Clinical outcome assessments of disease burden and progression in late-onset GM2 gangliosidoses.

The late-onset GM2 gangliosidoses, comprising late-onset Tay-Sachs and Sandhoff diseases, are rare, slowly progressive, neurogenetic disorders primarily characterized by neurogenic weakness, ataxia, and dysarthria. The aim of this longitudinal study was to characterize the natural history of late-onset GM2 gangliosidoses using a number of clinical outcome assessments to measure different aspects of disease burden and progression over time, including neurological, functional, and quality of life, to inform the design of future clinical interventional trials. Patients attending the United States National Tay-Sachs & Allied Diseases Family Conference between 2015 and 2019 underwent annual clinical outcome assessments. Currently, there are no clinical outcome assessments validated to assess late-onset GM2 gangliosidoses; therefore, instruments used or designed for diseases with similar features, or to address various aspects of the clinical presentations, were used. Clinical outcome assessments included the Friedreich's Ataxia Rating Scale, the 9-Hole Peg Test, and the Assessment of Intelligibility of Dysarthric Speech. Twenty-three patients participated in at least one meeting visit (late-onset Tay-Sachs, n = 19; late-onset Sandhoff, n = 4). Patients had high disease burden at baseline, and scores for the different clinical outcome assessments were generally lower than would be expected for the general population. Longitudinal analyses showed slow, but statistically significant, neurological progression as evidenced by worsening scores on the 9-Hole Peg Test (2.68%/year, 95% CI: 0.13-5.29; p = 0.04) and the Friedreich's Ataxia Rating Scale neurological examination (1.31 points/year, 95% CI: 0.26-2.35; p = 0.02). Time since diagnosis to study entry correlated with worsening scores on the 9-Hole Peg Test (r = 0.728; p < 0.001), Friedreich's Ataxia Rating Scale neurological examination (r = 0.727; p < 0.001), and Assessment of Intelligibility of Dysarthric Speech intelligibility (r = -0.654; p = 0.001). In summary, patients with late-onset GM2 gangliosidoses had high disease burden and slow disease progression. Several clinical outcome assessments suitable for clinical trials showed only small changes and standardized effect sizes (change/standard deviation of change) over 4 years. These longitudinal natural history study results illustrate the challenge of identifying responsive endpoints for clinical trials in rare, slowly progressive, neurogenerative disorders where arguably the treatment goal is to halt or decrease the rate of decline rather than improve clinical status. Furthermore, powering such a study would require a large sample size and/or a long study duration, neither of which is an attractive option for an ultra-rare disease with no available treatment. These findings support the development of potentially more sensitive late-onset GM2 gangliosidoses-specific rating instruments and/or surrogate endpoints for use in future clinical trials.

First-in-human in vivo genome editing via AAV-zinc-finger nucleases for mucopolysaccharidosis I/II and hemophilia B.

Zinc-finger nuclease (ZFN)-based in vivo genome editing is a novel treatment that can potentially provide lifelong protein replacement with single intravenous administration. Three first-in-human open-label ascending single-dose phase 1/2 studies were performed in parallel (starting November 2017) primarily to assess safety and tolerability of ZFN in vivo editing therapy in mucopolysaccharidosis I (MPS I) (n = 3), MPS II (n = 9), and hemophilia B (n = 1). Treatment was well tolerated with no serious treatment-related adverse events. At the 1e13 vg/kg dose, evidence of genome editing was detected through albumin-transgene fusion transcripts in liver for MPS II (n = 2) and MPS I (n = 1) subjects. The MPS I subject also had a transient increase in leukocyte iduronidase activity to the lower normal range. At the 5e13 vg/kg dose, one MPS II subject had a transient increase in plasma iduronate-2-sulfatase approaching normal levels and one MPS I subject approached mid-normal levels of leukocyte iduronidase activity with no evidence of genome editing. The hemophilia B subject was not able to decrease use of factor IX concentrate; genome editing could not be assessed. Overall, ZFN in vivo editing therapy had a favorable safety profile with evidence of targeted genome editing in liver, but no long-term enzyme expression in blood.

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.

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.

The existence of Aß strains and their potential for driving phenotypic heterogeneity in Alzheimer's disease.

Reminiscent of the human prion diseases, there is considerable clinical and pathological variability in Alzheimer's disease, the most common human neurodegenerative condition. As in prion disorders, protein misfolding and aggregation is a hallmark feature of Alzheimer's disease, where the initiating event is thought to be the self-assembly of Aß peptide into aggregates that deposit in the central nervous system. Emerging evidence suggests that Aß, similar to the prion protein, can polymerize into a conformationally diverse spectrum of aggregate strains both in vitro and within the brain. Moreover, certain types of Aß aggregates exhibit key hallmarks of prion strains including divergent biochemical attributes and the ability to induce distinct pathological phenotypes when intracerebrally injected into mouse models. In this review, we discuss the evidence demonstrating that Aß can assemble into distinct strains of aggregates and how such strains may be primary drivers of the phenotypic heterogeneity in Alzheimer's disease.

Clinical outcomes after 4.5 years of eliglustat therapy for Gaucher disease type 1: Phase 3 ENGAGE trial final results.

Eliglustat, an oral substrate reduction therapy, is approved for eligible adults with Gaucher disease type 1. In the Phase 3 ENGAGE trial of previously untreated adults with Gaucher disease type 1, eliglustat-treated patients had statistically significant improvements in organ volumes and hematologic parameters compared with placebo in the 9-month primary analysis. We report final outcomes by time on eliglustat among all patients who participated in the ENGAGE trial and extension. No patient deteriorated clinically or withdrew due to adverse events; 39/40 patients entered the open-label extension period and 34/40 (85%) remained in the trial until completion or switching to commercial eliglustat after its approval (2.3-6 years). Clinically meaningful improvements in Gaucher disease manifestations were seen in all patients concomitant with reductions in pathological lipid substrate levels (glucosylceramide and glucosylsphingosine). Among patients with 4.5 years of eliglustat exposure, mean spleen volume decreased by 66% (from 17.1 to 5.8 multiples of normal [MN], n = 13), mean liver volume decreased by 23% (from 1.5 to 1.1 MN, n = 13), mean hemoglobin increased 1.4 g/dl (from 11.9 to 13.4 g/dl, n = 12), mean platelet count increased by 87% (from 67.6 to 122.6 × 109 /L, n = 12), median chitotriosidase decreased by 82% (from 13 394 to 2312 nmol/h/ml, n = 11), median glucosylceramide decreased by 79% (from 11.5 to 2.4 µg/ml, n = 11), median glucosylsphingosine decreased by 84% (from 518.5 to 72.1 ng/ml, n = 10), and mean spine T-score increased from -1.07 (osteopenia) to -0.53 (normal) (n = 9). The magnitude of improvement in Gaucher disease manifestations and biomarkers over time was similar among the full trial cohort. Eliglustat was well-tolerated and led to clinically significant improvements in previously untreated patients with Gaucher disease type 1 during 4.5 years of treatment.

Mdm2 and MdmX RING Domains Play Distinct Roles in the Regulation of p53 Responses: A Comparative Study of Mdm2 and MdmX RING Domains in U2OS Cells.

Dysfunction of the tumor suppressor p53 occurs in most human cancers. Mdm2 and MdmX are homologous proteins from the Mdm (Murine Double Minute) protein family, which play a critical role in p53 inactivation and degradation. The two proteins interact with one another via the intrinsic RING (Really Interesting New Gene) domains to achieve the negative regulation of p53. The downregulation of p53 is accomplished by Mdm2-mediated p53 ubiquitination and proteasomal degradation through the ubiquitin proteolytic system and by Mdm2 and MdmX mediated inhibition of p53 transactivation. To investigate the role of the RING domain of Mdm2 and MdmX, an analysis of the distinct functionalities of individual RING domains of the Mdm proteins on p53 regulation was conducted in human osteosarcoma (U2OS) cell line. Mdm2 RING domain was observed mainly localized in the cell nucleus, contrasting the localization of MdmX RING domain in the cytoplasm. Mdm2 RING was found to possess an endogenous E3 ligase activity, whereas MdmX RING did not. Both Mdm2 and MdmX RING domains were able to dimerize with endogenous full-length Mdm2 and MdmX protein and affect their cellular function. The results showed that overexpression of the Mdm2 or MdmX RING domains interfered with the endogenous full-length Mdm2 and MdmX activity and resulted in p53 stabilization and p53 target gene activation. However, both Mdm RING domains showed oncogenic activity in a colony formation assay, suggesting that the Mdm RING domains possess p53-independent oncogenic properties. This study highlights the distinct structural and functional traits of the RING domain of Mdm2 and MdmX and characterized their role in cellular responses through interfering with p53 dependent signaling pathway.

Outcomes after 8 years of eliglustat therapy for Gaucher disease type 1: Final results from the Phase 2 trial.

Eliglustat is a first-line oral therapy for adults with Gaucher disease type 1 (GD1) and poor, intermediate or extensive CYP2D6-metabolizer phenotypes (>90% of patients). We report the final results of a Phase 2 trial and extension (NCT00358150) in previously untreated adult GD1 patients who had splenomegaly with thrombocytopenia and/or anemia and received 50 or 100 mg eliglustat tartrate (equivalent to 42 or 84 mg eliglustat) twice daily for 8 years. In total, 19 of 26 patients completed the trial. After 8 years of eliglustat, mean spleen and liver volumes decreased by 69% and 34%, respectively. Mean hemoglobin concentration and platelet count increased by 2.2 g/dL and 113%, respectively. All patients met at least 3 of 4 therapeutic goals established for patients on long-term enzyme replacement therapy. Mean final values for patients with severe splenomegaly (n = 6), moderate-to-severe anemia (n = 6), or severe thrombocytopenia (n = 8) were similar to patients with milder disease at baseline and within long-term therapeutic goal thresholds. Biomarker median percent changes from baseline were -91% for chitotriosidase, -87% for CCL18, -92% for glucosylsphingosine, and -80% for plasma glucosylceramide. Mean lumbar spine T-score increased by 0.96, moving from the osteopenic to the normal range. Mean quality-of-life scores, mostly below normal at baseline, moved into ranges seen in healthy adults. Eliglustat was well-tolerated; 98% of adverse events were mild or moderate and 94% were considered unrelated to treatment. Clinically meaningful improvements in all parameters continued or were maintained over 8 years, with the largest margins of improvement seen in the most severely affected patients.

Reported outcomes of 453 pregnancies in patients with Gaucher disease: An analysis from the Gaucher outcome survey.

Gaucher disease (GD) may worsen during pregnancy, leading to the discussion of continuing treatment during pregnancy. We examined fetal outcomes of pregnancies reported in the Gaucher Outcome Survey, an international GD-specific registry established in 2010. A total of 453 pregnancies were reported. Most pregnancies (336/453, 74.2%) were in women who did not receive GD-specific treatment during pregnancy, while enzyme replacement therapy (ERT) was received during 117/453 (25.8%) pregnancies. No pregnancies exposed to substrate reduction therapy were reported. The percentage of normal outcomes (live birth delivered at term with no congenital abnormalities) was similar in untreated and treated pregnancies (92.9% vs. 91.4%). The percentage of spontaneous abortions in untreated pregnancies was 3.6% (95% CI, 1.9%- 6.2%) compared with 6.9% (95% CI, 3.0%-13.1%) in treated pregnancies (p=0.1866). In women who received velaglucerase alfa <1month prior to conception and/or during pregnancy, 34/36 (94.4%) pregnancies had normal outcomes and 2 (5.6%) ended in spontaneous abortion. Normal outcomes were observed in the 20 pregnancies with velaglucerase alfa exposure starting <1month prior to conception and continuing through all trimesters. These observations, in addition to information in the literature, suggest that continuation of ERT during pregnancy may be appropriate for GD patients.

Demographics and patient characteristics of 1209 patients with Gaucher disease: Descriptive analysis from the Gaucher Outcome Survey (GOS).

The Gaucher Outcome Survey (GOS) is an international Gaucher disease (GD) registry established in 2010 for patients with a confirmed GD diagnosis, regardless of GD type or treatment status, designed to evaluate the safety and long-term effectiveness of velaglucerase alfa and other GD-related treatments. As of February 25, 2017, 1209 patients had enrolled, the majority from Israel (44.3%) and the US (31.4%). Median age at GOS entry was 40.4 years, 44.1% were male, and 13.3% had undergone a total splenectomy. Most patients had type 1 GD (91.5%) and were of Ashkenazi Jewish ethnicity (55.8%). N370S/N370S was the most prevalent genotype, accounting for 44.2% of genotype-confirmed individuals (n = 847); however, there was considerable variation between countries. A total of 887 (73.4%) patients had received ≥1 GD-specific treatment at any time, most commonly imiglucerase (n = 587), velaglucerase alfa (n = 507), and alglucerase (n = 102). Hematological and visceral findings at the time of GOS entry were close to normal for most patients, probably a result of previous treatment; however, spleen volume of patients in Israel was almost double that of patients elsewhere (7.2 multiples of normal [MN] vs. 2.7, 2.9 and 4.9 MN in the US, UK and rest of world), which may be explained by a greater disease severity in this cohort. This analysis aimed to provide an overview of GOS and present baseline demographic and disease characteristics of participating patients to help improve the understanding of the natural history of GD and inform the overall management of patients with the disease.

Parental-reported pain insensitivity in Dup15q.

Parents of children with chromosome 15q duplication syndrome (Dup15q) have anecdotally reported high pain threshold as a feature of the disorder. The purpose of this study was to document parental-reported estimates of the frequency of high pain tolerance and the stimuli that fail to evoke a normal pain response. We sent an online survey to 840 families with children with Dup15q to explore the frequency and clinical manifestations of high pain threshold. There were 216 respondents (25.7%). A high pain threshold was reported in 87% of children at some time. There was a trend (p=0.06) for high pain threshold to be more commonly observed among children with the isodicentric (85.6%) and other genetic variants (95%) than interstitial (69.6%) duplications. There was no association between reports of high pain threshold and reports of an intellectual disability (91% of cases), autism spectrum disorder (83% of cases), or self-injurious behavior (40% of cases). Reports included many dramatic cases such as severe burns, broken bones, and electrical traumas, which were associated with little or no evidence of a painful stimulus. A high pain threshold is reported in other disorders associated with intellectual disability and autism; the underlying mechanism in Dup15q and other disorders remains undefined.

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.

Cognitive, medical, and neuroimaging characteristics of attenuated mucopolysaccharidosis type II.

UNLABELLED: The phenotype of attenuated mucopolysaccharidosis type II (MPS II), also called Hunter syndrome, has not been previously studied in systematic manner. In contrast to the "severe" phenotype, the "attenuated" phenotype does not present with behavioral or cognitive impairment; however, the presence of mild behavior and cognitive impairment that might impact long-term functional outcomes is unknown. Previously, significant MRI abnormalities have been found in MPS II. Recent evidence suggests white matter abnormalities in many MPS disorders. METHODS: As the initial cross-sectional analysis of a longitudinal study, we studied the association of brain volumes and somatic disease burden with neuropsychological outcomes, including measures of intelligence, memory, and attention in 20 patients with attenuated MPS II with a mean age of 15.8. MRI volumes were compared to 55 normal controls. RESULTS: While IQ and memory were average, measures of attention were one standard deviation below the average range. Corpus callosum volumes were significantly different from age-matched controls, differing by 22%. Normal age-related volume increases in white matter were not seen in MPS II patients as they were in controls. Somatic disease burden and white matter and corpus callosum volumes were significantly associated with attention deficits. Neither age at evaluation nor age at starting treatment predicted attention outcomes. CONCLUSIONS: Despite average intelligence, attention is compromised in attenuated MPS II. Results confirm an important role of corpus callosum and cortical white matter abnormality in MPS II as well as the somatic disease burden in contributing to attention difficulties. Awareness by the patient and caregivers with appropriate management and symptomatic support will benefit the attenuated MPS II patient.

Safety and physiological effects of two different doses of elosulfase alfa in patients with morquio a syndrome: A randomized, double-blind, pilot study.

The primary treatment outcomes of a phase 2, randomized, double-blind, pilot study evaluating safety, physiological, and pharmacological effects of elosulfase alfa in patients with Morquio A syndrome are herewith presented. Patients aged ≥7 years and able to walk ≥200 m in the 6-min walk test (6MWT) were randomized to elosulfase alfa 2.0 or 4.0 mg/kg/week for 27 weeks. The primary objective was to evaluate the safety of both doses. Secondary objectives were to evaluate effects on endurance (6MWT and 3-min stair climb test [3MSCT]), exercise capacity (cardio-pulmonary exercise test [CPET]), respiratory function, muscle strength, cardiac function, pain, and urine keratan sulfate (uKS) levels, and to determine pharmacokinetic parameters. Twenty-five patients were enrolled (15 randomized to 2.0 mg/kg/week and 10 to 4.0 mg/kg/week). No new or unexpected safety signals were observed. After 24 weeks, there were no improvements versus baseline in the 6MWT, yet numerical improvements were seen in the 3MSCT with 4.0 mg/kg/week. uKS and pharmacokinetic data suggested no linear relationship over the 2.0-4.0 mg/kg dose range. Overall, an abnormal exercise capacity (evaluated in 10 and 5 patients in the 2.0 and 4.0 mg/kg/week groups, respectively), impaired muscle strength, and considerable pain were observed at baseline, and there were trends towards improvements in all domains after treatment. In conclusion, preliminary data of this small study in a Morquio A population with relatively good endurance confirmed the acceptable safety profile of elosulfase alfa and showed a trend of increased exercise capacity and muscle strength and decreased pain.

Long-Term Treatment of Gaucher Disease with Velaglucerase Alfa in ERT-Naïve Patients from the Gaucher Outcome Survey (GOS) Registry.

Background: Gaucher disease (GD) is a rare, autosomal, recessive condition characterized by hepatosplenomegaly, thrombocytopenia, anemia, and bone abnormalities, often requiring life-long treatment. Velaglucerase alfa has improved hematologic and visceral parameters in clinical trials; however, limited long-term efficacy and safety data are available. Methods: The Gaucher Outcome Survey (GOS), a structured and validated international registry for patients with confirmed GD, provides an opportunity to evaluate long-term data from patients receiving velaglucerase alfa. Results: This analysis included 376 treatment-naïve children and adults with GD enrolled in GOS, including 20 with type 3 GD, who initiated velaglucerase alfa through participation in clinical trials or as part of their clinical management and continued treatment for a mean (range) time of 6.6 (0.003-18.6) years. Initial improvements in hematologic and visceral parameters and the biomarkers glucosylsphingosine (lyso-GL1) and chitotriosidase were observed after one year of treatment and were maintained throughout the follow-up period. Of 129 (34.3%) patients who developed adverse events during the follow-up period, events were considered related to treatment in 33 (8.8%). None led to treatment discontinuation. There were 21 deaths overall, none of which were considered related to treatment. Conclusions: This analysis of data from the GOS registry supports the safety and efficacy of velaglucerase alfa in patients with GD.

Twelve Years of the Gaucher Outcomes Survey (GOS): Insights, Achievements, and Lessons Learned from a Global Patient Registry.

Background: Long-term patient registries are important for evaluating treatment outcomes in patients with rare diseases, and can provide insights into natural disease history and progression in real-world clinical practice. Initiated in 2010, the Gaucher Outcome Survey (GOS) is an ongoing, international, multicenter, observational registry (ClinicalTrials.gov Identifier: NCT03291223) for patients with a diagnosis of Gaucher disease (GD), irrespective of treatment type or status, with a primary objective to monitor safety and long-term effectiveness of velaglucerase alfa. Methods: Here, we evaluated the GOS population 12 years after the registry initiation. Results: As of 25 February 2023, 2084 patients enrolled in the GOS and 1643 received GD-specific treatment. Patients exhibited broad heterogeneity at baseline: age of diagnosis (0 to 85.3 years), hemoglobin concentrations (<80.0 g/L to >150 g/L), platelet counts (<50 × 109/L to >450 × 109/L), and liver and spleen volumes. Most patients treated with enzyme replacement therapy or substrate reduction therapy reported improvements in clinical parameters within 1 year of treatment initiation, maintained over the course of treatment up to 12 years, whereas untreated patients had baseline values closer to standard reference thresholds and showed stability over time. Conclusion: The 12-year data from the GOS confirm the impact of long-term treatment with GD-specific agents and offer insights into disease progression and outcomes in a real-world setting.

Clinical characteristics and somatic burden of patients with mucopolysaccharidosis II with or without neurological involvement: An analysis from the Hunter Outcome Survey.

Approximately two-thirds of patients with mucopolysaccharidosis II (MPS II; Hunter syndrome) have neuronopathic disease, with central nervous system involvement; one-third have non-neuronopathic disease. This analysis of data from the Hunter Outcome Survey (HOS) compared the clinical manifestations and surgical and nonsurgical procedure history in patients with neuronopathic or non-neuronopathic MPS II. Prospective patients were identified in July 2018 in HOS for inclusion in this analysis as those with stable cognitive impairment status as assessed at 10 years of age and at a minimum of one follow-up visit at 11 to <20 years of age. Patients were stratified according to cognitive impairment status at 10 years into neuronopathic and non-neuronopathic groups, and clinical manifestations and surgical and nonsurgical procedure history were compared between the two groups. In total, 193 patients had cognitive impairment status assessments available (at 10 years and 11 to <20 years of age), 151 of whom had stable cognitive impairment status and were included; 100/151 (66.2%) were in the neuronopathic group and 51/151 (33.8%) in the non-neuronopathic group. The proportion of patients demonstrating manifestations by system organ class and the number of surgical and nonsurgical procedures per patient were broadly comparable in the neuronopathic and non-neuronopathic groups both before and after patients' 10th birthdays. The most common manifestations before patients' 10th birthdays, including facial features, joint stiffness and limited function, and hepatomegaly were reported in >80% of patients in both groups. For the neuronopathic and non-neuronopathic groups, the median [10th percentile, 90th percentile] number of different types of surgical and nonsurgical procedures per patient (3 [1, 6] and 3 [1, 7], respectively) and of all procedures per patient (4 [1, 10] and 5 [2, 11], respectively) before patients' 10th birthdays were similar, although the type of procedure may have differed. Thus, in the first two decades of life, patients with non-neuronopathic disease were found to have similar somatic manifestations to those of the neuronopathic group and undergo procedures for complications as often as those with neuronopathic disease.

Efficacy and Safety of N-Acetyl-l-Leucine in Children and Adults With GM2 Gangliosidoses.

BACKGROUND AND OBJECTIVES: GM2 gangliosidoses (Tay-Sachs and Sandhoff diseases) are rare, autosomal recessive, neurodegenerative diseases with no available symptomatic or disease-modifying treatments. This clinical trial investigated N-acetyl-l-leucine (NALL), an orally administered, modified amino acid in pediatric (≥6 years) and adult patients with GM2 gangliosidoses. METHODS: In this phase IIb, multinational, open-label, rater-blinded study (IB1001-202), male and female patients aged ≥6 years with a genetically confirmed diagnosis of GM2 gangliosidoses received orally administered NALL for a 6-week treatment period (4 g/d in patients ≥13 years, weight-tiered doses for patients 6-12 years), followed by a 6-week posttreatment washout period. For the primary Clinical Impression of Change in Severity analysis, patient performance on a predetermined primary anchor test (the 8-Meter Walk Test or the 9-Hole Peg Test) at baseline, after 6 weeks on NALL, and again after a 6-week washout period was videoed and evaluated centrally by blinded raters. Secondary outcomes included assessments of ataxia, clinical global impression, and quality of life. RESULTS: Thirty patients between the age of 6 and 55 years were enrolled. Twenty-nine had an on-treatment assessment and were included in the primary modified intention-to-treat analysis. The study met its CI-CS primary end point (mean difference 0.71, SD = 2.09, 90% CI 0.00, 1.50, p = 0.039), as well as secondary measures of ataxia and global impression. NALL was safe and well tolerated, with no serious adverse reactions. DISCUSSION: Treatment with NALL was associated with statistically significant and clinically relevant changes in functioning and quality of life in patients with GM2 gangliosidosis. NALL was safe and well tolerated, contributing to an overall favorable risk:benefit profile. NALL is a promising, easily administered (oral) therapeutic option for these rare, debilitating diseases with immense unmet medical needs. TRIAL REGISTRATION INFORMATION: The trial is registered with ClinicalTrials.gov (NCT03759665; registered on November 30, 2018), EudraCT (2018-004406-25), and DRKS (DRKS00017539). The first patient was enrolled on June 7, 2019. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that NALL improves outcomes for patients with GM2 gangliosidoses.