Pooled safety data from the risdiplam clinical development programme

Risdiplam (EVRYSDI®) is a centrally and peripherally distributed, oral survival of motor neuron 2 (SMN2) premRNA splicing modifier approved by the EMA and MHRA for the treatment of patients aged ≥2 months, with a clinical diagnosis of Type 1, 2 or 3 spinal muscular atrophy (SMA) or 1–4 copies of SMN2.Safety data were pooled from three studies within the risdiplam clinical development programme:FIREFISH (NCT02913482) assesses safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of risdiplam in infants with Type 1 SMASUNFISH (NCT02908685) assesses safety, tolerability, PK, PD and efficacy of risdiplam in patients with Types 2/3 SMAJEWELFISH (NCT03032172) assesses safety, tolerability, PK and PD of risdiplam in patients who previously received RG7800 (RO6885247), nusinersen (SPINRAZA®), olesoxime or onasemnogene abeparvovec (ZOLGENSMA®).Pooled analyses from FIREFISH, SUNFISH and JEWELFISH showed no treatment-related safety findings leading to withdrawal from risdiplam in 465 patients treated for up to 38.9 months (data-cut-offs: 14 November 2019, 15 January 2020 and 31 January 2020, respectively). The differences in adverse event profiles between Type 1 and Types 2/3 SMA populations appeared to be driven by the severity of the underlying disease. Here we will present updated pooled safety analyses for the risdiplam studies.

Pregnancy-related psychopathology: A comparison between pre-COVID-19 and COVID-19-related social restriction periods.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic impacted in a still undefined way pregnant women's mental health. There are reports of mood and affect changes in the general population and the suggestion that similar changes occur also in the pregnant population. The greater vulnerability of women during the COVID-19 restriction period may translate into a greater risk for mental disorders in the gestational period. We hypothesised that pregnant women in the pre-pandemic period would have less psychopathology and more psychological support than pregnant women during the pandemic restriction period. AIM: To compare pregnant women for anxiety, prenatal depression, psychopathology, and social support before and after the awareness of the pandemic. METHODS: We administered to women willing to participate in their 2nd-3rd trimesters of pregnancy the Edinburgh Postnatal Depression Scale (EPDS), the State-Trait Anxiety Inventory Form Y (STAI-Y), and the Symptom CheckList-90-Revised (SCL-90R); we further collected sociodemographic variables and explored women's social support. The comparison was cross-sectional. The first sample was termed nonCOVID-19 because data were gathered before the COVID-19 outbreak (January 2020-February 2020) was declared, and the second sample termed COVID-19 because participants were already subjected to the COVID-19-related restrictive measures (January 2021-February 2021). Since normal distribution was not met (Shapiro-Wilk test applied), we applied nonparametric Mann-Whitney's U-test to compare psychometric tests. Ethical standards were met. RESULTS: The nonCOVID-19 group reported higher support from partners only, while the COVID-19 group reported multiple support (χ 2 = 9.7181; P = 0.021); the nonCOVID-19 group scored higher than the COVID-19 group only on state anxiety among psychometric scales [STAI-Y1, nonCOVID-19 median = 39 (95%CI: 39.19-51.10) vs COVID-19 median= 32 (95%CI: 30.83-38.90); Mann-Whitney's U=117.5, P = 0.00596]. Other measures did not differ meaningfully between the two groups. Scores on the EPDS, the state and trait subscales of the STAI-Y, and most SCL-90R subscales inter-correlated with one another. The anxiety component of the EPDS, EPDS-3A, correlated poorly with other measures, while it was the Global Symptom Index of the SCL-90-R that correlated most strongly with most measures. Our results are at odds with most literature and do not confirm increased depression and anxiety rates in pregnant women during the pandemic. CONCLUSION: The ability of pregnant women to deal with novel generalised threats involves mobilization of inner resources. Increasing sources of social support may have produced anxiolysis in the COVID-19 sample.

Nusinersen efficacy data for 24-month in type 2 and 3 spinal muscular atrophy.

The study reports real world data in type 2 and 3 SMA patients treated for at least 2 years with nusinersen. Increase in motor function was observed after 12 months and during the second year. The magnitude of change was variable across age and functional subgroup, with the largest changes observed in young patients with higher function at baseline. When compared to natural history data, the difference between study cohort and untreated patients swas significant on both Hammersmith Functional Motor Scale and Revised Upper Limb Module both at 12 months and at 24 months.

The social smile in infants during the COVID-19 pandemia.

The emergency created by Coronavirus disease 2019 (COVID-19) has inevitably changed human normal social and relational habits. The use of personal protective equipment, like surgical masks, by healthcare workers has been recommended to prevent human-to-human transmission of the novel coronavirus infection. However, the use of these masks could cause slight to considerable and reproducible changes in the infant's attitude towards the operator and health taker during routine clinical assessments. We reported a brief report on the impact of to the use of the surgical masks on the affective behaviour in 40 infants of age 2-9 months (study group) by using a scale to assess pain and distress among pediatric patients, the Face, Legs, Activity Cry and Consolability Scale (FLACC), and in 40 infants with the same ages and characteristics assessed before the COVID-19 pandemia onset (control group). Thirty-seven of the 40 infants in the study group had some signs of discomfort and appeared irritable and less prone to be engaged by the examiner with a different pattern of responses related to age with better responses for younger infants. These infants reported higher significant scores (p < 0.001) in the FLACC scale than those assessed before the COVID-19 onset. Infants appear to react negatively to the use of the surgical mask by the health operator. A different way to assess paediatric patients in early infancy with longitudinal studies should be proposed.

Nusinersen in pediatric and adult patients with type III spinal muscular atrophy.

OBJECTIVE: We report longitudinal data from 144 type III SMA pediatric and adult patients treated with nusinersen as part of an international effort. METHODS: Patients were assessed using Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM), and 6-Minute Walk Test (6MWT) with a mean follow-up of 1.83 years after nusinersen treatment. RESULTS: Over 75% of the 144 patients had a 12-month follow-up. There was an increase in the mean scores from baseline to 12 months on both HFMSE (1.18 points, p = 0.004) and RULM scores (0.58 points, p = 0.014) but not on the 6MWT (mean difference = 6.65 m, p = 0.33). When the 12-month HFMSE changes in the treated cohort were compared to an external cohort of untreated patients, in all untreated patients older than 7 years, the mean changes were always negative, while always positive in the treated ones. To reduce a selection bias, we also used a multivariable analysis. On the HFMSE scale, age, gender, baseline value, and functional status contributed significantly to the changes, while the number of SMN2 copies did not contribute. The effect of these variables was less obvious on the RULM and 6MWT. INTERPRETATION: Our results expand the available data on the effect of Nusinersen on type III patients, so far mostly limited to data from adult type III patients.

Contactless: a new personalised telehealth model in chronic pediatric diseases and disability during the COVID-19 era.

BACKGROUND: Suspending ordinary care activities during the COVID-19 pandemic made it necessary to find alternative routes to comply with care recommendations not only for acute health needs but also for patients requiring follow-up and multidisciplinary visits. We present the 'Contactless' model, a comprehensive operational tool including a plurality of services delivered remotely, structured according to a complexity gradient, aimed to cover diagnostic procedures and monitor disease progression in chronic pediatric patients. METHODS: A multidisciplinary and multiprofessional project team was recruited, in collaboration with patients' associations, to map a panel of available Evidence-Based solutions and address individual needs in full respect of the concept of personalized medicine. The solutions include a number of services from videoconsultations to more structure videotraining sessions. RESULTS: A modular framework made up of four three Macro-levels of complexity - Contactless Basic, Intermediate and Advanced - was displayed as an incremental set of services and operational planning establishing each phase, from factors influencing eligibility to the delivery of the most accurate and complex levels of care. CONCLUSION: The multimodal, multidisciplinary 'Contactless' model allowed the inclusion of all Units of our Pediatric Department and families with children with disability or complex chronic conditions. The strengths of this project rely on its replicability outside of pediatrics and in the limited resources needed to practically impact patients, caregivers and professionals involved in the process of care. Its implementation in the future may contribute to reduce the duration of hospital admissions, money and parental absence from work.

Children's Healthcare During Corona Virus Disease 19 Pandemic: the Italian Experience.

The unexpected outbreak of Corona Virus Disease 19 had several consequences worldwide and on the Italian Health System. We report our experience in the reorganization of our Pediatric Department to prevent the risk of infection for both children and staff. We strongly believe that the need to face an unpredictable emergency situation should not affect the quality of the assistance to the non-Corona Virus Disease patients.

Estimating the impact of COVID-19 pandemic on services provided by Italian Neuromuscular Centers: an Italian Association of Myology survey of the acute phase.

INTRODUCTION: Since February 2020, the outbreak of COVID-19 in Italy has forced the health care system to undergo profound rearrangements in its services and facilities, especially in the worst-hit areas in Northern Italy. In this setting, inpatient and outpatient services had to rethink and reorganize their activities to meet the needs of patients during the "lockdown". The Italian Association of Myology developed a survey to estimate the impact of these changes on patients affected by neuromuscular disorders and on specialized neuromuscular centers during the acute phase of COVID-19 pandemic. METHODS: We developed an electronic survey that was sent to neuromuscular centers affiliated with the Italian Association of Myology, assessing changes in pharmacological therapies provision, outpatient clinical and instrumental services, support services (physiotherapy, nursing care, psychological support) and clinical trials. RESULTS: 40% of surveyed neuromuscular centers reported a reduction in outpatient visit and examinations (44.5% of centers in Northern regions; 25% of centers in Central regions; 50% of centers in Southern regions). Twenty-two% of centers postponed in-hospital administration of therapies for neuromuscular diseases (23.4% in Northern regions; 13.0% in Central regions; 20% in Southern regions). Diagnostic and support services (physiotherapy, nursing care, psychological support) were suspended in 57% of centers (66/43/44% in Northern, Central and Southern centers respectively) Overall, the most affected services were rehabilitative services and on-site outpatient visits, which were suspended in 93% of centers. Strategies adopted by neuromuscular centers to overcome these changes included maintaining urgent on-site visits, addressing patients to available services and promoting remote contact and telemedicine. CONCLUSIONS: Overall, COVID-19 pandemic resulted in a significant disruption of clinical and support services for patients with neuromuscular diseases. Despite the efforts to provide telemedicine consults to patients, this option could be promoted and improved further. A close collaboration between the different neuromuscular centers and service providers as well as further implementation of telehealth platforms are necessary to ensure quality care to NMD patients in the near future and in case of recurrent pandemic waves.

Spinal muscular atrophy care in the COVID-19 pandemic era.

The coronavirus disease 2019 (COVID-19) pandemic has resulted in reorganization of healthcare settings affecting the delivery of clinical care to patients with spinal muscular atrophy (SMA). There is a concern that patients with SMA may be at increased risk of manifesting severe symptoms of COVID-19. Currently approved therapies for SMA improve survival and motor function; however, their delivery requires an increased exposure to the health system and a dedicated healthcare team. In this study, we discuss consensus recommendations pertaining to care of SMA patients during the pandemic. We highlight that SMA treatments should not be perceived as elective. Decisions regarding the delay of treatments should be made with consideration of the potential risks of COVID-19 exposure and the risk of that delay. We emphasize the importance of collaborative treatment decisions between the patient, family, and healthcare provider, considering any geographic- or institution-specific policies and precautions for COVID-19.