MDA 2025: SMA gene therapy OAV101 shows acceptable safety

OAV101 IT, a version of the gene therapy Zolgensma (onasemnogene abeparvovec-xioi) that’s administered into the spinal canal, can be safely given to people with spinal muscular atrophy (SMA) who were previously treated with other SMA therapies, according to new data from a clinical trial.

“No [adverse events] leading to death or study discontinuation were reported,” the researchers wrote in a study abstract.

The approved version of Zolgensma is given intravenously, or by infusion into the bloodstream. OAV101 IT is an experimental formulation of Zolgensma that’s instead given intrathecally, or by injection directly into the spinal canal. This version was tested in a Phase 3b clinical trial in children with SMA already given other disease-modifying therapies.

The study findings suggest that OAV101 IT treatment led to stabilization or improvement in motor function for most SMA patients who’d been previously treated with Spinraza (nusinersen) or Evrysdi (risdiplam).

These results were presented at the 2025 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference, ongoing in Texas, in a poster titled “Intrathecal Onasemnogene Abeparvovec for Treatment-Experienced Patients with Spinal Muscular Atrophy: Phase 3b, Open-Label STRENGTH Study.” The work was funded by Novartis, the company that sells Zolgensma.

Recommended Reading

August 5, 2024 News by Lindsey Shapiro, PhD

Double gene therapy leads to lasting benefits in SMA mouse model

OAV101 IT tested in treated children with SMA in Phase 3b clinical trial

Zolgensma is designed to deliver a healthy copy of the SMN1 gene, mutations of which cause SMA, to the body’s cells. It’s approved in the U.S. for SMA patients younger than 2.

Its experimental formulation OAV101 IT uses a different route of administration — one that effectively places the gene therapy right near the cells that are most impacted by SMA. As such, OAV101 IT is expected to require lower doses to achieve therapeutic effects.

The Phase 3b STRENGTH trial (NCT05386680) that tested OAV101 IT enrolled 27 SMA patients, ages 2 to 17, who’d previously been on the approved SMA treatments Spinraza or Evrysdi but had discontinued those therapies. To be eligible for the STRENGTH study, these children and teenagers needed to be able to sit independently but never have been able to walk independently.

All of the participants in STRENGTH were treated with OAV101 IT, with the main goal of assessing the therapy’s safety and tolerability in previously treated patients.

For treatment-experienced patients with SMA who received a one-time intrathecal [into-the-spinal-canal] infusion of [OAV101 IT] in STRENGTH, the safety of [this gene therapy version] was favorable and consistent with the expected profile.

The results showed that the therapy overall was well tolerated. The most commonly reported safety issues were the common cold, fever, and vomiting. About half of the patients experienced side effects related to treatment, but none were deemed serious. There were some serious safety issues reported, mainly infections, but these were not considered related to OAV101 IT treatment, and none of these safety problems were fatal or caused patients to quit the study early.

“For treatment-experienced patients with SMA who received a one-time intrathecal infusion of [OAV101 IT] in STRENGTH, the safety of [OAV101 IT] was favorable and consistent with the expected profile,” the researchers wrote in their abstract.

Recommended Reading

April 10, 2024 News by Marisa Wexler, MS

Study examines side effects observed with SMA gene therapy

Benefits seen for most patients given SMA gene therapy version

Two main measures of motor function were used: the Hammersmith Functional Motor Scale-Expanded (HFMSE), which measures overall motor function, and the Revised Upper Limb Module (RULM), used to measure arm and hand function. On both, participants tended to be stable over time in the year following OAV101 IT treatment. Specifically, the average scores on both the HFMSE and RULM changed by less than a point over a year of follow-up, the data showed.

Caregivers’ experiences, measured with the Assessment of Caregiver Experience in Neuromuscular Disease (ACEND), also showed stability in the year following OAV101 treatment, with an average improvement of slightly higher than one point.

Most patients maintained the motor milestones they’d already achieved, and some achieved new milestones following treatment.

For example, none of the patients could walk unassisted before OAV101 IT treatment. A year after therapy, two were able to walk on their own.

Conversely, however, some patients lost motor milestones. While all 27 patients could sit unassisted at the beginning of the trial, at the end of the yearlong study, two patients were no longer able to sit unassisted, according to the researchers.

Overall, “across motor efficacy assessments, the study population demonstrated stabilization in motor function over 52 weeks,” the researchers wrote.

Two other clinical trials have tested OAV101 IT in SMA patients who have not received other treatments previously. The Phase 1 STRONG trial (NCT03381729), enrolled 32 children, ages 6 months to 5, while the Phase 3 STEER trial (NCT05089656) involved 127 children, ages 2-17. Results from both trials have indicated that this formulation of the SMA gene therapy generally led to improved motor function among patients.

Note: The SMA News Today team is providing live coverage of the 2025 MDA Clinical & Scientific Conference March 16-19 in Dallas. Go here to see the latest stories from the conference.