Preventive dual therapy provides modest benefit in SMA type 1 study
Infants with a genetic diagnosis of spinal muscular atrophy (SMA) type 1 who were treated with Evrysdi (risdiplam) or Spinraza (nusinersen) in addition to Zolgensma (onasemnogene abeparvovec) could sit, but not walk, sooner than those on Zolgensma alone.
These are the findings of a small study in the U.S., in which treatment was given within the first six weeks of life, before the onset of symptoms. While dual therapy, or that combining Zolgensma with Evrysdi or Spinraza, was well tolerated, it “may provide limited if any additional benefit,” researchers say.
The study, “Preemptive dual therapy for children at risk for infantile-onset spinal muscular atrophy,” was published in the Annals of Clinical and Translational Neurology and conducted by a team of researchers in the U.S. Two authors served as paid consultants for Novartis Gene Therapies, which markets Zolgensma.
SMA is caused by mutations in both copies of the SMN1 gene, which provides instructions to produce a protein called SMN. Without SMN protein, motor neurons — the nerve cells that control voluntary movement — die, causing muscle weakness and other symptoms.
A backup gene, called SMN2, can also produce SMN, although significantly less of the working protein than SMN1. Most people have two SMN2 gene copies, but some have more.
SMA children with 2 or fewer SMN2 copies at higher risk
“The severity of SMA correlates with the number of … SMN2 gene copies: children with two or fewer SMN2 copies develop life-threatening disease within a few months after birth,” or SMA type 1, the researchers wrote.
If left untreated, this severe form is associated with death by age 2. Those who survive beyond that fail to meet motor milestones and are reliant on breathing support.
Three disease-modifying therapies are available for SMA. Evrysdi and Spinraza are given at regular intervals to boost SMN protein production by targeting the SMN2 gene, whereas Zolgensma is a one-time gene therapy that delivers a healthy copy of the SMN1 gene to motor neurons.
“All three work best when given before the onset of weakness, but many preemptively treated children with two SMN2 copies nevertheless have motor delays, and those with three as compared to two copies consistently achieve better functional outcomes,” the team wrote.
“For children with two or fewer SMN2 copies, it might be possible to improve outcome by combining agents with overlapping but distinct molecular actions,” the researchers added.
To see if this holds true, they compared preventive treatment with Zolgensma alone versus combined with Evrysdi or Spinraza in infants at risk for SMA type 1 based on genetic testing, but who were not yet showing overt symptoms.
Study included 23 infants, 18 with 2 SMN2 gene copies
The study included 23 infants from the Children’s Hospital of Philadelphia and the Clinic for Special Children in Gordonville, Pennsylvania. All began treatment within the first six weeks of life, before the onset of muscle weakness, and were followed for a median of three years.
A total of 18 infants had two SMN2 gene copies: 11 received Zolgensma alone, and the remaining seven were given dual therapy.
Zolgensma was administered at 7-43 days after birth, and either Evrysdi (six infants) or Spinraza (one infant) was started at a median age of 20 days. The one child on Spinraza switched to Evrysdi at 5.5 months.
At last follow-up, all but one of the 18 infants (94%) sat independently, with most (83%) achieving this motor milestone within the normal age. Children on dual therapy met this milestone at a significantly younger age than those on Zolgensma alone (median of 6 vs. 7.3 months).
The proportion of children who could walk independently was similar between groups (82% with Zolgensma alone vs. 86% with dual therapy), and nine (50%) did so within the normal age.
The one child in the dual therapy group who couldn’t walk at last follow-up was 14.8 months old, younger than the upper normal reference limit for independent walking (17.6 months).
Most children had normal-looking muscles on ultrasounds in first 2 months
Most children had normal-looking muscles on ultrasound scans within the first two months after birth. However, after that, fat infiltration and fasciculations, or muscle twitches, were seen in about 40% or more infants in each group. There were no significant differences between the two treatment groups.
“Dual therapy is well tolerated and may provide modest benefit for children at risk for severe spinal muscular atrophy but does not prevent widespread degenerative changes,” the researchers wrote.
The remaining five of the 23 infants carried three SMN2 gene copies and were treated with Zolgensma alone. At last follow-up, all could sit and walk independently, and within the normal time window. Their muscles appeared normal on ultrasound images.
“Children with three SMN2 copies experience more attenuated neurodegeneration over a longer period,” the researchers wrote. “They are born with more spinal motor neurons and therefore respond better to postnatal [after birth] treatment.”
While children on dual therapy could sit independently at an earlier age than those on Zolgensma alone, it appears “dual therapy within a few postnatal months” doesn’t “close the outcome gap between children with two versus three SMN2 copies,” the team concluded.
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