Positioning Gene Therapy in SMA: Insights From 64-Week STEER Study Outcomes

Spinal muscular atrophy (SMA) treatment has undergone a dramatic transformation over the past decade, with the introduction of disease-modifying therapies targeting survival motor neuron (SMN) protein deficiency. Despite these advances, many patients—particularly older children, adolescents, and adults—continue to experience disease progression, highlighting the need for therapies that offer sustained and potentially more durable benefits. Gene replacement approaches have emerged as a promising strategy to address the underlying genetic cause of SMA in a single administration.

At the 2026 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference, new 64-week data from the phase 3 STEER study evaluating onasemnogene abeparvovec-brve (Itvisma®) provided further insights into the long-term efficacy and safety of this one-time gene therapy approach. The randomized, sham-controlled trial demonstrated continued improvements in motor function, including gains in Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM) scores, with no new safety signals observed over extended follow-up. These findings build on earlier results and suggest durability of effect without the need for additional SMN-targeted therapies.

In a Q&A with NeurologyLive^®, Nazem Atassi, MD, SVP and Global Development Head of Neurology & Gene Therapy at Novartis, discussed the clinical implications of these findings, including the durability of motor improvements, the relevance of upper limb gains for functional independence, and how one-time gene therapy may fit into the evolving SMA treatment paradigm.

NeurologyLive: Can you briefly summarize the key efficacy and safety findings from the 64-week analysis of the phase 3 STEER study of onasemnogene abeparvovec-brve?

• Initial Phase III data showed that Itvisma® (onasemnogene abeparvovec-brve) led to a statistically significant 2.39-point improvement on the Hammersmith Functional Motor Scale Expanded (HFMSE), a gold standard for SMA-specific assessment of motor ability and disease progression, vs. 0.51 points in the sham control arm (P=0.0074).¹
  • In the treatment arm, Hammersmith Functional Motor Scale Expanded (HFMSE) scores increased by an average of 2.40 points at End of Follow-Up Period 1 and 2.75 points at Week 64, while Revised Upper Limb Module (RULM) scores increased by 2.47 points at End of Follow-Up Period 1 to 2.93 points at Week 64.²
• New follow-up data show motor function gains were sustained and continued to increase through week 64, without the addition of other SMN-targeted therapy.²
• The cumulative safety profile of Itvisma was consistent with previous data reported from the study, with no new safety signals identified.²
• The efficacy and safety of these new data continue to support Itvisma in improving motor function for patients living with SMA.

The data suggests continued improvements in motor function through Week 64. How clinically meaningful were these gains, particularly for older patients with SMA who may have more established disease?

• Despite available, chronically-administered treatment options targeting the SMN2 gene, many older children, teens, and adults continue to face unmet needs and disease progression.³
• In STEER, the 64-week follow-up data suggest that motor improvements with Itvisma continued over time across the age range of patients studied in the trial.²
  • Of the 75 patients who received Itvisma in part 1, 67 continued into part 2; 46 of 51 sham patients from part 1 entered into part 2 and received Itvisma.²
  • HFMSE changes from baseline were 2.40 at End of Follow-Up Period 1 and 2.75 at Week 64. Revised Upper Lim Module (RULM) increased from 2.47 at End of Follow-Up Period 1 to 2.93 at Week 64.²

• Improvements in HFMSE can translate into greater ability in performing daily activities.
  • Depending on the person, this level of score increase could potentially mean improved ability to reach, lift, feed themselves, operate a device, or perform other routine activities with less assistance.

Upper limb improvements were highlighted as a key outcome. From a clinical perspective, how might these changes translate into functional independence or quality-of-life benefits for patients?

• Upper limb improvements in SMA can be highly meaningful because arm and hand functions often determine how self-sufficient a non-ambulatory patient can be in daily life.
• From a clinical perspective, maintaining or improving upper-limb function may help preserve daily function and relative independence.
• The observed RULM improvements support the interpretation that Itvisma may provide meaningful functional benefit in a population where upper-limb performance is highly relevant to everyday life.

Given the availability of other SMN-targeted therapies that require ongoing dosing, how should clinicians think about positioning a one-time gene therapy option within the current SMA treatment paradigm?

• The US Food and Drug Administration (FDA) approved Itvisma® (onasemnogene abeparvovec-brve) for the treatment of children two years and older, teens and adults living with spinal muscular atrophy (SMA) – the first and only gene replacement therapy available for this broad population.
• Itvisma is designed to address the genetic root cause of SMA with a one-time fixed dose that does not need to be adjusted for age or body weight.
• By replacing the survival motor neuron 1 (SMN1) gene, Itvisma is designed to continuously increase the amount of SMN protein, offering the potential to reduce the need for chronic treatment associated with other available therapies for this population.⁴

Looking ahead, what additional long-term data will be important to monitor as more patients receive onasemnogene abeparvovec-brve in clinical practice?

• As more patients receive Itvisma in clinical practice, it will be important to monitor whether the motor function gains observed through Week 64 are maintained and continue to improve. Long-term safety monitoring will also remain essential.²
• Long-term monitoring beyond the 64-week STEER study is underway in the 5-year SPECTRUM study, which will be important for evaluating both durability of efficacy and longer-term safety in a real-world-like follow-up setting.²

REFERENCES
1. Proud, C., et al. Intrathecal onasemnogene abeparvovec for patients with spinal muscular atrophy: phase 3, randomized, sham-controlled, double-blind STEER study. Neuromuscul Disord. 53. (2025). https://doi.org/10.1016/j.nmd.2025.105578
2. Proud, C., et al. Intrathecal Onasemnogene Abeparvovec (OAV101) for Patients with Spinal Muscular Atrophy (SMA): Extended 64-Week Outcomes from the Phase 3 STEER Study. Abstract accepted for poster presentation at Muscular Dystrophy Association 2026 Clinical and Scientific Conference. Orlando, FL. Abstract ID 481.
3. Cure SMA. Address the Unmet Needs of Children and Adults with Spinal Muscular Atropy. Accessed October 22, 2025. https://www.curesma.org/wp-content/uploads/2024/08/NIH_SMA_Research_FactSheet.pdf
4 Itvisma^® (onasemnogene abeparvovec-brve). Prescribing Information. Novartis Gene Therapies, Inc.