Disclosures: Mendell reports receiving personal compensation for clinical trial consulting, serving on scientific advisory boards and research support for Novartis Gene Therapies outside the study. Please see the full study for all other researchers' relevant financial disclosures.
May 28, 2021
3 min read

Zolgensma demonstrates ‘remarkable’ long-term results for children with SMA

Disclosures: Mendell reports receiving personal compensation for clinical trial consulting, serving on scientific advisory boards and research support for Novartis Gene Therapies outside the study. Please see the full study for all other researchers' relevant financial disclosures.
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Ongoing follow-up in the START phase 1 study supported “the long-term favorable safety profile” of Zolgensma in children aged up to 6 years with spinal muscular atrophy type 1, according to findings published in JAMA Neurology.

The findings also provided evidence for “sustained clinical durability” of the therapeutic dose of 1.1 × 1014 vg/kg used in the START trial.

A baby playing with blocks.
A baby playing with blocks.

SMA “is the most common, fatal, autosomal recessive disease of infancy,” Jerry R. Mendell, MD, attending neurologist at Nationwide Children’s Hospital in Ohio, Dwight E. Peters and Juanita R. Curran Endowed Chair in Pediatric Research at the Abigail Wexner Research Institute at Nationwide Children’s Hospital and professor of pediatrics and neurology at Nationwide Children’s Hospital and The Ohio State University, told Healio Neurology. In SMA type 1, death occurs at a mean of 10.5 months and only 8% of patients are alive at 20 months, according to Mendell.

“Added to severe prognosis, untreated patients never learn to sit, talk or eat independently and are severely hypotonic,” he said.

However, gene therapies such as Zolgensma (onasemnogene abeparvovec; Novartis) “dramatically changes prognosis,” Mendell continued. He also described how Zolgensma works in SMA, a disease in which the survival motor neuron 1 (SMN1) gene is mutated and does not express, and the SMN protein is what “saves the motor neurons,” according to Mendell.

“There is also an SMN2 gene that expresses a small amount of the missing protein,” he said. “If there are multiple copies of the SMN2 gene and only partial expression from each, multiple copies of SMN2 can modify the disease.”

This includes SMA types 2, 3 and 4, which are all “milder phenotypes” of the disease, Mendell said.

In the present study, the researchers conducted a long-term follow-up study of the START trial that included patients who finished the phase 1 START study. The analysis described in the paper reported on interim results of this follow-up study, with a data cutoff date of June 11, 2020. The primary objective was safety and the secondary objective was to evaluate whether developmental milestones reached in the START phase 1 trial were maintained and whether new milestones were achieved.

Participants included symptomatic infants with SMA type 1 who had two copies of SMN2 who received prior treatment with IV doses of Zolgensma in the START trial (low dose, 6.7 × 1013 vg/kg; therapeutic dose, 1.1 × 1014 vg/kg). The present analysis included 13 of 15 original participants from the START trial, which was conducted from May 5, 2014, through Dec. 15, 2017, as two families declined to participate in follow-up. Mendell and colleagues analyzed data from Sept. 21, 2017, through June 11, 2020.

The patient population of 13 infants included more girls (54%) than boys and primarily white infants (92%), in addition to one Hispanic/Latino infant (8%). The infants’ ages ranged from 25.4 months to 48 months (median, 38.9 months) at the baseline visit in the long-term follow-up analysis. Weight ranged from 10 kg to 14.7 kg (median weight, 12 kg), according to the study results.

More patients received the therapeutic dose of Zolgensma (n = 10) than the low dose (n = 3). The researchers reported serious adverse events in eight patients (62%), though none resulted in study discontinuation or death. The most commonly reported serious adverse events included acute respiratory failure (n = 4; 31%), pneumonia (n = 4; 31%), dehydration (n = 3; 23%), respiratory distress (n = 2; 15%) and bronchiolitis (n = 2; 15%). All patients in the therapeutic dose arm remained alive with no need for permanent ventilation, Mendell and colleagues reported.

Prior to baseline, four patients (40%) in the therapeutic dose arm required noninvasive ventilatory support, while six patients (60%) did not. This did not change in the long-term follow-up and all 10 patients in the therapeutic dose arm retained motor milestones that had been achieved earlier. Additionally, two patients achieved a new milestone, “standing with assistance,” according to the study results, without the use of Spinraza (nusinersen, Ionis Pharmaceuticals).

“The START trial showed that all 15 of the original patients enrolled survived beyond 2 years when virtually all lives should be lost,” Mendell said. “The study published in JAMA Neurology was the long-term follow-up out to more than 5 years after treatment. There was no loss of milestones and, in addition, two patients were walking and two more patients were standing. It confirmed results of the START trial, which is very reassuring as we move ahead to treat these infants.”

The long-term follow-up analysis also demonstrated that earlier treatment was better, according to Mendell. That finding is being confirmed in a trial that includes newborns with SMA who were diagnosed by newborn screening, he said.

While the long-term follow-up analysis demonstrated no unexpected findings, Mendell said, he did note that “this is biology and confirmation of a trial done early in life is reassuring when it is confirmed in long-term follow-up.”

The finding that all patients were alive 5 years after gene therapy, with two participants walking and two standing, “is remarkable,” according to Mendell.

“The next step is to treat the youngest patients possible to rescue these infants before there is significant loss of neurons,” he said.