Efficacy and Safety of Intrathecal OAV101 (AVXS-101) in Pediatric Patients With Type 2 Spinal Muscular Atrophy (SMA)

To evaluate the efficacy, safety and tolerability of intrathecal (IT) OAV101 in treatment naive patients with Type 2 spinal muscular atrophy (SMA) who are ≥ 2 to \< 18 years of age over a 15 month trial duration.

This is a multi-center, randomized, sham-controlled, double-blind study to investigate the safety, tolerability, and efficacy of IT OAV101 in sitting and never ambulatory SMA participants. The study will enroll treatment naive Type 2 SMA participants who are ≥ 2 years to \< 18 years. The study consists of a Screening and a Baseline Period followed by a Treatment Period 1 and Follow-up Period 1 (total of 52 weeks) and a Treatment and Follow-up Period 2 (total of 12 weeks). The total trial duration period is 64 weeks.

The study will include a standard screening period that will last 45 to 60 days, during which eligibility will be assessed and baseline assessments will be performed prior to treatment. Participants who meet eligibility criteria at screening and baseline visits will be randomized in a 3:2 ratio to receive OAV101 by lumbar intrathecal injection or to receive a sham procedure.

Treatment Period 1 consists of OAV101/sham administration with in-patient hospitalization on Study Day 1, Day 2 and Day 3 (optional). Treatment Period 1 is followed by a 52-week out-patient Follow-Up Period 1 for safety and efficacy assessments.

At the time point each participant completes Follow-up Period 1, those who are eligible will subsequently enter into Treatment Period 2. Entry into Treatment Period 2 will occur immediately after each participant completes their participation in Follow-up Period 1. In Treatment Period 2, eligible participants who received a sham procedure on Study Day 1 of Treatment Period 1 will be hospitalized to receive OAV101 and participants who received OAV101 on Study Day 1 of Treatment Period 1 will be hospitalized to receive a sham procedure on Week 52 +1 Day. A sham procedure is a skin prick in the lumbar region without any medication. In-patient observation will continue on Week 52 +2 Days and Week 52 +3 Days (optional). Treatment Period 2 is followed by a 12-week follow-up period for safety and efficacy assessments. Blinding is maintained for all patients during both Treatment Period 1 and 2. At the end of the study all participants will be eligible to enroll in a long-term follow-up study (15 years) to monitor long-term safety and efficacy.

During the study, participants will complete visits as defined in the Schedule of Assessments. Prednisolone or placebo treatment will be given per study protocol.

Safety monitoring will be performed as per study schedule and protocol requirements. Safety for the participants enrolled in the study will be evaluated by a designated group of unblinded study team members together with the Data Monitoring Committee (DMC) as described in the charter.

The primary analysis will be performed after all participants have completed Week 52 or discontinued prior to Week 52. A final analysis will be performed after all participants have completed Week 64 (or discontinued prior to Week 64).

Eligibility Criteria:
Key Inclusion criteria:

* Diagnostic confirmation during screening period of 5q SMA
* The patient must be treatment naive (historical or current use) for all SMN-targeting therapies (e.g., risdiplam (Evrysdi) and nusinersen (Spinraza)).
* Onset of clinical signs and symptoms at ≥ 6 months of age
* A complete Hammersmith Functional Motor Scale - Expanded (HFMSE) assessment during the screening period for trial eligibility
* Able to sit independently at screening, but has never had the ability to walk independently.

Key Exclusion criteria:

* Anti-adeno-associated virus serotype 9 (AAV9) antibody titer reported as elevated (reference to \> 1:50 or validated result consistent with being elevated) at screening as determined by sponsor designated lab.
* Infectious process (e.g. viral, bacterial) or febrile illness prior to start of screening, and up to OAV101 treatment or sham procedure
* Hepatic dysfunction (i.e. alanine aminotransferase (ALT), total bilirubin, gamma-glutamyl transferase (GGT) or glutamate dehydrogenase (GLDH), \> upper limit of normal (ULN).
* Requiring invasive ventilation, awake noninvasive ventilation for \> 6 hours during a 24-hour period, noninvasive ventilation for \> 12 hours during a 24-hour period or requiring tracheostomy
* Complications at screening that would interfere with motor efficacy assessments including but not limited to, severe contractures or Cobb angle \> 40 in a sitting position
* Surgery for scoliosis or hip fixation in the 12 months prior to Screening or planned within the next 64 weeks
* Clinically significant sensory abnormalities in the neurological examination at Screening