#MDA2021 – Zolgensma Helped Pre-symptomatic Babies Achieve Age-Appropriate Motor Milestones

Editor’s note: The SMA News Today team is providing in-depth coverage of the 2021 MDA Virtual Clinical and Scientific Conference, March 15–18. Go here to read the latest stories from the conference.

Zolgensma safely and effectively halts disease progression in pre-symptomatic spinal muscular atrophy (SMA) infants, according to updated data from the SPR1NT Phase 3 clinical trial.

Notably, more than a year after the single dose, all of the now-toddlers were alive, able to breathe and swallow, and most achieved motor milestones they would not reach otherwise, and within the normal timeframe.

These findings highlight the significant therapeutic benefit of Novartis’ gene therapy when given shortly after birth in infants with a genetic diagnosis of SMA and likely to develop type 1 or 2 disease.

“When treated with Zolgensma prior to the onset of symptoms, children in the SPR1NT trial achieved milestones like sitting, standing and walking at an appropriate age, grew as expected without nutritional assistance, and remained free of all forms of mechanical ventilatory support,” Kevin Strauss, MD, said in a press release. Strauss is medical director of the Clinic for Special Children, Strasburg, Pennsylvania.

“This stands in sharp contrast to the natural progression of SMA Type 1, which would otherwise render them helpless within the first year of life and unable to swallow, breathe, or survive without mechanical support,” he said.

“The transformative benefit of early intervention, as seen in SPR1NT, further underscores the urgent need for newborn screening,” Strauss said.

SPR1NT’s updated results were presented in an oral presentation and a poster display at the 2021 MDA Virtual Clinical and Scientific Conference, held March 15–18.

Data related to toddlers expected to develop type 1 disease, a severe form, were shared in the poster “Onasemnogene Abeparvovec Gene Therapy in Presymptomatic Spinal Muscular Atrophy (SMA): SPR1NT study update in children with 2 copies of SMN2.”

Those of children likely to develop type 2 disease were presented by Strauss in an oral presentation titled “Onasemnogene Abeparvovec Gene Therapy in Presymptomatic Spinal Muscular Atrophy (SMA): SPR1NT study update in children with 3 copies of SMN2.”

A one-time gene therapy, Zolgensma uses a modified and harmless virus to deliver a healthy copy of SMN1, the mutated gene in SMA, to cells. It was approved in the U.S. in May 2019 for newborns and toddlers up to age 2, with similar decisions following soon after in other countries.

In Europe, the therapy was approved conditionally in May 2020 for patients, weighing up to 21 kilograms (about 46 pounds), with a clinical diagnosis of SMA type 1, or those still without symptoms but carrying up to three copies of the “backup” SMN2 gene.

A higher number of SMN2 copies is associated with lower disease severity, and patients with two gene copies are likely to have type 1 disease, a severe form, while those with three copies are expected to develop SMA type 2.

The two-year, ongoing SPR1NT Phase 3 trial (NCT03505099) is evaluating Zolgensma’s safety and effectiveness in 29 pre-symptomatic babies (up to 6 weeks old) with SMA and carrying two (14 patients) or three (15 patients) copies of the SMN2 gene.

Previous results, at a data cut-off date of Dec. 31, 2019, showed the therapy prolonged infants’ survival, improved lung and motor function, and allowed the attainment of motor milestones within the normal age range.

As of June 11, 2020, children’s mean age was 15.6 months (range, 8.8–18.8 months) for those carrying two SMN2 copies and 15.2 months (range, 3.3–21.1 months) for those with three. All participants had been followed for more than a year.

Infants received the single dose of Zolgensma between 8 and 27 days of age among those likely to develop SMA type 1, and 9 and 43 days old among those expected to have type 2 disease.

Notably, 63% of children expected to develop type 2 disease, “had a family history of SMA and 87% of them were diagnosed with SMA by either prenatal screening or newborn screening” Strauss said.

Results showed that all toddlers in the study were alive and free of ventilatory or feeding tube support, highlighting the therapy’s benefits in survival and in maintaining breathing and swallowing functions in this patient population.

In the group of toddlers with two SMN2 copies, 11 (78.6%) children were able to sit without support for at least 30 seconds — a motor milestone never achieved by these patients when left untreated and meeting the trial’s main goal for this group of patients. In addition, five (35.7%) could stand independently and four (28.6%) were able to walk alone.

Most of them achieved these milestones within the window of normal development defined by the World Health Organization (WHO), and similar to healthy, typically-developing children.

All children likely to develop type 1 disease achieved a score of 50 or higher on the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND), and most (93%) attained scores of at least 58.

The CHOP-INTEND assesses motor skills in infants using a scale of 0 to 64 points, with higher scores indicating better motor function, and a score of at least 40 is rarely observed among untreated type 1 infants.

Among the group of toddlers expected to develop type 2 disease, 13 (86.7%) were able to sit independently and most attained the milestone within the normal reference age interval.

Importantly, eight (53.3%) were able to stand unaided for at least three seconds — the main goal for this group — and six (40%) could walk alone for at least five steps, which was the secondary goal. Both milestones were achieved within the normal developmental window.

In both groups, most children yet to reach the referred milestones were still within the normal age interval for developing these skills. With further follow-up, the researchers expect to see more children with three SMN2 copies achieving these milestones, Strauss noted.

All children showed steady motor function gains in validated measures, and those likely to develop SMA type 2 had fine and gross motor performance “similar to healthy age-matched children,” the pediatrician said.

A total of 17 (58.6%) children experienced a Zolgensma-related adverse event (side effect); none serious in nature. Seven (24.1%) had serious adverse events, all of which were resolved and deemed unrelated to treatment. No side effect led to study discontinuation or death.

“Pre-symptomatic dosing was associated with a favorable safety profile as demonstrated by a low total number of serious AEs [adverse events] and the absence of serious AEs that were caused by the treatment,” Strauss said.

These findings highlighted that Zolgensma-treated infants achieved motor milestones “at an age similar to non-SMA typically developing children, and children with some delay, demonstrating a significant therapeutic benefit,” the researchers wrote.

The results also underscore the critical importance of identifying and treating SMA as early as possible.