Later-onset Spinal Muscular Atrophy Research Articles

Efficacy and safety of salbutamol in treatment of children with later-onset spinal muscular atrophy.

To investigate the clinical efficacy and safety of salbutamol in the treatment of children with later-onset spinal muscular atrophy (SMA). This study is a prospective single-arm phase Ⅲ clinical study. Pediatric patients with SMA type Ⅱ and Ⅲ who visited Department of Neurology, Children's Hospital, Zhejiang University School of Medicine from December 2020 to June 2022 were enrolled. All patients were evaluated with motor function scales, pulmonary function test and drug safety before study. Patients were treated with salbutamol tablets orally, with an initial dose of 1 mg (tid). If tolerable, the dose was increased to 1.5 mg (tid) in the second week, then increased to 2 mg (tid) from the third week and maintained for 6 months. Patients were followed up at 1, 3 and 6 months of treatment. Twenty-six patients were enrolled, including 10 boys and 16 girls. There were 16 cases of SMA type Ⅱ and 10 cases of type Ⅲ with age at treatment initiation of 5.67 (3.13, 7.02) years and disease duration of 2.54 (1.31, 4.71) years. The Hammersmith Functional Motor Scale-Expanded (HFMSE) scores were increased from 14.0 (6.5, 43.0) before treatment to 26.0 (15.0, 46.5) after treatment (Z=－4.144, P<0.01) in 25 cases. The Revised Upper Limb Module Scale scores were increased from 33.0 (25.5, 36.0) before treatment to 35.0 (31.0, 36.5) after treatment (Z=－2.214, P<0.05) in 9 cases. In 7 ambulant children with SMA type Ⅲ, the six minutes walking distance was increased by 30 (15, 52) m after a 6-month treatment (Z=－2.366, P<0.05). Compared with the baseline pulmonary functions the patients showed a significant increase in forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and peak expiratory flow (PEF) in 15 cases after treatment (all P<0.05). According to patients and caregivers subjective reporting, there were various degrees of improvement in coughing, sputum production ability and exercise endurance. No serious adverse events were observed during the study. Short-term oral administration of salbutamol may improve motor and pulmonary functions in later-onset SMA children with good safety.

Analysis of Free Circulating Messenger Ribonucleic Acids in Serum Samples from Late-Onset Spinal Muscular Atrophy Patients Using nCounter NanoString Technology.

5q-related Spinal muscular atrophy (SMA) is a hereditary multi-systemic disorder leading to progressive muscle atrophy and weakness caused by the degeneration of spinal motor neurons (MNs) in the ventral horn of the spinal cord. Three SMN-enhancing drugs for SMA treatment are available. However, even if these drugs are highly effective when administrated early, several patients do not benefit sufficiently or remain non-responders, e.g., adults suffering from late-onset SMA and starting their therapy at advanced disease stages characterized by long-standing irreversible loss of MNs. Therefore, it is important to identify additional molecular targets to expand therapeutic strategies for SMA treatment and establish prognostic biomarkers related to the treatment response. Using high-throughput nCounter NanoString technology, we analyzed serum samples of late-onset SMA type 2 and type 3 patients before and six months under nusinersen treatment. Four genes (AMIGO1, CA2, CCL5, TLR2) were significantly altered in their transcript counts in the serum of patients, where differential expression patterns were dependent on SMA subtype and treatment response, assessed with outcome scales. No changes in gene expression were observed six months after nusinersen treatment, compared to healthy controls. These alterations in the transcription of four genes in SMA patients qualified those genes as potential SMN-independent therapeutic targets to complement current SMN-enhancing therapies.

Safety and effectiveness of nusinersen, a treatment for spinal muscular atrophy, in 524 patients: results from an interim analysis of post-marketing surveillance in Japan

ABSTRACT Purpose Nusinersen is an antisense oligonucleotide approved for the treatment of spinal muscular atrophy (SMA). A post-marketing surveillance (PMS) has been ongoing (August 2017–August 2025) in all patients in Japan who were administered nusinersen intrathecally in real-world clinical settings. We report the interim analysis results for safety and effectiveness. Methods This interim analysis was conducted using data collected from 524 patients whose case report forms were obtained at least once by May 30, 2022. Collected data included patient demographics and adverse events (AEs) for safety, and motor function assessments and Clinical Global Impressions of Improvement (CGI-I) for effectiveness. Results Of the 524 patients in the safety analysis set, 522 patients who were diagnosed with SMA were included in the effectiveness analysis (infantile-onset SMA [n = 153, 29.3%], later-onset SMA [n = 369, 70.7%]). The median duration of treatment was 785.0 (range 1–1549) days. AEs occurred in 35.9% of patients (49.0% in infantile-onset SMA and 30.6% in later-onset SMA). Nusinersen treatment significantly improved Hammersmith Infant Neurological Examination scores in patients with infantile-onset SMA and Hammersmith Functional Motor Scale-Expanded scores in patients with later-onset SMA for up to nearly 3 years. Based on CGI-I assessments, 98.5–100% of patients receiving nusinersen "improved" or remain "unchanged". Conclusions This interim analysis of the large-scale, all-case PMS in patients who were administered nusinersen in Japan supports the safety and effectiveness of nusinersen. The benefit–risk balance of nusinersen treatment remains favorable.

Impact of nusinersen on the health-related quality of life and caregiver burden of patients with spinal muscular atrophy with symptom onset after age 6 months.

Novel disease-modifying approaches for spinal muscular atrophy (SMA) have highlighted the patient's perspective on functional changes over time. In this study, we evaluated the impact of nusinersen on the health-related quality of life (HRQoL) of patients with later-onset SMA and the caregiver burden. We assessed the changes in HRQoL using the Pediatric Quality of Life Inventory 4.0 Generic Core Scale (PedsQL GCS) and the Pediatric Quality of Life Inventory 3.0 Neuromuscular Module (PedsQL NMM) during 26 months of treatment. Caregiver burden was assessed using the Assessment of Caregiver Experience with Neuromuscular Disease. We also assessed motor function using the Hammersmith Functional Motor Scale-Expanded (HFMSE) and the Revised Upper Limb Module score. Twenty-four patients and their caregivers were included. The median age of patients at treatment onset was 148.8 (6.8 to 269.4) months. A significant improvement was observed in psychosocial health in proxy-reported PedsQL (P = .023). However, the physical health scores of the PedsQL GCS and About my neuromuscular disorder subscores of the PedsQL NMM did not change, although there was a significant increase in HFMSE scores. Regarding the caregiver burden, the financial burden was reduced, whereas time burden increased. A higher HFMSE score was associated with better self-reported PedsQL GCS total scores (P < .001). Our results provide insights into the multifaceted implications of disease-modifying therapies for SMA through patient-reported outcome measures (PROMs). PROMs should be taken into consideration to assess the clinical significance of the functional changes identified by clinician-reported scales.

Nusinersen Treatment of Children with Later-Onset Spinal Muscular Atrophy and Scoliosis Is Associated with Improvements or Stabilization of Motor Function.

Nusinersen has been shown to improve or stabilize motor function in individuals with spinal muscular atrophy (SMA). We evaluated baseline scoliosis severity and motor function in nusinersen-treated non-ambulatory children with later-onset SMA. Post hoc analyses were conducted on 95 children initiating nusinersen treatment in the CHERISH study or SHINE long-term extension trial. Participants were categorized by baseline Cobb angle (first nusinersen dose): ≤10°, >10° to ≤20°, and >20° to <40° (no/mild/moderate scoliosis, respectively). Outcome measures included the Hammersmith Functional Motor Score-Expanded (HFMSE) and the Revised Upper Limb Module (RULM). Regression analysis determined the relationships between baseline scoliosis severity and later motor function. For children with no, mild, and moderate scoliosis, the mean increase in HFMSE from baseline to Day 930 was 6.0, 3.9, and 0.7 points, and in RULM was 6.1, 4.6, and 2.3 points. In the linear model, a 10° increase in baseline Cobb angle was significantly associated with a -1.4 (95% CI -2.6, -0.2) point decrease in HFMSE (p = 0.02) and a -1.2 (95% CI -2.1, -0.4) point decrease in RULM (p = 0.006) at Day 930. Treatment with nusinersen was associated with improvements/stabilization in motor function in all groups, with greater response in those with no/mild scoliosis at baseline.

Brain Magnetic Resonance Imaging (MRI) in Spinal Muscular Atrophy: A Scoping Review.

5q Spinal Muscular Atrophy (SMA) is a prototypical lower motor neuron disorder. However, the characteristic early motor impairment raises the question on the scope of brain involvement with implications for further investigations on the brain as a potential therapeutic target. To review changes across the SMA clinical spectrum reported on brain magnetic resonance imaging (MRI). We conducted a scoping review of existing literature on PubMed and EMBASE. Two reviewers searched and retrieved relevant articles on magnetic resonance brain imaging in individuals with SMA censoring to April 2022. Full-text articles published in peer-reviewed journals or abstracts accepted to conferences in English and French were included. Twelve articles were identified describing a total of 39 patients [age range: 11 days to 41 years old, type 0 (n = 5), type 1 (n = 4), type 2 (n = 2), type 3 (n = 22), type 4 (n = 6)]. All reported structural changes and did not explore other MRI modalities. In individuals with infantile onset SMA, cortical and subcortical brain abnormalities in white matter, basal ganglia, thalamus, hippocampus, and high intensity areas around lateral ventricles and thalami were reported over time. In individuals with later-onset SMA, reduced cerebellar and lobular volume were observed as well as increased grey matter density in motor areas. Limited data on brain imaging in SMA highlights both cortical and subcortical involvement in SMA, supporting the hypothesis that changes are not restricted to lower motor neuron pathways. Further studies are needed to determine the extent and prevalence of structural and functional brain changes across SMA types.

CO108 Longitudinal Trends in Hospitalization Rates in Patients with Later-Onset Spinal Muscular Atrophy (SMA) Treated with Nusinersen up to 4.5 Years: Results from the Cherish and Shine Studies

CO108 Longitudinal Trends in Hospitalization Rates in Patients with Later-Onset Spinal Muscular Atrophy (SMA) Treated with Nusinersen up to 4.5 Years: Results from the Cherish and Shine Studies

Spinal astrocyte dysfunction drives motor neuron loss in late-onset spinal muscular atrophy

Spinal muscular atrophy (SMA) is a progressive neuromuscular disorder caused by a loss of the survival of motor neuron 1 (SMN1) gene, resulting in a loss of spinal motor neurons (MNs), leading to muscle weakness and wasting. The pathogenesis of MN loss in SMA and the selective vulnerability in different cellular populations are not fully understood. To investigate the role of spinal astrocytes in the pathogenesis of late-onset SMA, we used a mouse model in addition to in vitro approaches. Immunostaining, Western blot analysis, small interfering ribonucleic acid (siRNA) transfections, functional assays, enzyme-linked immunosorbent assay (ELISA), behavioral tests, and electrophysiological measurements were performed. Early activation of spinal astrocytes and a reduction of the excitatory amino acid transporter 1 (EAAT1) on postnatal day (P) 20 preceded the loss of spinal MNs in SMA mice occurring on P42. EAAT1 reduction resulted in elevated glutamate levels in the spinal cord of SMA mice at P20 and P42. SMA-like astrocytes generated by siRNA and an ex vivo model of glutamate excitotoxicity involving organotypic spinal cord slice cultures revealed the critical role of glutamate homeostasis in the degeneration of MNs. The pre-emptive administration of arundic acid (AA), as an inhibitor of astrocyte activation, to SMA mice prior to the loss of motor neurons (P28) resulted in elevated EAAT1 protein levels compared to vehicle-treated SMA mice and prevented the increase of glutamate in the spinal cord and the loss of spinal MNs. Furthermore, AA preserved motor functions during behavioral experiments, the electrophysiological properties, and muscle alteration of SMA mice. In a translational approach, we transfected healthy human fibroblasts with SMN1 siRNA, resulting in reduced EAAT1 expression and reduced uptake but increased glutamate release. These findings were verified by detecting elevated glutamate levels and reduced levels of EAAT1 in cerebrospinal fluid of untreated SMA type 2 and 3 patients. In addition, glutamate was elevated in serum samples, while EAAT1 was not detectable. Our data give evidence for the crucial role of spinal astrocytes in the pathogenesis of late-onset SMA, a potential driving force for MN loss by glutamate excitotoxicity caused by EAAT1 reduction as an early pathophysiological event. Furthermore, our study introduces EAAT1 as a potential therapeutic target for additional SMN-independent therapy strategies to complement SMN-enhancing drugs.

P.108 Clinical and electrophysiological evaluation of fatigue in adult patients with spinal muscular atrophy (SMA)

Fatigue is common in SMA, and negatively interferes with quality of life of affected individuals, especially in repetitive daily activities. Despite that, few studies assessed potential electrophysiological correlates of fatigue in late-onset SMA. To assess fatigue severity and its correlation with neuromuscular jitter in a cohort of 25 adult patients with SMA. Fatigue was quantified with 2 scales: the modified fatigue impact scale (MFIS) and the fatigue severity scale (FSS). Simultaneously, concentric needle evaluation of the stimulated jitter in the frontalis muscle was performed. Jitter was expressed as the mean of mean consecutive differences (MCD) in at least 100 potentials. Three distinct MCDs were obtained in each evaluation. The motor function measure (MFM), expanded Hammersmith motor functional scale (HFMSE) and revised upper limb module (RULM) scales were used to assess motor function in each individual. There were 16 men and 9 women, with a mean age of 33.4 years. Mean MFM, HFMSE and RULM scores were 46.59, 21.08 and 22.82, respectively. Regarding fatigue, mean FSS and MFIS physical scores were 3.1 (max possible of 7) and 20 (max possible of 36). Considering an upper normal limit of 28 us, thirteen subjects had abnormal jitter results (mean=32.69us), whereas 12 had normal results (mean=17.97us). The proportion of patients with abnormal jitter was significantly higher among patients with more severe fatigue (FSS score>4) compared to those with less severe fatigue (FSS score<4) (p=0.04). Although preliminary, these results indicate that neuromuscular junction failure may play a role in SMA-related fatigue and jitter may be a neurophysiological marker to assess fatigue in this condition.

The alteration of left ventricular strain in later-onset spinal muscular atrophy children.

BackgroundPatients with spinal muscular atrophy (SMA) may suffer from multisystem injury, including an impaired cardiovascular system. However, M-mode echocardiography, the current dominant echocardiographic modality, is limited in the detection of myocardial injury. We considered the use of left ventricular strain imaging in detecting myocardial injury and explored the serum lipid profile related to cardiovascular disease in later-onset SMA children.MethodsA case-control study involving 80 patients with later-onset SMA and 80 age-, gender-, and body surface area-matched control children was conducted in a single tertiary pediatric hospital in China. Data on the left ventricular strain measured using two-dimensional speckle tracking echocardiography, left ventricular function parameters assessed by M-mode echocardiography, and serum lipid profile of these two groups were retrospectively collected for differential analysis.ResultsThe mean age of the 80 SMA patients were (6.87 ± 2.87) years, of which 46 were type 2 and 34 were type 3 patients. The global longitudinal strain (GLS) of the SMA group (−18.7 ± 2.9%, p < 0.001) was lower than that of the control group; the time to peak longitudinal strain (TTPLS) of the SMA group (22.9 ± 13.6 ms, p < 0.001) was higher than that of the control group, while left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS), measured by the Teichholz method of M-mode echocardiography, showed no significant differences between the two groups. In addition, independent indicators for cardiovascular risk, including total cholesterol (TC)/HDL, low-density lipoprotein (LDL)/HDL, and Apo B/Apo A1 levels, were higher in SMA children than in the control group.ConclusionCompared with healthy controls, later-onset SMA children presented with reduced GLS and prolonged TTPLS while the LVEF and LVFS values were within normal range. In particular, whether a reduced GLS or prolonged TTPLS in later-onset SMA compared to the control group can predict the risk of future cardiomyopathy remains to be investigated.

Accuracy of muscle fasciculations for the diagnosis of later-onset spinal muscle atrophy

Diagnosis of later-onset spinal muscular atrophy (SMA) can be challenging. This study aimed to evaluate the diagnostic properties of the detection of muscle fasciculations for SMA diagnosis in adolescents and adults with proximal muscle weakness. A cross-sectional diagnostic accuracy study was performed, in which 10 subjects with SMA (5 with type II and 5 with type III) and 9 subjects with genetic muscle diseases were evaluated by physical examination, muscle ultrasound (MUS) and electromyography (EMG). Inter-rater reliability of MUS was higher than physical examination and in a sensitivity analysis of MUS, all SMA subjects and a single patient with genetic muscle disease presented fasciculations in at least 2 different muscle groups, resulting in a sensitivity of 1 (95% CI: 0.69 to 1) and a specificity of 0.89 (95% CI: 0.52 to 1) for SMA diagnosis. Forty-two percent of evaluated subjects did not agree to perform EMG, limiting this method results. Muscle ultrasound presented the best diagnostic accuracy and physical examination combined with MUS seemed to be a good strategy for screening adolescents and adults with proximal muscle weakness for SMA. These results might improve diagnostic guidelines for later-onset SMA, leading to earlier diagnosis, treatment and specific care.

Real-world safety and effectiveness of nusinersen, a treatment for spinal muscular atrophy, in 401 Japanese patients: results from an interim analysis of post-marketing surveillance

Purpose: Nusinersen is an antisense oligonucleotide for the treatment of spinal muscular atrophy (SMA). A post-marketing surveillance (PMS) has been ongoing (August 2017–August 2025) in all patients in Japan who received intrathecal nusinersen in real-world clinical settings. We report the interim analysis results of safety and effectiveness. Methods: This interim analysis was conducted using data collected from 401 patients whose case report forms were obtained at least once by 30 May 2020. Collected data included patient demographics and adverse events (AEs) for safety, and motor function assessments and Clinical Global Impressions of Improvement (CGI-I) for effectiveness. Results: All 401 patients were diagnosed with SMA and were included in the safety and effectiveness analysis (infantile-onset SMA [n = 126, 31.4%], later-onset SMA [n = 275, 68.6%]). The median duration of treatment was 330 days (range 1–823 days). The incidence proportion of AEs was 31.7% (37.3% in infantile-onset SMA and 29.1% in later-onset SMA). The most common AEs were headache (4.5%), pyrexia (4.2%), and pneumonia (3.7%). The incidence proportion of serious AEs was 11.5%. Nusinersen improved motor function scores and was assessed as ‘effective’ based on CGI-I in 99.7–100% of patients. Conclusions: This interim analysis of the PMS in Japanese patients treated with nusinersen found no new safety concerns, with the type of AEs consistent with the expected safety profile. The benefit–risk balance of nusinersen treatment remains favorable.

Induction of Survival of Motor Neuron (SMN) Protein Deficiency in Spinal Astrocytes by Small Interfering RNA as an In Vitro Model of Spinal Muscular Atrophy.

Spinal muscular atrophy (SMA) is a motor neuron disorder leading to progressive loss of ventral horn neurons resulting in muscle wasting. Here we investigate the contribution of spinal astrocytes to the pathogenesis of late-onset SMA forms using a mouse model. Furthermore, we generated SMA-like astrocytes using survival of motor neuron (SMN) siRNA transfection techniques. In the SMA mouse model, the activation of spinal astrocytes and the reduction of the inward rectifier potassium channel Kir4.1 and excitatory amino acid transporter 1 (EAAT1) were observed at postnatal day (P) 28, preceding the loss of spinal motor neurons appearing earliest at P42. Using SMA-like astrocytes, we could mimic the modulation of spinal astrocytes of the mouse model in a dish and perform electrophysiological assessments and functional assays. In SMA-like astrocytes, glutamate uptake was diminished due to a reduction in EAAT1. Furthermore, patch-clamp measurements revealed reduced potassium uptake into astrocytes with membrane depolarization. Additionally, exposure of healthy spinal motor neurons to a conditioned medium of SMA-like astrocytes resulted in increased firing frequency. These data demonstrate spinal astrocytes’ crucial role in the late-onset SMA forms’ pathogenesis.

Assessing the Value of Nusinersen for Spinal Muscular Atrophy: A Comparative Analysis of Reimbursement Submission and Appraisal in European Countries.

Background: Nusinersen is an orphan drug intended for the treatment of spinal muscular atrophy (SMA), a severe genetic neuromuscular disorder. Considering the very high costs of orphan drugs and the expected market entry of cell and gene therapies, there is increased interest in the use of health technology assessment (HTA) for orphan drugs. This study explores the role of the economic evaluation and budget impact analysis on the reimbursement of nusinersen. Methods: Appraisal reports for nusinersen were retrieved from reimbursement and HTA agencies in Belgium, Canada, France, England and Wales, Germany, Italy, Ireland, Scotland, Sweden, the Netherlands, and the United States. Detailed information was extracted on the economic evaluation, the budget impact, the overall reimbursement decision, and the managed entry agreement (MEA). Costs were adjusted for inflation and currency. Results: Overall, the reports included limited data on budget impact, excluding information on the sources of data for cost and patient estimates. Only three jurisdictions reported on total budget impact, estimated between 30 and 40 million euros per year. For early-onset SMA, the incremental cost-effectiveness threshold (ICER) ranged from €464,891 to €6,399,097 per quality-adjusted life year (QALY) gained for nusinersen versus standard of care. For later-onset SMA, the ICER varied from €493,756 to €10,611,936 per QALY. Although none of the jurisdictions found nusinersen to be cost-effective, reimbursement was granted in each jurisdiction. Remarkably, only four reports included arguments in favor of reimbursement. However, the majority of the jurisdictions set up an MEA, which may have promoted a positive reimbursement decision. Conclusion: There is a need for more transparency on the appraisal process and conditions included in the MEA. Additionally, by considering all relevant criteria explicitly during the appraisal process, decision-makers are in a better position to justify their allocation of funds among the rising number of orphan drugs that are coming to the market in the near future.

Relationship of pharmacokinetics and pharmacodynamics to apitegromab efficacy in patients with later-onset spinal muscular atrophy (Types 2 and 3 SMA): Results from the TOPAZ study

Apitegromab is an investigational, fully human, monoclonal antibody that inhibits myostatin activation by specific binding to myostatin proforms, promyostatin and latent myostatin. We will present data, from the Phase 2 TOPAZ clinical trial (NCT03921528), on the relationships of pharmacokinetics (PK) and pharmacodynamic (PD) (marker of target engagement, latent serum myostatin levels) to apitegromab efficacy.

A Phase 2 Study to Evaluate the Efficacy and Safety of SRK-015 in Patients with Later-Onset Spinal Muscular Atrophy (TOPAZ): A Study Update (1963)

A Phase 2 Study to Evaluate the Efficacy and Safety of SRK-015 in Patients with Later-Onset Spinal Muscular Atrophy (TOPAZ): A Study Update (1963)

Plasma Phosphorylated Neurofilament Heavy Chain (pNF-H) Level is Associated with Future Motor Function in Nusinersen-treated Individuals with Later-onset Spinal Muscular Atrophy (SMA) (2248)

Plasma Phosphorylated Neurofilament Heavy Chain (pNF-H) Level is Associated with Future Motor Function in Nusinersen-treated Individuals with Later-onset Spinal Muscular Atrophy (SMA) (2248)

Motor unit number index (MUNIX) in children and adults with 5q-spinal muscular atrophy: Variability and clinical correlations

Spinal muscular atrophy (SMA) is a motor neuron disease associated with progressive muscle weakness and motor disability. The motor unit number index (MUNIX) is a biomarker used to assess loss of motor units in later-onset SMA patients. Twenty SMA patients (SMA types 3 and 4), aged between 7 and 41 years, were clinically evaluated through the Hammersmith Motor Functional Scale Expanded and the Spinal Muscular Atrophy-Functional Rating Scale. The patients underwent compound motor action potential (CMAP) and MUNIX studies of the right abductor pollicis brevis, abductor digiti minimi and tibialis anterior (TA) muscles. Age-matched healthy controls (n = 20) were enrolled to obtain normative CMAP and MUNIX values from the same muscles. Compared to healthy controls, SMA patients showed significant reductions in MUNIX values among all muscles studied, whereas CMAP showed reductions only in the weaker muscles (abductor digiti minimi and TA). MUNIX variability was significantly higher in the SMA group than in the control group. MUNIX variability in TA correlated with CMAP variability. Motor functional scores correlated with TA MUNIX. The MUNIX study is feasible in later-onset SMA patients, and TA MUNIX values correlate with disease severity in patients with mild motor impairment.

Real-World Data from Nusinersen Treatment for Patients with Later-Onset Spinal Muscular Atrophy: A Single Center Experience.

BackgroundSpinal muscular atrophy (SMA) is a motor neuron disease associated with progressive muscle weakness and motor disability.ObjectiveThis study aims to report the evaluation of nusinersen, an antisense oligonucleotide, on motor function in patients with SMA types 2 and 3.MethodsThis single-center retrospective observational study assessed nusinersen therapy outcomes, measured by HSMFSE or CHOP-INTEND scales, in patients with SMA types 2 and 3, compared to untreated patients, for at least 24 months.ResultsA total of 41 patients with SMA types 2 and 3 under nusinersen treatment were included. In 30 treated patients (mean age: 10.6 years; 14 with SMA type 2), the mean change in HFMSE scores was +1.47 points (SD = 0.4) and +1.60 points (SD = 0.6) after 12 and 24 months of treatment, respectively. In contrast, the control group (N = 37) (mean age: 10.2 years; 20 with SMA type 2) presented a mean change of -1.71 points (SD = 0.02) and -3.93 points (SD = 0.55) after 12 and 24 months of follow-up, respectively. The most severe patients under nusinersen treatment (N = 11) showed a change of +2.37 (SD = 1.13) on the CHOP-INTEND scale after 12 months of follow-up. Disease duration at the beginning of treatment was the main predictor of functional improvement. Despite functional gain and motor stabilization, treatment with nusinersen did not prevent the progression of scoliosis.ConclusionsOur data provide evidence for the long-term safety and efficacy of nusinersen use in the treatment of later-onset SMA, and patients with shorter disease duration showed better response to treatment.

SMA – THERAPY: P.265 Escalating dose and randomized, controlled study of high-dose nusinersen in SMA; study design and updated enrollment for the DEVOTE Study

The Phase 2/3 DEVOTE study (NCT04089566) is a 3-part study that will examine the safety and efficacy of nusinersen administered intrathecally at higher doses in participants with 5q spinal muscular atrophy (SMA). Part A is an open-label safety evaluation of later onset SMA participants (n=6, age 2-15 years, inclusive; SMA onset age >6 months) who will receive three 28 mg loading doses at 14-day intervals followed by two 28 mg maintenance doses every 4 months. After safety evaluation, Part B will enrol ≤126 participants with infantile-onset (age ≤7 months at informed consent; 2 SMN2 copies; SMA onset age ≤6 months) or later-onset SMA (age 2 to <10 years; SMA onset age >6 months; sat but not walking independently; HFMSE score ≥10 to ≤54).