Immediate Treatment Advised for Newborns with 4 Copies of SMN2 in Updated Guidelines

Newborns diagnosed with spinal muscular atrophy (SMA) via newborn screening (NBS) and who carry four copies of the SMN2 gene should start treatment immediately, just as those with two or three SMN2 copies should, according to updated guidelines by a working group of SMA experts.

The group also emphasized new trial data supporting the importance of starting Spinraza (nusinersen) once a genetic diagnosis is confirmed, as its use prior to 6 weeks of age and before the onset of symptoms has been shown to have “dramatically altered disease course” in infants with two copies of SMN2.

The communication, “Revised Recommendations for the Treatment of Infants Diagnosed with Spinal Muscular Atrophy Via Newborn Screening Who have 4 Copies of SMN2,” was published in the Journal of Neuromuscular Diseases.

“Critically, the working group notes that the loss of even a small number of motor neurons is unacceptable when effective treatment is available, as this loss cannot be reversed after onset but can be prevented with earlier treatment,” the specialists wrote.

SMA is a neurodegenerative disease caused by mutations in the SMN1 gene, which provides instructions for the production of survival motor neuron (SMN), a protein essential to these specialized nerve cells (motor neurons).

As a result of SMN1 mutations,  patients produce little or no SMN, which leads to the signs and symptoms of SMA.

But people carry a variable number of copies of a nearly identical gene, called SMN2, which is also able to produce SMN protein, although in much lower amounts.

For this reason, disease severity is directly dependent on the number of SMN2 copies a patient carries. The more copies present in a patient’s genome, the less severe disease.

Cure SMA convened a group of expert clinicians and scientists in 2018 to develop treatment guidelines for infants diagnosed with SMA via newborn screening, now being done in 18 U.S. states.

Its action followed the approval of a first disease-modifying treatment, Spinraza by Biogen, which works by enabling cells to produce functional SMN protein from the SMN2 gene.

The group’s general recommendation at that time was to immediately treat all infants with two or three copies of the SMN2 gene, and likely to develop SMA type 1 or type 2 early in life.

No agreement, however, was reached about a best approach for infants diagnosed via newborn screening with four copies of SMN2 —  whether clinicians should immediately start treatment or remain on watchful waiting. Babies with four SMN2 copies are more likely to develop SMA type 3 or type 4.

Rather, the group recommended the decision be made case-by-case by parents and physicians.

This group met again in 2019 to update its recommendations, based on new clinical trial data and real-life experience with Spinraza’s use. A new treatment option had also surfaced.

Spinraza was the only targeted SMA therapy in 2018. One year later, the gene therapy Zolgensma, by AveXis and Novartis, was approved by the U.S. Food and Drug Administration (FDA) for all types of SMA in patients under age 2.

The working group now recommends immediate treatment for infants diagnosed with SMA via newborn screening who carry four copies of SMN2.

For newborns with five copies of SMN2, the experts voted unanimously to continue watchful waiting. All other recommendations remain as originally proposed.

In their update, experts highlighted the “dramatic impact” of starting treatment with Spinraza early, citing preliminary data from Biogen’s ongoing NURTURE trial.

NURTURE is an open-label Phase 2 study (NCT02386553) of Spinraza’s safety and efficacy in preventing or strongly attenuating SMA’s severity, when started up to 6 weeks of age and before infants have any disease symptoms, meaning when they are presymptomatic.

The study enrolled 25 newborns with two or three copies of the SMN2 gene. All are being given Spinraza intrathecally, or via the spinal canal, every four months.

Data shows that early Spinraza treatment — that started before 6 weeks old — “is significantly better than treatment after six weeks of age,” the experts wrote.

Patients in NURTURE with two SMN2 copies have a “dramatically altered disease course.” At a median followup of 2.9 years, 100% of these children were alive, 100% were sitting, 88% were walking with assistance, and 77% were able to walk independently, their communication noted. None needed permanent ventilation to breathe.

These are unprecedented gains in a group of SMA children, who in the absence of treatment would be unable to sit independently or need assistance to do so by age 3, and would never be able to walk.

This disease could also be “largely prevented” in infants with three copies of SMN2, the specialists wrote. These children in NURTURE were able to reach motor milestones equivalent to a normally developing child, and currently show no signs of SMA.

The same gains would be expected infants with four SMN2 copies, they added.

“With early treatment, disease would be mostly eradicated in presymptomatic patients with four copies of SMN2,” the updated guidelines state.

The recent availability of Zolgensma is also “pushing toward treatment instead of waiting,” the experts added.

Zolgensma works by restoring SMN protein production in neurons by delivering to cells a healthy copy of the SMN1 gene. The therapy uses an engineered adeno-associated viral (AAV) vector as its delivery shuttle.

Some children may develop anti-AAV antibodies that destroy AAV vectors, making them ineligible for Zolgensma. With age, the likelihood of developing such antibodies increases.

If errors are suspected during genetic testing to determine SMN2 copy number, or a test is unable to determine an exact number, the experts encourage further testing at a laboratory known to be able to distinguish exact SMN2 copy number.

“Many genetics laboratories are currently working to improve their SMN2 copy assays and the group is confident these assays will improve,” they concluded.