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Background and purpose: Following the commercial availability of nusinersen, there have been a number of new referrals of adults with spinal muscular atrophy (SMA) not regularly followed in tertiary‐care centers or enrolled in any disease registry. Methods: We compared demographics and disease characteristics, including assessment of motor and respiratory function, in regularly followed patients and newcomers subdivided according to the SMA type. Results: The cohort included 166 adult patients (mean age: 37.09 years): one type I, 65 type II, 99 type III, and one type IV. Of these 166, there were 67 newcomers. There was no significant difference between newcomers and regularly followed patients in relation to age and disease duration. The Hammersmith Functional Motor Scale Expanded and Revised Upper Limb Module scores were higher in the regularly followed patients compared to newcomers in the whole cohort and in both SMA II and II. A difference was also found on ventilatory status (p = 0.013) and Cobb's angle >50° (p = 0.039) between the two subgroups. No difference was found in scoliosis surgery prevalence (p > 0.05). Conclusions: Our results showed differences between the two subgroups, even if less marked in the type III patients. In the type II patients, there was a higher proportion of newcomers who were in the severe end of the spectrum. Of the newcomers, only approximately a third initiated treatment, as opposed to the 51% in the regularly followed patients. The identification of patients who were not part of the registries will help to redefine the overall prevalence of SMA and the occurrence of different phenotypes. [ABSTRACT FROM AUTHOR]

We examined the long-term safety and durability of intravenous or intrathecal onasemnogene abeparvovec in symptomatic and presymptomatic patients with SMA in the LT-002 study. Safety was assessed by medical history/record review, physical examination, laboratory evaluation, and pulmonary/cardiac assessments. Efficacy was assessed by developmental milestones and HFMSE. As of May 23, 2022, 81 patients (intravenous, n=63 [symptomatic, n=38; presymptomatic, n=25]; intrathecal, n=18) were enrolled. Mean (range) follow-up was 3.4 (1.0–4.3) and 3.6 (2.6–4.3) years for the intravenous and intrathecal cohorts, respectively. No deaths or treatment-emergent adverse events (TEAEs) causing discontinuation occurred. The most frequently reported TEAEs were gastroenteritis, nasopharyngitis, pneumonia, respiratory distress, and viral infection. All patients survived and maintained developmental milestones. Mean (range) age was 3.7 (2.4–4.7) and 5.3 (3.4–7.5) years for the intravenous and intrathecal cohorts, respectively. One patient required permanent ventilation. Twenty-seven patients achieved new milestones (presymptomatic-intravenous, n=6; symptomatic-intravenous, n=16; intrathecal, n=5); more than half (n=16) did so without add-on therapy. HFMSE improvements were clinically significant (≥3 points; presymptomatic-intravenous, 81.25%; symptomatic-intravenous, 66.7%; intrathecal, 50%). No patients treated presymptomatically required ventilatory/nutritional support; few symptomatic patients required ventilatory (intravenous-symptomatic, 32%; intrathecal, 5.6%) or feeding (intravenous-symptomatic, 20%; intrathecal, 0%) support. Most fed orally (intravenous, 92.1%; intrathecal, 100%). The majority (57/81) never received add-on therapy; of those who did, half did not achieve new milestones. Intravenous/intrathecal onasemnogene abeparvovec demonstrates consistent, substantial, and durable efficacy and no new safety signals in symptomatic and presymptomatic patients with SMA. [ABSTRACT FROM AUTHOR]

Abstract: The aim of this study was to validate the Hammersmith functional motor scale for children with spinal muscular atrophy in a large cohort of 90 non-ambulant children with spinal muscular atrophy type 2 or 3. All had a baseline assessment (T0) and were reassessed either at 3 months (T1) (n=66) or at 6 months (T2) (n=24). Inter-observer reliability, tested on 13 children among 3 examiners, was >95%. Of the 66 children examined after 3 months 4 had adverse effects in between assessments and were excluded from the analysis. Forty-two (68%) of the remaining 62 reassessed had no variation in scores between T0 and T1 and 13 (21%) were within ±1 point. 9 (37.5%) of the 24 children reassessed after 6 months had no variation in scores between T0 and T2 and another 9 (37.5%) had variations within ±1 point. Our study confirms previous observations of the reliability of the scale and helps to establish a baseline for assessing changes of functional ability over 3 and 6 month intervals. This information can be valuable in view of therapeutic trials. [Copyright &y& Elsevier]

Spinal muscular atrophy (SMA), a progressive genetic neuromuscular disorder resulting in neurodegeneration, skeletal muscle atrophy, and weakness, typically manifests in infancy and is associated with high morbidity. Current SMA therapies target motor neurons; however, motor function deficits remain due to muscle atrophy. Apitegromab, a fully human monoclonal antibody that inhibits activation of latent myostatin and enables muscle growth, is an investigational SMA treatment. The phase 3, randomized, double-blind, placebo-controlled SAPPHIRE (NCT05156320) study is evaluating efficacy and safety of apitegromab in nonambulatory patients with type 2 or 3 SMA aged ≥2y receiving SMN therapy (≥10mo nusinersen or ≥6mo risdiplam) with Hammersmith Functional Motor Scale Expanded (HFMSE) scores of ≥10 and ≤45 at screening. A main efficacy population (MEP; 2y–12y) and exploratory subpopulation (EXP; 13y–21y) will be assessed for 12mo. The MEP was randomized 1:1:1 to receive 10 or 20 mg/kg apitegromab or placebo every 4 weeks (Q4W) and the EXP 2:1 to receive 20 mg/kg apitegromab or placebo Q4W. At enrollment, the MEP (mean age, 7.8y, n=156) and EXP (15.8y; n=32) was 47.4% and 62.5% female, respectively. Mean±SD age at SMN therapy initiation was 3.2y±1.6y in the MEP, with 77.6% receiving nusinersen vs risdiplam, and 11.0y±3.8y in the EXP (nusinersen, 56.3%). Most participants had 3 SMN2 copies (MEP, 83.3%; EXP, 62.5%). Mean±SD baseline total HFMSE and Revised Upper Limb Module (RULM) scores were 26.2±10.1 and 26.2±6.1 in the MEP and 21.3±10.3 and 26.3±5.7 in EXP, respectively; World Health Organization (WHO) motor milestones met were 1.6±0.9 for MEP and 1.3±0.8 for EXP. Despite SMN-targeted therapy, low baseline HFMSE and RULM scores and WHO milestones met indicate prevalent motor function deficits. The study will assess if apitegromab addresses this unmet need by directly targeting muscle atrophy to enhance motor function. [ABSTRACT FROM AUTHOR]

The advent of disease-modifying therapies has completely changed the natural history of type 1 Spinal muscular atrophy (SMA). Before the advent of the therapies less than 10% of type 1 infants survived beyond the age of 2 years and none of the type 0 SMA survived beyond a few months. The aim of this study was to assess survival in a large cohort of type 1 SMA including all patients born after March 2016, when the first drug became commercially available in Italy. The study is part of a nationwide registry including all the centres recognized as reference centres for SMA in Italy. Type 0 infants were also included but analyzed separately. 225 type 1 infants born after March 2016 were identified. Their age ranged between 3 months and 8 years, one month. All but 26 had reached two years of age. Only 7 of the 225 patients opted for palliative care and another 4 discontinued treatment after one or a few doses. Another five infants were identified as type 0. The infants who died during follow-up were approximately 7% of the whole type 1 cohort and less than 9% of those who had reached two years of age. In over 65% of the infants who died the family had opted for no treatment or had discontinued treatment. The other 6 patients had been treated with Zolgensma (n=3), Nusinersen (n=2) and Risdiplam (n=1) and all died of severe acute respiratory events. All the five type 0 infants, all with severe clinical signs at birth, died within the first year. Only one of the 5 had been treated. Our results, including all infants followed in Italian reference centres confirm that, following the availability of the new drugs, the near totality of patients had been treated, with only a few electing to discontinue treatment. Our findings also confirm long-term survival in treated type 1 patients. [ABSTRACT FROM AUTHOR]

Disease-modifying treatments, such as nusinersen, have significantly improved the disease trajectory of Spinal Muscular Atrophy (SMA) patients. Treatment response is heterogeneous, and predicting response is crucial for clinicians to give realistic guidance to patients and carers when counselling about treatment options. We collected data on 124 patients from the SMA Reach UK and Italian Network studies. Participants were included if they were treated under 4 years and were non-sitters at nusinersen initiation, were randomly allocated to training (80%) and testing cohorts (20%). Tree and regression-based machine learning for survival outcomes were compared, and oblique random forests were selected, with a testing C-Index of 0.74. The features were selected from items of the CHOP and HINE-2, respiratory symptoms and bulbar interventions using mutual information. In total, 62 (50%) have achieved sitting, at a median age of 2.4 years. The predicted median time-to-sitting in those requiring NG or G-Tubes at treatment was 4-months later on average than those without, and this was the most influential factor. The ability to kick at treatment, (≥1 on the HINE-2 item) was also influential in predicting the likelihood of sitting, as was antigravity shoulder movement in supine and ability to reach in side-lying (4 on items 1 and 8), and neck muscle activation in pull to sit (≥2 on item 14) and rolling fully prone from supine when elicited from arms (≥3 on item 7) on the CHOP at treatment. Most notably, those who could roll fully prone from supine had a median predicted time-to-sit 5.8 months earlier than an identical patient who could not. Nusinersen starting and symptom onset age were less influential, whilst SMN2 copy numbers did not improve the model. This work provides a tool to predict treatment response in nusinersen-treated patients and has the potential to be extended to other treatment options, moving clinicians towards personalised treatment plans for each patient. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy (SMA) Type III is characterized by the loss of the SMN1 gene, resulting in progressive neuron degeneration. While initially ambulatory, patients may later face gait impairments, fatigue, and the risk of ambulation loss (LOA). This study investigates the variability of LOA and its correlation with treatments in a nationwide cohort of SMA Type III cases. Retrospective data from 28 Italian centers, representing the national segment of the ISMAC registry, were utilized. The analysis involved 429 individuals with Type III SMA. Initially, individual variables such as sex, SMN2 copy number, and SMA III subtype (IIIA and IIIB) were analyzed independently of treatment effects. Subsequently, treatment effects were incorporated, and interactions between variables were explored. Initial analysis revealed that individuals with higher SMN2 copy numbers had a lower risk of LOA, with a 57% lower risk for those with 4+ copies compared to 2 copies. Similarly, SMA IIIB individuals had a 78% lower risk of LOA compared to SMA IIIA. The second phase of analysis revealed that treatment status significantly influenced LOA risk, with treated individuals experiencing a 96% lower risk of LOA compared to untreated individuals. Subgroup analyses by SMA subtype and SMN2 copy number further revealed substantial associations. Treated SMA IIIA individuals had a 91% lower risk of LOA compared to untreated counterparts, while treated SMA IIIB individuals had an 88% lower risk. Moreover, higher SMN2 copy numbers were associated with a reduced risk of LOA among treated individuals. Those with 3SMN2 copies had an 85% lower risk, and those with 4+SMN2 copies had a 93% lower risk compared to untreated counterparts. These findings underscore the potential benefits of treatment in delaying ambulation loss in SMA Type III patients and highlight the importance of incorporating treatment effects into prognostic models for improved patient management. [ABSTRACT FROM AUTHOR]

Disease-modifying therapies (DMT) have revolutionized Spinal Muscular Atrophy (SMA) treatment, prompting ongoing exploration of the impact of treatment durability on motor function in adults. This study aims to characterize the treated adult SMA population and evaluate longitudinal motor responses over 4 years. Data from 207 SMA individuals (15-74 years; x=33.1; SD=13.7) with diverse functional abilities were collected. Follow-up visits occurred in the USA and Italy post-nusinersen (2016) and risdiplam (2020) availability. Motor response was assessed using validated scales: Revised Upper Limb Module (RULM), Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Hammersmith Scale (RHS), and 6-Minute Walk Test (6MWT). Long-term response was analyzed using linear mixed models and piecewise models, considering covariates: age, treatment duration, disease duration, SMN2 copy number, and functional status. Clinical outcomes showed stability across all groups longitudinally. Sensitivity analysis revealed significance for all covariates. Yearly changes ranged: RULM -0.1 (walker) to -0.5 (stander); HFMSE -0.0 (non-sitter) to -1.0 (stander); RHS -0.1 (non-sitter) to -1.3 (stander). 6MWT showed negative association with treatment duration (-6.56 meters/year). Significant positive slope differences were initially observed: HFMSE in walkers (p<0.036, yr1 vs 2-4); RHS in standers (p<0.043, yr 2 vs 3-4); RULM in non-sitters (p=0.034, yr1 vs 3); and standers (p=0.007, year 1 vs 3). No significant differences were found for 6MWT between years. Sitters also showed no changes longitudinally. With increasing global availability of DMTs, understanding their long-term impact on motor function continues to evolve. While clinical stability was observed across functional groups, significant differences in yearly changes underscore the need for tailored treatment strategies and further investigation into underlying mechanisms and the role adjunctive therapies. [ABSTRACT FROM AUTHOR]

There is emerging evidence that SMA1 children treated with disease modifying therapies (DMTs) develop expressive language abilities although these do not follow typical trajectories. Very little is known about other aspects of communication, including social communication abilities. We conducted a cross-sectional study aiming to investigate parents-reported expressive language and social communication skills in SMA1 patients treated with DMTs at two Neuromuscular Centres, the Dubowitz Neuromuscular Centre, London (UK) and the Centro Clinico Nemo Pediatrico, Rome (Italy). Parents of SMA1 children were asked to complete the MacArthur-Bates Communicative Development Inventory (MB-CDI) for children aged 8months+, to investigate the developing abilities in early language, and the Social Communication Questionnaire (SCQ) for children aged 4years+, to identify potential social communication difficulties. For the SCQ, a cut-off ≥ 11 was selected to improve sensitivity and reduce the likelihood of false negatives. Fifteen parents agreed to complete the MB-CDI (age range: 2 years 2 months – 6 years 9 months). Results demonstrated the acquisition of some verbal skills in 13/15, although with scores below normal ranges. Thirty-seven parents agreed to complete the SCQ (age range: 4 years 0 months – 9 years 0 months). Twenty-one/37 parents were unable to answer one or more questions (range 1–22) due to their child being nonverbal and/or not strong enough to perform the action(s) so, those items were excluded from the total score. Four/37 (11%) showed a total SCQ score ≥11, suggesting the need of further investigations for autism spectrum disorder. Three/4 had completed the MB-CDI and were among the children able to say the lowest number of words. Other areas of concern emerging from the SCQ included routines/ritualized patterns of behaviour (14/37, 38%), and hyperreactivity to sensory input (5/37, 13%). Treated SMA1 children can acquire expressive language skills, although this can be delayed. A noteworthy percentage of them also present with social communication difficulties later on in life, especially when expressive language is more severely affected. Large prospective studies are warranted to better characterize the spectrum of language and social communication abilities in this population. [ABSTRACT FROM AUTHOR]

The advent of disease modifying therapies in Spinal Muscular Atrophy (SMA) has changed the natural history of the disease, increasing life expectancy and quality of life but, at the same time, raising new clinical challenges. The aim of this study is to explore the neurobehavioral profile in treated individuals with SMA type I and subjects identified by newborn screening (NBS). Twenty-eight individuals aged 2-10 years underwent a comprehensive behavioral assessment using three screening questionnaires (Strengths and Difficulties Questionnaire (SDQ), Social Communication Questionnaire (SCQ), and Sensory Profile (SP)), which provide information regarding the risk of behavioral disorders and autism. A cognitive evaluation, and a clinical observation were performed by two independent observers. Twenty-two individuals with SMA type I and 6 patients identified with NBS were included. None had abnormal clinical scores in the SCQ questionnaire, 4 had borderline scores, but in two of the 4 the scores were normal when the motor items were removed. SDQ showed some abnormal results in 10/28 subjects. The clinical observation confirmed the result of the screening questionnaires in 17/28 subjects and highlighted behavioral issues in 4/28 not detected by the questionnaires. Our findings confirm that neurobehavioral disorders may occur in subjects with SMA and highlight the challenges in choosing the appropriate assessment tools. Questionnaires such as SCQ do not appear to be adequate as they often failed to identify signs detected by other tools. SDQ appeared to be the most appropriate tool in our cohort. In our experience, a structured clinical observation was also helpful to identify behavioral problems, suggesting that, in the absence of disease specific tools, the use of different instruments may help to better identify the type and the frequency of behavioral problems. [ABSTRACT FROM AUTHOR]

Spinal Muscular Atrophy (SMA) is a progressive neuromuscular disorder, with untreated patients displaying variable gross motor acquisition and loss. The Revised Hammersmith Scale (RHS) is a specifically developed motor function outcome, which captures disease progression in SMA Type 2 and Type 3. We present the variable rates of achievement of the RHS items by functional group: non-sitters, sitters, transitional and walkers. We present the newly developed "transitional group" (TG) as participants able to crawl, stand, or walk with assistance but not walk independently. A total of 618 RHS assessments, across 178 treatment-naïve paediatric participants (47% girls, age range 1-18), were obtained between 2015-2019, with 27 non-sitters, 110 sitters, 21 TG and 50 walkers at baseline. The TG included 5 crawlers, 5 standers-with-assistance, 8 independent standers and 11 walkers-with-assistance. Over 95% of TG participants were able to complete items 2-6 (score 1 or 2), which significantly differentiated them from the sitters (50%-92% able across the items). The hip flexion items (item 5 and 6) significantly differentiated the walker, TG and sitter participants (p<0.001 for all pairwise comparisons), with 75/74%, 35/27% and 5/3% scoring a 2 respectively. In items 8, 9, 13, and 14 (supine to side lying, roll supine to prone, roll prone to supine and supine to sit), the TG patients scored the maximum item score in 100, 96, 79 and 40% of assessments respectively, and this was significantly more often (p<0.001 for all items) than the sitters 79, 22, 11, 3% respectively, but not significantly less often than the walkers (100, 98, 96, 69% respectively). As disease modifying treatment continues to evolve, more patients may fit into this TG, which is functionally distinct from sitters and walkers. This work demonstrates better granularity in items on the RHS that are more likely to respond to change with more distinct functional subtypes. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy (SMA) affects individuals with a broad age range and spectrum of disease severity. Risdiplam (EVRYSDI®) is a centrally and peripherally distributed, oral survival of motor neuron 2 (SMN2) pre-mRNA splicing modifier that has been approved in more than 70 countries worldwide. SUNFISH (NCT02908685) is a multicenter, two-part, randomized, placebo-controlled, double-blind study in patients with Types 2 and 3 SMA (inclusion criteria: 2–25 years at enrollment). Part 1 (N=51) assessed the safety, tolerability and pharmacokinetics/pharmacodynamics of different risdiplam dose levels in patients with Types 2 and 3 SMA (ambulant and non-ambulant). Part 2 (N=180) assessed the efficacy and safety of the Part 1-selected dose of risdiplam versus placebo in Type 2 and non-ambulant type 3 SMA. In part 2, participants were treated with risdiplam or placebo for 12 months; all participants then received risdiplam until month 24. At month 24, patients were offered the opportunity to enter the open-label extension phase. The primary outcome of Part 2 was met, showing a statistically significant difference in the change from baseline in 32-item motor function measure total score at month 12 in patients treated with risdiplam (n=120) versus placebo (n=60). The gains observed with risdiplam treatment at month 12 were maintained between months 12 and 36. At month 36, there were no treatment-related safety findings leading to withdrawal. Here we present 36-month efficacy and safety data from SUNFISH. SUNFISH is ongoing and will provide further long-term efficacy and safety data of risdiplam in a broad population of children, teenagers and adults with SMA. [ABSTRACT FROM AUTHOR]

Background: Spinal muscular atrophy is an autosomal recessive neuromuscular disorder that is caused by an insufficient level of survival motor neuron (SMN) protein. Nusinersen is an antisense oligonucleotide drug that modifies pre-messenger RNA splicing of the SMN2 gene and thus promotes increased production of full-length SMN protein.Methods: We conducted a randomized, double-blind, sham-controlled, phase 3 efficacy and safety trial of nusinersen in infants with spinal muscular atrophy. The primary end points were a motor-milestone response (defined according to results on the Hammersmith Infant Neurological Examination) and event-free survival (time to death or the use of permanent assisted ventilation). Secondary end points included overall survival and subgroup analyses of event-free survival according to disease duration at screening. Only the first primary end point was tested in a prespecified interim analysis. To control the overall type I error rate at 0.05, a hierarchical testing strategy was used for the second primary end point and the secondary end points in the final analysis.Results: In the interim analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (21 of 51 infants [41%] vs. 0 of 27 [0%], P<0.001), and this result prompted early termination of the trial. In the final analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (37 of 73 infants [51%] vs. 0 of 37 [0%]), and the likelihood of event-free survival was higher in the nusinersen group than in the control group (hazard ratio for death or the use of permanent assisted ventilation, 0.53; P=0.005). The likelihood of overall survival was higher in the nusinersen group than in the control group (hazard ratio for death, 0.37; P=0.004), and infants with a shorter disease duration at screening were more likely than those with a longer disease duration to benefit from nusinersen. The incidence and severity of adverse events were similar in the two groups.Conclusions: Among infants with spinal muscular atrophy, those who received nusinersen were more likely to be alive and have improvements in motor function than those in the control group. Early treatment may be necessary to maximize the benefit of the drug. (Funded by Biogen and Ionis Pharmaceuticals; ENDEAR ClinicalTrials.gov number, NCT02193074 .). [ABSTRACT FROM AUTHOR]

Risdiplam (EVRYSDI®) is a centrally and peripherally distributed, oral survival of motor neuron 2 (SMN2) pre-mRNA splicing modifier that has been approved in more than 70 countries worldwide. JEWELFISH (NCT03032172) is a multicenter, open-label study that assesses the safety, tolerability and pharmacokinetic/pharmacodynamic (PD) relationship of daily risdiplam in non-treatment-naïve patients with SMA (aged 6 months–60 years at enrollment) who previously received RG7800 (RO6885247), nusinersen (SPINRAZA®), olesoxime or onasemnogene abeparvovec (ZOLGENSMA®). The enrolled population (N=174) included a broad range of ages (1–60 years), SMA types (1–3), SMN2 copy numbers (1–4) and motor functions (non-sitters, sitters and walkers). We previously presented safety data from 173 patients (data cut-off: 29 January 2021) who received risdiplam for up to 47 months. One patient withdrew from the study at baseline; of the remaining patients, 13 previously received RG7800, 76 received nusinersen, 70 received olesoxime and 14 received onasemnogene abeparvovec. Risdiplam treatment led to a rapid and sustained >2-fold increase in SMN protein levels in blood compared with baseline levels (data cut-off: 29 January 2021), consistent with PD data from the SUNFISH (NCT02908685) study of treatment-naïve patients with Types 2/3 SMA. No drug-related safety findings leading to withdrawal were reported for any patients exposed to risdiplam in JEWELFISH at month 12. The risdiplam safety profile was consistent with the safety profile observed in risdiplam treatment-naïve trials. Here we will present the month 24 results from JEWELFISH for the first time. The JEWELFISH study is ongoing at sites across Europe and the USA and is providing important data on the safety and PD of risdiplam in a broad population of non-treatment-naïve patients with SMA. [ABSTRACT FROM AUTHOR]

Nusinersen treatment provides significant functional motor benefit in the chronic forms of spinal muscular atrophy (SMA). Less is known on respiratory outcomes in nusinersen treated patients. Only short-term results on forced vital capacity (FVC) have been reported in heterogeneous treated SMA cohorts. Aim of this study is to evaluate the impact of nusinersen on respiratory function across the iSMAC international cohort of paediatric SMA2 and non-ambulant SMA3 patients (Italian SMA network, US PNCR, UK SMA REACH) when compared to the natural history data (NH) recently published by the consortium. Five-year retrospective study of SMA2 and non-ambulant SMA3 children (age 5-16years) treated with nusinersen within iSMAc centres. We collected lung function expressed as Forced vital capacity absolute and %predicted (FVC %pred), use of non-invasive ventilation (NIV) and cough device. Data was available for 100 patients 81 SMA2, 19 SMA3. Mean (SD) age at first injection was 8(3.3) and 9.4(3.8) years in SMA2 and 3 respectively. Mean disease duration prior to treatment was 7.1(3.3) and 7.3(3.9) years. At first injection 34/65(52%) SMA2 and 2/19 SMA3(11%) were on NIV; 49/65 (75%) SMA2 and 6/20(30%) SMA3 used cough devices. Mean FVC%pred (SD) at first treatment was 53.9(25.8) and 80.6(12.0) respectively. Up to age 13 years, when the respiratory decline is steeper, in treated SMA2 FVC% declined by 2.2%/year vs 4.2% NH, in treated SMA3 FVC% declined by 1.4% vs 6.3%. In the few patients older than 13 years (13 SMA2, 7 SMA3), a clear treatment effect was not detected. One year post treatment 4/36 patients were weaned off NIV, whilst 7, who were self-ventilating at baseline, were established on NIV. This study on the largest cohort of chronic SMA reported so far, confirms the positive role of nusinersen in delaying the respiratory decline in paediatric patients with SMA2 and non-ambulant SMA3 younger than 13 years when compared to natural history. Larger cohorts and longer observation are required to evaluate the role of nusinersen on older patients. [ABSTRACT FROM AUTHOR]

Risdiplam (EVRYSDI®) is a centrally and peripherally distributed, oral survival of motor neuron 2 (SMN2) pre-mRNA splicing modifier that has been approved in more than 70 countries worldwide. FIREFISH (NCT02913482) is a multicenter, open-label, two-part study of risdiplam in infants with Type 1 SMA and two SMN2 gene copies (inclusion criteria: 1–7 months old at enrollment). FIREFISH Part 1 assessed the safety, tolerability and pharmacokinetics/pharmacodynamics of different risdiplam doses. Pivotal Part 2 assessed the safety and efficacy of risdiplam over 24 months at the dose selected from Part 1. Thereafter, infants entered a 3-year open-label extension phase and continue to receive risdiplam at the pivotal dose. Pooled safety and efficacy data were available from 58 enrolled infants who received risdiplam treatment (Part 1 high-dose cohort, n=17; and Part 2, N=41). As of the cut-off date (23 November 2021), there were no treatment-related adverse events leading to withdrawal, no additional deaths and no additional infants meeting the definition of permanent ventilation since Month 24. At Month 36, 84% of infants were alive and did not require permanent ventilation. In FIREFISH, infants have achieved motor milestones not observed in the natural history of Type 1 SMA. Overall, infants have maintained or improved their motor skills in terms of developmental milestones and motor function between Month 24 and Month 36. Here we present longer-term pooled safety and efficacy data from infants who have received risdiplam at the pivotal dose for ≥36 months. FIREFISH Parts 1 and 2 are ongoing globally and will provide further safety and efficacy data of risdiplam in Type 1 SMA. [ABSTRACT FROM AUTHOR]

Nusinersen 12 mg (approved dose) has a positive benefit–risk profile in profile in infants, children, teenagers, and adults with spinal muscular atrophy (SMA). Pharmacokinetic (PK)/pharmacodynamic modeling indicates higher dose nusinersen (2 loading doses of 50 mg 2 weeks apart followed by 28 mg maintenance doses every 4 months) may achieve higher cerebrospinal fluid (CSF) exposure, potentially providing greater benefit than 12mg nusinersen. Population PK modeling shows steady-state CSF nusinersen exposure is similar across a wide range of body weights. Risdiplam is approved for people with SMA age ≥2 months. A subgroup analysis from SUNFISH showed that while risdiplam improved motor function in younger participants (age 2–5 y) with SMA Type II/III, efficacy was lower in those age 6–25 y. Due to the maximum daily dose of 5 mg, lower risdiplam exposure in people weighing >20 kg may limit potential for optimal benefit in these individuals. ASCEND (NCT05067790) is an open-label, single-arm study of higher dose nusinersen in participants with SMA previously treated with risdiplam. ASCEND is enrolling later-onset, non-ambulatory participants with SMA (symptom onset age >6 months) who were previously treated with risdiplam (stopped treatment pre-enrollment) and are either nusinersen-naïve or nusinersen-experienced. Nusinersen-naive participants must be age 5–39 y and have received risdiplam for ≥6 months and ≤12 months pre-enrollment. Nusinersen-experienced participants must be age 18–39 y, have stopped nusinersen for ≥16 months pre-enrollment, and have received risdiplam for ≥12 months and ≤18 months pre-enrollment. Approximately 135 participants enrolled globally will receive higher dose nusinersen for ∼2 y with a visit 4 months after the last nusinersen dose. Endpoints include the Revised Upper Limb Module, safety, and other clinical assessments. ASCEND will evaluate the benefit-risk of higher dose nusinersen in participants with SMA previously treated with risdiplam. [ABSTRACT FROM AUTHOR]

Abstract: The motor skills of patients with spinal muscular atrophy, type I (SMA-I) are very limited. It is difficult to quantify the motor abilities of these patients and as a result there is currently no validated measure of motor function that can be utilized as an outcome measure in clinical trials of SMA-I. We have developed the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (“CHOP INTEND”) to evaluate the motor skills of patients with SMA-I. The test was developed following the evaluation of 26 infants with SMA-I mean age 11.5months (1.4–37.9months) with the Test of Infant Motor Performance and The Children’s Hospital of Philadelphia Test of Strength in SMA, a newly devised motor assessment for SMA. Items for the CHOP INTEND were selected by an expert panel based on item mean and standard deviation, item frequency distribution, and Chronbach’s alpha. Intra-rater reliability of the resulting test was established by test–retest of 9 infants with SMA-I over a 2month period; Intraclass correlation coefficient (ICC) (3,1)=0.96. Interrater reliability was by video analysis of a mixed group of infants with neuromuscular disease by 4 evaluators; ICC (3,4)=0.98 and in a group of 8 typically developing infants by 5 evaluators ICC (3,5)=0.93. The face validity of the CHOP INTEND is supported by the use of an expert panel in item selection; however, further validation is needed. The CHOP INTEND is a reliable measure of motor skills in patients with SMA-I and neuromuscular disorders presenting in infancy. [Copyright &y& Elsevier]

Abstract: The aim of this study was to assess sleep disorders in children with type II SMA. More specifically, we wished to establish a profile of various aspects of sleep behavior and their possible relation with motor functional aspects or the presence of ventilator devices or ortheses used at night time. Fifty children with type II SMA (mean age: 9.5years) were included in the study. All were assessed using the Sleep Disturbance Scale for Children,SDSC, a questionnaire specifically developed to assess a variety of sleep-related behaviors in childhood. The questionnaire provides a total score and subscores related to specific aspects of sleep: Disorders of initiating and maintaining sleep, Sleep breathing disorders, Disorders of arousal, nightmares, Sleep wake transition disorders, Disorders of excessive somnolence, Sleep hyperhydrosis. All the patients were also assessed using Hammersmith Functional Motor Scale (HFMS). 74% of the patients had a total SDSC score within normal limits and 26% had scores that were considered outside the normal range. In a number of patients the total SDSC scores were normal but the subscores on one or more subscales were not and only 17/50 (34%) had normal scores on all the subscales. Sleep hyperhydrosis and disorders of initiating and maintaining sleep were more commonly found to be outside the normal range. We did not find any specific association with the presence of night splints or with functional motor levels. Although all but one of the children with abnormal scores on the sleep questionnaire had low scores on the HFMS the opposite was not always true as a number of other children with similar low scores on the HFMS had normal scores on the questionnaires. Our results suggest that sleep-related behaviors are frequent in type II SMA and they are mainly related to hyperhydrosis. [Copyright &y& Elsevier]

Abstract: In the last few years there has been increasing evidence of possible cardiac involvement in SMA. Severe, symptomatic bradycardia suggesting a possible concomitant autonomic dysfunction have been found in up to 24% of patients affected by type I SMA. A number of children with type I SMA have also been found to have congenital heart defects. These results were mirrored by evidence of bradyarrhythmia with progressive heart block and reduced ventricular depolarization efficiency in the SMNÄ7 SMA mouse model. Evidence of atrial fibrillation, A–V block, atrial flutter and other abnormalities in some patients with the milder form of SMA (type III) has raised the question whether heart function should be routinely investigated in type II and III SMA patients. A recent study has reported no evidence of cardiac abnormalities on echocardiography and standard ECG in 37 patients with type II and III but 24hour ECG were not systematically performed. The aim of this study was to review 24hour Holter ECG in two cohorts including 136 patients of age between 2 and 74years (mean 26.2, and median 25years). The first cohort includes 62 type II and 25 type III SMA patients who had a 24 ECG as part of our clinical routine before starting treatment with albuterol. The second cohort includes 49 adult type III patients from five centers (Milan, Padova, Turin, Messina, Rome) enrolled in a prospective study aimed at establishing the effect of albuterol on SMN transcripts. Patients in the second cohort had a 24 ECG and echocardiography. 24-Hour ECG monitoring was normal in all patients in the two cohorts and none had signs of bradycardia. Echocardiography, assessed in the second cohort, showed no abnormalities. Our results suggest that, despite early reports of cardiac abnormalities in type I and type III SMA and the evidence in animal models, cardiac abnormalities are not common in type II and type III SMA. [Copyright &y& Elsevier]

Abstract: In the last few years there has been increasing evidence of the lack of outcome measures in non ambulant patients affected by Duchenne muscular dystrophy. We report an exploratory study on upper limb function in 61 DMD patients using three measures previously used in DMD and an upper limb module previously developed for spinal muscular atrophy. This study, rather than being a formal suitability study, explored whether the existing scales were appropriate for DMD patients at different ages and spectrum of abilities. The Brooke scale proved to be easily and quickly administered and useful to subdivide patients into motor performance domains but comprises only few categories providing ordinal data and does not specifically assess hand function. The Jebsen Hand Function test is a standardized timed test. Most items are composite tasks that do not take into account compensatory strategies in the scoring system and are biased by testing positions and contractures. Some items proved not to be suitable due to age and IQ dependency. The MFM is a functional scale developed in NMD to assess motor performance. It includes items subdivided in functional domains and also assesses distal function. A floor and ceiling effect were observed in some items across the whole spectrum of abilities and age range. The ULM was developed for non-ambulant SMA patients and evaluates upper limb activities on all planes of workspace. When used in DMD the scoring system and weight bearing did not fully assess patients across spectrum of abilities with a ceiling effect in the stronger ones. Each measure had pros and cons and several shortcomings, related to posture, contractures and pattern of weakness requiring compensatory strategies. None of the existing scales proved to be suitable alone, this probably reflecting the fact that most of them had not been specifically designed for use in DMD. Studies are in progress to overcome some of these difficulties. [Copyright &y& Elsevier]