Spinal muscular atrophy is a rare, autosomal recessive, neuromuscular disease caused by biallelic loss of the survival motor neuron 1 (SMN1) gene, resulting in motor neuron dysfunction. In this ...STR1VE-EU study, we aimed to evaluate the safety and efficacy of onasemnogene abeparvovec gene replacement therapy in infants with spinal muscular atrophy type 1, using broader eligibility criteria than those used in STR1VE-US.
STR1VE-EU was a multicentre, single-arm, single-dose, open-label phase 3 trial done at nine sites (hospitals and universities) in Italy (n=4), the UK (n=2), Belgium (n=2), and France (n=1). We enrolled patients younger than 6 months (180 days) with spinal muscular atrophy type 1 and the common biallelic pathogenic SMN1 exon 7–8 deletion or point mutations, and one or two copies of SMN2. Patients received a one-time intravenous infusion of onasemnogene abeparvovec (1·1 × 1014 vector genomes vg/kg). The outpatient follow-up consisted of assessments once per week starting at day 7 post-infusion for 4 weeks and then once per month until the end of the study (at age 18 months or early termination). The primary outcome was independent sitting for at least 10 s, as defined by the WHO Multicentre Growth Reference Study, at any visit up to the 18 months of age study visit, measured in the intention-to-treat population. Efficacy was compared with the Pediatric Neuromuscular Clinical Research (PNCR) natural history cohort. This trial is registered with ClinicalTrials.gov, NCT03461289 (completed).
From Aug 16, 2018, to Sept 11, 2020, 41 patients with spinal muscular atrophy were assessed for eligibility. The median age at onasemnogene abeparvovec dosing was 4·1 months (IQR 3·0–5·2). 32 (97%) of 33 patients completed the study and were included in the ITT population (one patient was excluded despite completing the study because of dosing at 181 days). 14 (44%, 97·5% CI 26–100) of 32 patients achieved the primary endpoint of functional independent sitting for at least 10 s at any visit up to the 18 months of age study visit (vs 0 of 23 untreated patients in the PNCR cohort; p<0·0001). 31 (97%, 95% CI 91–100) of 32 patients in the ITT population survived free from permanent ventilatory support at 14 months compared with six (26%, 8–44) of 23 patients in the PNCR natural history cohort (p<0·0001). 32 (97%) of 33 patients had at least one adverse event and six (18%) had adverse events that were considered serious and related to onasemnogene abeparvovec. The most common adverse events were pyrexia (22 67% of 33), upper respiratory infection (11 33%), and increased alanine aminotransferase (nine 27%). One death, unrelated to the study drug, occurred from hypoxic-ischaemic brain damage because of a respiratory tract infection during the study.
STR1VE-EU showed efficacy of onasemnogene abeparvovec in infants with symptomatic spinal muscular atrophy type 1. No new safety signals were identified, but further studies are needed to show long-term safety. The benefit–risk profile of onasemnogene abeparvovec seems favourable for this patient population, including those with severe disease at baseline.
Novartis Gene Therapies.
IMPORTANCE: Based on studies with relatively small sample size, fragility fractures are commonly reported in glucocorticoid (GC)-treated boys with Duchenne muscular dystrophy (DMD). OBJECTIVE: To ...determine the fracture burden and growth impairment in a large contemporary cohort of boys with DMD in the United Kingdom and in relation to GC regimen. DESIGN, SETTING, AND PARTICIPANTS: A retrospective review of fracture morbidity and growth from 832 boys with DMD in the UK NorthStar database (2006-2015), which systematically captures information from 23 participating centers. A total of 564 boys had more than 1 visit. No numbers of boys who refused were collected, but informal data from 2 centers in London and from Scotland show that refusal is very low. Data were analyzed between October 2006 and October 2015. MAIN OUTCOMES AND MEASURES: Fracture incidence rate per 10 000 person-years was determined. Cox regression analysis was used to identify factors associated with first fracture. RESULTS: Median age at baseline was 6.9 years (interquartile range, 4.9-7.2 years). At baseline, new fractures were reported in 7 of 564 participants (1.2%). During a median follow-up of 4 years (interquartile range, 2.0-6.0 years), incident fractures were reported in 156 of 564 participants (27.7%), corresponding to an overall fracture incidence rate of 682 per 10 000 person-years (95% CI, 579-798). The highest fracture incidence rate was observed in those treated with daily deflazacort at 1367 per 10 000 person-years (95% CI, 796-2188). After adjusting for age at last visit, mean hydrocortisone equivalent exposure, mobility status, and bisphosphonate use prior to first fracture, boys treated with daily deflazacort had a 18.6-fold increase risk for first fracture (95% CI, 1.7-208.6; P = .02). Using adjusted regression models, change in height standard deviation scores was −1.6 SD lower (95% CI, −3.0 to −0.1; P = .03) in those treated with daily deflazacort compared with GC-naive boys, whereas there were no statistical differences in the other GC regimen. CONCLUSIONS AND RELEVANCE: In this large group of boys with DMD with longitudinal data, we document a high fracture burden. Boys treated with daily deflazacort had the highest fracture incidence rate and the greatest degree of linear growth failure. Clinical trials of primary bone protective therapies and strategies to improve growth in boys with DMD are urgently needed, but stratification based on GC regimen may be necessary.
Functional variability among boys with Duchenne muscular dystrophy (DMD) is well recognised and complicates interpretation of clinical studies. We hypothesised that boys with DMD could be clustered ...into groups sharing similar trajectories of ambulatory function over time, as measured by the North Star Ambulatory Assessment (NSAA) total score. We also explored associations with other variables such as age, functional abilities, and genotype. Using the NorthStar Clinical Network database, 395 patients with >1 NSAA assessment were identified. We utilised latent class trajectory analysis of longitudinal NSAA scores, which produced evidence for at least four clusters of boys sharing similar trajectories versus age in decreasing order of clinical severity: 25% of the boys were in cluster 1 (NSAA falling to ≤ 5 at age ~10y), 35% were in cluster 2 (NSAA ≤ 5 ~12y), 21% in were cluster 3 (NSAA≤ 5 ~14y), and 19% in cluster 4 (NSAA > 5 up to 15y). Mean ages at diagnosis of DMD were similar across clusters (4.2, 3.9, 4.3, and 4.8y, respectively). However, at the first NSAA assessment, a significant (p<0.05) association was observed between earlier declining clusters and younger age, worse NSAA, slower rise from supine, slower 10 metre walk/run times, and younger age of steroid initiation. In order to assess the probability of observing complete loss of function for individual NSAA items, we examined the proportion of patients who shifted from a score of 1 or 2 at baseline to a score of 0. We also assessed the probability of gain of function using the inverse assessment and stratified the probability of deterioration, improvement-or static behavior-by age ranges and using baseline functional status. Using this tool, our study provides a comprehensive assessment of the NSAA in a large population of patients with DMD and, for the first time, describes discrete clusters of disease progression; this will be invaluable for future DMD clinical trial design and interpretation of findings.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The UK Facioscapulohumeral Muscular Dystrophy (FSHD) Patient Registry is a patient self-enrolling online database collecting clinical and genetic information about FSHD type 1 (FSHD1) and type 2 ...(FSHD2). The registry was established in May 2013 with support from Muscular Dystrophy UK and is coordinated by Newcastle University. The registry aims to facilitate academic and clinical research, better characterise and understand FSHD, collect patient voice, and to disseminate information relating to upcoming studies and research advancements. The registry also collects real-world evidence and supports data enquiries from industry. The registry captures longitudinal, self-reported data through an online portal available to patients and clinicians. Where specialised clinical or genetic information is required, the neuromuscular specialist involved in the patient's care can be invited to provide some additional information and the patient can select them from a pre-populated list at the registration stage. The registry is a Core Member of the TREAT-NMD Global Registries Network for FSHD. As of March 2023, there were 906 active, UK based patient registrations. For those reporting a clinical diagnosis, 95.4% have FSHD or FSHD1, and 3.3% have FSHD2. Currently, 58% of patients have had genetic confirmation of their condition. In addition to collecting specific genetic data inputted by clinicians, the registry is now able to receive digital copies of patient's genetic reports directly via a secure upload portal. The registry has supported 32 registry enquiries to date, recent examples including supporting a Health Economics and Outcomes project, patient preference studies, and surveys capturing information on dysphagia, pregnancy, sleep and the patient/caregiver experience. The registry is currently one of the largest national FSHD patient registries and is an example of a versatile, cost-effective research tool, helping facilitate and advance a wide range of FSHD research. Additional work continues to be done to improve reporting of genetic information on the registry, and to facilitate the collection of patient reported outcome measures and trial preferences. There are also future data linkage plans between the registry and the Newcastle Research Biobank for Rare and Neuromuscular Diseases, to support real world evidence data collection.
There is increasing evidence suggesting that exercise is safe and might be beneficial for patients with neuromuscular disorders (NMD). The aim of this clinical audit was to establish the proportion ...of patients with a NMD and followed up at the John Walton Muscular Dystrophy Research Centre that perform aerobic, resistance and stretching exercise. We also sought to establish if there were any associations between cohorts of different diagnoses and compliance with guidelines and whether mobility status and presence of pain were significant factors for aerobic exercise exposure. Data was gathered from 664 patients with a variety of NMD over a 12-month period using the Rapid Assessment of Physical Activity (RAPA) questionnaire, administered as part of the routine clinical assessment. In addition to the RAPA, information about overall mobility was collected using the summary of functional tasks (SOFT) scale. Presence of pain was also recorded. We found that only 8% of our patients were meeting the national guidelines for aerobic exercise although 27% were partially meeting the guidelines. We found no association with compliance to these guidelines for aerobic exercise and the diagnostic subsets. We did, however, find a significant association between compliance to aerobic exercise guidelines and mobility status and the presence of pain. Patients with greater motor ability and patients without current pain were more likely to comply with government guidelines. These results suggest that there is a great need to increase general activity levels among all patients with NMD and to consider the opportunities and barriers existing for those with lower levels of mobility, particularly wheelchair users. We also found that resistance exercise was the least performed type of exercise among our patients.
Most neuromuscular disorders (NMD) are characterised by progressive muscle weakness which may result in loss of ambulation. Capturing patients’ Health-related Quality of Life (HRQoL) together with ...their functional abilities can help identify potential factors of reduced HRQoL. Understanding the relationship between HRQoL and motor function can guide care management discussions, target problematic areas of care, and identify potential gaps in existing specialist and community services. This study aims to quantify HRQoL in adult patients with a NMD, and to explore the interaction between diagnoses, mobility status and HRQoL. Adult patients with a NMD were asked to fill in The Quality of Life Measure for people with slowly progressive and genetic neuromuscular disease (QOL-gNMD), via an online portal, prior to attending their routine clinical appointment at the John Walton Muscular Dystrophy Research Centre in Newcastle, U.K. During the clinical visit, physiotherapists administered the Summary of Function Test (SOFT), which describes levels of overall mobility, arm function, ability to rise from floor, ability to get up from the floor or from a chair, and ability to manage stairs. Over 500 adult patients (male=58%, female=42%; aged 18-89 years, mean=46 years) have been included in the study, with responses collected between 2019 to 2023. This includes patients with 53 different neuromuscular diagnoses. Preliminary data shows that wheelchair users reported better health and HRQoL, compared to those who are still ambulant but require walking aids to mobilise outside the home. There was variability in reported HRQoL between diagnoses. This is particularly evident when looking at specific domains of HRQoL.
The UK Myotonic Dystrophy Patient Registry is a patient self-enrolling online database collecting clinical and genetic information about myotonic dystrophy type 1 (DM1) and type 2 (DM2). The registry ...was established in May 2012 by Newcastle University and is supported by Muscular Dystrophy UK, Cure-DM and the Myotonic Dystrophy Support Group. The registry facilitates academic and clinical research, enables better characterisation and understanding of DM, and disseminates information relating to upcoming studies and research advancements to participants. The registry is used to capture longitudinal, self-reported data through an online portal available to patients and clinicians. Where specialised clinical or genetic information is available, the neuromuscular specialist involved in the patient's care can provide some additional data. The registry is a Core Member of the TREAT-NMD Global Registries Network for DM1, collecting the standardised dataset and contributing to global data enquiries. As of April 2023, there are 844 active patient registrations. For those reporting a clinical diagnosis, 95% have DM1 (of which 12% report a diagnosis of congenital DM) and 5% report DM2. Overall, 40% of patients have genetic confirmation of their condition. The registry has successfully assisted with recruitment to clinical trials and has supported over 30 research enquiries to date. These include anonymised data reports to industry, and academic research surveys into topics including COVID-19, dysphagia, pregnancy, patient preferences for future treatments and the patient/caregiver experience. The registry continues to be a versatile, cost-effective research tool to facilitate and advance a range of DM research. Additional work continues to be done to improve reporting of genetic information on the registry, and to overcome perceived boundaries to registration and participation.
The UK SMA Patient Registry collects patient-reported outcome measures (PROMs) from individuals living with spinal muscular atrophy (SMA) in the UK and Ireland. In 2022, PROMs collection was ...introduced in the registry to supplement clinical and genetic data held therein. PROMs capture the perspectives of adults and caregivers of young people living with SMA about the impact of their condition and treatment, their quality of life and activities of daily living. Importance of the patient voice is increasingly recognised and valued. Currently, SMA therapies Nusinersen and Risdiplam are available in the UK via managed access agreements (MAAs). The collection of clinical and patient-reported data will inform review of treatment impact by UK regulatory authorities. In collaboration with clinical networks Adult SMA REACH and SMA REACH UK, the registry aims to collect PROMs data of 100 Nusinersen and 100 Risdiplam patients. PROMs will be aligned with SMA REACH clinical data, anonymised, analysed and submitted to regulatory authorities for consideration as part of the treatment MAAs. Registration in the UK SMA Patient Registry is patient-initiated through a secure online portal. Patients are invited to complete questionnaires about their condition and PROMs: EQ-5D-5L; Patient Global Impression of Change; SMA Independence Scale (SMAIS-ULM); and a free-text box. Enabled through patient consent and data sharing agreements, patient-level PROMs data is shared with each patient's SMA REACH clinic and with the SMA REACH coordination teams. In clinic, the data informs patient care. At project coordination level, PROMs are aligned with clinical data collected by SMA REACH. The registry has 641 participants: 429 adult (16+years); 212 paediatric (<16years). PROMs have been completed by 153 adults and by the caregivers of 62 paediatric patients. The fraction of PROMs able to be aligned with SMA REACH clinical data is growing and will be presented. The UK SMA Patient Registry represents a trial-ready cohort of individuals and is a valuable tool for the collection of SMA natural history data from treated and treatment-naïve patients. Expansion of the registry to collect PROMs supports UK SMA data collection and supplements SMA REACH clinical data, assisting in therapy evaluation by regulatory authorities.
Motor function in spinal muscular atrophy (SMA) is assessed using several physiological measures, including the Hammersmith Functional Motor Scale Extended (HFMSE) and the newer Revised Hammersmith ...Scale (RHS). Factors such as SMA type, sex and scoliosis affect the trajectory of the HFMSE. In this study, we present trajectories for the RHS, contextualised using the HFMSE, in an international cohort of 149 treatment naïve paediatric SMA 2 and 3 patients. We analysed 531 assessments collected between 2015 and 2019. At baseline, of the 96 SMA 2’s, 18 were non-sitters, 74 sitters and 4 transitioners (i.e. crawlers, standers, or walkers with assistance) and of the 53 SMA 3’s, 1 was a sitter, 5 transitioners and 37 walkers. Spinal fusion was observed in 15% of participants. Patient trajectories were modelled using a random intercept natural cubic spline with age. Over time, there is no significant difference between the sexes in either the RHS or HFMSE in the SMA 2 population (p=0.10 and p=0.13 respectively). In the SMA 2’s, the average peak RHS of 13 and 12 was achieved between 3.3-6.1 years and 4.1-6.8 years in females and males respectively, whilst the average peak HFMSE of 19 and 17 was achieved between 3.6-5.6 years and 4.3 -6.4 years in females and males respectively. In the SMA 3a's, the average peak RHS of 44 and 48 was achieved between 5.8-7.7 and 7.3-9.9 years in females and males respectively. In the SMA 3a's, the average peak HFMSE of 49 and 52 was achieved between the age of 5.7-7.6 and 8.2-10.1 years in females and males respectively, and this was significant (p=0.02). Scoliosis surgery was associated with a reduction of in the RHS and HFMSE total in the SMA 2 (3 and 5 points respectively) and SMA 3a (12 and 13 points respectively) populations. When considered longitudinally, the RHS captures a similar trajectory to the HFMSE, across age, SMA Type, and gender. However, the impact of scoliosis surgery on the trajectories is markedly lower in the RHS.
PDF
