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.
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.
Percentages of regularly followed patients and newcomers.
Over the past few years, the field of medicine has witnessed significant advances in the treatment of Spinal Muscular Atrophy (SMA) with the approval of three disease-modifying drugs worldwide. ...However, little is known about the role that various clinical variables could play in contributing to the overall phenotype. To explore this possibility, we will employ a novel machine learning-based approach, which involves the development of a predictive algorithm using retrospective data from treated SMA patients. The study underway aims to gather data from patients with SMA, including those afflicted with SMA I, II, III, and pre-symptomatic cases, whether or not they have already received treatment. The inclusion of data from a broad range of SMA patients will provide researchers with a more comprehensive understanding of the disease and increase the potential of the machine learning algorithm to predict therapeutic response. The ultimate goals are to identify novel biomarkers associated with the disease, to develop personalized treatments and to improve the management of patients with SMA. The data collected will consist of clinical, biological, and Patient Reported Outcome Measures (PROMs) data. The clinical data will include information about patients' demographics, medical history, neurological assessment, motor function measures and laboratory results. PROMs will be collected using standardized questionnaires to assess patient-reported outcomes, such as the PEDI-CAT, SMA-HI and other. Additionally, the RNA molecular signature profiling will be carried out using Next-Generation Sequencing (NGS) to identify possible novel biomarkers. Machine learning algorithms are proving to be useful tools in predicting individual responses to treatments and interpreting outcomes. By leveraging the power of machine learning, researchers hope to identify patterns and associations within the large amounts of data being collected, leading to new potential treatment approaches. The machine learning algorithm can perform clinical predictions and provide an insight into the biological mechanisms behind the disease progression. The use of machine learning algorithms in SMA research represents a significant shift towards personalized medicine. The ability to predict individual responses to treatments can lead to the development of tailored treatments that cater to the specific needs of each patient. This, in turn, could improve the quality of life for SMA patients, enhance the efficiency of clinical trials, already-approved treatments, and reduce healthcare costs. In conclusion, the study underway seeks to collect data from SMA patients to investigate the potential use of machine learning algorithms in predicting individual responses to treatments, identifying novel biomarkers, and molecular signatures associated with the disease. This novel approach has the potential to offer a better understanding of the disease and support the development of personalized treatments for individual patients. Ultimately, the use of machine learning algorithms in SMA research could lead to better outcomes for patients and enable more efficient use of healthcare resources.
The purpose of this pictorial essay is to present the computed tomography (CT) and magnetic resonance imaging (MRI) findings of Wernicke’s encephalopathy, a rare, severe, acute neurological syndrome ...due to thiamine (vitamin B1) deficiency, associated with high morbidity and mortality. The classical clinical triad, which includes ocular signs, altered consciousness and ataxia, can be found in only one-third of patients. Although chronic alcoholic patients are the most commonly affected, Wernicke’s encephalopathy may complicate malnutrition conditions in nonalcoholic patients, in whom it is greatly underestimated. CT and above all MRI of the brain play a fundamental role in diagnosing the condition and ruling out other diseases. MRI is the most sensitive technique and is required in all patients with a clinical suspicion of Wernicke’s encephalopathy. Medial thalami, mamillary bodies, tegmentum, periaqueductal region, and tectal plate are typical sites of abnormal MRI signal. The dorsal medulla, red nuclei, cranial nerve nuclei, cerebellum, corpus callosum, frontal and parietal cerebral cortex are less common sites of involvement although they are more frequently affected in nonalcoholic patients. Paramagnetic contrast material may help to identify lesions not otherwise visible.
The Performance of Upper Limb (PUL) module measures upper limb motor performance in ambulant and non-ambulant DMD. Two versions of the PUL exist: the originally developed version (PUL 1.2) and a ...revised version (PUL 2.0). While PUL 2.0 is currently in broader use in clinical trials and practice, prior studies contain extensive historical data on PUL 1.2. A cross-walk between PUL 1.2 and PUL 2.0 is needed to make full use of historical data, e.g., for contextualization of outcomes in clinical trials and across periods of natural history. In this study, using data from 1137 visits from 208 patients in the DMD Italian Group database, we applied machine learning (LASSO) to predict PUL 2.0 total and domain scores from concurrently measured PUL 1.2 item scores. Models were fit in a training sample (858 visits, 166 patients) and predictions were evaluated in a held-out validation sample (279 visits, 42 patients). Mean age of patients at 1st visit in the training sample was 11.4 years; 64% of included patients were ambulatory at their 1st visit. In the held-out sample, PUL 1.2 item scores explained 98% of the variation in PUL 2.0 total scores, and the prediction error was 1.76 units; explained variation exceeded 95% for the shoulder, mid, and distal domain scores shoulder with prediction errors <1.1 units. These results are promising for accurate prediction of PUL 2.0 total scores from PUL 1.2 item scores and harmonization of PUL outcomes across multiple data sources. Future analyses are needed to benchmark prediction accuracy against the standard error of measurement of PUL 2.0 and to validate performance in an external data source.
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.
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.
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