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

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

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).

Zolgensma, OAV101, AVXS 101, gene therapy, Muscle atrophy, SBMA, spinal and bulbar muscular atrophy, spinal muscular atrophy, bulbar muscular atrophy, muscle function, myopathy, muscle wasting, atrophied muscle, loss of muscle strength, pediatric

The sham procedure will consist of a small needle prick on the lower back at the location where the LP injection is normally made. The needle will break the skin, but no needle insertion for lumbar puncture will occur.

Change from baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE) total score at the end of Follow-up Period 1 in treated patients compared to sham controls in the ≥ 2 to < 18 years age group

The HFMSE is a validated SMA specific assessment devised for use in children with SMA to give objective information on motor ability and clinical progression. The HFMSE contains 33 items rated from 0 (unable to perform) to 2 (performs without modification/adaptation/compensation). Total scores range from 0-66. Higher scores indicate higher levels of motor ability.

Change from baseline in HFMSE total score at the end of Follow-up Period 1 in treated patients compared to sham controls in the ≥ 2 to < 5 years age group

The HFMSE is a validated SMA specific assessment devised for use in children with SMA to give objective information on motor ability and clinical progression. The HFMSE contains 33 items rated from 0 (unable to perform) to 2 (performs without modification/adaptation/compensation). Total scores range from 0-66. Higher scores indicate higher levels of motor ability.

Change from baseline in Revised Upper Limb Module (RULM) total score at the end of Follow-up Period 1 in treated patients compared to sham controls in the ≥ 2 to < 18 years age group

The RULM is a validated SMA specific assessment of motor performance in the upper limbs from childhood through adulthood in ambulatory and non-ambulatory individuals with SMA. The scale consists of 19 scorable items: 18 items scored on 0 (unable) to 2 (full achievement) scale, and one item that is scored from 0 (unable) to 1 (able). Total scores range from 0-37 points. Higher scores reflect higher level of motor ability.

Change from baseline in the RULM total score at the end of Follow-up Period 1 in treated patients compared to sham controls in the ≥ 2 to < 5 years age group

The RULM is a validated SMA specific assessment of motor performance in the upper limbs from childhood through adulthood in ambulatory and non-ambulatory individuals with SMA. The scale consists of 19 scorable items: 18 items scored on a 0 (unable) to 2 (full achievement) scale, and one item that is scored from 0 (unable) to 1 (able). Total scores range from 0-37 points. Higher scores reflect higher level of motor ability.

An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical investigation participant after providing written informed consent for participation in the study. A Treatment Emergent Adverse Event (TEAE) is defined as an event that emerges during treatment, having been absent pretreatment, or worsens relative to the pretreatment state. The occurrence of AEs must be sought by non-directive questioning of the participant at each visit during the study. Adverse events also may be detected when they are volunteered by the participant during or between visits or through physical examination findings, laboratory test findings, or other assessments.

Achievement of at least a 3-point improvement from baseline in HFMSE total score at the end of Follow-up Period 1 in the ≥ 2 to < 18 years age group

The HFMSE is a validated SMA specific assessment devised for use in children with SMA to give objective information on motor ability and clinical progression. The HFMSE contains 33 items rated from 0 (unable to perform) to 2 (performs without modification/adaptation/compensation). Total scores range from 0-66. Higher scores indicate higher levels of motor ability.

Achievement of at least a 3-point improvement from baseline in HFMSE total score at the end of Follow-up Period 1 in the ≥ 2 to < 5 years age group

The HFMSE is a validated SMA specific assessment devised for use in children with SMA to give objective information on motor ability and clinical progression. The HFMSE contains 33 items rated from 0 (unable to perform) to 2 (performs without modification/adaptation/compensation). Total scores range from 0-66. Higher scores indicate higher levels of motor ability.

An AESI is primarily defined by using standard Medical Dictionary for Regulatory Activities (MedDRA) queries, and identified as follows: Hepatotoxicity Thrombocytopenia Cardiac adverse events Dorsal Root Ganglia Toxicity Thrombotic microangiopathy

Low cardiac function is defined as left ventricular ejection fraction <56% or left ventricular fractional shortening <28% on post-baseline echocardigrams

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 dosing OAV101 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

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