Phase 3b SMART Study Findings Complement Real-World Evidence for Zolgensma in SMA

Hugh McMillan, MD, MSc

Investigators recently published study data from the phase 3b SMART study (NCT04851873), the first trial to evaluate intravenous (IV) onasemnogene abeparvovec (Zolgensma; Novartis), an FDA-approved therapy for spinal muscular atrophy (SMA), in patients with the disease weighing 8.5-21 kg. Using a heterogenous patient population, results showed that treatment with the gene therapy resulted in maintenance or improvement of motor function, with observed adverse events (AEs) like transaminase elevation that were consistent with clinical evidence.¹

The study, led by Hugh McMillan, MD, MSc, a professor in the department of pediatrics at the University of Ottawa, enrolled 24 patients with SMA, a majority of which had type 2 (n = 11), 3 SMN2 copies (n = 18), and were on prior disease-modifying treatment (n = 21). Each of the patients were stratified into 3 weight cohorts (≥8.5-13 [n = 7], >13-17 [n = 8], and >17-21 kg [n = 9]), administered the one-time gene therapy, and followed for 52 weeks. Corticosteroids were started 24 hours before the infusion, with doses adjusted to manage AEs and tapered thereafter at the investigator’s discretion.

All participants completed the 52-week study, with no deaths or AEs leading to discontinuation. Published in Neurology, the safety findings showed that vomiting, found in 63% of patients, was the most frequently reported treatment-related AE (TEAE). Serious AEs were reported in 15 participants, with 7 deemed treatment-related. The most common serious AEs included thrombocytopenia (13%) and vomiting (8%). Adverse events of special interest (AESIs) occurred in 23 participants (96%), notable hepatotoxicity (83%), thrombocytopenia (71%), and cardiac events (13%).

Most participants experienced increases in transaminases (ALT or AST), with 88% (21/24) exceeding three times the upper limit of normal (ULN), 58% (14/24) exceeding 10 times the ULN, and 21% (5/24) exceeding 20 times the ULN during the study. ALT elevations were consistent across weight groups. No participants had a total bilirubin increase as much as twice the ULN, and none met the biochemical criteria for Hy's law. In terms of timing, ALT and AST elevations peaked between weeks 1 and 10 post-dosing.

"The safety profile for onasemnogene abeparvovec was similar across weight groups in this heterogeneous population of participants weighing up to 21 kg, although this required a more prolonged exposure to corticosteroids and demonstrated thrombocytopenia more often than expected, especially for those participants heavier than 13 kg," the study authors wrote.¹ "In addition, the nature of the AEs was consistent with the existing clinical evidence. Compared with previous clinical trials including participants weighing <8.5 kg, there was increased frequency of asymptomatic aminotransferase elevations and thrombocytopenia, as well as longer duration of transaminase elevation and related corticosteroid treatment in this study. Transaminase elevations were manageable with the adequate use of corticosteroids adapted on a case-by-case basis per the discretion of the treating physician.”

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At the end of the 52-week study, 67% of participants had an ALT value greater than ULN and 8% of participants had an AST value greater than ULN. All cases were asymptomatic and managed with corticosteroid treatment. Many participants received greater dosages and longer duration of corticosteroid than anticipated, with the median duration of corticosteroids being 175 days.

Secondary outcomes, which included change in Hammersmith Functional Motor Scale-Expanded (HFMSE), were observed in 20 patients who were at least 24 months of age at study start. Here, results showed that the majority of participants in all 3 weight groups achieved improvements from baseline in their HFMSE score during the study, with median increases in HFMSE total score of 4.0 (–5 to 11) at week 26 and 4.0 (–5 to 11) at week 52 overall. Of the 20 participants with available data, 18 had an increase in HFMSE score and 2 participants had a decrease in score. Notably, at week 52, 61% (11 of 18) of participants had a clinically meaningful increase of at least 3 points in HFMSE total score.

Another secondary analysis included 18 patients who had post-baseline data on the Revised Upper Limb Module (RULM) leading out to at least 30 months. Similar to the HFMSE, the majority of participants had stable or improved RULM total scores during the study, with median increases in RULM total score of 2.0 (–1 to 8) points at week 26 and 2.0 (–5 to 10) at week 52 overall. At week 52, 41% (7 of 17) of participants had a clinically meaningful increase of at least 3 points in RULM total score. Notably, two participants, both in the 17-21 kg weight group, had a decrease in RULM total score at that time point.

At baseline, all participants achieved head control and sitting with support. Among them, 88% sat without support, 42% demonstrated hands-and-knees crawling, and 38% pulled to stand. Additionally, 29% stood and walked with assistance, while 25% stood or walked alone. Most participants maintained their developmental milestones at week 52, though three lost previously demonstrated milestones. Four participants achieved new developmental milestones during the study, including standing with assistance (3 participants) and walking with assistance (2 participants), with one also demonstrating standing alone by week 52.

These data were published weeks before Novartis announced positive topline data from its phase 3 STEER study (NCT05089656) assessing an intrathecal formulation of Zolgensma for SMA. Also known as OAVIT101, the agent met its primary end point in change on HFMSE scores among treatment-naïve patients with SMA, in addition to demonstrating a favorable safety profile. Based on these data, the company plans to advance the therapy further in its development, continuing discussions with the FDA about its path to market.

REFERENCES
1. McMillan HG, Baranello G, Farrar MA, et al. Safety and efficacy of IV onasemnogene abeparvovec for pediatric patients with spinal muscular atrophy: the phase 3b SMART study. Neurology. 2025;102(2). doi:10.1212/WNL.0000000000210268
2. Novartis intrathecal onasemnogene abeparvovec Phase III study meets primary endpoint in children and young adults with SMA. News release. Novartis. December 30, 2024. Accessed January 3, 2025. https://www.novartis.com/news/media-releases/novartis-intrathecal-onasemnogene-abeparvovec-phase-iii-study-meets-primary-endpoint-children-and-young-adults-sma