MDA 2024: Spinraza may benefit some SMA children after Zolgensma

Marisa Wexler MS avatar

by Marisa Wexler MS |

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In children with spinal muscular atrophy (SMA) who have a less-than-optimal response to the gene therapy Zolgensma (onasemnogene abeparvovec-xioi), subsequent treatment with Spinraza (nusinersen) can improve motor function and may reduce nerve damage.

That’s according to interim data from the Phase 4 RESPOND study (NCT04488133), which enrolled children who still had substantial SMA symptoms following the one-time Zolgensma treatment.

“The available data support the potential benefit and safety of [Spinraza] administration in infants and children with suboptimal clinical response to [Zolgensma],” Crystal Proud, MD, an investigator on the RESPOND trial, said in a talk at the Muscular Dystrophy Association 2024 Clinical and Scientific Conference, being held this week in Portugal.

Proud’s presentation was titled “Interim results from the RESPOND study of nusinersen in children with spinal muscular atrophy (SMA) previously treated with onasemnogene abeparvovec.” The work was funded by Biogen, the company that sells Spinraza.

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Motor function improves for SMA children given Spinraza after Zolgensma

SMA is caused by mutations in the SMN1 gene, leading to low levels of the protein SMN, which causes motor neurons — the nerve cells that control movement — to sicken and die. Spinraza was the first treatment for SMA to become widely approved; it won approval in the U.S. in 2016. It’s administered by injection into the spinal canal every four months, and works to boost SMN protein levels.

Zolgensma is an approved gene therapy, given just one time, that delivers a healthy copy of the SMN1 gene to a patient’s cells.

Since the gene therapy came on the market in 2019, there have been some reports of patients who received Zolgensma and then were also treated with routine injections of Spinraza. The safety and effectiveness of this combination hasn’t been systematically investigated, however.

RESPOND was launched in 2021 with the goal of collecting more information on children — those enrolled ranged in age from 2 months to 3 years — treated with Zolgensma and then Spinraza. The study, conducted at Children’s Hospital of the King’s Daughters, in Virginia, specifically recruited patients whose SMA symptoms remained, and were substantial, despite Zolgensma treatment.

“These patients were diagnosed with SMA, subsequently received [Zolgensma], and then at least two months later they were enrolled in RESPOND if they were identified as having suboptimal clinical status” in domains, or ability areas, such as motor function, breathing, and feeding ability, said Proud, a pediatric neuromuscular neurologist at the Children’s Hospital where the study took place.

Six months in, we see mean total [motor function test] scores increased across age groups [with Spinraza treatment].

Proud’s presentation covered data from 29 patients who had taken Spinraza for at least six months. Among them 14 had started on Spinraza before reaching the age of 9 months. These patients had a much shorter median time between receiving Zolgensma and starting on Spinraza than the other children (4.8 vs. 13.3-14.4 months). Most of these patients had two copies of the so-called backup gene SMN2, while three patients had three copies of this gene.

No infants younger than 9 months had the ability to sit without support, and a significant number of older patients had also yet not achieved sitting.

In the six months after starting Spinraza, virtually all of the children experienced improvements in motor function, the results showed. Average scores on a standardized test of motor function called the HINE-2 — fully the Hammersmith Infant Neurological Examination, section two — improved by more than five points, with similar improvements seen for patients started on Spinraza before or after 9 months of age.

“Six months in, we see mean total HINE-2 scores increased across age groups,” Proud said.

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NfL levels, a marker of nerve damage, drop after Spinraza treatment

The ongoing RESPOND study also is tracking how Spinraza treatment affects levels of neurofilament light chain (NfL), a well-established marker of nerve damage, in these SMA children.

At the start of the trial, participants had NfL levels higher than the normal range for typically-developing children, indicating that these youngsters had substantial nerve damage despite prior treatment with Zolgensma.

“Prior to receiving Spinraza at the start of RESPOND, we saw that participants had elevated neurofilament levels, as compared to healthy children suggesting ongoing neuronal injury,” Priya Singhal, MD, Biogen’s head of development and interim chief medical officer, said in a company press release on the new data.

NfL levels were especially high among children with just two copies of the SMN2 backup gene. After six months on Spinraza, however, the average NfL levels in these children decreased by 70% in those who received Spinraza before they were 9 months old, and by 78% in those who received it after that age.

Two of the three patients with three copies of the backup gene also experienced reductions in NfL after six months on Spinraza, albeit less dramatic ones. NfL levels remained stable in the one patient without elevated NfL levels at the beginning of the study.

Proud noted that NfL levels decreased regardless of the age at which patients received the first dose of Spinraza — or the time between getting Zolgensma and starting on Spinraza. She said the data suggest that the addition of Spinraza therapy is leading to less nerve degeneration for these children.

For her part, Singhal noted that NfL levels were a particularly useful tool for making comparisons.

“The RESPOND findings underscore the value of neurofilament as an objective marker for assessing remaining unmet needs in SMA patients who have previously received gene therapy,” Singhal said.

Safety data, which cover all 38 patients enrolled in the RESPOND study so far, have revealed no unexpected findings. No serious side effects related to Spinraza have been reported.

In the press release, Proud said the goal is “to further maximize benefits” for children with SMA given any treatment.

“Our evolving understanding of gene therapy indicates there may be an opportunity for better outcomes” for some patients after that treatment, Proud said.

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