Zolgensma Demonstrates Clinical Benefit and Safety in Heavier Patients With Spinal Muscular Atrophy


The phase 3b SMART trial included 24 patients in total who each weighed from 8.5 kg to 21 kg at the time of treatment.

Hugh McMillan, MD, a pediatric neurologist at the Children’s Hospital of Eastern Ontario

Hugh McMillan, MD
Credit: uOttawa

Patients with spinal muscular atrophy (SMA) treated with onasemnogene abeparvovec (Zolgensma; Novartis), a marketed adeno-associated virus vector (AAV)-based gene therapy, in the phase 3b SMART clinical trial (NCT04851873), showed clinical benefit, despite being heavier than patients treated in previous clinical trials.1 The data, which also included safety findings similar to previous clinical trials, were presented in a poster at the 2024 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference, held March 3-6, in Orlando, Florida.

SMART included 24 patients in total who each weighed from 8.5 to 21 kg at the time of treatment. Participants were divided into 3 cohorts based on their weight range within this: 7 patients weighed 8.5 kg to 13 kg (inclusive); 8 patients weighed more than 13 kg, but not more than 17 kg; and 9 patients weighed more than 17 kg, but not more than 21 kg.

It was noted that at 52 weeks posttreatment (Week 52), most of the 24 patients maintained or improved their motor milestones from baseline. At Week 52, 4 patients showed at least 1 new milestone. Furthermore, most patients showed sustained or improved outcomes on Revised Upper Limb Module (RULM), Hammersmith Functional Motor Scale – Expanded (HFMSE), and motor milestone assessments. At Week 52, the mean change from baseline on RULM was 2.0 points (SD, 4.0) and the mean change from baseline on HFMSE was 3.7 (SD, 4.3).

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Clinical Takeaways

  1. Despite higher weights, SMA patients treated with onasemnogene abeparvovec maintained or improved motor milestones at 52 weeks, indicating efficacy across weight groups.
  2. Safety remained consistent across weights, with similar adverse event frequencies and severity. Aminotransferase elevations were managed with prophylactic prednisolone, and no new safety concerns emerged.
  3. In the case of prior SMA therapy use, patients showed motor function maintenance or improvement at Week 52, highlighting the clinical benefit of onasemnogene abeparvovec, especially for heavier patients and treatment switchers.

In terms of safety, first author Hugh McMillan, MD, a pediatric neurologist at the Children’s Hospital of Eastern Ontario, and colleagues pointed out that the frequency and severity of adverse events (AEs) were similar across the 3 weight cohorts in SMART. All patients in SMART had at least 1 treatment-emergent AE (TEAE) and 15 of the 24 patients (62.5%) had at least 1 serious TEAE. Serious TEAEs deemed related to Zolgensma were reported in 7 patients (29.2%). In total, 4 cardiac AEs were reported across 3 patients in SMART, but all were deemed unrelated to the gene therapy. Twenty patients (83.3%) in SMART had cases of hepatotoxicity, with the majority of these events being cases of transaminase increases. All transaminase increases were asymptomatic. One case of prothrombin time prolongation was reported among the hepatotoxicity AEs. There were cases of transient asymptomatic thrombocytopenia reported in 17 (70.8%) patients in the trial. No cases of thrombotic microangiopathy or dorsal root ganglionopathy were observed.

Notably, 2 patients had grade 2 alanine aminotransferase (ALT) increases, 14 patients had grade 3 ALT increases, and 5 patients had grade 4 ALT increases. In all 21 patients (87.5%) who had any-grade ALT increases, ALT levels increased to more than 3x the upper limit of normal (ULN) at some point during the follow-up period. Five patients had ALT increase to levels above 20x ULN. Although, at Week 52 0 patients had ALT levels greater than 3x ULN and only 14 of 22 patients (63.6%) had ALT levels above ULN. Twenty-one patients (87.5%) received prophylactic steroid treatment at a dose of more than 1 mg/kg/day and 9 patients (37.5%) received prophylactic steroid treatment at a dose of more than 2 mg/kg/day. There were no bilirubin elevations, Hy’s law cases, study withdrawals, or patient deaths in SMART. Platelet count decreases were reported in 20 patients (83.3%), but all platelet count decrease events resolved and there were no associated bleeding events.

The ages of patients in SMART at dosing ranged from 1.5 to 9.1 years (mean, 4.69; SD, 1.82). The overall group equally split between boys and girls. Eleven (45.8%) of the 24 patients had SMA type 2, 8 patients had SMA type 1 (33.3%), and 5 patients had SMA type 3 (20.8%). Furthermore, 18 of the 24 patients (75%) had 3 SMN2 gene copies, 5 patients (20.8%) had 2 SMN2 gene copies, and 1 patient (4.2%) had 4 or more SMA2 gene copies. Notably, 21 of the 24 patients (87.5%) in SMART had previously been treated with either nusinersen or risdiplam, which are both considered disease-modifying treatments (DMTs) for SMA, and only 3 patients (12.5%) were treatment-naive before receiving Zolgensma.

“SMART enrolled a heterogeneous population of patients who weighed more than patients included in previous clinical trials with onasemnogene abeparvovec, and most had been treated with another DMT for SMA before receiving onasemnogene abeparvovec,” McMillan and colleagues concluded. “The observed safety profile of onasemnogene abeparvovec was similar across the different weight groups and no new safety signals were observed. The pattern of AE types was similar to previous reports, clinical evidence, and real-world experience. Aminotransferase elevations were observed in the majority of patients, but all cases were asymptomatic and managed with prophylactic prednisolone. Most patients received higher doses as prescribed in the protocol, with 9 patients receiving doses >2 mg/kg. Serum transaminase elevations (all grade 1) were ongoing for a majority of patients at Week 52. Across all assessed efficacy measures, most patients demonstrated maintenance or improvement of motor function at Week 52, suggesting clinical benefit of IV onasemnogene abeparvovec for heavier patients with SMA, and for patients switching from nusinersen or risdiplam “

1. McMillan H, Baranello G, Farrar M, et al. Safety and efficacy of intravenous onasemnogene abeparvovec in pediatric patients with spinal muscular atrophy: findings from the phase 3b SMART study. Presented at: 2024 MDA Clinical and Scientific Conference; March 3-6; Orlando, FL. Poster #S110
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