Intrathecal Zolgensma Shows Early Efficacy in SMA


Nearly all patients in this cohort achieved a clinically meaningful >3-point increase during the study period, demonstrating a consistent response to the gene therapy.

Richard Finkel, MD

Richard Finkel, MD

Interim data from the phase 1 STRONG study of AveXis’s intrathecal (IT) Zolgensma (AVXS-10) in sitting but nonambulatory patients with spinal muscular atrophy (SMA) demonstrated significant change in Hammersmith Functional Motor Scale-Expanded (HFMSE) score from baseline to 12 months postdose.1

Results were presented by lead investigator Richard Finkel, MD, division chief of Neurology at Nemours Childrens Health System, during the virtual Clinical Trials Session of the 2020 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference on March 24, 2020.

The FDA previously approved Zolgensma in May 2019 for the treatment of SMA in pediatric patients <2 years of age with mutations in the SMN1 gene. Zolgensma is the first and only gene therapy FDA-approved for SMA, including for patients who are presymptomatic.

In the current study, researchers observed 18 motor milestones gained following treatment in patients >6 to <24 months, including 2 standing independently and 1 who achieved the ability to walk alone. Additionally, 3 out of 12 (25%) patients aged ≥24 to <60 months gained motor milestones as well, including 1 who walked with assistance.

The results of this study come just months after the FDA had placed a partial hold on the program, citing dorsal root ganglia mononuclear cell inflammation in the animal model treated with AVXS-101.

“Among patients with SMA type 2 between 2 and 5 years of age, STRONG data demonstrated potential best-in-category profile with remarkable motor function improvement following a single, one-time intrathecal dose,” Dave Lennon, PhD, president of AveXis, said in a statement.2

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The phase 1, open-label study used a 1-time administration of intrathecal Zolgensma in patients with SMA with confirmed biallelic survival motor neuron 1 [SMN1] loss and 3 copies of SMN2, aged >6 to <60 months who could sit but not stand or walk. Investigators used 3 dose levels: dose A, 6.0 x 1013 vg; B, 1.2 x 1014 vg; and C, 2.4 x 1014 vg.

Researchers used safety/tolerability, optimal dose, unsupported standing >3 seconds (>6 to <24 months) and change in HFMSE score from baseline (≥24 to 60 months) at 12 months postdose as primary end points.

A 3-point increase in HFMSE represented the minimum change considered clinically meaningful. Notably, a 1-point increase in HFMSE was considered a meaningful change to caregivers of nonambulatory patients with SMA type 2.

In total, 31 patients were enrolled in the study as of May 31, 2019 (dose A, n = 3, ≥6 to <24 months; dose B, n = 13, ≥6 to <24 months; n = 12, ≥24 to <60 months; dose C, n = 3). At that time, HFMSE increased a mean 5.9 points from baseline at most recent visit in patients >24 to <60 months (mean [range] duration of follow-up, 9.3 [7.2—11.9] months).

Researchers also noted that 92% of patients who received dose B achieved a clinically meaningful >3-point increase in HFMSE at any post-baseline visit during the study period (P <.0001). Additionally, 4 motor milestones were achieved in the same group, but the secondary end point of the ability to walk independently for >5 steps was not achieved by any patient.

Among all the patients included in the study, 12 (38%) reported a treatment-emergent adverse event (TEAE). Nearly all the patients in the study reported at least 1 AE and serious AEs were reported in 22% (n = 7) of patients. Pneumonia (n = 2), influenza, bronchitis, rhinovirus infection, respiratory tract infection, elevated ALT, elevated AST, acute respiratory failure, asthma, respiratory failure (n = 1 each), and increase of blood alkaline phosphate (n = 2) made up the 13 serious AEs found in the 7 patients who experienced them.

Investigators reported no clinical data of sensory neuropathy in 335 patients following intravenous or intrathecal treatment with Zolgensma in response to the partial clinical hold put on the program in October. The FDA is expected to respond by Q2 2020.

“Given the robust response, these STRONG data indicate AVXS-101 delivered intrathecally could potentially be a new one-time treatment option for patients and their clinicians,” Olga Santiago, MD, chief medical officer, AveXis, said in a statement.


1. One-time intrathecal (IT) administration of AVXS-101 IT gene therapy for spinal muscular atrophy: phase 1 study (strong). Presented at 2020 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference. March 24, 2020; Abstract 52.

2. AveXis presents AVXS-101 IT data demonstrating remarkable increases in HFMSE scores and a consistent clinically meaningful response in older patients with SMA Type 2 [news release]. Basel, Switzerland: Novartis; Published March 24, 2020. Accessed March 24, 2020.

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