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

A Randomized, Sham-controlled, Double-blind Study to Evaluate the Efficacy and Safety of Intrathecal OAV101 in Type 2 Spinal Muscular Atrophy (SMA) Patients Who Are ≥ 2 to < 18 Years of Age, Treatment Naive, Sitting, and Never Ambulatory

This was a Phase III multi-center, single dose (1.2 x 10^14 vector genomes), randomized, sham controlled, double-blind study that investigates the efficacy, safety and tolerability of OAV101B in treatment naive, sitting and never ambulatory SMA patients 2 to <18 years of age.

Eligible participants received a single administration of OAV101B at the dose of 1.2 x 10^14 vector genomes intrathecally or the sham procedure on Day 1 (Treatment Period 1), and were followed for a period of 52 weeks for Period 1. In Period 2, participants who received the sham treatment in Period 1 were administered OAV101B, and participants who received OAV101B in Period 1 underwent the sham procedure. Participants were followed up for 12 weeks in Period 2.

The study consisted of a Screening and Baseline Period followed by two Treatment and Follow-up Periods. Participants were admitted to the hospital on Day 1 (or Day -1 as per local standards of care). After receiving OAV101B or the sham procedure on Day 1, participants underwent in-patient safety monitoring through Day 2 and optionally for Day 3.

After Period 1, eligible participants could continue to Period 2 subsequently entering Period 2 in a rolling seamless fashion as participants completed Follow-up Period 1. In Treatment Period 2, eligible participants who received a sham procedure on Study Day 1 of Treatment Period 1 were hospitalized to receive OAV101B on Week 52 + 1 day and participants who received OAV101B on Study Day 1 of Treatment Period 1 were hospitalized to receive a sham procedure on the Week 52 + 1 Day. The total duration of the study including both Period 1 and Period 2 was 64 weeks. At the end of the study, all participants who received OAV101B were eligible to enroll in a long-term follow-up study to monitor long-term safety and efficacy.

Approximately 125 participants were planned to be randomized in a 3:2 ratio to receive OAV101B (N= ~75) or a sham procedure (N= ~50). The unequal randomization ratio allowed more participants to receive active treatment in Period 1. It was anticipated that approximately 65 randomized participants would be aged 2 to <5 years and approximately 60 randomized participants would be aged 5 to <18 years.

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 within 30 days prior 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