High-dose nusinersen for spinal muscular atrophy: a phase 3 randomized trial

Nature Medicine · 2026-02-03 · 2 citations

Despite the remarkable benefits of nusinersen and other disease-modifying therapies in spinal muscular atrophy (SMA), patients may still experience clinical manifestations of the disease. Here we assessed the potential for high-dose nusinersen to rapidly slow neurodegeneration and lead to improved outcomes for patients. The global, three-part, phase 2/3 DEVOTE trial evaluated the efficacy and safety of high-dose nusinersen (50-mg loading dose; 28-mg maintenance dose) in individuals with SMA. In Part B, treatment-naive individuals (n = 75) were randomized 2:1 to 50/28 mg or 12/12 mg nusinersen. In a supportive open-label cohort (Part C), nusinersen-experienced individuals (12/12 mg for more than 1 year) were enrolled. The primary endpoint (Part B infantile-onset participants) was a 6-month change in the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) total score comparing 50/28 mg with matched ENDEAR participants (n = 20) who received sham. DEVOTE met its primary endpoint: at day 183, the CHOP-INTEND total score significantly improved (+15.1 points) in those who received 50/28 mg nusinersen and worsened (-11.1 points) in matched ENDEAR participants who received sham (difference, 26.19 (95% confidence interval = 20.7 to 31.74); statistical testing was performed using the joint-rank test where the difference in ranks was 26.06 (95% confidence interval = 17.9 to 34.2; P < 0.0001). The safety profile of 50/28 mg nusinersen was similar to the 12/12 mg regimen. The data support that high-dose nusinersen provides benefit in patients with SMA, with a generally well-tolerated safety profile. ClinicalTrials.gov registration: https://clinicaltrials.gov/study/NCT04089566 . EudraCT no: 2019-002663-10.

Loss of ambulation in SMA III at the time of disease-modifying treatments: an international study

Journal of Neurology Neurosurgery & Psychiatry · 2026-01-30

BACKGROUND: Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder caused by survival motor neuron (SMN1) deletion. While loss of ambulation in SMA type III typically occurs at a median age of 13.4 years, outcomes in the treatment era remain unclear. This study aims to address that gap by investigating ambulation outcomes in individuals with type III receiving disease-modifying therapies. METHODS: This retrospective study analysed prospectively collected international data. Time-dependent Cox models assessed the association between treatment initiation and age at loss of ambulation, adjusting for age at onset, sex, SMN2 copies, birth year and country. Treatment was modelled as a time-dependent covariate to avoid immortal time bias. Descriptive analyses used Mann-Whitney U and χ² tests. RESULTS: Among 555 individuals with type III, treatment halved the risk of ambulation loss (HR=0.50), with median loss at 44 vs 32 years in treated and untreated groups. Later onset, ≥4 SMN2 copies and female sex were also protective. The treatment effect was significant in type IIIA (HR=0.34) but not IIIB, with no significant interactions by sex, country or SMN2, though effects remained directionally protective. CONCLUSIONS: Treatment in type III reduced the risk of ambulation loss by 50%, extending median ambulation by 12 years, with the greatest benefit in type IIIA. Later onset, female sex and higher SMN2 copy number were also protective but did not modify treatment effect. These findings underscore the value of early treatment and support its broad use to preserve ambulation across clinical subgroups.

Serial casting for contractures in SMA: consensus derived guidelines for treatment

Frontiers in Neurology · 2025-04-16

Background: Individuals with Spinal Muscular Atrophy (SMA) often present with muscle contractures. Serial casting has been used in a variety of other peripheral nerve, muscle, and central nervous system disorders to improve knee and ankle range of motion limitations and functional performance in both ambulatory and non-ambulatory individuals. Objective: The goal of this study was to reach a consensus about the parameters, considerations and general guidelines that should inform practice when serial casting to improve flexibility in individuals with SMA. Methods: This international effort was conducted between August 2020 and May 2023. An expert panel of physical therapists was assembled with multiple panel meetings and a 2-round Delphi survey performed covering topics relevant to serial casting which included three domains: clinical appropriateness, program-based considerations and program adherence/feasibility. Consensus was reached for all items in the three topic areas using a validity index of >75%. Following completion of the Delphi survey, community insights from patients and caregivers were collected via semi-structured interview. Results: This study included the synthesis of meetings from the initial expert panel which produced a comprehensive survey for the different considerations when performing serial casting for an individual with SMA. The study also included the completion of a Delphi survey by 18 therapists in round 1 and 15 therapists in round 2 for a consensus on 296 items. Strong consensus was obtained in all three domains with 96.6% agreement for clinical appropriateness, 95.0% agreement for program-based considerations, and 96.9% for program adherence/feasibility. A guideline document was developed enumerating the specific items detailed in the survey. Community perspectives were utilized to support the results of the Delphi survey and to add insight into real-world experience. Conclusion: The serial casting guidelines developed upon collaborative discussions from the expert panel and from the Delphi survey consensus and semi-structured interviews, should be utilized when applying serial casts to patients with spinal muscular atrophy. Future endeavors should look to apply the guideline recommendations to determine casting efficacy for improving joint contracture and impact on function for those with SMA.

Correction: Serial casting for contractures in SMA: consensus derived guidelines for treatment

Frontiers in Neurology · 2025-07-16 · 2 citations

[This corrects the article DOI: 10.3389/fneur.2025.1502495.].

Longitudinal Assessment of 4‐Year <scp>HFMSE</scp> Changes in <scp>SMA II</scp> and <scp>III</scp> Patients Treated With Nusinersen

European Journal of Neurology · 2025-06-27 · 5 citations

BACKGROUND: The aim of this international retrospective study was to assess 4-year change using the Hammersmith Functional Motor Scale Expanded (HFMSE) in individuals with type II and III spinal muscular atrophy (SMA) treated with nusinersen and to establish predictors of HFMSE changes. METHODS: Individuals with type II or III SMA, and at least 4 years of nusinersen-only treatment were included. All were assessed using the HFMSE. Age at baseline, sex, motor function, SMN2 copy number, and age of onset were also retrospectively collected. Linear mixed effect models were used to calculate yearly changes and trajectory predictors. RESULTS: We included 73 individuals with SMA type II (mean age 8.58 years, SD 7.91, IQR 3.04-10.70) and 111 type III (mean age 7.91 years, SD 17.83, IQR 8.15-34.42). Over 4 years, mean changes were + 4.18 (95% CI: 2.85-5.50) for SMA II and + 1.08 (95% CI: 0.12-2.04) for SMA III. Age (SMA II: -0.34\[-0.51 to -0.17]; SMA III: -0.13\[-0.20 to -0.06], p < 0.001) and baseline HFMSE (SMA II: 1.02\[0.70-1.34]; SMA III: 0.79\[0.71-0.87], p < 0.001) were the strongest predictors of progression, with younger age and higher baseline scores associated with better outcomes. Functional status was only predictive for type III (6.96\[4.26-9.66]). CONCLUSION: Our results confirm that, given a follow up of 4 years, there is a persistent impact of nusinersen on clinical progression that is better observed in younger patients with higher HFMSE scores at baseline, especially during the first 2 years of treatment.

Spinal Muscular Atrophy Functional Composite Score Revised (SMA-FCR) in Untreated and Nusinersen-Treated Patient Cohorts

Neurology · 2025-06-27 · 2 citations

BACKGROUND AND OBJECTIVES: The Spinal Muscular Atrophy Functional Composite (SMA-FC) combines scores from the Hammersmith Functional Motor Scale Expanded (HFMSE), Upper Limb Module (ULM), and Six-Minute Walk Test (6MWT) into a single score and removes the floor and ceiling effects of the HFMSE. Our objective was to evaluate a revised version of the SMA-FC (SMA-FCR) by including the Revised ULM (RULM) in untreated and nusinersen-treated SMA. METHODS: We included participants with HFMSE, RULM, and 6MWT data at the same visit. The SMA-FCR represented the average of the 3 test scores, each expressed as the percentage of the maximum possible score (HFMSE and RULM) or the percent of predicted normative performance (6MWT). Mean annual rates of change were calculated in participants who had SMA-FCR data at 2 or more visits while untreated and/or while treated. RESULTS: = 0.94). DISCUSSION: The SMA-FCR broadens the spectrum of abilities captured in SMA. Analyses of the treated-untreated differences in mean annual rate of change suggest that the SMA-FCR may be more sensitive to change than the HFMSE. The use of the SMA-FCR in clinical trials might allow for study designs with broader eligibility criteria including weaker individuals who score minimally on the HFMSE and stronger individuals who score maximally on the RULM.

Therapeutic Scoliosis-Specific Exercises for a Child With Spinal Muscular Atrophy: A Case Report

Pediatric Physical Therapy · 2025-02-13 · 3 citations

PURPOSE: The purpose of this study is to report on therapeutic scoliosis-specific exercises (PSSE) for a child with spinal muscular atrophy (SMA) who had spinal fusion. METHODS: PSSE were recommended after scoliosis was diagnosed and exercises focused on posture and improving strength preoperatively and restoring function postoperatively. RESULTS: Gross motor function remained stable before spinal fusion, briefly decreased after the procedure, and then stabilized post-surgery. Distance walked on the 6-minute walk test decreased post-surgery but improved after the addition of PSSE to the Standard of Care. CONCLUSIONS: Including PSSE as an adjunct to traditional interventions may be beneficial for children with SMA. Evidence supports incorporating PSSE to improve posture preoperatively in idiopathic scoliosis. Its use postoperatively and in children with SMA is not well studied. Controlled studies are needed to understand the impact of pre- and post-op PSSE in children with SMA.

First-in-human study of epidural spinal cord stimulation in individuals with spinal muscular atrophy

Nature Medicine · 2025-02-05 · 18 citations

Wearable‐Derived Patterns of Performance Fatigability During Gait in Spinal Muscular Atrophy

Muscle & Nerve · 2025-06-25

INTRODUCTION/AIMS: Despite disease-modifying therapies, fatigability persists in spinal muscular atrophy (SMA). Performance fatigability (PF) during the six-minute walk test (6MWT) is mostly unchanged in treated SMA. This cross-sectional study characterized PF using instrumented insoles. METHODS: Ambulatory individuals with SMA (n = 14) and controls (HC) (n = 10) were included. Spatiotemporal and kinetic parameters were collected with custom-engineered instrumented insoles during the 6MWT. Linear mixed models analyzed parameter trends, with trend slope representing PF. Changes in mean velocity (Vavg) and stride-by-stride parameters were compared between minute 1 and 6 and between groups. RESULTS: Decreases in Vavg were greatest for severe SMA (p < 0.001). Changes were found in stride length (SL) (p = 0.048) and stride velocity (SV) (p = 0.030) for severe SMA, and in stance phase (%St) (p = 0.012) and percent terminal double support (%DS) (p = 0.02) for mild SMA. SMA subgroups showed downward trends from minute 1 to 6 in SL, SV, and anterior-posterior center of pressure (AP-COP) (p < 0.001), and increases in Absolute COP-Cyclogram Asymmetry Index (|ASI|) (p < 0.05). Trends differed between severe SMA and other groups for SL, SV, %St, and %DS (p < 0.001), and for AP-COP and |ASI| (p < 0.05). Trends for SL (p < 0.001), SV and AP-COP (p < 0.01) differed between HC and mild SMA. DISCUSSION: PF in SMA manifests as changes in gait parameters. Instrumented insoles revealed fatigue-related changes not captured with the conventional method of comparing the first and last minutes of the 6MWT. Spatiotemporal and kinetic parameters contribute to understanding of impairments and inform therapeutic development. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04193085.

Development of the SMA EFFORT: A new approach to characterize perceived physical fatigability in spinal muscular atrophy

Journal of Neuromuscular Diseases · 2025-01-01 · 6 citations

Background: Fatigue and fatigability are commonly reported in spinal muscular atrophy (SMA). Physical fatigability, proposed to be the most relevant to SMA pathophysiology, encompasses performance-based and perceived physical fatigability (PPF) assessments. While performance-based measures have highlighted physical fatigability as an SMA hallmark, PPF is not well characterized due to the lack of disease- and construct-specific scales. Objective: Our aim was to create a patient-reported outcome measure tailored for SMA, named the SMA EFFORT, to improve PPF assessment. Here, we describe the scale development process, assess scale properties, and discuss future research and application. Methods: SMA and scale development experts organized a comprehensive physical activity item bank, relevant across the SMA phenotypic spectrum. Activities were systematically categorized by varying intensities and durations. The SMA EFFORT was completed by an international cohort of individuals with all types of SMA. To compare PPF across demographic and clinical variables, SMA EFFORT PPF percent (PPF%) composite scoring was established. Results: One hundred eighteen participants completed the SMA EFFORT. Total PPF% scores were broadly distributed within functional groups, with differences between non-sitters (35.1 ± 21.0) and sitters (24.9 ± 15.1) ( p = 0.006), and those with (34.4 ± 18.1) and without respiratory support (26.4 ± 17.8) ( p = 0.02). Participants treated with disease modifying therapy (DMT) showed similar scores to those without treatment ( p = 0.70). Further, no differences in scores were observed in participants with scoliosis surgery and those without ( p = 0.71). Subscale analyses revealed differences in mean PPF% subscale scores by functional group. Conclusions: The novel SMA EFFORT standardizes PPF ratings by anchoring activity to intensity and duration. Item and scale data insights will inform the next iteration, which will undergo additional investigation. The SMA EFFORT aims to improve upon current measures to better assess treatment impact on physical well-being across the SMA spectrum.