Initiating Treatment Early Called More Critical Than Therapy Choice

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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Initiating a disease-modifying therapy (DMT) before the onset of symptoms and at the earliest time possible results in the best outcomes in infants with spinal muscular atrophy (SMA), with most achieving otherwise unachievable motor milestones and within the normal age range.

This is particularly crucial for infants likely to develop SMA type 1, a severe form of the disease wherein damage to motor neurons, the specialized nerve cells that control voluntary movement, is thought to start before birth.

These are the conclusions of two neurologists with experience in SMA care following the publication of the final data from the Phase 3 SPR1NT clinical trial (NCT03505099), which tested Zolgensma in pre-symptomatic infants genetically diagnosed with SMA.

Its promising findings were consistent with those of pre-symptomatic trials of the other two approved DMTs for SMA — Spinraza (nusinersen) and Evrysdi (risdiplam) — suggesting treatment timing may be more critical than therapy choice, the neurologists noted.

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Their views were detailed in the study “Early treatment is a lifeline for infants with SMA,” published in Nature Medicine.

Its authors, Charlotte J. Sumner, MD, and Thomas O. Crawford, MD, were both with the Johns Hopkins University School of Medicine and both worked as consultants for all the pharmaceutical companies marketing SMA DMTs.

SMA is a progressive neuromuscular disease caused by the deficient production of SMN — a protein essential for motor neuron and muscle health — due to mutations in both copies of the SMN1 gene. The number of copies of a “backup” SMN gene, SMN2, influences SMA severity, with a higher number typically predicting less severe disease.

Three DMTs have been approved for SMA to date. While they all work to increase SMN levels, they do so through different mechanisms and involve distinct routes of administration.

Both Biogen’s Spinraza (delivered into the spinal canal) and Roche’s oral therapy Evrysdi target the SMN2 gene, while Novartis’ one-time gene therapy Zolgensma, administered directly into the bloodstream, delivers a working copy of SMN1.

Treatment before onset of symptoms

A large body of clinical trial and real-world data support the notion that earlier treatment results in better outcomes than delayed treatment, especially when it’s initiated before symptom onset.

With the recent expansion of Evrysdi’s label to include children under 2 months, all three SMA DMTs are now available in the U.S. for infants with all SMA types before symptom onset.

In other countries, only certain pre-symptomatic children may be eligible for the one-time gene therapy Zolgensma, and Evrysdi, the most recent to get approval, is still available only to patients 2 months and older.

The two-year SPR1NT trial evaluated the safety and effectiveness of Zolgensma in 29 pre-symptomatic babies (up to 6 weeks old) with SMA: 14 likely to develop type 1 disease, and 15 predicted to have SMA type 2 (a milder form), based on their SMN2 copy number. They received the therapy’s single dose within 32 days of life.

Final results showed 79% of those in the type 1 group were able to stand without help and 64% could walk independently. Many met these milestones at an age typical for children without SMA.

This was considerably better than the 3–5% of type 1 infants achieving these milestones when treated with Zolgensma after symptom onset in the STR1VE (NCT03306277) and STR1VE-EU (NCT03461289) Phase 3 trials, the neurologists noted.

Also, 93% of children likely to develop SMA type 2 were able to walk independently, with 73% of them attaining this within the normal age range.

Since these motor milestones are never achieved by untreated type 1 and 2 patients, these findings underscored Zolgensma’s ability to pronouncedly defy SMA’s natural course when given before the onset of symptoms.

These promising outcomes “are strikingly similar” to those reported in trials of pre-symptomatic infants treated with Spinraza or with Evrysdi, the neurologists wrote, suggesting that optimal SMN levels “can be achieved with any of the three therapies when given very early.”

Still, “although all infants enrolled in [SPR1NT] were ‘presymptomatic’ by clinical neurological examination at the time of dosing,” those at risk of type 1 disease “fared less well” than those in the type 2 group, they added.

At the end of the study, one-third of type 1 infants scored below the normal range in the Bayley Gross Motor Scale, which assesses the ability to perform certain whole-body movements. All of those at risk of SMA type 2 scored within the normal range.

“These observations, mirrored in the presymptomatic trials of other therapies, emphasize that the timing of treatment initiation and the magnitude of neurodegeneration at that time are key drivers of therapeutic response — possibly even more so than the choice of specific treatment,” the researchers wrote.

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‘Race against time’ for SMA type 1 infants

This is especially true for infants at risk of SMA type 1, in whom disease-associated damage is thought to begin before birth and to progress rapidly shortly after.

“In this group it is truly a race against time, and we strongly encourage initiation of any one of the therapeutics as soon after birth as possible,” the neurologists wrote.

They also emphasized the urgent need of biomarkers that can predict functional outcomes in infants with distinct SMN2 copy numbers.

Zolgensma’s single dose has an advantage over the other DMTs, but “once administered, treatment cannot be withdrawn,” and short-term toxicities have been reported and added as warnings to the therapy’s label, the researchers wrote,

Its long-term risks remain unclear and having a two-year follow-up “for a putative lifelong treatment is relatively short,” the neurologists wrote, adding that longer-term studies are needed to assess safety and improve its effectiveness.

“The reversal of a relentless degenerative disorder of infancy with a one-time treatment is an extraordinary accomplishment; now is the time to build on this foundation with vigilant follow-up and biomarker studies,” the neurologists said.