 SMA.

The trial is divided into two groups: one group will receive a single intrathecal injection of GC101 at a dose of 1.2E+14 vg per person and discontinue their previous standard-of-care treatment with nusinersen; the other group will continue their previous standard-of-care treatment with nusinersen. Participants will be randomly assigned to the trial group or the control group in a 1:1 ratio.

Inclusion Criteria:

• Patients with a confirmed diagnosis of Type 2 5q-SMA through clinical phenotype and genetic testing.
• Patients who have been receiving regular treatment with nusinersen for more than one year prior to screening.
• Patients who have not received treatment with risdiplam within 2 months prior to screening and have no plans to receive risdiplam treatment within 12 months after enrollment.
• Patients who can sit independently but cannot walk independently at the time of screening (according to the definitions of independent sitting and walking in the WHO-MGRS motor milestones scale), and have an HFMSE score of ≥10 points.
• Patients and/or their legal guardians are able to understand and are willing to comply with the requirements and procedures of the trial protocol, and voluntarily participate and sign the informed consent form

Exclusion Criteria:

• Patients with serum anti-AAV9 neutralizing antibody titers > 1:50 at the time of screening.
• Patients who have received nusinersen treatment within 2 months prior to enrollment.
• Patients with any medical conditions that may affect the interpretation of study results or pose a risk to the safety of the participants, including but not limited to organ dysfunction of any cause, acute infectious diseases, primary/acquired immunodeficiency diseases, severe cardiovascular/cerebrovascular diseases, gastrointestinal diseases, diabetes, known epilepsy, meningitis, seizure or convulsion history, or a family history of psychiatric disorders; and those with cerebrospinal fluid circulation disorders.
• Patients with severe liver injury/hepatic insufficiency of any cause, including but not limited to alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≥3 times the upper limit of normal (ULN); total bilirubin (TBil) ≥1.5 times the ULN.
• Patients deemed by the investigator to have contraindications to glucocorticoid use, such as severe hypertension, diabetes, systemic infectious diseases, fungal infections, glaucoma, osteoporosis, peptic ulcer disease, tuberculosis, etc.
• Patients with contraindications to lumbar puncture or intrathecal injection therapy.
• Patients with any medical conditions that may affect the assessment of motor function, such as severe scoliosis, severe joint contracture deformities, planned spinal correction surgery during the trial period, severe osteoporosis, or a history of fractures.
• Patients positive for hepatitis B surface antigen (HBsAg), human immunodeficiency virus (HIV) antibodies, hepatitis C virus (HCV) antibodies, or syphilis antibodies.
• Patients who have received vaccinations within 2 weeks prior to dosing.
• Patients who have previously received gene therapy or participated in any clinical trial within 3 months prior to screening.
• Patients deemed by the investigator to be unsuitable for participation in this study.