In children with SMA, Spinraza demonstrates Zolgensma safety


Spinraza (Nusinersen) treatment appears to be safe in infants and children with spinal muscular atrophy (SMA) who have responded poorly to Zolgensma gene therapy, according to early safety data from the first nine patients in the RESPOND study.

Motor and lung function were the most common domains showing disease progression in these children despite treatment with Zolgensma. At the study’s August 2021 cut-off, none of the adverse events reported in the study were considered to be related to Spinraza use.

The study is currently recruiting SMA patients up to 3 years of age at sites in the US, Italy, Germany, Spain and Israel; more information can be found here.

These preliminary results were presented in a biogenic-funded poster at the 2022 American Academy of Neurology Annual Meeting held April 2-7 and April 24-26 virtually in Seattle.

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The poster was entitled “Baseline Characteristics and Initial Safety Results in RESPOND: A Phase 4 Trial of Nusinersen in Children with Spinal Muscular Atrophy (SMA) Receiving Onasemnogene Abeparvovec.”

SMA is caused by low to no levels of the SMN protein due to mutations in the SMN1 Gen. Motor neurons, the specialized nerve cells that control voluntary movement, are particularly sensitive to SMN deficiency and die as a result.

Biogen’s Spinraza and NovartisZolgensma (onasemnogene abeparvovec-xioi) are two approved disease-modifying therapies for SMA that increase SMN levels through different mechanisms.

While Spinraza boosts SMN production through targeting SMN2a backup gene that can partially compensate for the loss SMN1-derived SMN, the gene therapy Zolgensma uses a modified and harmless virus to provide a working copy SMN1 to cells.

Spinraza is administered directly into the spinal canal after four loading doses every four months and is approved for children and adults with all types of SMA.

Zolgensma, given directly into the bloodstream through a single infusion, is available in the US and Japan for children up to the age of 2 years and in Europe for children with almost all types of SMA and weighing up to 21 kilograms (about 46 pounds) available.

While Zolgensma is expected to promote sustained SMN production in cells such as motor neurons, previous preclinical research has occurred suggests that therapy may only target a subset of these cells.

Therefore, single-dose therapy may not always deliver the intended therapeutic effect, and additional approaches may be required.

According to real-world and clinical reports, some children treated with Zolgensma have subsequently received Spinraza, but no study has systematically analyzed the safety and clinical outcomes of such a combination.

To clarify the safety and efficacy of Spinraza post-Zolgensma, Biogen initiated the Phase 4 RESPOND study (NCT04488133), which aims to enroll up to 60 infants and children with SMA aged 3 months to 3 years who have had a suboptimal response to Zolgensma.

Your unmet clinical needs may include mild improvements in motor skills, the need for temporary respiratory support, swallowing or feeding problems that are unusual for the patient’s age, or other responses that are not up to the standard considered relevant by the investigator.

Phase 4 trials begin after a drug has been approved by regulators and are typically conducted to verify a therapy’s performance in real life.

Eligible patients must have received the single dose of Zolgensma at least three months before starting Spinraza treatment, which is given for up to two years.

The study will include two study groups. One is expected to include 40 infants up to 9 months of age carrying two SMN2 Gene copies (suggesting type 1 disease) and Zolgensma given after symptoms appear but before the age of 6 months.

This group is designed to study the effect of Spinraza in younger patients with a shorter mean interval between the two therapies.

The other group consists of 20 children up to 3 years old.

The main goal of RESPOND is to assess changes in children’s ability to achieve specific motor milestones – such as head control, sitting, crawling, standing and walking. Secondary objectives include other validated measures of motor function, time to death or permanent ventilation, and safety.

Newly presented data involved the first nine enrolled children (five boys and four girls) who were followed for a median of 64 days (about two months) and up to six months from August 16, 2021.

All but one had two SMN2 gene copies. They were treated with Zolgensma at a mean age of 2.7 months (range 1.2-17.2 months) and started Spinraza at a mean age of 16.4 months (range 5.1-30.4 months or about 2.5 years).

On admission, all children had suboptimal clinical responses in at least two areas. Motor function was most common (eight children), followed by lung function (six children) and swallowing/feeding skills (five children).

One child left the study at the request of a parent or guardian.

The safety data showed adverse events in six children (67%), all of which were mild to moderate in severity. The most commonly reported were infections (44.4%) and vomiting (22.2%).

Two children experienced serious adverse events (all infections) that were successfully managed and did not prevent continued Spinraza dosing. No adverse event or serious adverse event associated with the use of Spinraza was considered.

These early results highlighted suboptimal clinical responses “in multiple areas, including motor and respiratory function [Zolgensma] treatment” and suggested a favorable safety profile for subsequent treatment with Spinraza, the researchers wrote.

“The results of the RESPOND study will provide valuable information on the efficacy and safety of [Spinraza] in children with SMA who have received prior treatment [Zolgensma]’ the researchers added, and may help inform future treatment decisions for infants and young children with SMA.

Half of the 12 researchers on this poster are Biogen employees.

The SMA News Today team reports on the 2022 American Academy of Neurology (AAN) Annual Meeting.


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