Gene Therapy Now Leads Spinal Muscular Atrophy Treatment as Real-World Sequencing Patterns Emerge

Spinal muscular atrophy was once among the most feared diagnoses in pediatric neurology, a genetic disease that steadily destroyed the motor neurons of the spinal cord and, in its most severe form, claimed the lives of infants before their second birthdays. A decade ago, doctors could offer only supportive care. Today, the United States has three approved disease-modifying therapies, and a new large-scale analysis of real-world treatment data reveals just how dramatically clinical practice has shifted. In the years following the nationwide rollout of newborn screening, a one-time gene replacement therapy has become the dominant first treatment for babies diagnosed with the condition, while a substantial share of patients are now moving between different therapies over the course of their disease, a pattern that was virtually unheard of in the early days of treatment.

The study, published in the journal Advances in Therapy, drew on the Komodo Health Research Database, one of the largest longitudinal healthcare claims datasets in the country, covering approximately 330 million individuals across commercial insurance, Medicare, and Medicaid programs. Researchers led by Walter Toro Jimenez of Novartis Pharmaceuticals Corporation, together with colleagues at Analysis Group, examined claims recorded between January 2016 and October 2024 to reconstruct how patients with spinal muscular atrophy actually move through the therapeutic landscape. Because the data capture routine clinical care rather than the carefully controlled conditions of a clinical trial, the findings offer a rare window into how the promise of these therapies is being translated into everyday practice.

The biology underlying the disease explains why treatment has evolved so rapidly. Spinal muscular atrophy results from homozygous deletions or mutations in the SMN1 gene, which deprives the body of survival motor neuron protein and triggers the progressive degeneration of motor neurons in the spinal cord. A second gene, SMN2, produces small amounts of the same protein, and the severity of disease generally tracks with how much functional protein the SMN2 copies can generate. All three approved therapies work by increasing the output of that backup gene, but they do so through strikingly different mechanisms. Nusinersen, approved in 2016, is an antisense oligonucleotide injected into the spinal canal that corrects the splicing of SMN2 transcripts. Risdiplam, approved in 2020, is an oral small molecule that achieves the same splicing modulation through daily dosing. Onasemnogene abeparvovec, approved in 2019 as an intravenous infusion for children under two, delivers a functional copy of the SMN1 gene directly into cells using a viral vector, effectively replacing the missing genetic instructions in a single administration.

The clearest signal in the new analysis comes from the youngest patients. Among 257 children who initiated their first disease-modifying therapy at age two or younger during 2022 through 2024, a period after newborn screening had become widely available across most of the United States, 64.6 percent began with onasemnogene abeparvovec, 24.9 percent with risdiplam, and only 10.5 percent with nusinersen. The contrast with the immediate post-approval era is stark. An earlier study using a different claims database covering January 2017 through March 2021 found that just 16.2 percent of children under two received the gene therapy, while 83.8 percent received nusinersen. The researchers attribute the reversal largely to newborn screening, which was introduced in the US in 2018 and now identifies affected infants before symptoms appear, allowing treatment to begin at the stage when clinical trials have shown the greatest benefit.

Equally revealing is what happens after the first treatment. Children who started with the gene therapy were the least likely to add a second therapy type: only 12.0 percent of them did so, compared with 20.3 percent of those who began with risdiplam and 55.6 percent of those who began with nusinersen. Among the subset of 209 children with the most severe, type 1 form of the disease, the pattern held, with 8.3 percent of gene therapy recipients adding a second therapy versus 60.9 percent of nusinersen recipients and 18.5 percent of risdiplam recipients. The implication is that a single gene replacement appears to satisfy treatment needs for most infants, whereas patients on the chronic, repeat-dosing therapies more often end up adding or switching to another modality, most frequently the gene therapy itself.

To understand sequencing across the full age spectrum, the researchers assembled a second cohort of 341 patients with types 1 through 3 of the disease who received at least two different therapy types between May 2019, when at least two options became available, and October 2024. This group was markedly older, with a mean age of 15.4 years at the start of their first recorded therapy, and reflected an era when nusinersen was the only option: 75.4 percent of them began with the antisense oligonucleotide, 15.2 percent with risdiplam, and 9.4 percent with the gene therapy. Within this cohort, risdiplam was the most common second treatment, received by 76.2 percent of patients, followed by nusinersen at 13.2 percent and the gene therapy at 10.6 percent. Only five patients, or 1.5 percent, progressed to a third therapy type. The median interval between the first and second treatments was 18.9 months, though the timing varied by starting therapy, from 21.7 months for nusinersen starters to 13.2 months for those who began with risdiplam.

The picture changes again when the analysis is restricted to the 44 children who received multiple therapies and began treatment at age two or younger during 2022 through 2024, the true newborn screening generation. In this group, first treatments were distributed far more evenly, with 36.4 percent starting on the gene therapy, 34.1 percent on nusinersen, and 29.5 percent on risdiplam. When these children did move to a second therapy, the gene therapy dominated: 52.3 percent received onasemnogene abeparvovec as their second treatment, 45.5 percent received risdiplam, and just 2.3 percent received nusinersen. All of the children who had started on risdiplam, and most of those who had started on nusinersen, went on to receive the gene therapy. The median time from first to second treatment in this young cohort was 13.4 months, and the researchers suggest that some patients may have received the oral or injectable therapies as a bridge while awaiting gene therapy, while others switched because of the demonstrated value of gene replacement in previously treated patients.

The data also expose the growing complexity of managing a disease that now has multiple viable treatment pathways. A 2023 community survey cited in the study reported that 47.4 percent of children with spinal muscular atrophy had received more than one therapy type, with families and physicians citing reasons that included wanting a different treatment, physician recommendation, the desire to pursue every available option, and loss of motor function. The claims analysis adds a further wrinkle: among young children treated with multiple therapies, 20.0 percent of those who started on nusinersen and 38.5 percent of those who started on risdiplam later received the same therapy again after initiating a second one. Whether this reflects concurrent use, re-initiation after a gap, or something else cannot be determined from claims data alone, but the authors note that it points to increasing treatment complexity and burden for patients and caregivers alike.

The study has important caveats, which the authors acknowledge candidly. Claims databases lack the clinical measures, such as motor function scores, disease severity, and genetic modifiers like SMN2 copy number, that would allow researchers to connect treatment sequencing to outcomes. The specific reasons behind any switch, whether efficacy concerns, adverse effects, or issues of access and insurance coverage, are invisible in billing records. Disease type itself had to be inferred from an established algorithm based on age at diagnosis and patterns of clinical activity, raising the possibility of misclassification, particularly among pre-symptomatic infants identified by screening in whom distinguishing clinical features have not yet emerged. Birth-year service dates are masked for privacy, which forced the exclusion of the small fraction of patients, 5.2 percent, who received multiple therapy types in their first year of life, and small subgroup sizes limit the precision of some estimates.

Even with those limitations, the analysis stands as the first large-scale, real-world description of how patients with spinal muscular atrophy navigate an era of multiple disease-modifying options, and its message is unambiguous: newborn screening has reshaped the field, gene replacement therapy now anchors early treatment, and sequential multi-therapy strategies have become an ordinary feature of care rather than an exception. The landscape is still shifting. In 2025, regulators approved an intrathecal formulation of onasemnogene abeparvovec for patients aged two and older, meaning that for the first time all three therapeutic modalities are available across the full age range. Future studies, the authors write, will need to examine treatment sequencing across that broader population, control for the confounding factors that claims data cannot capture, and, most critically, link sequencing strategies to long-term clinical outcomes as the therapeutic story of this once untreatable disease continues to unfold.

Subject of Research: Real-world treatment sequencing patterns among patients with spinal muscular atrophy receiving multiple disease-modifying therapies

Article Title: Real-World Treatment Patterns in Patients with Spinal Muscular Atrophy Receiving Multiple Disease-Modifying Therapies

Article References: Toro Jimenez, W., Yang, M., Song, W., Ye, D., Lemus Wirtz, E., Meehan, J., & Reyna, S. (2026). Real-World Treatment Patterns in Patients with Spinal Muscular Atrophy Receiving Multiple Disease-Modifying Therapies. Advances in Therapy. https://doi.org/10.1007/s12325-026-03710-4

Image Credits: AI Generated

DOI: 10.1007/s12325-026-03710-4

Keywords: spinal muscular atrophy, onasemnogene abeparvovec, nusinersen, risdiplam, gene therapy, newborn screening, disease-modifying therapy, treatment patterns, SMN1, SMN2, motor neuron disease, real-world evidence