Longitudinal developmental profile of newborns and toddlers treated for spinal muscular atrophy.

Background: Spinal muscular atrophy (SMA) results from a loss-of-function mutation in the SMN1 gene. SMA patients suffer progressive motor disability, although no intellectual impairments have been described. Three drugs have been recently approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). These drugs result in longer life expectancy for SMA type 1 (SMA1) patients. Objective: The objective of the study was to assess longitudinally the psychomotor development of patients with SMA1 treated after the symptom onset and of patients treated presymptomatically. Design: Longitudinal, monocentric, noninterventional, prospective study. Methods: Our study included 11 SMA1 patients and seven presymptomatic SMA patients. The SMA1 patients were treated with an approved drug beginning after onset of symptoms; treatment for the presymptomatic patients was begun before symptom onset. They were longitudinally evaluated between September 2018 and January 2022 using the Bayley Scales of Infant and Toddler Development™ - Third Edition. Results: At each time point, all patients treated presymptomatically scored above those treated postsymptomatically on the motor scale. The cognitive scores of six of the seven patients treated presymptomatically were average; one patient was in the low average range. In the 11 postsymptomatically treated patients, four scored either in the low average or the abnormal range on the cognitive scale, but a positive trend was observed during the follow-up. Conclusion: A significant proportion of patients treated postsymptomatically scored below average on cognitive and communicative scales, with most significant concerns raised about the age of 1 year. Our study indicates that intellectual development should be considered as an important outcome in treated SMA1 patients. Cognitive and communicative evaluations should be performed as part of standard of care, and guidance should be provided to parents for optimal stimulation.

Successful integration of newborn genetic testing into UK routine screening using prospective consent to determine eligibility for clinical trials.

OBJECTIVE: INGR1D (INvestigating Genetic Risk for type 1 Diabetes) was a type 1 diabetes (T1D) genetic screening study established to identify participants for a primary prevention trial (POInT, Primary Oral Insulin Trial). METHODS: The majority of participants were recruited by research midwives in antenatal clinics from 18 weeks' gestation. Using the NHS Newborn Bloodspot Screening Programme (NBSP) infrastructure, participants enrolled in INGR1D had an extra sample taken from their day 5 bloodspot card sent for T1D genetic screening. Those at an increased risk of T1D were informed of the result, given education about T1D and the opportunity to take part in POInT. RESULTS: Between April 2018 and November 2020, 66% of women approached about INGR1D chose to participate. 15 660 babies were enrolled into INGR1D and 14 731 blood samples were processed. Of the processed samples, 157 (1%) had confirmed positive results, indicating an increased risk of T1D, of whom a third (n=49) enrolled into POInT (20 families were unable to participate in POInT due to COVID-19 lockdown restrictions). CONCLUSION: The use of prospective consent to perform personalised genetic testing on samples obtained through the routine NBSP represents a novel mechanism for clinical genetic research in the UK and provides a model for further population-based genetic studies in the newborn.

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.

First Regulatory Qualification of a Novel Digital Endpoint in Duchenne Muscular Dystrophy: A Multi-Stakeholder Perspective on the Impact for Patients and for Drug Development in Neuromuscular Diseases

Background: Functional outcome measures used to assess efficacy in clinical trials of investigational treatments for rare neuromuscular diseases like Duchenne muscular dystrophy (DMD) are performance-based tasks completed by the patient during hospital visits. These are prone to bias and may not reflect motor abilities in real-world settings. Digital tools, such as wearable devices and other remote sensors, provide the opportunity for continuous, objective, and sensitive measurements of functional ability during daily life. Maintaining ambulation is of key importance to individuals with DMD. Stride velocity 95th centile (SV95C) is the first wearable acquired digital endpoint to receive qualification from the European Medicines Agency (EMA) to quantify the ambulation ability of ambulant DMD patients aged ≥5 years in drug therapeutic studies;it is also currently under review for the US Food and Drug Administration (FDA) qualification. Summary: Focusing on SV95C as a key example, we describe perspectives of multiple stakeholders on the promise of novel digital endpoints in neuromuscular disease drug development.

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.