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

The first patient has been dosed in a Phase 4 trial exploring the safety and potential benefits of Spinraza (nusinersen) in children with spinal muscular atrophy (SMA) who failed to respond adequately to Zolgensma.

The two-year study, called RESPOND (NCT04488133), was launched last year by Biogen, Spinraza’s developer, and aims to enroll around 60 children, from 3 months to 3 years old, who have the potential to gain additional clinical improvements beyond those provided by Zolgensma. These may include children who experienced suboptimal motor improvements, required respiratory support, or were unable to swallow or feed normally after receiving Zolgensma.

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RESPOND will be carried out at approximately 20 clinical sites worldwide. More information about study sites will become available here.

“SMA treatments have changed what is possible for children born with the disease but they have also raised new questions,” Nicole Gusset, PhD, president of SMA Europe and mother of a child with SMA, said in a press release. “We appreciate that the RESPOND study will collect data to help provide answers so individuals living with SMA can make informed treatment decisions.”

Zolgensma is a one-time gene therapy, originally developed by AveXis, now part of Novartis, that has been approved in the U.S. and Japan to treat all types of SMA in children up to age 2, and nearly all SMA types in children weighing up to 21 kilograms (about 46 pounds) in Europe.

It uses the shell (capsid) of a harmless adeno-associated virus (AAV), called AAV9, to deliver a functional copy of the SMN1 gene, which is defective in SMA patients, to motor neurons — nerve cells responsible for controlling voluntary muscles. Through this mechanism, Zolgensma aims to restore the production of the SMN protein in these cells, ensuring their survival and preventing muscle weakness and wasting.

Spinraza, the first disease-modifying therapy to be approved in the U.S. to treat children and adults with all types of SMA, uses an alternative mechanism to increase the production of the SMN protein. Instead of providing cells with a functional copy of SMN1 like Zolgensma, it increases the ability of SMN2 — a backup gene that can partially compensate for the loss of SMN1-derived SMN — to produce the protein.

RESPOND is designed to investigate if infants and children previously treated with Zolgensma may experience additional benefits from receiving Spinraza, due to its alternative mechanism of increasing SMN production and promoting motor neuron survival.

“In clinical practice, there is a sense of urgency to address motor neuron loss in SMA from the earliest sign or even prior to symptoms, to prevent additional disease progression,” said Julie Parsons, MD, a professor at Children’s Hospital Colorado and the University of Colorado School of Medicine, and primary investigator of RESPOND.

“In some patients treated with gene therapy, we have recognized that further motor neuron protection may be needed,” she added. “Our hope is that results from RESPOND will demonstrate if SPINRAZA can optimize treatment for some of our youngest patients.”

RESPOND will have two study groups. The first group will include 40 children up to nine months old, who have two copies of the SMN2 gene (likely to develop type 1 SMA) and were treated with Zolgensma before or at six months of age. The second group will include 20 children up to three years old.

All study participants will receive four loading doses of Spinraza, followed by maintenance doses every four months, for two years. Spinraza will be given at its 12 mg approved dose.

The study’s main goal is to assess changes in motor function and ability to achieve certain milestones (e.g. crawling, standing, and walking), based on total score on the Hammersmith Infant Neurological Examination Section 2.

Additional goals include assessing the therapy’s safety, effects on other motor function measures, clinical outcomes (e.g. swallowing), and caregiver burden. Exploratory goals include measuring the levels of neurofilaments — proteins that have been proposed to be used as markers of neurodegeneration and biological disease activity.