Long-term efficacy and safety of vestronidase alfa enzyme replacement therapy in pediatric subjects < 5 years with mucopolysaccharidosis VII.

Mucopolysaccharidosis (MPS) VII is an ultra-rare, autosomal-recessive, metabolic disease caused by a deficiency of ß-glucuronidase, a lysosomal enzyme that hydrolyzes glycosaminoglycans (GAGs), including dermatan sulfate (DS), chondroitin sulfate, and heparan sulfate (HS). ß-glucuronidase deficiency leads to progressive accumulation of undegraded GAGs in lysosomes of affected tissues, which may cause hydrops fetalis, short stature, hepatosplenomegaly, and cognitive impairment. An open-label, multicenter, phase II study was conducted in 8 pediatric subjects <5 years of age with MPS VII. Subjects received the recombinant human ß-glucuronidase vestronidase alfa 4 mg/kg by intravenous infusion every other week for 48 weeks (treatment period). Those who completed the 48-week treatment were offered to continue treatment with vestronidase alfa 4 mg/kg for up to 240 weeks or until withdrawal of consent, discontinuation, or study termination (continuation period). The level of GAG excreted in urine (uGAG) above normal has been shown to correlate with disease severity and clinical outcomes in MPS diseases. Therefore, the primary efficacy endpoint of this study was to determine the mean percentage change in uGAG DS excretion from baseline to week 48. Statistically significant reductions in uGAG DS from baseline were observed at each visit (p < 0.0001), with a least square mean (standard error) percentage change of -60% (6.6) at week 4 (first post-baseline assessment) and -61% (6.41) at week 48 (final assessment during treatment period). Secondary efficacy endpoints included change from baseline to week 48 in growth and hepatosplenomegaly. Positive trends were observed toward increased standing height Z-score (mean [standard deviation] at baseline, -2.630 [1.17], n = 8; at week 48, -2.045 [0.27], n = 7) and growth velocity (mean [SD] Z-score at baseline, -2.59 [1.49], n = 4; at week 48, -0.39 [2.10], n = 4; p = 0.27). Hepatomegaly was resolved in 3 of 3 subjects assessed by ultrasound and in 5 of 6 subjects assessed by physical examination; splenomegaly was resolved in 1 of 3 subjects assessed by ultrasound and in 2 of 2 subjects assessed by physical examination. There were no new safety signals identified during this study. Mild-to-moderate infusion-associated reactions occurred in 4 (50%) subjects. In conclusion, long-term vestronidase alfa treatment demonstrated a rapid and sustained reduction in uGAGs, maintained growth, and improved hepatosplenomegaly in pediatric subjects with MPS VII <5 years of age. Trial registration: NCT02418455.

Screening, patient identification, evaluation, and treatment in patients with Gaucher disease: Results from a Delphi consensus.

Several guidelines are available for identification and management of patients with Gaucher disease, but the most recent guideline was published in 2013. Since then, there have been significant advances in newborn screening, phenotypic characterization, identification of biomarkers and their integration into clinical practice, and the development and approval of new treatment options. Accordingly, the goal of this Delphi consensus exercise was to extend prior initiatives of this type by addressing issues related to newborn screening, diagnostic evaluations, and treatment (both disease directed and adjunctive). The iterative Delphi process involved creation of an initial slate of statements, review by a steering committee, and three rounds of consensus development by an independent panel. A preliminary set of statements was developed by the supporting agency based on literature searches covering the period from 1965 to 2020. The Delphi process reduced an initial set of 185 statements to 65 for which there was unanimous support from the panel. The statements supported may ultimately provide a framework for more detailed treatment guidelines. In addition, the statements for which unanimous support could not be achieved help to identify evidence gaps that are targets for future research.

A new approach to identifying patients with elevated risk for Fabry disease using a machine learning algorithm.

BACKGROUND: Fabry disease (FD) is a rare genetic disorder characterized by glycosphingolipid accumulation and progressive damage across multiple organ systems. Due to its heterogeneous presentation, the condition is likely significantly underdiagnosed. Several approaches, including provider education efforts and newborn screening, have attempted to address underdiagnosis of FD across the age spectrum, with limited success. Artificial intelligence (AI) methods present another option for improving diagnosis. These methods isolate common health history patterns among patients using longitudinal real-world data, and can be particularly useful when patients experience nonspecific, heterogeneous symptoms over time. In this study, the performance of an AI tool in identifying patients with FD was analyzed. The tool was calibrated using de-identified health record data from a large cohort of nearly 5000 FD patients, and extracted phenotypic patterns from these records. The tool then used this FD pattern information to make individual-level estimates of FD in a testing dataset. Patterns were reviewed and confirmed with medical experts. RESULTS: The AI tool demonstrated strong analytic performance in identifying FD patients. In out-of-sample testing, it achieved an area under the receiver operating characteristic curve (AUROC) of 0.82. Strong performance was maintained when testing on male-only and female-only cohorts, with AUROCs of 0.83 and 0.82 respectively. The tool identified small segments of the population with greatly increased prevalence of FD: in the 1% of the population identified by the tool as at highest risk, FD was 23.9 times more prevalent than in the population overall. The AI algorithm used hundreds of phenotypic signals to make predictions and included both familiar symptoms associated with FD (e.g. renal manifestations) as well as less well-studied characteristics. CONCLUSIONS: The AI tool analyzed in this study performed very well in identifying Fabry disease patients using structured medical history data. Performance was maintained in all-male and all-female cohorts, and the phenotypic manifestations of FD highlighted by the tool were reviewed and confirmed by clinical experts in the condition. The platform's analytic performance, transparency, and ability to generate predictions based on existing real-world health data may allow it to contribute to reducing persistent underdiagnosis of Fabry disease.

Characterization of Strength and Function in Ambulatory Adults With GNE Myopathy.

OBJECTIVE: To characterize the pattern and extent of muscle weakness and impact on physical functioning in adults with GNEM. METHODS: Strength and function were assessed in GNEM subjects (n = 47) using hand-held dynamometry, manual muscle testing, upper and lower extremity functional capacity tests, and the GNEM-Functional Activity Scale (GNEM-FAS). RESULTS: Profound upper and lower muscle weakness was measured using hand-held dynamometry in a characteristic pattern, previously described. Functional tests and clinician-reported outcomes demonstrated the consequence of muscle weakness on physical functioning. CONCLUSIONS: The characteristic pattern of upper and lower muscle weakness associated with GNEM and the resulting functional limitations can be reliably measured using these clinical outcome assessments of muscle strength and function.

Impact of Elosulfase Alfa on Pain in Patients with Morquio A Syndrome over 52 Weeks: MOR-008: A Randomized, Double-Blind, Pilot Study

Abstract Patients with mucopolysaccharidosis (MPS), and Morquio A syndrome (MPS IVA) in particular, often report substantial pain burden. MOR-008 was a randomized, double-blind, pilot study assessing the safety and efficacy, including impact on patient-reported pain, of 52 weeks of treatment with elosulfase alfa (at a dose of 2.0 or 4.0 mg/kg/week) in patients with Morquio A syndrome (?7 years old). Assessment of pain at baseline revealed that patients (N = 25) had a mean number of pain locations of 5.7, mean pain intensity score of 4.6 (indicative of medium pain), and a mean number of selected pain descriptors of 7.4 words. Treatment with elosulfase alfa improved subjective pain score (reduced to 3.2), pain locations (reduced by a mean of 1 location), and pain descriptor words (reduced to 4.9 words) over 1 year (52 weeks), suggesting that elosulfase alfa can reduce pain in some patients with Morquio A.

Novel Nonsense Calmodulin-Binding Transcription Activator 1 Mutation Presenting as a Tremor-Predominant Phenotype.

A 25-year-old right-handed male presented with head and bilateral arm and leg tremor. His symptoms began at age 10 years with action tremor of both hands and progressed in severity with time. He had difficulty with social interactions but did not have intellectual disabilities. His past medical history was significant for obsessive compulsive disorder and anxiety, asthma, gastroesophageal reflux disease, and scoliosis; and his family history was significant for tremor in his father and paternal grandfather. Genetic testing was performed and identified a deleterious sequence variation in exon 19 of the calmodulin-binding transcription activator 1 (CAMTA1) gene. The presence of this sequence variation was confirmed in the patient and in his affected father. The case is novel because of tremor predominance and because the mutation is a sequence variation rather than a deletion or duplication.

Skeletal Muscle in Healthy Subjects versus Those with GNE-Related Myopathy: Evaluation with Shear-Wave US--A Pilot Study.

PURPOSE: To determine whether quantitative differences in shear-wave velocity (SWV) exist between normal skeletal muscle and those affected by GNE-related myopathy and to examine the effects of muscle anisotropy, depth, and axial preload on SWV in a healthy control group. MATERIALS AND METHODS: This study was approved by the institutional review board and compliant with HIPAA. Informed consent was obtained from all study volunteers. Eight patients (four women and four men aged 30-50 years) with genetically and biopsy-proved GNE-related myopathy and five healthy volunteers (three women and two men aged 27-33 years) underwent SWV imaging with use of a 9-MHz linear transducer. The gastrocnemius muscles were evaluated in the patients with GNE-related myopathy, and the gastrocnemius, vastus lateralis, and rectus femoris muscles were evaluated in the healthy cohort. The effect of muscle anisotropy, axial preload, and sample volume depth were examined in the healthy cohort. The effect of anisotropy at a fixed depth and preload were examined in the patients with GNE-related myopathy. RESULTS: Irrespective of the muscle, the mean SWV was significantly higher with the transverse orientation than with the longitudinal orientation (P < .001). In the healthy cohort, the mean SWV for superficial measurements was significantly lower than that for deep measurements (P < .02). The mean SWV with preload was significantly higher with compression (P < .001) for the rectus femoris only. The mean SWV was significantly lower in patients with GNE-related myopathy than in control subjects (P < .02). CONCLUSION: SWV parametric imaging may provide a useful quantitative adjunct in the assessment of disease activity in patients with GNE-related myopathy. There is diminished SWV and muscle anisotropy in GNE-related myopathy.

Multi-domain impact of elosufase alfa in Morquio A syndrome in the pivotal phase III trial.

OBJECTIVE: To report and discuss the multi-domain impact of elosulfase alfa, with focus on tertiary and composite endpoints, in the 24-week, randomized, double-blind, placebo-controlled phase 3 trial in patients with Morquio A syndrome (mucopolysaccharidosis IVA). METHODS: Patients with Morquio A syndrome aged ≥5 years were randomized 1:1:1 to elosulfase alfa 2.0mg/kg/week (qw; N=58), elosulfase alfa 2.0mg/kg/every other week (qow; N=59), or placebo (N=59) for 24 weeks. Primary and secondary efficacy measures were 6-minute walk test (6MWT; primary), 3-minute stair climb test (3-MSCT) and urinary keratan sulfate (KS). Safety was also evaluated. Tertiary efficacy measures included respiratory function measures, activities of daily living (MPS Health Assessment Questionnaire [MPS-HAQ]), anthropometric, echocardiographic and radiographic measures, hearing and corneal clouding assessment. In order to fully characterize treatment impact in this heterogeneous disorder, the effect of elosulfase alfa on composite efficacy measures was evaluated as well. RESULTS: The study was not designed to have sufficient power for any of the tertiary outcomes. For most tertiary endpoints, subjects treated with the weekly dose of elosulfase alfa improved more than those receiving placebo. The largest treatment effects were seen in maximal voluntary ventilation (MVV), MPS-HAQ, height, and growth rate. The qow group appeared similar to placebo. The analysis of a pre-specified composite endpoint (combining changes from baseline in 6MWT, 3MSCT and MVV z-scores equally weighted) showed a modest positive impact of elosulfase alfa qw versus placebo group (P=0.053). As a pre-specified supportive analysis, the O'Brien Rank Sum composite endpoint (changes from baseline in 6MWT, 3MSC, and MVV), analysis also showed that the qw group performed better than the placebo group (P=0.011). In post-hoc analyses, combinations of other endpoints were also explored using the O'Brien Rank Sum test and showed statistically significant differences between elosulfase alfa qw and placebo favoring elosulfase alfa qw. Differences between elosulfase alfa qow and placebo were not statistically significant. Positive changes were observed in most tertiary variables, demonstrating the efficacy of weekly treatment with elosulfase alfa. CONCLUSIONS: Treatment with weekly elosulfase alfa led to improvements across most efficacy measures, resulting in clinically meaningful benefits in a heterogeneous study population.