Lochmüller Lab

Pediatric neurologist Dr Hugh McMillan publishes clinical study examining the safety and efficacy of IV onasemnogene abeparvovec in the broadest cohort of SMA patients to date.

Spinal muscular atrophy (SMA) is a rare, progressive, neuromuscular disease that affects motor neurons – the nerve cells responsible for controlling movement of the skeletal muscles. SMA is caused by defects in the survival motor neuron 1 (SMN1) gene, which is responsible for making a protein called the survival motor neuron (SMN) protein and critical for motor neuron survival. A similar backup gene called survival motor neuron 2 (SMN2) acts as a disease modifier, with greater number of copies of the SMN2 gene associated with less severe form of the condition. 

Significant disease-modifying therapies for SMA developed in the past decade have improved treatment outcomes, with three drugs currently approved in Canada including onasemnogene abeparvovec (OA), an adeno-associated virus gene replacement therapy. OA was approved by Health Canada in 2020 for patients with three or fewer copies of SMN2 or with infantile-onset SMA, with no age or weight limit specified. However, current reimbursement recommendations in many Canadian provinces for OA are limited to patients under six months of age but can be considered for children up to 24 months of age on a case-by-case basis, due to limited clinical trial studies examining the safety and efficacy of the drug in a wider SMA population. 

SMART Study

Dr Hugh McMillan, a leading specialist in clinical and translational research in pediatric neurology and neuromuscular medicine at the Children’s Hospital of Eastern Ontario and Clinical Research Chair at the University of Ottawa recently published a clinical study examining the safety and efficacy of intravenous onasemnogene abeparvovec in the broadest cohort of SMA patients to date. The publication Safety and Efficacy of IV Onasemnogene Abeparvovec for Pediatric Patients With Spinal Muscular Atrophy: The Phase 3b SMART Study addresses the need identified in the 2022 Canadian gene therapy guidance publication for more robust evidence of the safety and efficacy of OA in a broader SMA population, evidence that may be used to advocate for expanded treatment access for OA in Canada. 

The SMART study enrolled a broad cohort of SMA patients, expanding on past studies that were limited to treatment-naïve participants weighing less than 8.5 kg, to include a heterogenous population across different weights up to 21 kg, past treatment history with other SMA treatments, and different SMN copy numbers. The study results show that the safety profile for OA was similar across weight groups in this heterogeneous population and that most participants demonstrated maintenance or improvement of motor function, suggesting clinical benefit for patients with SMA weighing up to 21 kg. 

Notably, while elevated asymptomatic aminotransferase levels during treatment were consistent with previous studies in the population weighing less than 8.5 kg, a prolonged elevation in asymptomatic aminotransferase levels was observed in older or heavier participants. This resulted in a prolonged corticosteroid cycle of prophylactic prednisolone, due to guidelines indicating the dose be gradually reduced as aminotransferase levels decreased. The authors recommend further studies to better understand the underlying pathophysiology involved in the prolonged aminotransferase elevations, which will guide future management strategies. 

Outcome

The findings from the SMART study complement the increasing real-world evidence of OA safety and efficacy for a heterogenous patient group with different SMA types, previous treatment exposure, and a wider range of ages and weights compared to previous onasemnogene abeparvovec trial populations.  

Reference

McMillan, H. J., Baranello, G., Farrar, M. A., Zaidman, C. M., Moreno, T., De Waele, L., … & SMART Study Group. (2025). Safety and Efficacy of IV Onasemnogene Abeparvovec for Pediatric Patients With Spinal Muscular Atrophy: The Phase 3b SMART Study. Neurology, 104(2), e210268.

Click here to access the article.