Zolgensma Produces Promising Results in Young Children with Type 2 SMA, Early Trial Data Show

A single injection of Zolgensma into the spinal canal (intrathecal) can provide a clinically meaningful response in motor function gains among young children, 2 to 5 years old, who have spinal muscular atrophy (SMA) type 2, recent trial data show.

Half of these older patients (six out of 12) experienced significant motor gains, starting at one month after treatment. One gained the ability to walk with assistance. No serious side effects led to withdrawal, and no deaths were reported.

Infants and toddlers treated with Zolgensma also gained motor milestones, including the ability to stand independently and to walk alone.

The findings were presented during the recent 24th World Muscle Society (WMS) International Annual Congress, in Copenhagen, Denmark.

Zolgensma is a gene therapy that has been approved by the U.S. Food and Drug Administration to treat all SMA types in children up to age 2, and is administered as a one-time infusion into the vein (intravenous injection).

AveXis — the company that originally developed Zolgensma, which is now owned by Novartis — is running several clinical trials to evaluate the therapy’s use in older patients with different types of SMA, and using a different route of administration.

Its STRONG study (NCT03381729) is an ongoing, open-label, multicenter Phase 1/2 trial evaluating the safety, tolerability, and preliminary efficacy of Zolgensma in SMA type 2 children up to 5 years (60 months) of age.

Enrolled patients carry three copies of the SMN2 gene — a higher number of copies is associated with reduced SMA severity — and were able to sit, but not stand or walk at the time they started the study.

The trial is testing two different doses of Zolgensma, with each patient receiving a single dose injected into the spinal canal. Patients were divided into two groups according to age at the time of dosing — younger patients from 6 months up to 2 years, and older ones ages 2 to 5.

As of the May 31, data cut-off date, 31 patients had been given one of three doses of Zolgensma — dose A (6 x 10¹³ vectors genomes, vg), dose B (1.2 x 10¹⁴ vg), and a higher dose C (2.4 x 10¹⁴ vg).

Data updates presented at the WMS meeting cover the two lowest doses, A and B.

As of that date, 18 motor milestones had been achieved among the younger patient group (younger than 2), including two children who gained the ability to stand independently, one of whom went on to walk without assistance.

Notable effects were seen in the older patient group (12 children, ages 2–5), who achieved a mean increase of 5.9 points in the Hammersmith Functional Motor Scale Expanded (HFMSE) scores — a validated scale to measure physical ability in SMA children — after a mean follow-up of 9.3 months.

This is nearly twice as high as the minimum benefit in motor function defined as clinically meaningful (3-point or better improvement), and represents progress from previous results presented in May 2019 at the American Academy of Neurology (AAN) annual meeting.

Half of the older children displayed meaningful improvements in motor scores, which began to be noticeable at one month after treatment. To date, four motor milestones were achieved by 12 children in the dose B group, including one patient who gained the ability to walk with assistance.

These results are particularly meaningful considering the natural course of SMA. Untreated SMA type 2 patients usually experience a worsening in HFMSE scores over time, and aren’t able to walk without support, often needing a wheelchair.

Regarding safety, all patients experienced at least one treatment-emergent adverse event (TEAE), and in 13 patients (43%), adverse events were considered related to treatment. Serious TEAEs were reported in four patients (13%), including flu, pneumonia, respiratory syncytial virus infection, elevated blood levels of ALT, AST or alkaline phosphatase (markers of liver function), and respiratory failure.

In one patient, elevated ALT and AST were considered likely related to treatment.

None of these serious side effects resulted in study discontinuation.

“Given the natural history of this devastating and rare genetic disease, many children will never stand or walk independently without therapeutic intervention. Today’s results — although early — are extremely encouraging for families who hope to see their children with SMA Type 2 experience meaningful improvement in motor function and important milestones, like standing and walking, following a one-time intrathecal administration of AVXS-101,” Douglas M. Sproule, MD, vice president of SMA therapeutic head at AveXis, said in a news release.

“These data presented at the congress, along with long-term follow-up data from the STR1VE and SPR1NT studies, support a continually advancing body of evidence on the clinical impact gene therapy treatment may have for those fighting this devastating and rare genetic disease, regardless of type or severity,” he added.

The STR1VE trial (NCT03306277) is designed to assess the safety and efficacy of a single intravenous infusion of Zolgensma in babies with type 1 SMA, under six months of age.

SPR1NT (NCT03505099) is assessing the safety and efficacy of a single intravenous infusion in newborns under 42 days old who have type 1 or 2 SMA, do not show symptoms yet, and carry either two or three copies of the SMN2 gene.