Faculty Bibliography

Thank you for allowing us the opportunity to respond to the commentary from Mistry and colleagues (Comment: The two substrate reduction therapies for type 1 Gaucher disease are not equivalent) [...].

BACKGROUND AND OBJECTIVE/OBJECTIVE: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, multi-national, 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/day in patients ≥13 years, weight-tiered doses for patients 6-12 years), followed by a 6-week post-treatment washout period. For the primary Clinical Impression of Change in Severity analysis, patient performance on a pre-determined 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:30 patients between the age of 6 and 55 were enrolled. 29 had an on-treatment assessment and were included in the primary modified intention-to-treat analysis. The study met its CI-CS primary endpoint (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. CONCLUSIONS: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 favourable risk: benefit profile. NALL is a promising, easily administered (oral) therapeutic option for these rare, debilitating diseases with immense unmet medical needs. CLASSIFICATION OF EVIDENCE/METHODS:This study provides Class IV evidence that NALL improves outcomes for patients with GM2 gangliosidoses. TRIAL REGISTRATION INFORMATION/UNASSIGNED:The trial is registered with ClinicalTrials.gov (NCT03759665; registered 30-Nov-2018), EudraCT (2018-004406-25), and DRKS (DRKS00017539). The first patient was enrolled 07-June-2019.

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.

Switching between enzyme replacement therapies (ERT) and substrate reduction therapies (SRT) in patients with type 1 Gaucher disease (GD1) is not uncommon; however, the reasons for switchng treatments have not been explored in detail. Data from the Gaucher Outcome Survey (GOS), an international registry for patients with confirmed GD, were used to evaluate the reasons for, and consequences of, switching between these treatment types. Of the 1843 patients enrolled in GOS on 25 February 2020, 245 had undergone a treatment switch: 222 from initial ERT to SRT (of whom 88 later switched back to ERT) and 23 from initial SRT to ERT. The most common reasons for ERT-SRT switching were duration of infusion (25.4%), drug shortage (22.0%), and adverse events (AEs; 11.9%), and for SRT-ERT switching, AEs (63.6%), lack of beneficial effect (16.4%), and participation in a clinical trial (9.1%). Bodyweight and hematologic parameters largely remained stable before and after switching between ERT and SRT, although with substantial variation between patients. These findings contribute to understanding why treatment switching occurs in patients with GD, and may help physicians recognize the real-world impact of treatment switching between ERT and SRT for patients with GD.

Mucopolysaccharidosis (MPS) VII is an ultra-rare, autosomal-recessive, metabolic disease caused by a deficiency of β-glucuronidase, a lysosomal enzyme that hydrolyzes glycosaminoglycans (GAGs), including dermatan sulfate (DS), chondroitin sulfate, and heparan sulfate (HS). β-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 β-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.

BACKGROUND:Late-Onset Tay-Sachs (LOTS) disease is a rare, progressive neurological condition that can dramatically affect the life of these patients. The diagnosis of LOTS is easily missed because of the multifaced presentation of these patients, who can initially be assessed by neuromuscular or movement disorder specialists, or psychiatrists. Clinical trials are now becoming available for LOTS. Therefore, early diagnosis can be detrimental for these patients and for insuring informative research outcomes. METHODS:We characterized a cohort of nine patients with LOTS through a detailed clinical and video description. We then reviewed the available literature regarding the clinical description of patients with LOTS. Our findings were summarized based on the predominant phenotype of presentation to highlight diagnostic clues to guide the diagnosis of LOTS for different neurology specialists (neuromuscular, movement disorders) and psychiatrist. RESULTS:We described a cohort of 9 new patients with LOTS seen at our clinic. Our literature review identified 76 patients mainly presenting with a neuromuscular, cerebellar, psychiatric, stuttering, or movement disorder phenotype. Diagnostic tips, such as the triceps sign, distinct speech patterns, early psychiatric presentation and impulsivity, as well as neurological symptoms (cerebellar or neuromuscular) in patients with a prominent psychiatric presentation, are described. DISCUSSION:Specific diagnostics clues can help neurologists and psychiatrists in the early diagnosis of LOTS disease. Our work also represent the first video presentation of a cohort of patients with LOTS that can help different specialists to familiarize with these features and improve diagnostic outcomes. HIGHLIGHTS:Late-Onset Tay-Sachs (LOTS) disease, a severe progressive neurological condition, has multifaced presentations causing diagnostic delays that can significantly affect research outcomes now that clinical trials are available. We highlight useful diagnostic clues from our cohort (including the first video representation of a LOTS cohort) and comprehensive literature review.

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 to 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 x 10⁹ /L, n=12), median chitotriosidase decreased by 82% (from 13,394 to 2312 nmol/hr/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). Together, these outcomes regardless of time on eliglustat showed comparable improvements in Gaucher manifestations and disease biomarkers. 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. This article is protected by copyright. All rights reserved.

Introduction: Mucopolysaccharidosis VII (MPS VII) is an ultra-rare, autosomal recessive, debilitating, progressive lysosomal storage disease caused by beta-glucuronidase (GUS) enzyme deficiency. Vestronidase alfa (recombinant human GUS) enzyme replacement therapy is approved in the United States, Europe, and Latin America for the treatment of MPS VII.
Method(s): The disease monitoring program (DMP) is an ongoing, multicenter observational study collecting standardized real-world data from patients with MPS VII (N~35) treated with vestronidase alfa or with any other management approach. Investigational sites are centers with expertise in the treatment of mucopolysaccharidosis. Data will be collected for up to 10 years and include demographics, clinical history, clinical characteristics, cognition, mobility, skeletal disease, pulmonary function, patient/caregiver-reported healthrelated quality of life, and long-term vestronidase alfa safety and effectiveness. Data are monitored and recorded in compliance with Good Clinical Practice (GCP) guidelines. Annual individual patient reports will be provided to respective patients and caregivers.
Result(s): As of May 31, 2020, sixteen patients are enrolled: 11 prescribed vestronidase alfa and 5 not treated with vestronidase alfa. Median (min, max) age at MPS VII diagnosis was 4.1 (0.1, 12.0) years. Six patients (38%) had a history of non-immune hydrops fetalis. Four patients who reached one year of treatment in the DMP had a mean (SD) decrease of 1.18 (0.35) g GAG/g creatinine in dermatan sulfate uGAG excretion from the parent (clinical) study baseline (88% reduction). Three serious adverse events (SAEs) unrelated to vestronidase alfa occurred: recurrent cervical spinal stenosis, corneal opacity, and parainfluenza virus infection. One SAE, intermittent hypotension, was assessed as an infusion-associated reaction to vestronidase alfa. All SAEs were consistent with the known safety profile of vestronidase alfa. No deaths were reported.
Conclusion(s): Reductions in uGAG demonstrate ongoing effectiveness of vestronidase alfa at Year 1 of the DMP. No newsafety concernswere identified, and all patients continue on-study. Enrollment is ongoing.
Copyright 2021 Elsevier Inc. All rights reserved

During the height of the pandemic in NYC (March-June 2020), the NYU Langone Health Lysosomal Storage Disorders (LSD) Program reached out to 183 patients to provide information on how to mitigate exposure to COVID19 and to ascertain who had been exposed and/or infected. 139 patients were successfully contacted. Recommendations on how to safely continue enzyme replacement therapy (ERT) or substrate reduction therapy (SRT) were provided. 135 of the 139 respondents during March 2020-June 2020 had Gaucher disease (GD). Twenty-six patients with GD endorsed 2 or more symptoms consistent with COVID19 infection and/or were confirmed to have COVID19 either through RT-PCR test for SARS-CoV-2 RNA or through antibodies to the virus. The remaining 4 who had suspected or confirmed COVID19 infection were patients with Fabry (2), Pompe (1), and Mucopolysaccharidosis Type IIIA (1). This case series describes the impact of COVID19 on 30 patients with LSDs with details of symptomatology, duration of illness, and treatment. Baseline demographics were collected including age, sex, genotype, current disease burden, LSD treatment history, biomarkers and co-morbidities. At time of infection, 21 patients were on ERT (20 GD, 1 PD), 3 on SRT for GD, and 6 were naive to therapy. There was only 1 hospitalization of a 55 year old woman with GD on ERT that resulted in ARDS who subsequently died due to SARS-CoV-2. Her co-morbidities included morbid obesity, COPD, hypertension and diabetes. Her GD burden was minimal. The rest of the affected patients had a mild to moderate COVID19 course. In conclusion, patients with LSDs experienced varied symptomatology and severity from COVID19 infection, ranging from asymptomatic to critically ill. Risk factors included baseline health status regardless of specific LSD, age, and associated co-morbidities. The sample is too small to make conclusions on specific impact of treatment status on COVID19 severity.-.
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