Vamorolone is a synthetic steroidal drug with potent anti-inflammatory properties. Initial open-label, multiple ascending dose-finding studies of vamorolone among boys with Duchenne muscular ...dystrophy (DMD) found significant motor function improvement after 6 months treatment in higher-dose (ie, ≥2.0 mg/kg/d) groups.
To investigate outcomes after 30 months of open-label vamorolone treatment.
This nonrandomized controlled trial was conducted by the Cooperative International Neuromuscular Research Group at 11 US and non-US study sites. Participants were 46 boys ages 4.5 to 7.5 years with DMD who completed the 6-month dose-finding study. Data were analyzed from July 2020 through November 2021.
Participants were enrolled in a 24-month, long-term extension (LTE) study with vamorolone dose escalated to 2.0 or 6.0 mg/kg/d.
Change in time-to-stand (TTSTAND) velocity from dose-finding baseline to end of LTE study was the primary outcome. Efficacy assessments included timed function tests, 6-minute walk test, and NorthStar Ambulatory Assessment (NSAA). Participants with DMD treated with glucocorticoids from the Duchenne Natural History Study (DNHS) and NorthStar United Kingdom (NSUK) Network were matched and compared with participants in the LTE study receiving higher doses of vamorolone.
Among 46 boys with DMD who completed the dose-finding study, 41 boys (mean SD age, 5.33 0.96 years) completed the LTE study. Among 21 participants treated with higher-dose (ie, ≥2.0 mg/kg/d) vamorolone consistently throughout the 6-month dose-finding and 24-month LTE studies with data available at 30 months, there was a decrease in mean (SD) TTSTAND velocity from baseline to 30 months (0.206 0.070 rises/s vs 0.189 (0.124) rises/s), which was not a statistically significant change (-0.011 rises/s; CI, -0.068 to 0.046 rises/s). There were no statistically significant differences between participants receiving higher-dose vamorolone and matched participants in the historical control groups receiving glucocorticoid treatment (75 patients in DNHS and 110 patients in NSUK) over a 2-year period in NSAA total score change (0.22 units vs NSUK; 95% CI, -4.48 to 4.04; P = .92), body mass index z score change (0.002 vs DNHS SD/mo; 95% CI, -0.006 to 0.010; P = .58), or timed function test change. Vamorolone at doses up to 6.0 mg/kg/d was well tolerated, with 5 of 46 participants discontinuing prematurely and for reasons not associated with study drug. Participants in the DNHS treated with glucocorticoids had significant growth delay in comparison with participants treated with vamorolone who had stable height percentiles (0.37 percentile/mo; 95% CI, 0.23 to 0.52 percentile/mo) over time.
This study found that vamorolone treatment was not associated with a change in TTSTAND velocity from baseline to 30 months among boys with DMD aged 4 to 7 years at enrollment. Vamorolone was associated with maintenance of muscle strength and function up to 30 months, similar to standard of care glucocorticoid therapy, and improved height velocity compared with growth deceleration associated with glucocorticoid treatment, suggesting that vamorolone may be an attractive candidate for treatment of DMD.
ClinicalTrials.gov Identifier: NCT03038399.
Real-world data on the efficacy and safety of onasemnogene abeparvovec (OA) in spinal muscular atrophy (SMA) are needed, especially to overcome uncertainties around its use in older and heavier ...children. This study evaluated the efficacy and safety of OA in patients with SMA type 1 in the UK, including patients ≥2 years old and weighing ≥13.5 kg.
This observational cohort study used data from patients with genetically confirmed SMA type 1 treated with OA between May 2021 and January 2023, at 6 infusion centres in the United Kingdom. Functional outcomes were assessed using age-appropriate functional scales. Safety analyses included review of liver function, platelet count, cardiac assessments, and steroid requirements.
Ninety-nine patients (45 SMA therapy-naïve) were treated with OA (median age at infusion: 10 range, 0.6–89 months; median weight: 7.86 range, 3.2–20.2 kg; duration of follow-up: 3–22 months). After OA infusion, mean ± SD change in CHOP-INTEND score was 11.0 ± 10.3 with increased score in 66/78 patients (84.6%); patients aged <6 months had a 13.9 points higher gain in CHOP-INTEND score than patients ≥2 years (95% CI, 6.8–21.0; P < 0.001). Asymptomatic thrombocytopenia (71/99 patients; 71.7%), asymptomatic troponin-I elevation (30/89 patients; 33.7%) and transaminitis (87/99 patients; 87.9%) were reported. No thrombotic microangiopathy was observed. Median steroid treatment duration was 97 (range, 28–548) days with dose doubled in 35/99 patients (35.4%). There were 22.5-fold increased odds of having a transaminase peak >100 U/L (95% CI, 2.3–223.7; P = 0.008) and 21.2-fold increased odds of steroid doubling, as per treatment protocol (95% CI, 2.2–209.2; P = 0.009) in patients weighing ≥13.5 kg versus <8.5 kg. Weight at infusion was positively correlated with steroid treatment duration (r = 0.43; P < 0.001). Worsening transaminitis, despite doubling of oral prednisolone, led to treatment with intravenous methylprednisolone in 5 children. Steroid-sparing immunosuppressants were used in 5 children to enable steroid weaning. Two deaths apparently unrelated to OA were reported.
OA led to functional improvements and was well tolerated with no persistent clinical complications, including in older and heavier patients.
Novartis Innovative Therapies AG provided a grant for independent medical writing services.
The β-tropomyosin gene encodes a component of the sarcomeric thin filament. Rod-shaped dimers of tropomyosin regulate actin-myosin interactions and β-tropomyosin mutations have been associated with ...nemaline myopathy, cap myopathy, Escobar syndrome and distal arthrogryposis types 1A and 2B. In this study, we expand the allelic spectrum of β-tropomyosin-related myopathies through the identification of a novel β-tropomyosin mutation in two clinical contexts not previously associated with β-tropomyosin. The first clinical phenotype is core-rod myopathy, with a β-tropomyosin mutation uncovered by whole exome sequencing in a family with autosomal dominant distal myopathy and muscle biopsy features of both minicores and nemaline rods. The second phenotype, observed in four unrelated families, is autosomal dominant trismus-pseudocamptodactyly syndrome (distal arthrogryposis type 7; previously associated exclusively with myosin heavy chain 8 mutations). In all four families, the mutation identified was a novel 3-bp in-frame deletion (c.20_22del) that results in deletion of a conserved lysine at the seventh amino acid position (p.K7del). This is the first mutation identified in the extreme N-terminus of β-tropomyosin. To understand the potential pathogenic mechanism(s) underlying this mutation, we performed both computational analysis and in vivo modelling. Our theoretical model predicts that the mutation disrupts the N-terminus of the α-helices of dimeric β-tropomyosin, a change predicted to alter protein-protein binding between β-tropomyosin and other molecules and to disturb head-to-tail polymerization of β-tropomyosin dimers. To create an in vivo model, we expressed wild-type or p.K7del β-tropomyosin in the developing zebrafish. p.K7del β-tropomyosin fails to localize properly within the thin filament compartment and its expression alters sarcomere length, suggesting that the mutation interferes with head-to-tail β-tropomyosin polymerization and with overall sarcomeric structure. We describe a novel β-tropomyosin mutation, two clinical-histopathological phenotypes not previously associated with β-tropomyosin and pathogenic data from the first animal model of β-tropomyosin-related myopathies.
Manufacturing industry can improve its competitiveness through innovation and technological excellence, and appropriate Industrial Learning can help to achieve this goal through allowing the ...manufacturing workforce to acquire new skills related to the advanced developments in information and communication technologies. This raises the need for new Industrial Learning tools and methods from the viewpoint of learning content, learning processes, and delivery mechanisms. In this paper, we present a generic competence-based approach for Industrial Learning developed in the framework of ActionPlanT project. The approach is composed of (i) an Industrial Learning model which serves to represent and understand competence-based learning, and (ii) a methodology which implements through a number of steps the Industrial Learning actions defined using the Industrial Learning model in industrial organisations. Both the model and the methodology are presented in details. A metrics-based method for evaluating the implementation of the learning actions defined using the approach is also described.
We introduce a measure called width, quantifying the amount of nondeterminism in automata. Width generalises the notion of good-for-games (GFG) automata, that correspond to NFAs of width 1, and where ...an accepting run can be built on-the-fly on any accepted input. We describe an incremental determinisation construction on NFAs, which can be more efficient than the full powerset determinisation, depending on the width of the input NFA. This construction can be generalised to infinite words, and is particularly well-suited to coB\"uchi automata. For coB\"uchi automata, this procedure can be used to compute either a deterministic automaton or a GFG one, and it is algorithmically more efficient in the last case. We show this fact by proving that checking whether a coB\"uchi automaton is determinisable by pruning is NP-complete. On finite or infinite words, we show that computing the width of an automaton is EXPTIME-complete. This implies EXPTIME-completeness for multipebble simulation games on NFAs.
Mutations in COL4A1 are responsible for a spectrum of clinical phenotypes characterized by neurological, ocular, and renal involvement. Neurological features are the most prominent but as such are ...rather nonspecific.
Here, we report three new cases that, like five patients we previously described, show the novel common finding of raised creatine kinase (CK) concentration.
Raised CK concentration, in addition to intracranial calcification, is to be considered another useful pointer to a final diagnosis of COL4A1-related disease.
We consider a scenario in which dark matter particles are accelerated to semi-relativistic velocities through their scattering with the Diffuse Supernova Neutrino Background. Such a subdominant, but ...more energetic dark matter component can be then detected via its scattering on the electrons and nucleons inside direct detection experiments. This opens up the possibility to probe the sub-GeV mass range, a region of parameter space that is usually not accessible at such facilities. We analyze current data from the XENONnT and LUX-ZEPLIN experiments and we obtain novel constraints on the scattering cross sections of sub-GeV boosted dark matter with both nucleons and electrons. We also highlight the importance of carefully taking into account Earth's attenuation effects as well as the finite nuclear size into the analysis. By comparing our results to other existing constraints, we show that these effects lead to improved and more robust constraints.
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