Biogen is continuing to actively recruit patients for its Phase 4 RESPOND trial, which is evaluating the benefits of Spinraza (nusinersen) in infants and children with spinal muscular atrophy (SMA) who responded poorly to the gene therapy Zolgensma.

Participants are now being enrolled at 10 sites in the U.S. and one in Italy, with more sites expected to open; further information on contacts and locations can be found here. As of July 31, nine patients had been enrolled in RESPOND (NCT04488133), according to researchers.

RESPOND is a Phase 4 trial, one that begins after a medicine has been approved by regulators and is usually conducted to check a therapy’s performance in real life.

The trial’s design was outlined at the World Muscle Society (WMS) 2021 Virtual Congress, being held Sept. 20–24, in a poster presentation titled “Nusinersen in Children With Spinal Muscular Atrophy (SMA) Who Received Onasemnogene Abeparvovec: Design of the Phase 4, Open-label RESPOND Study.”

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Spinraza Trial Begins Treating Children Who Failed to Respond to Gene Therapy

SMA is caused by low to no levels of the SMN protein, due to mutations in the SMN1 gene. While SMN is found in virtually every cell in the body, motor neurons — the specialized nerve cells that control voluntary movement — are particularly sensitive to SMN deficiency, dying as a result.

Biogen’s Spinraza was the first approved disease-modifying therapy for children and adults with all SMA types. Given directly into the spinal canal every four months, it boosts SMN production by targeting SMN2, a backup gene that can partially compensate for the loss of SMN1-derived SMN.

Novartis’ gene therapy Zolgensma (onasemnogene abeparvovec-xioi) now also is approved for SMA and targets the disease’s underlying genetic cause. It is available in the U.S. and Japan for children with SMA up to age 2, and in Europe for those with almost all SMA types and weighing up to 21 kilograms (about 46 pounds).

Administered directly into the bloodstream (intravenously), it uses a modified and harmless adeno-associated virus to deliver a working copy of the SMN1 gene to cells. Due to the body’s natural production of antibodies against its viral carrier, Zolgensma can be given only once.

Still, a single dose is expected to promote a sustained SMN production in cells (like motor neurons) that do not divide into new cells, and are thereby less likely to lose the delivered gene. However, prior preclinical research suggests that Zolgensma may target only a subset of motor neurons.

In addition, real-world and clinical data show that some children treated with Zolgensma have subsequently received Spinraza. But no study to date has systematically analyzed the clinical outcomes of such a combination.

Now, the RESPOND trial is evaluating the safety and effectiveness of Spinraza in up to 60 infants and children with SMA, between 3 months and 3 years of age, who still have unmet clinical needs following Zolgensma treatment.

Suboptimal responses to the gene therapy may include mild motor improvements, a need for temporary respiratory support, swallowing or feeding difficulties abnormal for the patient’s age, or other responses not up to the standard considered relevant by the investigator.

Eligible patients must have received Zolgensma’s single dose at least three months before initiating Spinraza treatment. Spinraza therapy consists of four 12 mg loading doses, followed by similar maintenance doses every four months for up to nearly two years.

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Spinraza Improves Motor Function in SMA Type 3 Children, Too

RESPOND will have two study groups. The first group is expected to include 40 infants up to age 9 months old, who carry two SMN2 gene copies (suggestive of type 1 disease) and received Zolgensma at 6 months or younger, after symptom onset.

This group is meant to explore Spinraza’s impact among younger SMA patients who may have a shorter mean interval between the two therapies.

The second group is expected to include 20 children with ages up to 3.

The trial’s main goal is to assess changes in the children’s ability to achieve certain motor milestones, such as head control, sitting, crawling, standing, and walking — as assessed with the Hammersmith Infant Neurological Examination Section 2 motor milestone score.

Secondary goals include assessing the proportion of children attaining World Health Organization motor milestones, changes in other validated motor function measures, and time to death or permanent ventilation, as well as safety measures.

Motor function measures will include the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders, the Hammersmith Functional Motor Scale Expanded, the Revised Upper Limb Module.

The levels of biomarkers in the cerebrospinal fluid — the liquid that surrounds the brain and spinal cord — blood, and urine also will be measured as exploratory goals.

Assessments will be completed every four months for most outcomes.

RESPOND’s findings are expected to help inform future treatment decisions for infants and young children with SMA, according to researchers.

“Results from the RESPOND study will provide valuable information on the efficacy and safety of [Spinraza] in children with SMA who previously received [Zolgensma],” the researchers wrote.

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