Long-term Follow-up of Onasemnogene Abeparvovec Gene Therapy for Patients with Spinal Muscular Atrophy Type 1 from the START Trial

Topic:

Clinical Trials

Poster Number: P278

Author(s):

Megan Waldrop, MD, Center for Gene Therapy, Nationwide Children’s Hospital, Roberto Bernardo Escudero, MD, Novartis Development – Neuroscience & Gene Therapy, Rebekah Camarata, CPNP-AC, Nationwide Children’s Hospital, Emily Branic, FNP, Nationwide Children’s Hospital, Lesa Mehl, PT, DPT, MSPT, BioMedical Research, Novartis, Andreja Ilic, MA, Novartis Pharmaceuticals, Anne M. Connolly, MD, Nationwide Children’s Hospital, Columbus, Ohio, USA

Background: Patients with spinal muscular atrophy type 1 (SMA1; biallelic SMN1 deletions, two SMN2 copies) demonstrated improvements following onasemnogene abeparvovec (OA) treatment in START (phase 1, open-label, single-arm, dose-escalation trial, n=15; NCT02122952). Data are presented for START patients enrolled in long-term follow-up in LT-001 (NCT03421977).
Objective/Methods: Primary objective was to assess long-term safety and efficacy (survival without permanent ventilatory support) in START patients who received OA low-dose (LD) (6.7×1013 vg/kg) or therapeutic dose (TD) (1.1×1014 vg/kg) in LT-001. Motor milestones were assessed.
Results: As of July 1, 2024, 13 START patients enrolled in LT-001 (n=3, LD; n=10, TD). Mean age at dosing was 6.3 months (LD) and 2.8 months (TD); mean follow-up was 9.9 years [min–max: 9.8–10.1 years] (LD) and 8.3 years [min–max: 6.8–9.6 years] (TD). Most received nusinersen/risdiplam post-OA (100%, LD; 70%, TD). Most common adverse events (AEs) were: acute respiratory failure (n=6, 46%), dehydration (n=5, 39%), pneumonia (n=5, 39%). AEs of special interest were: transient thrombocytopenia (n=2, LD), cardiac AEs (n=1 per group), new incidence of neurological disorders (n=2, TD). All were deemed unrelated to study treatment. There were no reports of hepatotoxicity, thrombotic microangiopathy, dorsal root ganglia toxicity, new malignancies, autoimmune, or hematological disorders. All patients survived as of data cutoff (n=8 ongoing) or last visit before discontinuation (n=5, TD). All patients were free of permanent ventilation except one (LD). The highest motor milestone achievement for LD was sitting with support (n=1); the other two LD patients did not achieve milestones. All 10 TD patients achieved motor milestones at least once. The highest motor milestone achievements for the TD group were sitting without support (n=5), standing with assistance (n=3), and walking alone (n=2). At their last assessment, TD patients were able to demonstrate the highest milestone demonstrated at their first assessment. Two patients (TD) newly achieved standing with assistance in LT-001.
Conclusions: OA demonstrated a favorable benefit-risk profile and durable efficacy up to 10 years post-dose.