SMA – THERAPY: P.279 Efficacy and safety of nusinersen treated adult patients with spinal muscular atrophy (SMA) types 2-3-4

BackgroundNusinersen is an approved disease-modifying therapy for spinal muscular atrophy (SMA), a rare neuromuscular disease characterized by degeneration of alpha motor neurons in the brainstem and spinal cord (SC), leading to progressive muscle atrophy and weakness. This exploratory study investigated the potential of quantitative SC magnetic resonance imaging (MRI) as a biomarker for monitoring treatment-related changes in pediatric and adult SMA patients treated with nusinersen at different disease stages.MethodsFive pediatric and three adult SMA patients underwent clinical assessments, including the Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM), along with SC MRI at multiple time points (TPs) during nusinersen treatment. At each TP, total cross-sectional area (TCA), grey matter area (GMarea), and magnetization transfer saturation (MTsat) were measured at multiple cervical SC levels.ResultsAll pediatric patients showed a progressive increase in SC TCA and GMarea over time, paralleled by improvements in HFMSE and RULM scores. In contrast, adult patients exhibited stable SC MRI measures with modest functional gains. MTsat values remained largely stable across time points, with a mild decrease observed at TP5. TCA and GMarea showed positive association trends with clinical scales.ConclusionNusinersen showed beneficial effects in both adult and pediatric SMA patients, with more marked improvements in children. Quantitative SC MRI metrics, especially TCA and GMarea, reflected clinical trends and may serve as non-invasive biomarkers for monitoring treatment effects, pending validation in larger cohorts.

Nusinersen recently became available as the first treatment for Spinal Muscular Atrophy (SMA) and data on its effectiveness and safety in adult SMA patients are still scarce. We evaluated the effectiveness and safety of nusinersen treatment during 14months in 16 adult patients with SMA types 3 and 4 in a prospective study, and retrospectively detailed the natural history of 48 adult SMA patients types 2, 3 and 4. Hand grip strength (p = 0.03), hand motor function (p = 0.04) as assessed by a sub-score of the Revised Upper Limb Module (RULM) and the Medical Research Council (MRC) sum score (p = 0.04) improved significantly at month 14. Importantly, the MRC sum score had declined significantly (p < 0.01) prior to start of treatment in these patients. A minimal clinically important difference (MCID) in the Hammersmith Functional Motor Scale Expanded (HFMSE) and RULM scores was achieved in 31% and 50% of the patients, respectively, but the mean changes from baseline failed to reach significance. Forced Vital Capacity (FVC) transiently increased at month 6 (p = 0.01), whereas the Peak Expiratory Flow (PEF) did not. The Activity Limitations scale declined significantly prior to start of treatment (p < 0.01) and showed an improvement with nusinersen which was not significant. The safety evaluation did not reveal serious adverse events and no signs of nephrotoxicity or antisense oligonucleotide (ASO)-mediated inflammation. We conclude that hand grip strength and hand motor function, as well as MRC sum scores improved significantly in nusinersen-treated adult patients with SMA types 3 and 4.

Background and objectivesMultisystem involvement in spinal muscular atrophy (SMA) is gaining prominence since different therapeutic options are emerging, making the way for new SMA phenotypes and consequent challenges in clinical care. Defective immune organs have been found in preclinical models of SMA, suggesting an involvement of the immune system in the disease. However, the immune state in SMA patients has not been investigated so far. Here, we aimed to evaluate the innate and adaptive immunity pattern in SMA type 1 to type 3 patients, before and after nusinersen treatment.MethodsTwenty one pediatric SMA type 1, 2, and 3 patients and 12 adult SMA type 2 and 3 patients were included in this single-center retrospective study. A Bio-Plex Pro-Human Cytokine 13-plex Immunoassay was used to measure cytokines in serum and cerebrospinal fluid (CSF) of the study cohort before and after 6 months of therapy with nusinersen.ResultsWe detected a significant increase in IL-1β, IL-4, IL-6, IL-10, IFN-γ, IL-17A, IL-22, IL-23, IL-31, and IL-33, in serum of pediatric and adult SMA patients at baseline, compared to pediatric reference ranges and to adult healthy controls. Pediatric patients showed also a significant increase in TNF-α and IL-17F levels at baseline. IL-4, IFN-γ, Il-22, IL-23, and IL-33 decreased in serum of pediatric SMA patients after 6 months of therapy when compared to baseline. A significant decrease in IL-4, IL-6, INF-γ, and IL-17A was detected in serum of adult SMA patients after treatment. CSF of both pediatric and adult SMA patients displayed detectable levels of all cytokines with no significant differences after 6 months of treatment with nusinersen. Notably, a higher baseline expression of IL-23 in serum correlated with a worse motor function outcome after treatment in pediatric patients. Moreover, after 6 months of treatment, patients presenting a higher IL-10 concentration in serum showed a better Hammersmith Functional Motor Scale Expanded (HFMSE) score.DiscussionPediatric and adult SMA patients show an inflammatory signature in serum that is reduced upon SMN2 modulating treatment, and the presence of inflammatory mediators in CSF. Our findings enhance SMA knowledge with potential clinical and therapeutic implications.

Natural history data for adult patients with spinal muscular atrophy (SMA) remain scarce, which is particularly relevant in the current therapeutic era. This study aimed to identify the most sensitive clinical, patient-reported, and neurophysiological measures to detect short-term disease progression in untreated adult SMA patients. This prospective, one-year longitudinal study included 21 genetically confirmed adult patients with SMA types 2B and 3. Clinician-reported outcomes (CROs) included the Motor Function Measure (MFM), Hammersmith Functional Motor Scale Expanded (HFMSE), and Revised Upper Limb Module (RULM). Additionally, patient-reported outcomes (PROs) were assessed using the Modified Fatigue Impact Scale (MFIS). Neurophysiological evaluations included compound muscle action potential (CMAP) amplitude and motor unit number index (MUNIX) recorded from the ulnar nerve. Sensitivity to change was determined using standardized response means (SRMs), and associations between clinical and neurophysiological data were analyzed via Spearman correlation. The majority of participants were non-ambulatory (16/21). The MFM total score was the only outcome to show a statistically significant decline over 12 months (p = 0.02), with the highest SRM (-0.55), indicating superior sensitivity. MFM also demonstrated the strongest correlations with CMAP amplitude (ρ = 0.90) and MUNIX (ρ = 0.75), compared to other CROs. No significant longitudinal changes were observed in RULM, HFMSE, MFIS, CMAP, or MUNIX. Among evaluated outcome measures, the MFM was the most sensitive to short-term progression and most closely aligned with neurophysiological markers. These findings support the use of MFM as a primary outcome in clinical trials involving adult SMA patients.

Buying time for infants with spinal muscular atrophy

Background:Nusinersen is an intrathecally administered antisense oligonucleotide (ASO) and the first approved drug for the treatment of spinal muscular atrophy (SMA). However, progressive neuromyopathic scoliosis and the presence of spondylodesis can impede lumbar punctures in SMA patients. Our aim was to assess the feasibility and safety of the treatment in adults with SMA.Methods:For the intrathecal administration of nusinersen, we performed conventional, fluoroscopy-assisted and computer tomography (CT)-guided lumbar punctures in adult patients with type 2 and type 3 SMA. We documented any reported adverse events and performed blood tests.Results:We treated a total of 28 adult SMA patients (9 patients with SMA type 2 and 19 patients with SMA type 3) aged between 18–61 years with nusinersen. The mean Revised Upper Limb Module (RULM) score at baseline in SMA type 2 and SMA type 3 patients was 9.9 ± 4.6 and 29.5 ± 8.5, respectively. The mean Hammersmith Functional Motor Scale Expanded (HFMSE) score at baseline was 3.1 ± 2.5 and 31.2 ± 18.1, respectively. Half of the SMA type 3 patients were ambulatory at treatment onset. In total, we performed 122 lumbar punctures with 120 successful intrathecal administrations of nusinersen. Lumbar punctures were well tolerated, and no serious adverse events occurred.Conclusions:Our data demonstrate the feasibility and tolerability of intrathecal treatment with nusinersen in adults with SMA type 2 and type 3. However, treatment can be medically and logistically challenging, particularly in patients with SMA type 2 and in patients with spondylodesis.

ABSTRACTBackgroundThis study aimed to evaluate changes in compound muscle action potential (CMAP) amplitude in adults with spinal muscular atrophy (SMA) undergoing nusinersen treatment and its association with motor function improvements.MethodsThis multicenter study assessed median, ulnar, and peroneal CMAP over a follow‐up of up to 4.5 years using linear mixed models. Motor function was measured using the Revised Upper Limb Module (RULM) and the Hammersmith Functional Motor Scale Expanded (HFMSE). Correlations between CMAP and motor function scores were analyzed.ResultsSeventy‐eight patients (27 ambulatory, 51 non‐ambulatory) were included. Baseline ulnar CMAP ≥ 2.0 mV distinguished SMA type 3 from type 2 with 91.3% sensitivity and 88.9% specificity (AUC 0.96, 95% CI 0.92–1.0), while baseline median nerve CMAP ≥ 6.5 mV showed 91.7% sensitivity and 77.3% specificity (AUC 0.84, 95% CI 0.72–0.96). No significant changes over time were observed in median, ulnar, and peroneal CMAP amplitudes (p > 0.05). CMAP trajectories did not differ between SMA types 2 and 3 (p > 0.05). No significant difference in the change in RULM or HFMSE at any time point was observed between SMA patients with baseline median nerve CMAP < 5 mV and those with CMAP of ≥ 5 mV (p > 0.05). No significant correlations were found between changes in median nerve CMAP and HFMSE or RULM (p > 0.05).DiscussionCMAP amplitudes remained stable during nusinersen treatment, with no differences in trajectories between SMA types 2 and 3. Our findings suggest that while CMAP amplitude correlates with disease severity, it may not serve as a sensitive biomarker of treatment response in adult SMA patients.

Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by progressive muscle weakness due to SMN protein deficiency. While effective therapies exist, their impact on slowly progressive adult SMA patients remains unclear. Reliable biomarkers for monitoring disease progression and treatment response are urgently needed. This pilot study evaluated the utility of longitudinal quantitative muscle MRI (qMRI) to monitor disease progression in adult SMA patients treated with nusinersen over an extended period. Nine adult patients with genetically confirmed 5q-SMA underwent whole-body muscle MRI and clinical assessment, including the Hammersmith Functional Motor Scale-Expanded (HFMS-EXP), Revised Upper Limb Module (RULM), and 6 min walk test (6MWT). Muscular fat fraction (mFF) was quantified in 20 muscles over a median follow-up of 54 months. Baseline mFF correlated strongly with clinical measures (HFMS-EXP: r = -0.90, p = 0.001; 6MWT: r = -0.96, p < 0.001), but not with age at onset or age at MRI. Over the observation period, a significant increase in mFF was detected (averaged annual increase of all studied muscles: 0.47%, p = 0.011), accentuated in the lower leg muscles. In contrast, clinical measures showed no consistent change. Consequently, no significant correlations were found between changes in mFF and clinical scores. This study provides the longest reported longitudinal qMRI assessment in adult SMA patients treated with nusinersen, demonstrating that mFF progressively increases despite stable clinical scores. The results suggest that qMRI may be a sensitive and objective biomarker for detecting subtle disease progression in adult SMA, potentially surpassing clinical measures.

BackgroundSpinal muscular atrophy (SMA) issues from mutations in the survival of motor neuron (SMN) 1 gene. Loss or reduction of the SMN protein results in progressive muscle weakness. Whether this protein deficiency also affects cortical function remains unclear. While no data on adult patients exists so far, prior studies in children with SMA indicate cognitive abilities equal or even superior to healthy controls. This may suggest a possible compensatory—neuropsychological and interactional—process. The goal of this study was to assess the cognitive profile of adult patients with SMA, with a special focus on social cognition as a potential candidate for enhanced cognitive function through compensatory processes.MethodsIn a cross-sectional design, N = 31 adult SMA patients (types II and III) were assessed for language, verbal fluency, memory, visuospatial abilities and executive function with the Edinburgh Cognitive and Behavioural ALS Screen and for social cognition with the Reading the Mind in the Eyes Test. Physical function was evaluated using the Hammersmith Functional Motor Scale Expanded. N = 19 neurologically healthy controls were matched with patients for age, sex and years of education.ResultsIn none of the abovementioned cognitive domains significant differences between SMA patients and controls were found. Among patients, no differences between type II SMA and type III SMA were detected for any domain. However, a trend towards better social cognition in patients with type II SMA, compared to those with type III SMA was observed. Furthermore, a significant inverse correlation of physical function and executive function was detected: lower motor function was associated with a better executive function.ConclusionsThis study shows cognitive abilities in adult SMA in the normal range for all assessed domains. Thus, reduction of SMN protein has no obvious negative impact on cognitive function. Executive functions are identified as the only cognitive domain correlated with disease severity. Therefore, executive functions may play a role in the adaptation to physical restrictions in SMA, making them a promising target for future research.

Nusinersen was effective in improving motor function and survival in infantile and childhood-onset spinal muscular atrophy (SMA), and the value of real-world experiences in adult SMA patients increase gradually. Here, we present our clinical experience in adult SMA patients treated with nusinersen according to CHERISH study. Thirty-two SMA patients treated with nusinersen were included in the study. Median age at nusinersen initiation was 33.5 (20.0-60.0) years and 23 of SMA patients were male. Six (18.8%) patients had SMA type 2, and 26 (81.2%) had SMA type 3. Median follow-up period of patients under nusinersen treatment was 17 months (9-21). Twenty-three patients improved by at least 3 Hammersmith Functional Motor Scale Expanded (HFMSE) points after loading doses. There was significant HFMSE score increase in type 3 patients at each time point, whereas type 2 patients seem to benefit from nusinersen loading doses, subsequently stayed stable. Motor improvement was positively correlated with baseline HFMSE scores in patients whose baseline HFMSE scores were ≤47. There was a correlation between the changes in Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) score and HFMSE scores. Ambulatory patients who could not show clinically meaningful increase in HFMSE scores improved at least 30 m by 6-min walk test (6MWT). Overall, 78% of patients have responded to treatment according to HFMSE or 6MWT. ALSFRS-R and 6MWT may be alternative tools to monitor nusinersen effect.

Long-term efficacy of nusinersen and its evaluation in adolescent and adult patients with spinal muscular atrophy types 1 and 2

To retrospectively evaluate quality of life (QoL) in a large multicenter cohort of adult patients affected by spinal muscular atrophy (SMA) during nusinersen treatment. We included adult (≥ 18years) patients clinically and genetically defined as SMA2, SMA3 and SMA4, who started nusinersen treatment in adulthood. QoL was rated by the Individualized Neuromuscular Quality of Life (INQoL) questionnaire. Concurrent motor function evaluation included the Hammersmith Functional Motor Scale Expanded (HFMSE), the Revised Upper Limb Module (RULM), the 6min walking test (6MWT). 189 completed questionnaires were collected during a 14months' treatment period. 78 patients were included (7 SMA2 and 69 SMA3 and 2 SMA4) with mean disease duration at first nusinersen administration of 33.2years (± 12.5years). All the scores for each INQoL domain (weakness, fatigue, activities, independence, social relationship, emotions, body images) and the derived QoL total score, significantly improved during the observation period, except the muscle locking and pain items. Exploratory analyses suggested that emotions and social relationships were more relevant issues for females compared to males. Social relationships were affected also by a longer disease duration (> 30years). In SMA3 non-walker patients, activities ameliorate better compared to walkers. The HFMSE and RULM significantly improved from baseline; however, no associations with QoL total score and weakness, activities or independence were demonstrated. In our cohort, adult SMA patients showed a global improvement at the INQoL assessment over 14months of nusinersen treatment. QoL assessment is relevant to SMA multidisciplinary evaluation.

Patient and parent oriented tools to assess health-related quality of life, activity of daily living and caregiver burden in SMA. Rome, 13 July 2019

To determine the diagnostic and monitoring value of serum neurofilament light chain (NfL) in spinal muscular atrophy (SMA). We measured serum NfL in 46 SMA patients at baseline and over 14months of treatment with the antisense-oligonucleotide (ASO) nusinersen using the ultrasensitive single molecule array (Simoa) technology. Serum NfL levels of SMA patients were compared to controls and related to cerebrospinal fluid (CSF) NfL, blood-CSF barrier function quantified by the albumin blood/CSF ratio (Qalb) and motor scores (Hammersmith Functional Motor Scale Expanded, HFMSE; Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised, ALSFRS-R). Serum NfL levels of SMA patients were in the range of controls (p = 0.316) and did not correlate with CSF NfL (ρ = 0.302, p = 0.142) or Qalb (ρ = - 0.160, p = 0.293). During therapy, serum NfL levels were relatively stable with notable concentration changes in single SMA patients, however, within the control range. Higher NfL levels were associated with worse motor performance in SMA (baseline: HFMSE ρ = - 0.330, p = 0.025, ALSFRS-R ρ = - 0.403, p = 0.005; after 10months: HFMSE ρ = - 0.525, p = 0.008, ALSFRS-R ρ = - 0.537, p = 0.007), but changes in motor scores did not correlate with changes in serum NfL. Diagnostic and monitoring performance of serum NfL measurement seems to differ between SMA subtypes. Unlike to SMA type 1, in adolescent and adult SMA type 2 and 3 patients, neurodegeneration is not reflected by increased NfL levels and short-term therapeutic effects cannot be observed. Long-term follow-up has to be performed to see if even low levels of NfL might be good prognostic markers.

ABSTRACTIntroduction/AimsThe biological changes in motor neurons and motor axons that correlate with the clinical benefits of nusinersen, an antisense oligonucleotide, in spinal muscular atrophy (SMA) remain poorly understood. This study aimed to investigate changes in axonal excitability and motor unit number estimation (MUNE) parameters following a four‐dose loading regimen of nusinersen in adult SMA patients.MethodsAdult patients with SMA were assessed using the Hammersmith Functional Motor Scale Expanded (HFMSE) and the Medical Research Council (MRC) scale at baseline and after nusinersen treatment. Axonal excitability studies and MScanFit MUNE were conducted in SMA patients before and after treatment. Baseline axonal excitability and MScanFit MUNE parameters in SMA patients were compared with those of a healthy control (HC) group.ResultsCompared to the HC group (n = 10), SMA patients (n = 12) exhibited a significantly prolonged strength‐duration time constant (SDTC), a higher resting current/voltage (I/V) slope, and prolonged refractoriness at 2.5 ms. However, no significant changes in axonal excitability parameters were observed following nusinersen treatment. Similarly, there were no significant changes in MUNE or in other parameters, including D50, compound muscle action potentials, and steps%. In contrast, a significant increase in HFMSE and MRC scores was observed after treatment (p < 0.01 and p = 0.01, respectively).DiscussionA prolongation of SDTC, likely due to its effect on sodium channel function, was observed in this study, consistent with existing literature. Despite improvements in motor function, no significant electrophysiological changes were detected in adult SMA patients.