Treatment Evolution in 5q-Spinal Muscular Atrophy: Real-World Evidence and Clinical Insights from the SMArtCARE Registry

Highlights

• Analysis of 2,140 patients from 84 centers in the DACH region confirms a rapid shift in the SMA treatment paradigm following the sequential approval of three disease-modifying treatments (DMTs).
• Nusinersen remains the most prevalent first-line therapy (60.5%), though risdiplam and onasemnogene abeparvovec are increasingly utilized upon approval.
• Approximately 36.2% of patients switched therapies, with regulatory approvals acting as the primary driver rather than objective motor function decline.
• Real-world data underscore that motor milestone stability is maintained in most patients during treatment transitions, highlighting a multi-factorial decision-making process.

Background

5q-Spinal Muscular Atrophy (SMA) is a devastating neurodegenerative disorder caused by biallelic mutations in the SMN1 gene, leading to a deficiency in the survival motor neuron (SMN) protein and subsequent degeneration of alpha motor neurons in the spinal cord. Historically, SMA was the leading genetic cause of infant mortality, characterized by progressive muscle weakness, respiratory failure, and severe motor impairment. The clinical severity is inversely correlated with the copy number of the SMN2 backup gene, which produces a truncated, mostly non-functional SMN protein.

The therapeutic landscape has undergone a revolutionary shift since 2016. The approval of nusinersen (an antisense oligonucleotide), onasemnogene abeparvovec (an AAV9-based gene replacement therapy), and risdiplam (a small molecule SMN2 splicing modifier) has transitioned the clinical focus from palliative management to early, proactive intervention. However, while randomized controlled trials (RCTs) established the efficacy of these agents in specific cohorts, the real-world application across diverse age groups and disease severities requires robust registry data to guide long-term clinical strategy. The SMArtCARE registry, covering Germany, Austria, and Switzerland, provides an unprecedented view into how these treatments are sequenced and utilized in daily clinical practice.

Key Content

Chronological Development and Regulatory Context

The evolution of SMA treatment is strictly tied to the sequential regulatory approvals of the three primary DMTs. Nusinersen was the first to market (FDA 2016, EMA 2017), followed by the gene therapy onasemnogene abeparvovec (FDA 2019, EMA 2020), and finally the oral agent risdiplam (FDA 2020, EMA 2021). The SMArtCARE study mapped the timing of treatments for 2,140 patients, revealing that 1,294 (60.5%) initiated treatment with nusinersen. As newer therapies became available, the initiation of risdiplam (24.0%) and onasemnogene abeparvovec (11.4%) rose significantly.

Analysis of Treatment Regimens: Stayers vs. Switchers

The SMArtCARE data categorized patients based on their therapeutic journey. Of the total cohort, 1,366 patients (63.8%) remained on their initial DMT. In contrast, 774 patients moved to a second agent. Interestingly, the study found that most switches occurred shortly after the approval of a new DMT class. For example, a significant wave of transitions from intrathecal nusinersen to oral risdiplam occurred immediately following risdiplam’s availability, suggesting that route of administration and patient preference were influential factors.

Motor Function and Clinical Determinants

A critical finding of the SMArtCARE registry is that most patients who switched DMTs showed no significant change in motor milestone status between the start of the first and second therapies. This suggests that switching is often not a reaction to treatment failure in terms of motor decline, but rather a pursuit of optimized administration or the perceived advantages of a newer mechanism of action. The analysis evaluated several factors influencing these decisions:

• Age at Initiation: Younger patients were more likely to receive gene therapy as a first-line or early second-line treatment.
• SMN2 Copy Number: Patients with lower copy numbers (indicative of higher severity) were prioritized for rapid initiation of intensive therapy.
• Support Requirements: The presence of scoliosis, the need for ventilator support, or tube feeding influenced the choice, particularly when considering the logistical challenges of repeated intrathecal injections in patients with spinal deformities.

Methodological Advances in Registry-Based Research

The SMArtCARE registry utilizes standardized assessments across 84 participating centers, ensuring high-quality longitudinal data. By integrating real-world evidence (RWE), researchers can observe the impact of DMTs on populations typically excluded from RCTs, such as older adults with SMA Type 3 or patients with advanced scoliosis. This provides a more representative view of the “treatment evolution” than isolated clinical trials.

Expert Commentary

The Rationale for Switching and Clinical Thresholds

The observation that switches are not primarily driven by motor failure is significant. In other progressive neuromuscular conditions, such as Late-Onset Pompe Disease (LOPD), clinical thresholds like the Minimal Clinically Important Difference (MCID) are used to monitor disease progression (PMID: 41785434). For SMA, the registry data suggests that the medical community is still defining what constitutes a “non-responder.” In LOPD, deterioration in hip muscle strength and walking speed are sensitive markers; similarly, clinicians in the SMA field may need to look beyond gross motor milestones to more sensitive parameters, such as the Revised Upper Limb Module (RULM) or dynamometry, to justify switching based on efficacy.

Early Intervention and Age-Related Disability

Drawing parallels from other neuroinflammatory and neurodegenerative diseases, such as Neuromyelitis Optica Spectrum Disorder (NMOSD), we see that older age at onset is often linked to more rapid disability accrual despite similar relapse rates (PMID: 41785437). This underscores the importance of the SMArtCARE finding that most treatment initiations are now occurring earlier. The objective for SMA management is to treat in the pre-symptomatic phase, where the benefit of gene therapy and other DMTs is maximized before irreversible motor neuron loss occurs.

Genetics and Ancestral Diversity

While the SMArtCARE registry focused on a specific geographic region, global insights into neurogenetics highlight the importance of understanding genetic architecture in diverse populations. For instance, studies on Multiple Sclerosis (MS) susceptibility across different ancestries (PMID: 41791023) show that while disease mechanisms are often shared, allele frequencies vary. In SMA, while the SMN1 deletion is near-universal, the modifying effects of SMN2 and other genetic modifiers across different ethnic backgrounds remain an area for future exploration in global registries.

Conclusion

The treatment of 5q-SMA has evolved from a state of therapeutic nihilism to a complex landscape of multiple effective DMTs. The SMArtCARE registry provides a vital real-world perspective, showing that while most patients remain stable on their first-line therapy, switches are common and largely driven by the arrival of new therapeutic options and logistical considerations rather than acute clinical failure. As we look forward, the challenge for the clinical community will be to refine the criteria for switching, optimize the sequencing of therapies (e.g., nusinersen followed by risdiplam or gene therapy), and ensure that long-term safety and efficacy data continue to inform treatment guidelines. The paradigm is shifting from simply extending survival to maximizing functional independence and quality of life across the entire lifespan of patients with SMA.

References

• Voigt-Müller C, Pfaffenlehner M, Bernert G, et al. Treatment evolution in spinal muscular atrophy: insights from the SMArtCARE registry. Brain. 2026;149(3):818-827. PMID: 41431300.
• Peeters N, et al. Longitudinal Motor Function Changes in Adults With Late-Onset Pompe Disease: Key Determinants and Clinical Thresholds. Neurology. 2026;106(7):e214751. PMID: 41785434.
• Aykut G, et al. Impact of Age at Onset on Relapse and Disability in AQP4-IgG Neuromyelitis Optica Spectrum Disorder. Neurology. 2026;106(7):e214707. PMID: 41785437.
• Kirschner J, et al. SMArtCARE – a platform to collect real-world data of patients with spinal muscular atrophy in German-speaking countries. Orphanet J Rare Dis. 2021;16(1):18.