Presentation of ichthyosis after substrate reduction therapy in Gaucher type 1.

We describe a case in which a type 1 Gaucher patient developed ichthyosis weeks after starting substrate reduction therapy (SRT) with eliglustat. There are no reports of ichthyosis in the literature in enzyme replacement or SRT for Gaucher disease. Ichthyosis is seen with type 2 and 3 Gaucher disease, but not type 1. This raises the question: Why would a patient develop ichthyosis after starting SRT?

Eliglustat exerts anti-fibrotic effects by activating SREBP2 in TGF-ß1-treated myofibroblasts derived from patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive chronic lung disease. Myofibroblasts play a critical role in fibrosis. These cells produce the extracellular matrix (ECM), which contributes to tissue regeneration; however, excess ECM production can cause fibrosis. Transforming growth factor-ß (TGF-ß)/Smad signaling induces ECM production by myofibroblasts; therefore, the inhibition of TGF-ß/Smad signaling may be an effective strategy for IPF treatment. We recently reported that miglustat, an inhibitor of glucosylceramide synthase (GCS), ameliorates pulmonary fibrosis by inhibiting the nuclear translocation of Smad2/3. In the present study, we examined the anti-fibrotic effects of another GCS inhibitor, eliglustat, a clinically approved drug for treating Gaucher disease type 1, in myofibroblasts derived from patient with IPF (IPF-MyoFs). We found that eliglustat exerted anti-fibrotic effects independent of GCS inhibition, and inhibited TGF-ß1-induced expression of α-smooth muscle actin, a marker of fibrosis, without suppressing the phosphorylation and nuclear translocation of Smad2/3. RNA sequencing analysis of eliglustat-treated human lung fibroblasts identified sterol regulatory element-binding protein 2 (SREBP2) activation. Transient overexpression of SREBP2 attenuated the TGF-ß1-induced increase in the expression of Smad target genes in IPF-MyoFs, and SREBP2 knockdown nullified the inhibitory effect of eliglustat on TGF-ß1-induced expression of α-SMA. These results suggested that eliglustat exerts its anti-fibrotic effects through SREBP2 activation. The findings of this study may contribute to the development of novel therapeutic strategies for IPF treatment.

Impact of COVID-19 pandemic on healthcare delivery for lysosomal storage disorders at a tertiary care public hospital in Mumbai.

Introduction: Management of lysosomal storage disorders (LSDs) requires periodic visits for medical surveillance and hospitalizations. Management of LSDs may have been adversely impacted during the COVID-19 pandemic. Objective: To identify the factors impacting health care for patients with LSDs during the COVID-19 pandemic. Methods: An observational study was conducted in Mumbai comparing infusion practices and reasons for missed infusions for 15 months before March 2020 versus two phases during the pandemic (April 2020-March 2021 and April 2021-March 2022) in patients receiving intravenous enzyme replacement therapy (ERT) and on oral substrate reduction therapy (SRT). Results: Fifteen patients with LSDs were enrolled. Before the pandemic, 6/13 (46%) were receiving ERT at the study site, 4/13 (31%) at a local hospital, and 3/13 (23%) at home; two were on SRT. The median distance traveled for receiving ERT was 37 km, and 4.4 infusions/patient were missed. From April 2020 to March 2021, two more patients opted for home ERT infusions. The median distance traveled for receiving ERT was 37 km, and 11.6 infusions/patient were missed. From April 2021 to March 2022, one more patient opted for home ERT infusions. The median distance traveled for receiving ERT was 7 km, and 5.6 infusions/patient were missed. The pandemic also affected SRT compliance adversely. For all patients, the cause of disrupted treatment was travel curbs (69%) and fear of getting COVID-19 infection (38%). Conclusions: Treatment of LSDs was disrupted during the pandemic, with an increase in missed ERT infusions and SRT doses.

Real life data: follow-up assessment on Spanish Gaucher disease patients treated with eliglustat. TRAZELGA project.

BACKGROUND: The availability of multiple treatments for type 1 Gaucher disease increases the need for real-life studies to evaluate treatment efficacy and safety and provide clinicians with more information to choose the best personalized therapy for their patients. AIMS: To determine whether treatment with eliglustat produces, in adult GD1 patients, ans optimal response in daily clinical practice. METHODS: We designed a real-life study with 2 years of follow-up (TRAZELGA [GEE-ELI-2017-01]) to uniformly evaluate the response and adverse events to eliglustat treatment. This study, conducted in 30 patients across Spain and previously treated with other therapies, included the evaluation of safety and efficacy by assessing visceral enlargement, bone disease (DEXA and T and Z scores), concomitant treatments and adverse events, as well as a quality of life evaluation (SF-36). In addition, the quantification of classical biomarkers (chitotriosidase activity, CCL18/PARC and glucosylsphingosine (GluSph)) and new candidates for GD biomarkers (YKL-40, cathepsin S, hepcidin and lipocalin-2 determined by immunoassay) were also assessed. Non-parametric statistical analysis was performed and p < 0.05 was considered statistically significant. MAIN RESULTS: Thirty patients were enrolled in the study. The median age was 41.5 years and the male-female ratio was 1.1:1. 84% of the patients had received ERT and 16% SRT as previous treatment. The most common symptoms at baseline were fatigue (42%) and bone pain (38%), no patient had a bone crisis during the study, and two years after switching, 37% had reduced their use of analgesics. Patient-reported outcomes showed a significant increase in physical function scores (p = 0.027) and physical pain scores (p = 0.010). None of the enrolled patients discontinued treatment due to adverse events, which were mild and transient in nature, mainly gastrointestinal and skin dryness. None of the biomarkers show a significant increase or decompensation after switching. CCL18/PARC (p = 0.0012), YKL-40 (p = 0.00004) and lipocalin-2 (p = 0.0155) improved after two years and GluSph after one year (p = 0.0008) and two years (p = 0.0245) of oral therapy. CONCLUSION: In summary, this real-life study, showed that eliglustat maintains stability and can improve quality of life with few side effects. Significant reductions in classic and other novel biomarkers were observed after two years of therapy.

Effectiveness and Safety of Eliglustat Treatment in Gaucher Disease: Real-life Unicentric Experience.

PURPOSE: The therapy and management of Gaucher disease (GD) have radically changed with the use of substrate reduction therapy, of which eliglustat is the most widely known drug, allowing it to overcome the limits of enzyme replacement therapy (ERT). The rarity of GD and the limited use of eliglustat outside clinical trials require further study of its strengths and weaknesses. METHODS: In this study, we evaluated the effectiveness and safety of eliglustat in a cohort of 12 patients with GD followed up in our center, reporting a reduction in both chitotriosidase (394.3 vs 181.1 nmol/h/mL, P = 0.027) and glucosylsphingosine values (45.1 vs 18.9 ng/mL, P <0.001) after at least 12 months of therapy compared with baseline, regardless of patient demographic characteristics and GD characteristics. FINDINGS: There were no drug-related serious adverse effects and no drug-related cardiac events. Most adverse events were mild and transient, mainly dyspepsia and abdominal pain. Of interest, we reported an absence of statistical difference in terms of response regarding glucosylsphingosine reduction in relation to naive or prior exposure to ERT (P = 0.296), which was confirmed also when patients were placed in naive and treated groups for <5 vs >5 years (P = 0.667). IMPLICATIONS: The use of eliglustat immediately after diagnosis may guarantee the best treatment for patients with milder phenotypes or with aggressive disease after an initial stabilization with ERT compared with ERT, which cannot adequately remove the disease burden despite the apparent response, thus potentially reducing future complications caused by substrate deposits.

Patient reported outcomes of patients with Gaucher disease type 1 treated with eliglustat in real-world settings: The ELIPRO study.

INTRODUCTION: Gaucher disease type 1 (GD1) is a rare genetic lysosomal storage disorder. Eliglustat is a first-line oral therapy for adult patients with GD1. The aim of the ELIPRO (ELIglustat Patient Reported Outcomes) study was to assess real-world outcomes of eliglustat treatment for over 1 year in patients with GD1, with a focus on patient-reported outcomes (PROs), including treatment adherence. METHODS: This was a non-interventional, prospective, multicentric study. Patients were stratified according to their previous time on eliglustat: >6 months (Group1) and ≤ 6 months (Group2). The primary endpoint was adherence to eliglustat, measured by the eight-items Morisky Medication Adherence Scale (MMAS-8; scale of 0-8) at 6 months in Group2. Secondary endpoints were quality of life (QoL) measured by patient input using the European Quality of Life five-dimensional three-level [EQ-5D-3L] questionnaire, fatigue and pain measured by numeric rating scale [NRS; on a scale of 0-10], the evaluation of patient satisfaction level regarding eliglustat treatment measured by Likert scale [scale of 0-7] and treatment adherence at 12 months in both groups. The study also evaluated the safety and effectiveness of eliglustat in the adult GD1 population. RESULTS: Sixty patients with GD1 (approximatively 52% male, mean age: 46.6 ± 13.9 years) were analyzed: 29 in Group1 and 31 in Group2. GD1 was mostly of mild severity (90%) and 95% of patients had extensive CYP2D6 metabolizer phenotype. Fifty-seven patients had previously received treatment for GD1 (91% enzyme replacement therapy) and 15% were splenectomized. Groups1 and 2 were not necessarily matching for all characteristics. At 6 months, 58% of Group2 patients showed medium adherence (6 < MMAS-8 < 7.75) while 21% showed high adherence (MMAS-8: 8) (mean MMAS-8: 6.7 ± 1.0); similar results were obtained in Group1 (50% showed high compliance, 35% showed medium compliance; mean MMAS-8: 6.8 ± 1.4). The mean MMAS-8 for Group1 and Group2 were 7.1 ± 1.2 (vs 7.0 ± 1.0 at baseline) and 6.5 ± 1.0, respectively, at 12 months. At 12 months, the mean NRS scores in Group1 and Group2 were 72.0 ± 18.5 and 77.3 ± 13.7 for QoL (vs. 71.7 ± 18.4 and 80.2 ± 12.4, respectively at baseline), 4.8 ± 2.6 and 3.6 ± 2.7 for fatigue (vs. 4.6 ± 2.7 and 3.6 ± 2.6, respectively at baseline) and 3.3 ± 2.7 and 2.3 ± 2.3 for pain (vs. 3.3 ± 2.7 and 2.0 ± 2.4, respectively at baseline). GD1 assessments (biological, clinical and imaging parameters) remained stable during 12 months in both groups. At the end of the study, majority (97.4%) of patients were satisfied with their treatment with eliglustat (satisfaction score over 5 out of 7). Sixty-six percent of patients (n = 41) experienced mostly mild adverse events (AE) (including four study withdrawals), of whom 27.4% (n = 17) of patients experienced eliglustat-related AEs. Treatment adherence remained stable during 12 months in both groups. CONCLUSIONS: Eliglustat treatment compliance was good and sustained, along with overall health state, fatigue and pain levels, which was consistent with overall patients' clinical status. Eliglustat was well tolerated, and had a good safety profile, aligned with a good patient satisfaction. Our study should encourage greater use of PROs for evaluation of impact of the GD treatment on patient's symptoms and well-being.

Glucosylceramide Synthase Inhibitors Induce Ceramide Accumulation and Sensitize H3K27 Mutant Diffuse Midline Glioma to Irradiation.

H3K27M mutant (mut) diffuse midline glioma (DMG) is a lethal cancer with no effective cure. The glycosphingolipids (GSL) metabolism is altered in these tumors and could be exploited to develop new therapies. We tested the effect of the glucosylceramide synthase inhibitors (GSI) miglustat and eliglustat on cell proliferation, alone or in combination with temozolomide or ionizing radiation. Miglustat was included in the therapy protocol of two pediatric patients. The effect of H3.3K27 trimethylation on GSL composition was analyzed in ependymoma. GSI reduced the expression of the ganglioside GD2 in a concentration and time-dependent manner and increased the expression of ceramide, ceramide 1-phosphate, sphingosine, and sphingomyelin but not of sphingosine 1-phosphate. Miglustat significantly increased the efficacy of irradiation. Treatment with miglustat according to dose recommendations for patients with Niemann-Pick disease was well tolerated with manageable toxicities. One patient showed a mixed response. In ependymoma, a high concentration of GD2 was found only in the presence of the loss of H3.3K27 trimethylation. In conclusion, treatment with miglustat and, in general, targeting GSL metabolism may offer a new therapeutic opportunity and can be administered in close proximity to radiation therapy. Alterations in H3K27 could be useful to identify patients with a deregulated GSL metabolism.

Plasma glucosylsphingosine correlations with baseline disease burden and response to eliglustat in two clinical trials of previously untreated adults with Gaucher disease type 1.

In Gaucher disease type 1 (GD1), accumulation of the lipid substrates glucosylceramide and glucosylsphingosine (lyso-GL-1 or lyso-Gb1), primarily in the spleen, liver, and bone marrow, leads to progressive hepatosplenomegaly, anemia, thrombocytopenia, and skeletal disease. Plasma glucosylceramide elevations are modest, variable, and normalize within weeks of starting treatment before clinical changes are evident, and therefore, have limited value for monitoring treatment responses. Serum chitotriosidase activity, a widely used GD biomarker, is also elevated in many other conditions but is not measurable in 5-10% of individuals due to a common CHIT1 null variant. Plasma glucosylsphingosine is increasingly recognized as a useful biomarker for GD1: elevations are highly specific to the disease and show no overlap with normal controls, it is in the causal pathway of disease, and levels are reliably measured by liquid chromatography-tandem mass spectrometry. We report correlations of plasma glucosylsphingosine with baseline disease burden and eliglustat treatment response in previously untreated adults with GD1 in the Phase 2 (NCT00358150), open-label, single-arm trial of 26 patients with up to 8 years of follow-up and the placebo-controlled Phase 3 ENGAGE trial (NCT00891202) of 40 patients with up to 4.5 years of follow-up. At baseline, untreated patients showed moderate to strong correlations between plasma glucosylsphingosine and spleen volume, liver volume, and hemoglobin level. Organ volumes and hematologic parameters improved in parallel with reductions in plasma glucosylsphingosine during eliglustat treatment in both trials. Moderate correlations were seen between plasma glucosylsphingosine reduction and spleen and liver volume reductions during eliglustat treatment. These clinical trial data add to the growing body of evidence supporting plasma glucosylsphingosine as both a diagnostic and pharmacodynamic/response biomarker for GD1.

Suicidal attempt with eliglustat overdose.

Eliglustat is an orphan medicine used for long-term treatment of Gaucher disease type 1 (GD1) in adults. GD1 is a genetic condition, in which glucosylceramide builds up in the body, typically in liver, spleen, and bone. Clinical signs and symptoms of the disease are anemia, tiredness, easy bruising, hepatosplenomegaly, bone pain, and fractures. Eliglustat works by blocking glucosylceramide synthase (substrate reduction therapy). This medicine is subject to additional safety monitoring by regulatory authorities in the European Union. Scientific literature on eliglustat overdose is not available. We herein describe successful treatment of a suicidal attempt with massive eliglustat overdose. A 29-year-old female with GD1, a poor metabolizer of cytochrome P450 2D6 on a recommended daily dose of 84 mg of eliglustat, had taken 94 capsules of eliglustat (84 mg per capsule). One hour after ingestion of almost 8 g of eliglustat, the patient suffered from somnolence, severe bradycardia (37 bpm), and hypotension (systolic blood pressure of 70 mm Hg). After intravenous administration of atropine (1 mg) and cafedrine/theoadrenaline (100 mg/5 mg) by the called emergency physician, the patient resolved gradually. She remained 24 h with stable hemodynamics at a nearby intensive care unit. During continuous ECG monitoring, increased frequency of supraventricular ectopic activity and a first-degree atrioventricular block were observed. To our knowledge, this is the first case report on a suicidal attempt with eliglustat.

Inhibitors of Glucosylceramide Synthase.

Glucosylceramide synthase can be targeted by high affinity small molecular weight inhibitors for the study of glycosphingolipid metabolism and function or for the treatment of glycosphingolipid storage disorders, including Gaucher and Fabry disease. This work is exemplified by the discovery and development of eliglustat tartrate, the first stand-alone small chemical entity approved for the treatment of Gaucher disease type 1. The development of inhibitors of glucosylceramide synthase that have utility for either research or clinical purposes begins with a testing funnel for screening candidate inhibitors for activity against this enzyme and for activity in lowering the content of glucosylceramide in intact cells. Two common assays for glucosylceramide synthase, one enzyme based and another cell based, are the focus of this chapter.

Long-term effects of eliglustat on skeletal manifestations in clinical trials of patients with Gaucher disease type 1.

PURPOSE: Most patients with Gaucher disease have progressive and often disabling skeletal manifestations. We examined the long-term effect of eliglustat treatment on bone outcomes in clinical trials in adults with Gaucher disease type 1. METHODS: Data from 4 completed phase 2 and 3 trials were evaluated in treatment-naïve patients or patients switching to eliglustat from enzyme replacement therapy (ERT). RESULTS: Overall, 319 of 393 (81%) eliglustat-treated patients remained in their trials until completion or commercial eliglustat became available. Mean eliglustat treatment duration ranged from 3.3 to 6.5 years. In treatment-naïve patients and ERT-switch patients, frequency and severity of bone pain decreased during eliglustat treatment. Mean lumbar spine T-scores shifted from abnormal to normal in treatment-naïve patients and remained in the healthy reference range or improved modestly in ERT-switch patients. Mean total bone marrow burden score shifted from marked-to-severe to moderate in treatment-naïve patients and remained moderate in ERT-switch patients. MIP-1ß (marker of active bone disease) was elevated at baseline and decreased to the healthy reference range in treatment-naïve patients and remained in the healthy reference range among ERT-switch patients. CONCLUSION: These findings confirm the long-term efficacy of eliglustat on skeletal complications of Gaucher disease in treatment-naïve and ERT-switch patients.

Recomendaciones para el tratamiento oral de pacientes adultos con enfermedad de Gaucher tipo 1 / Recommendations for oral treatment for adult patients with type 1 Gaucher disease

Revisión de la evidencia científica sobre el tratamiento oral de pacientes adultos con enfermedad de Gaucher tipo 1 (EG1), con formato de guía clínica, según la normativa Agree II. Se describen las principales diferencias entre los 2 tratamientos orales disponibles actualmente para el tratamiento de esta entidad (miglustat y eliglustat).En esta revisión se recuerda que los criterios para iniciar el tratamiento oral en los pacientes con EG1 deben valorarse de forma individualizada. Si bien miglustat y eliglustat son inhibidores de la enzima glucosilceramida sintetasa, los 2 presentan diferentes mecanismos de acción y propiedades farmacológicas y nunca se deben considerar como equivalentes. Miglustat está indicado en pacientes con EG1 no grave que no pueden recibir otro tratamiento de primera línea, mientras que eliglustat está indicado en pacientes con EG1 con cualquier gravedad, en primera línea y sin necesidad de estabilización previa con tratamiento de reemplazo enzimático. Es importante enfatizar que para iniciar tratamiento con eliglustat debemos conocer el fenotipo metabólico CYP2D6 y que su asociación con fármacos metabolizados a través de los citocromos CYP2D6 y CYP3A4 –o bien que utilicen la glucoproteína P– se debe evaluar individualmente. Durante el embarazo se debe evitar el uso de eliglustat, pudiéndose emplear únicamente el tratamiento de reemplazo enzimático. A diferencia de miglustat, cuyos efectos adversos han limitado su utilización, eliglustat no solo ha demostrado una eficacia similar a la del tratamiento de reemplazo enzimático, sino que ha demostrado mejoría en la calidad de vida de los pacientes EG1. (AU)

This work is a review of the scientific evidence on the oral treatment of adult patients with Gaucher disease type 1 (GD1) with a clinical guideline format according to the Agree II regulations. It describes the main differences between the 2 oral treatments currently available for treating this disease (miglustat and eliglustat).This review reminds us that the criteria for starting oral treatment in patients with GD1 must be assessed individually. Although miglustat and eliglustat are both glucosylceramide synthase enzyme inhibitors, they have different mechanisms of action and pharmacological properties and should never be considered equivalent. Miglustat is indicated in patients with non-severe GD1 who cannot receive other first-line treatments, while eliglustat is indicated as first-line treatment for patients with GD1 of any severity without the need for prior stabilization with enzyme replacement therapy. It is important to emphasize that in order to start treatment with eliglustat, we must know the CYP2D6 metabolic phenotype and its association with drugs metabolized through the CYP2D6 and CYP3A4 cytochromes –or alternatively those that use P-Glycoprotein– must be evaluated on an individual basis. During pregnancy, the use of eliglustat should be avoided; only enzyme replacement therapy can be used. Unlike miglustat, whose adverse effects have limited its use, eliglustat has not only demonstrated similar efficacy to enzyme replacement therapy but has also been shown to improve the quality of life of patients with GD1. (AU)

Real-Life Experience with Oral Eliglustat in Patients with Gaucher Disease Previously Treated with Enzyme Replacement Therapy.

Three types of enzyme replacement therapies (ERTs) and two substrate reduction therapies (SRTs) are approved for symptomatic patients with type 1 Gaucher disease (GD1). Eliglustat is the second SRT approved, yet the first to be approved as first-line therapy for any adult patients with compatible CYP2D6 metabolizer genotype. Herein we report safety and efficacy data of the first 29 patients switched from ERT to eliglustat from the Gaucher Unit at Shaare Zedek Medical Center (SZMC) between 07/2017 and 06/2022; the median (range) time on ERT was 13 (0.66-30) years, and the median (range) time on eliglustat was 7 (1-52) months. Most patients switched due to oral preference or sub-optimal response to low-dose ERT. Twelve patients stopped eliglustat after a median (range) of 4 (1-18) months; 11 due to adverse events (AEs) and one due to personal request. There were no drug-related serious AEs and no drug-related cardiac events. Most AEs were mild and transient, mainly dyspepsia. Efficacy achievements were reflected by maintaining stability. We concluded that switching from ERT to eliglustat is safe if choosing the appropriate patients. Reassuring patients to tolerate early AEs may reduce discontinuation. Following the response and compliance to therapy is important to ensure long-term efficacy.

Safety and efficacy of eliglustat combined to enzyme replacement therapy for lymphadenopathy in patients with Gaucher disease type 3.

Patients with Gaucher disease type 3 (GD3), especially those with GBA p.L444P homozygous mutation, often suffer from complications including lymphadenopathy even under regular enzyme replacement therapy (ERT). In order to improve their outcome, we administrated eliglustat, a substrate reduction therapy (SRT), in combination with ERT to four patients, age ranged 9-18 years, for two years. The results revealed that patients' plasma glucosylsphingosine (lyso-GL1) level and chitotriosidase activity both decreased after adding eliglustat. In three patients who completed follow-up MRI scanning, sizes of lymph nodes all decreased. No severe adverse events were attributed to eliglustat. Therefore, our data suggest that a combined SRT and ERT treatment may improve the ERT-resistant symptoms in patients with GD3.

Recommendations for oral treatment for adult patients with type 1 Gaucher disease.

This work is a review of the scientific evidence on the oral treatment of adult patients with Gaucher disease type 1 (GD1) with a clinical guideline format according to the Agree II regulations. It describes the main differences between the two oral treatments currently available for treating this disease (miglustat and eliglustat). This review reminds us that the criteria for starting oral treatment in patients with GD1 must be assessed individually. Although miglustat and eliglustat are both glucosylceramide synthase (GCS) enzyme inhibitors, they have different mechanisms of action and pharmacological properties and should never be considered equivalent. Miglustat is indicated in patients with non-severe GD1 who cannot receive other first-line treatments, while eliglustat is indicated as first-line treatment for patients with GD1 of any severity without the need for prior stabilization with enzyme replacement therapy (ERT). It is important to emphasize that in order to start treatment with eliglustat, we must know the CYP2D6 metabolic phenotype and its association with drugs metabolized through the CYP2D6 and CYP3A4 cytochromes-or alternatively those that use P-Glycoprotein must be evaluated on an individual basis. During pregnancy, the use of eliglustat should be avoided; only ERT can be used. Unlike miglustat, whose adverse effects have limited its use, eliglustat has not only demonstrated similar efficacy to ERT but has also been shown to improve the quality of life of patients with GD1.

Total Synthesis of Eliglustat via Diastereoselective Amination of Chiral para-Methoxycinnamyl Benzyl Ether.

Eliglustat (Cerdelga®, Genzyme Corp. Cambridge, MA, USA) is an approved drug for a non-neurological type of Gaucher disease. Herein, we describe the total synthesis of eliglustat 1 starting from readily available 1,4-benzodioxan-6-carbaldehyde via Sharpless asymmetric dihydroxylation and diastereoselective amination of chiral para-methoxycinnamyl benzyl ethers using chlorosulfonyl isocyanate as the key steps. Notably, the reaction between syn-1,2-dibenzyl ether 6 and chlorosulfonyl isocyanate in the mixture of toluene and hexane (10:1) afforded syn-1,2-amino alcohol 5 at a 62% yield with a diastereoselectivity > 20:1. This observation can be explained by competition between the SNi and the SN1 mechanisms, leading to the retention of stereochemistry.

The Shiga Toxin Receptor Globotriaosylceramide as Therapeutic Target in Shiga Toxin E. coli Mediated HUS.

In 90% of the cases, childhood hemolytic uremic syndrome (HUS) is caused by an infection with the Shiga toxin (Stx) producing E. coli bacteria (STEC-HUS). Stx preferentially binds to its receptor, the glycosphingolipid, globotriaosylceramide (Gb3), present on the surface of human kidney cells and various organs. In this study, the glycosphingolipid pathway in endothelial cells was explored as therapeutic target for STEC-HUS. Primary human glomerular microvascular endothelial cells (HGMVECs) and human blood outgrowth endothelial cells (BOECs) in quiescent and activated state were pre-incubated with Eliglustat (Cerdelga®; glucosylceramide synthase inhibitor) or Agalsidase alpha (Replagal®; human cell derived alpha-galactosidase) in combination with various concentrations of Stx2a. Preincubation of endothelial cells with Agalsidase resulted in an increase of α-galactosidase activity in the cell, but had no effect on the binding of Stx to the cell surface when compared to control cells. However, the incubation of both types of endothelial cells incubated with or without the pro-inflammatory cytokine TNFα in combination with Eliglustat resulted in significant decrease of Stx binding to the cell surface, a decrease in protein synthesis by Stx2a, and diminished cellular Gb3 levels as compared to control cells. In conclusion, inhibition of the synthesis of Gb3 may be a potential future therapeutic target to protect against (further) endothelial damage caused by Stx.

Incremental biomarker and clinical outcomes after switch from enzyme therapy to eliglustat substrate reduction therapy in Gaucher disease.

In Gaucher disease (GD), genetic deficiency of acid ß-glucosidase leads to accumulation of its substrate glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph). Lipid-laden cells, most prominently seen as macrophages engorged with GlcCer and GlcSph-laden lysosomes, trigger chronic metabolic inflammation and multisystemic phenotypes. Among the pleiotropic effects of inflammatory cascades, the induction of glucosylceramide synthase accentuates the primary metabolic defect. First-line therapies for adults with GD type 1 include Enzyme Replacement Therapy (ERT) and eliglustat Substrate Reduction Therapy (SRT). The ENCORE phase 3 clinical trial of eliglustat demonstrated non-inferiority compared to ERT. It is not known whether switching stable patients from long-term ERT to SRT results in the incremental reversal of the disease phenotype and its surrogate indicators. Herein, we report real-world experience from a single tertiary referral center of 38 adult GD type 1 patients, stable on long-term ERT (mean 13.3 years), who switched to eliglustat SRT (mean 3.1 years). After switch to SRT, there was significant reduction in spleen volume (P = 0.003) while liver volume, which was normal at baseline, remained unchanged. Platelet counts increased significantly (P = 0.026). Concomitantly, there was reduction of three validated biomarkers of Gaucher disease activity: plasma GlcSph decreased from 63.7 ng/ml (95% CI, 37.6-89.8) to 26.1 ng/ml (95% CI, 15.7-36.6) (P < 0.0001); chitotriosidase fell from 1136.6 nmol/ml/h (95% CI, 144.7-2128.6) to 466.9 nmol/ml/h (95% CI, 209.9-723.9) (P = 0.002); and glycoprotein non-metastatic melanoma B (gpNMB) decreased from 59.3 ng/ml (95% CI, 39.7-78.9) to 43.6 ng/ml (95% CI, 30.7-56.6) (P = 0.0006). There were no episodes of avascular necrosis or fractures in patients on SRT. Patients reported favorable experiences of switching from alternate week infusions to oral therapy. Collectively, these results demonstrate that the switch to eliglustat SRT from ERT leads to incremental response, even in stable patients after long-term ERT.

Exploiting Gangliosides for the Therapy of Ewing's Sarcoma and H3K27M-Mutant Diffuse Midline Glioma.

The ganglioside GD2 is an important target in childhood cancer. Nevertheless, the only therapy targeting GD2 that is approved to date is the monoclonal antibody dinutuximab, which is used in the therapy of neuroblastoma. The relevance of GD2 as a target in other tumor entities remains to be elucidated. Here, we analyzed the expression of GD2 in different pediatric tumor entities by flow cytometry and tested two approaches for targeting GD2. H3K27M-mutant diffuse midline glioma (H3K27M-mutant DMG) samples showed the highest expression of GD2 with all cells strongly positive for the antigen. Ewing's sarcoma (ES) samples also showed high expression, but displayed intra- and intertumor heterogeneity. Osteosarcoma had low to intermediate expression with a high percentage of GD2-negative cells. Dinutuximab beta in combination with irinotecan and temozolomide was used to treat a five-year-old girl with refractory ES. Disease control lasted over 12 months until a single partially GD2-negative intracranial metastasis was detected. In order to target GD2 in H3K27M-mutant DMG, we blocked ganglioside synthesis via eliglustat, since dinutuximab cannot cross the blood-brain barrier. Eliglustat is an inhibitor of glucosylceramide synthase, and it is used for treating children with Gaucher's disease. Eliglustat completely inhibited the proliferation of primary H3K27M-mutant DMG cells in vitro. In summary, our data provide evidence that dinutuximab might be effective in tumors with high GD2 expression. Moreover, disrupting the ganglioside metabolism in H3K27M-mutant DMG could open up a new therapeutic option for this highly fatal cancer.

Pregnancy outcome in women with Gaucher disease type 1 who had unplanned pregnancies during eliglustat clinical trials.

Gaucher disease type 1 (GD1) is an inherited lysosomal storage disorder caused by deficient enzymatic activity of acid ß-glucosidase, resulting in accumulation of its substrate glucosylceramide, leading to debilitating visceral, hematologic, and skeletal manifestations. Women with GD1 are at increased risk for complications during pregnancy, delivery, and postpartum. Treatment with enzyme replacement therapy is generally recommended before and during pregnancy to reduce risks. Eliglustat, an oral substrate-reduction therapy, is a first-line treatment for adults with GD1 adults who have extensive, intermediate, or poor CYP2D6-metabolizer phenotypes (>90% of patients). We report on pregnancy outcomes among women in eliglustat trials who had unplanned pregnancies and female partners of men in the trials. In four phase 2 and 3 eliglustat trials of 393 adults with GD1, women of childbearing potential were required to use contraception, have monthly pregnancy tests, and discontinue eliglustat promptly if pregnant. In phase 2 and 3 trials, 18 women had 19 pregnancies, resulting in 14 healthy infants from 13 pregnancies (one set of twins), three elective terminations, one ectopic pregnancy, one spontaneous abortion, and one in utero death. Median estimated eliglustat exposure duration during pregnancy was 38 days. In phase 1 trials (non-GD1 subjects), one woman had a spontaneous abortion. Partners of 16 eliglustat-treated men with GD1 had 18 pregnancies, all resulting in healthy infants. Eliglustat is not approved during pregnancy due to limited data. Guidelines for clinicians and patients with GD that address use of eliglustat in women of childbearing potential are needed.