Real-world study shows Zolgensma treatment helps SMA kids

Treatment with Zolgensma (onasemnogene abeparvovec-xioi) helped children with spinal muscular atrophy (SMA) gain or maintain motor milestones and motor function, a real-world study in Japan found.

The RESTORE patient registry (NCT04174157) is assessing the long-term safety and efficacy of Zolgensma in clinical settings across 99 locations in the U.S. and elsewhere. The study also found that the safety profile of Zolgensma was consistent with earlier reports.

“Ongoing follow-up is expected to provide more insight into the value of early initiation of gene replacement therapy in patients with SMA, including in patients diagnosed following [newborn screening],” the investigators wrote.

The study, “Onasemnogene Abeparvovec in Patients With SMA: Interim Results of the RESTORE Registry in Japan,” was published in the Annals of Clinical and Translational Neurology. It was funded by Novartis Gene Therapies, which makes Zolgensma.

SMA is caused by mutations in the SMN1 gene that result in an inadequate amount of SMN protein. This leads to the progressive loss of motor neurons (specialized nerve cells responsible for movement), resulting in muscle weakness and wasting.

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Disease severity is generally associated with the number of copies of SMN2, a gene also able to produce SMN protein but to a much lower extent. A higher number of SMN2 copies is associated with less severe disease.

Zolgensma is a one-time gene therapy that delivers a healthy copy of the SMN1 gene to cells. The treatment has been approved in the U.S. and Japan for children younger than 2.

A team including multiple scientists at Novartis analyzed the real-world use and outcomes of the gene therapy in 80 Japanese children with SMA, most of them with SMA type 1 (78.3%). Forty children had two or three SMN2 gene copies.

Median age was 3 months at symptom onset and 10 months at Zolgensma infusion. Most of the children had been followed for more than two years by the time the analysis was conducted.

The vast majority (93%) were alive and did not need permanent breathing support three years after receiving Zolgensma. Among 39 children with two or more motor milestone assessments, 64.1% achieved new milestones, and 15.4% maintained their milestones. Milestones included sitting without support, standing alone, and walking alone.

Those diagnosed through newborn screening (NBS) achieved their first milestone four to 26 months earlier than children diagnosed clinically. “This evidence will be important in the future when we expect most cases of SMA to be detected by NBS in the presymptomatic stage, allowing prompt initiation of gene replacement therapy,” the researchers wrote.

A higher percentage of children with three SMN2 copies were more likely to reach new milestones (71.4% vs. 60%) or maintain their milestones (28.6% vs. 8%) than those with two copies of the gene.

Motor function was assessed with the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND), the Hammersmith Infant Neurological Examination-2 (HINE-2), and the Hammersmith Functional Motor Scale Expanded (HFMSE).

Clinically important improvements were defined as an increase of four or more points for CHOP INTEND, three or more for HFMSE, and two or more points with HINE-2.

Among 66 children with available CHOP INTEND scores, 81.8% experienced a clinically important increase. Similar percentages achieved such a benefit, as assessed with HFMSE and HINE-2.

All children had at least one adverse event. About two-thirds (68.8%) experienced serious adverse events. Approximately one-quarter experienced serious adverse events deemed related to treatment. One child died due to respiratory failure, considered unrelated to Zolgensma.

The most common adverse events included fever, elevation of liver enzymes, decreased platelet counts, and vomiting. All patients took corticosteroids to control adverse events for a median of 2.7 months.

“The real-world findings suggest there were gains in or maintenance of motor milestones or motor function scores that were sustained over the observation period,” the researchers wrote. “These findings were apparent in patients with two or three SMN2 gene copies.”