Motor Gains and Safety with Zolgensma’s IT Use Continue, STRONG Data Show

Young children given a single injection of Zolgensma into the spinal canal continue to show gains in motor function and safety, new interim data from the STRONG trial in spinal muscular atrophy (SMA) type 2 patients up to age 5 show.

These findings from the open-label Phase 1/2 clinical trial, placed on partial hold in October over safety concerns seen in an animal study, were recently presented at a virtual Clinical Trial Session conducted by the Muscular Dystrophy Association (MDA). The session was scheduled after the 2020 MDA Annual Conference was canceled due to the Covid-19 pandemic.

Zolgensma (onasemnogene abeparvovec-xioi) is a gene therapy originally developed by AveXis, now part of Novartis, to treat all types of SMA. It was approved by the U.S. Food and Drug Administration (FDA) in 2019 as a one-time intravenous (IV) infusion for newborns and toddlers up to age 2.

STRONG (NCT03381729) is evaluating the therapy’s safety, tolerability, and early efficacy — given as a one-time intrathecal (IT) injection directly into the spinal canal — in up to 51 children with SMA type 2, ages 6 months to 5 years, carrying three copies of the SMN2 gene. A higher number of this gene’s copies is associated with lesser disease severity.

All enrolled were able to sit independently for up to 10 seconds, but could not stand or walk, at the study’s start.

The trial is testing three ascending doses of Zolgensma — dose A (6.0 x 10¹³ vg), dose B (1.2 x 10¹⁴ vg), and dose C (2.4 x 10¹⁴ vg) — with patients divided into two groups, according to their age at the time of dosing: 6 months to up to 2 years, and 2- to 5-year-olds.

To date, 32 children have been treated: three at dose A, 25 at dose B, and four at dose C.

Previous findings in STRONG, with data through May 2019, showed that children in both age groups given doses A and B (the two lowest doses) achieved clinically meaningful improvements in their motor function, as measured by the Hammersmith Functional Motor Scale-Expanded (HFMSE). This scale is a validated measure of physical ability in SMA children, is specifically designed for patients older than age 2, and is able to monitor changes in both weaker and stronger groups.

These earlier findings, at about nine months of follow-up after a single Zolgensma infusion, showed a mean increase of 5.9 points in HFMSE scores in the 2- to 5-year-olds. Half of these children displayed meaningful improvements in motor scores, researchers reported at that time.

New interim data, collected through Dec. 2, 2019, continue to show safety with IT infusion treatment. Adverse events reported were consistent with those seen in intravenous use of the gene therapy, and no new safety signals were seen, a Novartis press release stated.

At one year of follow-up, data also show a mean increase of six points in HFMSE scores for the 12 older children treated at dose B (medium dose), the release stated. (HFMSE changes are a primary trial goal for the 2- to 5-year old age group.)

This six-point mean rise from the study’s start (baseline) is double what would be considered a clinically meaningful improvement in motor abilities, established in previous SMA studies. It reflected improvement in three to six skills measured using HFMSE, including trunk control when rolling and sitting, and transitioning from lying to sitting.

Nearly all these children (92%, 11 of 12) achieved the clinically meaningful three-point increase in their HFMSE scores, reflecting consistent improvement with Zolgensma’s use compared to SMA’s natural history. Untreated type 2 children would experience a continual decline in motor function.

According to trial investigators, motor gains as reflected by rising HFMSE scores indicate that motor neurons — nerve cells responsible for controlling voluntary muscles — are being preserved.

None of the older children to date show an ability to walk independently for five or more steps, a secondary trial goal.

In the younger children, five of the six who are now at least 2 years old and able to be evaluated using HFMSE also had three-point increases from their baseline scores.

A total of 18 motor milestones were achieved among six of the 13 patients treated at dose B in this younger age group, including one who could stand and walk independently.

“Nearly all patients evaluated on the gold standard Hammersmith scale achieved a clinically meaningful response, consistently demonstrating improved motor function through continuous, stable SMN protein expression,” Dave Lennon, president of AveXis, said in the release.

“Among patients with SMA Type 2 between two and five years of age, STRONG data demonstrated … remarkable motor function improvement following a single, one-time intrathecal dose,” he added. “We look forward to sharing these data with regulators to further our discussions toward registration of intrathecal AVXS-101.”

No data was presented on the four children treated with Zolgensma at the trial’s high, C dose. Further enrollment in STRONG awaits a lifting of the partial hold, placed by the U.S. Food and Drug Administration (FDA) after a preclinical study showed inflammation that can damage nerve cells in primates given Zolgensma by IT injection.