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Pilar Giraldo - One of the best experts on this subject based on the ideXlab platform.
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Miglustat therapy in type 1 Gaucher disease: clinical and safety outcomes in a multicenter retrospective cohort study.
Blood cells molecules & diseases, 2013Co-Authors: David J. Kuter, Atul Mehta, Derralynn Hughes, Pilar Giraldo, Nadia Belmatoug, Carla E. M. Hollak, Monika Brand, Audrey Muller, Berthold Schaaf, Ruben GiorginoAbstract:We evaluated clinical and safety outcomes in adult patients with type 1 Gaucher disease receiving Miglustat in clinical practice settings. An observational, retrospective cohort study was conducted in centers across the EU and the USA. Medical chart data were collected from consecutive patients between the 20th November 2002 and 31st December 2008. A total of 115 patients were included; 34 (30%) were enzyme replacement therapy-naive ('naive') and 81 (70%) were enzyme pretreated ('pretreated'). Median (range) Miglustat exposures in these groups were 15.1 (0.6-52.9)months and 15.2 (0.3-62.1)months, respectively. Low numbers of patients were anemic (10/101) or thrombocytopenic (21/101) at initiation of Miglustat therapy. The median (range) hemoglobin concentration at Miglustat initiation was 12.8 (10.2-16.4)g/dl in naive patients and 13.6 (7.3-17.4)g/dl in pretreated patients; median (range) changes in hemoglobin were 0.3 (-2.5-3.6) and -0.3 (-4-4.6)g/dl, respectively. The median (range) platelet counts at Miglustat initiation were 101 (37-730)×10(9)/l in naive patients and 173 (43-382)×10(9)/l in pretreated patients; median (range) changes in platelet count were 8 (-77-145)×10(9)/l and -10 (-144-434)×10(9)/l, respectively. Plasma chitotriosidase was substantially reduced in naive but not in pretreated patients. Organ volumes were not routinely monitored. Forty-nine (43%) patients discontinued Miglustat; most due to gastrointestinal manifestations and some due to tremor. Overall, hemoglobin and platelet counts tended to increase in naive patients treated with Miglustat, and to remain stable or decrease slightly in pretreated patients. The profile of safety and tolerability observed with Miglustat in the current study is similar to previous studies.
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Miglustat Therapy in Type 1 Gaucher Disease: Long-Term Treatment Experience From a Multicenter, Retrospective Cohort Study,
Blood, 2011Co-Authors: David J. Kuter, Atul Mehta, Derralynn Hughes, Pilar Giraldo, Nadia Belmatoug, Carla E. M. Hollak, Monika Brand, Audrey Muller, Berthold Schaaf, Ruben GiorginoAbstract:Abstract 3207 Introduction: Miglustat (Zavesca®) was approved for the treatment of adults with mild-to-moderate type 1 Gaucher disease (GD1) for whom enzyme replacement therapy (ERT) is either unsuitable or not a therapeutic option in the EU in 2002 and in the USA in 2003. However, data from real-world clinical experience with Miglustat remain limited. Methods: Medical chart data were collected from consecutive adult GD1 patients who initiated commercial Miglustat therapy at centers in 9 EU countries or the US after 20th November 2002. Both ERT-naive and ERT-pretreated patients were included. Follow-up data were collected from Miglustat initiation to the end of the observation period (i.e. last information/visit before the end of the study on 31st December 2008, death or loss to follow up). Data on patient demographics, medical history and disease characteristics were collected. Outcome assessments included hematological and biochemical parameters, liver/spleen volumes, gastrointestinal signs/symptoms and neurological manifestations. Results: 115 patients (55% female; mean±SD age at Miglustat initiation 45±14 years) were enrolled, among whom 34 (30%) were ERT-naive and 81 (70%) were ERT-pretreated. The median (range) Miglustat exposure was 15 (1 – 53) months in ERT-naive and 15 (0 – 62) months in ERT-pretreated patients. At the time of Miglustat initiation the median (range) hemoglobin concentration in ERT-naive patients (n=24) was 12.8 (10.2 – 16.4) g/dl, and in ERT-pretreated patients (n=65) it was 13.6 (7.3 – 17.4) g/dl; 5 patients in each group had anemia. The median (range) change in hemoglobin from Miglustat initiation to last assessment in ERT-naive patients was 0.3 (−2.5 – 3.6) g/dl, and in ERT-pretreated patients it was −0.3 (−4 – 4.6) g/dl. In the subgroup of patients with anemia the median (range) change was 1.3 (0.1 – 3.6) g/dl in the 5 ERT-naive patients and 2.6 (−2.7 – 4.6) in the 5 ERT-pretreated patients. At the time of Miglustat initiation the median (range) platelet count in ERT-naive patients (n=25) was 101 (37 – 730) ×109/l, and in ERT-pretreated patients (n=65) it was 173 (43 – 382) ×109/l; 12 patients in the ERT-naive and 9 in the ERT-pretreated group had thrombocytopenia. The median (range) change in platelet count was 8 (−77 – 145) ×109/l in ERT-naive patients and −10 (−144 – 434) ×109/l in ERT-pretreated patients. In the subgroup of patients with thrombocytopenia, the median (range) change was 31 (−29 – 145) ×109/l in the 12 ERT-naive patients and 14 (−32 – 434) ×109/l in the 9 ERT-pretreated patients. Plasma chitotriosidase was highly variable. Substantial median (range) reductions were seen in 20 evaluable ERT-naive patients [−1365 (−13216 – 3477) nmol/ml/h] but not in the 43 evaluable ERT-pretreated patients [20 (−2700 – 12431) nmol/ml/h]. Few patients had spleen and liver organ volume data recorded. Forty-nine patients (43%) discontinued Miglustat during the observation period. Tolerability issues, primarily gastrointestinal, were the most frequent reason for discontinuation, accounting for 32 (28%) of all 115 patients. Other reasons included: non-medical (n=7), insufficient efficacy (n=5), switch to ERT (n=4), and patient death (n=1). Tremor was observed in 3/115 (3%) patients before, and in 18/115 (16%) after Miglustat initiation. Conclusions: Based on hematological parameters, we observed that Miglustat can maintain disease stability in GD1 patients, irrespective of previous ERT therapy. Although based on a limited number of patients, benefits appeared more pronounced in analyses of anemic and thrombocytopenic patients. Gastrointestinal manifestations remain a concern, leading to discontinuation in around one-third of patients. The safety profile of Miglustat was similar to that in previous clinical trials. Disclosures: Kuter:Actelion: Consultancy. Mehta:Actelion: Consultancy. Hollak:Actelion: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau. Hughes:Actelion: Consultancy. Belmatoug:Actelion: Consultancy, Research Funding. Brand:Actelion: Employment. Muller:Actelion: Employment. Schaaf:Factum Gmbh: Consultancy. Giorgino:Actelion: Employment. Zimran:Actelion: Honoraria.
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Gastrointestinal disturbances and their management in Miglustat-treated patients
Journal of Inherited Metabolic Disease, 2011Co-Authors: Nadia Belmatoug, Pilar Giraldo, Alberto Burlina, Chris J. Hendriksz, David J. Kuter, Eugen Mengel, Gregory M. PastoresAbstract:Miglustat (Zavesca®) is approved for the oral treatment of adult patients with mild to moderate type 1 Gaucher disease (GD1) for whom enzyme replacement therapy is unsuitable, and for the treatment of progressive neurological manifestations in adult and paediatric patients with Niemann-Pick disease type C (NP-C). Gastrointestinal disturbances such as diarrhoea, flatulence and abdominal pain/discomfort have consistently been reported as the most frequent adverse events associated with Miglustat during clinical trials and in real-world clinical practice settings. These adverse events are generally mild or moderate in severity, occurring mostly during the initial weeks of therapy. The mechanism underlying these gastrointestinal disturbances is the inhibition by Miglustat of intestinal disaccharidase enzymes (mainly sucrase and maltase), leading to sub-optimal hydrolysis of carbohydrates and subsequent osmotic diarrhoea and altered colonic fermentation. Transient decreases in body weight, which are often observed during initial Miglustat therapy, are considered likely due to gastrointestinal carbohydrate malabsorption and associated negative caloric balance. While most cases of diarrhoea resolve spontaneously during continued Miglustat therapy, diarrhoea also responds well to anti-propulsive medications such as loperamide. Dietary modifications such as reduced consumption of dietary sucrose, maltose and lactose have been shown to improve the gastrointestinal tolerability of Miglustat and reduce the magnitude of any changes in body weight, particularly if initiated at or before the start of therapy. Miglustat dose escalation at treatment initiation may also reduce gastrointestinal disturbances. This article discusses these aspects in detail, and provides practical recommendations on how to optimize the gastrointestinal tolerability of Miglustat.
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Real-world clinical experience with long-term Miglustat maintenance therapy in type 1 Gaucher disease: the ZAGAL project
Haematologica, 2009Co-Authors: Pilar Giraldo, Koldo Atutxa, Abelardo Barez, Pilar Alfonso, Rafael Franco, Dora Alonso, Alejandro Martín, Paz Latre, M.a. Fernandez-galan, Miguel PocoviAbstract:There are few published data from real-world clinical experience with Miglustat (Zavesca®), an oral inhibitor of glucosylceramide synthase, in type 1 Gaucher disease. We report data from a prospective, open-label investigational study that evaluated substrate reduction therapy with Miglustat 100 mg t.i.d. as a maintenance therapy in patients with Type 1 Gaucher disease who had been switched from previous enzyme replacement therapy. Long-term data on changes in organ size, blood counts, disease severity bio-markers, bone marrow infiltration, overall clinical status and safety/tolerability were analyzed from 28 patients with Type 1 Gaucher disease who were attending routine clinic visits. Assessments were performed at six, 12, 24, 36 and 48 months of therapy. Disease severity biomarkers improved up to 48 months after initiation of Miglustat, while other disease parameters remained stable. Miglustat showed an acceptable profile of safety and tolerability throughout treatment. In conclusion, Miglustat is an effective therapy for the long-term maintenance of patients with Type 1 Gaucher disease previously stabilized with enzyme replacement therapy.
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Goal-oriented therapy with Miglustat in Gaucher disease
Current medical research and opinion, 2008Co-Authors: Gregory M. Pastores, Pilar Giraldo, Patrick Chérin, Atul MehtaAbstract:ABSTRACTBackground: Gaucher disease (GD) is a highly heterogeneous disorder with multisystem involvement. Specific therapeutic goals for each manifestation of type 1 GD (GD1) were established in 2004 by an international panel of experts, to facilitate better management of GD1 patients. The goals were defined based on experience with enzyme replacement therapy (ERT) using imiglucerase. Miglustat, a small iminosugar, is the only commercially available substrate reduction therapy (SRT) for patients with GD1. Several clinical studies have demonstrated the beneficial effects of Miglustat on cardinal disease manifestations of GD1.Objective: To review the currently available data on Miglustat, and provide guidance on the attainment of the GD therapeutic goals with Miglustat therapy.Methods: A literature search identified publications on Miglustat using MEDLINE, HighWire Press, and Google Scholar databases. Articles were identified using the terms ‘Miglustat’ and ‘Gaucher disease type 1’.Findings: Improvements in...
Derralynn Hughes - One of the best experts on this subject based on the ideXlab platform.
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results from a 9 year intensive safety surveillance scheme is 3 in Miglustat zavesca treated patients
Pharmacoepidemiology and Drug Safety, 2015Co-Authors: Monika Brand, Audrey Muller, Bruno Bembi, Jonathan Alsop, Ivo N. Van Schaik, Derralynn HughesAbstract:Background Following approval in the EU in 2002 and the USA in 2003, an Intensive Safety Surveillance Scheme (IS3) was initiated to educate prescribers on the appropriate use of Miglustat for the treatment of type I Gaucher disease (GD1), and to actively solicit safety-relevant information. This report summarises data from all patients enrolled in IS3 between its initiation in 2003 and its closure in October 2012. Methods The IS3 was a prospective observational drug registry with a secure internet-based data capture system. All patients receiving Miglustat at participating sites received standard medical care according to routine medical practice. Data on patient and disease characteristics were collected at patient enrolment, subsequent follow-up visits and treatment discontinuation (if applicable). Data were summarised using descriptive statistics. Results During the 9 years of IS3, 407 patients were enrolled at 111 sites across 15 European countries. Approximately half (n = 202) had GD1, and half had other diseases (mainly Niemann–Pick disease type C (NP-C), for which Miglustat was approved in Europe in 2009). In total, 368 patients had data from at least one follow-up visit, 192 of whom had GD1. IS3 provided data from 798 patient-years exposure to Miglustat. Safety-relevant data were consistent with earlier published 5-year findings from IS3, the safety profile reported for Miglustat in GD1 clinical trials and other published information on GD1 manifestations. Conclusions Overall, the results of this long-term safety surveillance programme were in line with the well-known, documented safety profile of Miglustat. Copyright © 2015 John Wiley & Sons, Ltd.
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Results from a 9-year Intensive Safety Surveillance Scheme (IS(3) ) in Miglustat (Zavesca(®) )-treated patients.
Pharmacoepidemiology and drug safety, 2015Co-Authors: Monika Brand, Audrey Muller, Bruno Bembi, Jonathan Alsop, Ivo N. Van Schaik, Derralynn HughesAbstract:Background Following approval in the EU in 2002 and the USA in 2003, an Intensive Safety Surveillance Scheme (IS3) was initiated to educate prescribers on the appropriate use of Miglustat for the treatment of type I Gaucher disease (GD1), and to actively solicit safety-relevant information. This report summarises data from all patients enrolled in IS3 between its initiation in 2003 and its closure in October 2012. Methods The IS3 was a prospective observational drug registry with a secure internet-based data capture system. All patients receiving Miglustat at participating sites received standard medical care according to routine medical practice. Data on patient and disease characteristics were collected at patient enrolment, subsequent follow-up visits and treatment discontinuation (if applicable). Data were summarised using descriptive statistics. Results During the 9 years of IS3, 407 patients were enrolled at 111 sites across 15 European countries. Approximately half (n = 202) had GD1, and half had other diseases (mainly Niemann–Pick disease type C (NP-C), for which Miglustat was approved in Europe in 2009). In total, 368 patients had data from at least one follow-up visit, 192 of whom had GD1. IS3 provided data from 798 patient-years exposure to Miglustat. Safety-relevant data were consistent with earlier published 5-year findings from IS3, the safety profile reported for Miglustat in GD1 clinical trials and other published information on GD1 manifestations. Conclusions Overall, the results of this long-term safety surveillance programme were in line with the well-known, documented safety profile of Miglustat. Copyright © 2015 John Wiley & Sons, Ltd.
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Miglustat therapy in type 1 Gaucher disease: clinical and safety outcomes in a multicenter retrospective cohort study.
Blood cells molecules & diseases, 2013Co-Authors: David J. Kuter, Atul Mehta, Derralynn Hughes, Pilar Giraldo, Nadia Belmatoug, Carla E. M. Hollak, Monika Brand, Audrey Muller, Berthold Schaaf, Ruben GiorginoAbstract:We evaluated clinical and safety outcomes in adult patients with type 1 Gaucher disease receiving Miglustat in clinical practice settings. An observational, retrospective cohort study was conducted in centers across the EU and the USA. Medical chart data were collected from consecutive patients between the 20th November 2002 and 31st December 2008. A total of 115 patients were included; 34 (30%) were enzyme replacement therapy-naive ('naive') and 81 (70%) were enzyme pretreated ('pretreated'). Median (range) Miglustat exposures in these groups were 15.1 (0.6-52.9)months and 15.2 (0.3-62.1)months, respectively. Low numbers of patients were anemic (10/101) or thrombocytopenic (21/101) at initiation of Miglustat therapy. The median (range) hemoglobin concentration at Miglustat initiation was 12.8 (10.2-16.4)g/dl in naive patients and 13.6 (7.3-17.4)g/dl in pretreated patients; median (range) changes in hemoglobin were 0.3 (-2.5-3.6) and -0.3 (-4-4.6)g/dl, respectively. The median (range) platelet counts at Miglustat initiation were 101 (37-730)×10(9)/l in naive patients and 173 (43-382)×10(9)/l in pretreated patients; median (range) changes in platelet count were 8 (-77-145)×10(9)/l and -10 (-144-434)×10(9)/l, respectively. Plasma chitotriosidase was substantially reduced in naive but not in pretreated patients. Organ volumes were not routinely monitored. Forty-nine (43%) patients discontinued Miglustat; most due to gastrointestinal manifestations and some due to tremor. Overall, hemoglobin and platelet counts tended to increase in naive patients treated with Miglustat, and to remain stable or decrease slightly in pretreated patients. The profile of safety and tolerability observed with Miglustat in the current study is similar to previous studies.
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Miglustat Therapy in Type 1 Gaucher Disease: Long-Term Treatment Experience From a Multicenter, Retrospective Cohort Study,
Blood, 2011Co-Authors: David J. Kuter, Atul Mehta, Derralynn Hughes, Pilar Giraldo, Nadia Belmatoug, Carla E. M. Hollak, Monika Brand, Audrey Muller, Berthold Schaaf, Ruben GiorginoAbstract:Abstract 3207 Introduction: Miglustat (Zavesca®) was approved for the treatment of adults with mild-to-moderate type 1 Gaucher disease (GD1) for whom enzyme replacement therapy (ERT) is either unsuitable or not a therapeutic option in the EU in 2002 and in the USA in 2003. However, data from real-world clinical experience with Miglustat remain limited. Methods: Medical chart data were collected from consecutive adult GD1 patients who initiated commercial Miglustat therapy at centers in 9 EU countries or the US after 20th November 2002. Both ERT-naive and ERT-pretreated patients were included. Follow-up data were collected from Miglustat initiation to the end of the observation period (i.e. last information/visit before the end of the study on 31st December 2008, death or loss to follow up). Data on patient demographics, medical history and disease characteristics were collected. Outcome assessments included hematological and biochemical parameters, liver/spleen volumes, gastrointestinal signs/symptoms and neurological manifestations. Results: 115 patients (55% female; mean±SD age at Miglustat initiation 45±14 years) were enrolled, among whom 34 (30%) were ERT-naive and 81 (70%) were ERT-pretreated. The median (range) Miglustat exposure was 15 (1 – 53) months in ERT-naive and 15 (0 – 62) months in ERT-pretreated patients. At the time of Miglustat initiation the median (range) hemoglobin concentration in ERT-naive patients (n=24) was 12.8 (10.2 – 16.4) g/dl, and in ERT-pretreated patients (n=65) it was 13.6 (7.3 – 17.4) g/dl; 5 patients in each group had anemia. The median (range) change in hemoglobin from Miglustat initiation to last assessment in ERT-naive patients was 0.3 (−2.5 – 3.6) g/dl, and in ERT-pretreated patients it was −0.3 (−4 – 4.6) g/dl. In the subgroup of patients with anemia the median (range) change was 1.3 (0.1 – 3.6) g/dl in the 5 ERT-naive patients and 2.6 (−2.7 – 4.6) in the 5 ERT-pretreated patients. At the time of Miglustat initiation the median (range) platelet count in ERT-naive patients (n=25) was 101 (37 – 730) ×109/l, and in ERT-pretreated patients (n=65) it was 173 (43 – 382) ×109/l; 12 patients in the ERT-naive and 9 in the ERT-pretreated group had thrombocytopenia. The median (range) change in platelet count was 8 (−77 – 145) ×109/l in ERT-naive patients and −10 (−144 – 434) ×109/l in ERT-pretreated patients. In the subgroup of patients with thrombocytopenia, the median (range) change was 31 (−29 – 145) ×109/l in the 12 ERT-naive patients and 14 (−32 – 434) ×109/l in the 9 ERT-pretreated patients. Plasma chitotriosidase was highly variable. Substantial median (range) reductions were seen in 20 evaluable ERT-naive patients [−1365 (−13216 – 3477) nmol/ml/h] but not in the 43 evaluable ERT-pretreated patients [20 (−2700 – 12431) nmol/ml/h]. Few patients had spleen and liver organ volume data recorded. Forty-nine patients (43%) discontinued Miglustat during the observation period. Tolerability issues, primarily gastrointestinal, were the most frequent reason for discontinuation, accounting for 32 (28%) of all 115 patients. Other reasons included: non-medical (n=7), insufficient efficacy (n=5), switch to ERT (n=4), and patient death (n=1). Tremor was observed in 3/115 (3%) patients before, and in 18/115 (16%) after Miglustat initiation. Conclusions: Based on hematological parameters, we observed that Miglustat can maintain disease stability in GD1 patients, irrespective of previous ERT therapy. Although based on a limited number of patients, benefits appeared more pronounced in analyses of anemic and thrombocytopenic patients. Gastrointestinal manifestations remain a concern, leading to discontinuation in around one-third of patients. The safety profile of Miglustat was similar to that in previous clinical trials. Disclosures: Kuter:Actelion: Consultancy. Mehta:Actelion: Consultancy. Hollak:Actelion: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau. Hughes:Actelion: Consultancy. Belmatoug:Actelion: Consultancy, Research Funding. Brand:Actelion: Employment. Muller:Actelion: Employment. Schaaf:Factum Gmbh: Consultancy. Giorgino:Actelion: Employment. Zimran:Actelion: Honoraria.
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Miglustat zavesca in type 1 gaucher disease 5 year results of a post authorisation safety surveillance programme
Pharmacoepidemiology and Drug Safety, 2009Co-Authors: Carla E. M. Hollak, Derralynn Hughes, Ivo N Van Schaik, B Schwierin, Bruno BembiAbstract:SUMMARY Purpose Miglustat (Zavesca 1 ) is an orally-available substrate reduction therapy (SRT) for treatment of mild-to-moderate type 1 Gaucher disease (GD1) in adult patients unsuitable for enzyme replacement therapy (ERT). Miglustat has not been evaluated inchildren with GD1, and isnot used during pregnancy and breast-feeding. A non-interventional, prospective, web-based safety surveillance programmewas initiated at the time of the European launch of Miglustat in 2003, and is ongoing. We report the first 5 years of collected data, focusing on neurological manifestations. Methods Data were collected on 122 GD1 patients between March 2003 and April 2008, representing 244 patient-years cumulative Miglustat post-authorisation experience. The electronically-captured data collected from participating physicians includes patient demographics, prior and current therapies, baseline disease manifestations and concurrent conditions, disease severity, duration of Miglustat exposure, and safety-relevant information. Results Mean (SD) age at baseline was 46.1 (16.5) years. At baseline, bone disease and neurological manifestations were reported in 55.6 and 28.6% of patients, respectively; the latter included peripheral neuropathy (7.2%) and a wide variety of neurological symptoms and signs. In addition, 23.2% had other health conditions relevant to neurological status. During the reporting period, new neurological manifestations were reported in 23 (18.9%) patients, principally tremor. Thirty-five (28.7%) patients discontinued treatment, predominantly for gastrointestinal (GI) disturbances (11.5%), two-thirds of which occurred during the first 6 months. Conclusion The safety profile of Miglustat in GD1 patients included in the safety surveillance programme is overall consistent with that reported in the registration and other clinical trials, and no new safety finding was identified. Copyright # 2009 John Wiley & Sons, Ltd. key words—Miglustat; type 1 Gaucher disease; neurological manifestations; post-authorisation safety surveillance programme
Rafael Franco - One of the best experts on this subject based on the ideXlab platform.
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substrate reduction therapy with Miglustat in type 1 gaucher disease in spain nine years outcomes update on zagal study
Blood, 2013Co-Authors: Marcio M Andrade, Pilar Irún, Blanca Medrano, Koldo Atutxa, Angeles M Fernandezgalan, Abelardo Barez, Inmaculada Roig, Pilar Alfonso, Rafael Franco, Vicente GinerAbstract:Substrate reduction therapy (SRT) has showed as an useful therapy in type 1 GD patients with mild or moderate disease. The main limitation to use Miglustat has been the gastrointestinal adverse events. Since 2004 we have conducted the ZAGAL (Zavesca en Gaucher Leve) study for monitoring the real-life use of Miglustat in Spanish adult patients with mild-to moderate disease. The study included GD1 patient’s naive to therapy as well as patients who have previously been treated with ERT. For follow-up, the therapeutic goals for GD therapy by Pastores GM et al were applied. To date a total of 351 GD1 patients have been diagnosed in Spain (FEETEG unpublished. 2013); from 2004 until 2013, 53 of them have been exposed of Miglustat (15.1%). In 16 patients (30.2%) Miglustat was the first line of therapy and the remaining 38 switched from ERT. Currently 37 patients (mean age 43.6 y, range 22-83) 50.9% females, are on Miglustat therapy (20 at least for 5 years and 13 during more than 8 years). Related to efficacy, the therapy permit to achieve a stable hemoglobin concentration level and spleen reduced volume, but we recorded a decrease of absolute platelet count in 15 patients (28.3%) (mean: 35x109/L, range: 10-86x109/L). Related to biomarkers changes an increase in CT activity was observed in 56.6% of patients (mean: 2,448 nmol/mL.h, range 135-13,687) and 43.4 % for CCL18/PARC (mean: 250 ng/mL, range: 19-1016). Seventeen patients (32.1%) had transitory gastrointestinal disturbances. Sixteen patients (30.2%) discontinued therapy: one of them for pregnancy, two by bone crisis, two by weight loss, one for bad compliance and ten by gastrointestinal discomfort or intolerance (18.8%). 60% of patients has a fine tremor in first months on therapy. 4 died by non-related causes (2 cancer, 1 hearth attack, 1 liver failure), Conclusion The long term follow-up of GD patients treated with Miglustat shows that more than 69% had achieved and maintains the therapeutic goals. A high individual variability had been observed related to Miglustat gastrointestinal intolerance apparently no related with GBA genotype, gender and age, but possibly associated with disacaridases inhibition and food habits. Disclosures: No relevant conflicts of interest to declare.
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Real-world clinical experience with long-term Miglustat maintenance therapy in type 1 Gaucher disease: the ZAGAL project
Haematologica, 2009Co-Authors: Pilar Giraldo, Koldo Atutxa, Abelardo Barez, Pilar Alfonso, Rafael Franco, Dora Alonso, Alejandro Martín, Paz Latre, M.a. Fernandez-galan, Miguel PocoviAbstract:There are few published data from real-world clinical experience with Miglustat (Zavesca®), an oral inhibitor of glucosylceramide synthase, in type 1 Gaucher disease. We report data from a prospective, open-label investigational study that evaluated substrate reduction therapy with Miglustat 100 mg t.i.d. as a maintenance therapy in patients with Type 1 Gaucher disease who had been switched from previous enzyme replacement therapy. Long-term data on changes in organ size, blood counts, disease severity bio-markers, bone marrow infiltration, overall clinical status and safety/tolerability were analyzed from 28 patients with Type 1 Gaucher disease who were attending routine clinic visits. Assessments were performed at six, 12, 24, 36 and 48 months of therapy. Disease severity biomarkers improved up to 48 months after initiation of Miglustat, while other disease parameters remained stable. Miglustat showed an acceptable profile of safety and tolerability throughout treatment. In conclusion, Miglustat is an effective therapy for the long-term maintenance of patients with Type 1 Gaucher disease previously stabilized with enzyme replacement therapy.
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Real-World Clinical Experience with Long-Term Miglustat Therapy in Type 1 Gaucher Disease: The ZAGAL Project
Blood, 2008Co-Authors: Pilar Giraldo, Abelardo Barez, Pilar Alfonso, Rafael Franco, Mangeles Fernández-galán, Guillermo Martín-núñez, Dora Alonso, Antonio Acedo, Alejandro Martín, Elvira Martinez-estefanoAbstract:Background and objectives: Several reports describe the use of Miglustat (Zavesca ® ), an oral inhibitor of glucosylceramide synthase, for type 1 Gaucher disease (GD1) in clinical trials. There are few data on the use of Miglustat for GD1 in the real-world clinical experience. Here, we assess the long-term efficacy, tolerability and safety of Miglustat in a prospective, open-label, observational study of GD1 patients attending routine clinic visits. Design and Methods: 48 patients with mild-to-moderate GD1 received Miglustat 100 mg t.i.d. over 36 months. Patients were analysed in two groups: therapy-naive patients (n = 11) and those switched from previous treatment with enzyme replacement therapy (ERT; n = 37). Assessments of clinical status, haematological parameters, and organomegaly were performed before treatment and after 6, 12, 24 and 36 months of therapy. Data were compared with a historical reference cohort 29 GD1 patients treated for 36 months with ERT. Results: Nine treatment-naive patients completed 36 months of Miglustat therapy. Sustained improvements in haemoglobin were seen in all patients who had anaemia before treatment. Platelet counts improved in patients with initial thrombocytopenia, and were maintained in patients with normal counts at baseline. Plasma chitotriosidase activity decreased in treatment-naive patients during the first year on therapy and remained stable thereafter. S-MRI findings indicated improved bone status at 36 months. In patients switched from ERT, 15 completed 36 months of Miglustat therapy, and displayed maintained or improved clinical and haematological parameters, and surrogate disease severity markers. No statistically significant differences were observed at 36 months between treatmentnaive patients with similar baseline characteristics treated with either Miglustat or ERT. Overall, Miglustat was well tolerated. Interpretation and conclusions: Miglustat provided appreciable therapeutic responses on clinical, haematological, biomarker and S-MRI parameters at 36 months in patients with GD1, and was well tolerated. Therapeutic responses with Miglustat were comparable with those seen with ERT.
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neurologic improvement in a type 3 gaucher disease patient treated with imiglucerase Miglustat combination
Epilepsia, 2007Co-Authors: Jose Luis Capablo, Pilar Alfonso, Rafael Franco, Miguel Pocovi, Alicia Saenz De Cabezon, Pilar GiraldoAbstract:Summary: Purpose: Gaucher disease (GD) is an autosomal recessive lysosomal disorder caused by a deficiency of glucocerebrosidase. The neurologic manifestations of GD patients have to date been refractory to any treatment approach. We present a report of a neuronopathic GD patient whose myoclonic epilepsy improved after combination therapy with imiglucerase and Miglustat. Methods: In an adult type 3 GD patient who, despite good visceral and analytic response to ERT, developed progressive neurologic deterioration with marked myoclonic epilepsy and dystonia, we added Miglustat to the enzyme-replacement therapy. Results: After 2 years of combined Miglustat (200 mg, 3 t.i.d.) and imiglucerase (60 IU/kg every 2 weeks), generalized tonic–clonic seizures decreased, speech improved, and the general neurologic clinical picture improved markedly. The EEG showed a reduction in focal and generalized paroxysmal discharges. No significant adverse effects were observed. Conclusions: Combined imiglucerase and Miglustat therapy may be beneficial for some neuronopathic forms of GD.
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Neurologic improvement in a type 3 Gaucher disease patient treated with imiglucerase/Miglustat combination.
Epilepsia, 2007Co-Authors: Jose Luis Capablo, Pilar Alfonso, Rafael Franco, Miguel Pocovi, Alicia Saenz De Cabezon, Pilar GiraldoAbstract:Summary: Purpose: Gaucher disease (GD) is an autosomal recessive lysosomal disorder caused by a deficiency of glucocerebrosidase. The neurologic manifestations of GD patients have to date been refractory to any treatment approach. We present a report of a neuronopathic GD patient whose myoclonic epilepsy improved after combination therapy with imiglucerase and Miglustat. Methods: In an adult type 3 GD patient who, despite good visceral and analytic response to ERT, developed progressive neurologic deterioration with marked myoclonic epilepsy and dystonia, we added Miglustat to the enzyme-replacement therapy. Results: After 2 years of combined Miglustat (200 mg, 3 t.i.d.) and imiglucerase (60 IU/kg every 2 weeks), generalized tonic–clonic seizures decreased, speech improved, and the general neurologic clinical picture improved markedly. The EEG showed a reduction in focal and generalized paroxysmal discharges. No significant adverse effects were observed. Conclusions: Combined imiglucerase and Miglustat therapy may be beneficial for some neuronopathic forms of GD.
Bruno Bembi - One of the best experts on this subject based on the ideXlab platform.
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results from a 9 year intensive safety surveillance scheme is 3 in Miglustat zavesca treated patients
Pharmacoepidemiology and Drug Safety, 2015Co-Authors: Monika Brand, Audrey Muller, Bruno Bembi, Jonathan Alsop, Ivo N. Van Schaik, Derralynn HughesAbstract:Background Following approval in the EU in 2002 and the USA in 2003, an Intensive Safety Surveillance Scheme (IS3) was initiated to educate prescribers on the appropriate use of Miglustat for the treatment of type I Gaucher disease (GD1), and to actively solicit safety-relevant information. This report summarises data from all patients enrolled in IS3 between its initiation in 2003 and its closure in October 2012. Methods The IS3 was a prospective observational drug registry with a secure internet-based data capture system. All patients receiving Miglustat at participating sites received standard medical care according to routine medical practice. Data on patient and disease characteristics were collected at patient enrolment, subsequent follow-up visits and treatment discontinuation (if applicable). Data were summarised using descriptive statistics. Results During the 9 years of IS3, 407 patients were enrolled at 111 sites across 15 European countries. Approximately half (n = 202) had GD1, and half had other diseases (mainly Niemann–Pick disease type C (NP-C), for which Miglustat was approved in Europe in 2009). In total, 368 patients had data from at least one follow-up visit, 192 of whom had GD1. IS3 provided data from 798 patient-years exposure to Miglustat. Safety-relevant data were consistent with earlier published 5-year findings from IS3, the safety profile reported for Miglustat in GD1 clinical trials and other published information on GD1 manifestations. Conclusions Overall, the results of this long-term safety surveillance programme were in line with the well-known, documented safety profile of Miglustat. Copyright © 2015 John Wiley & Sons, Ltd.
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Results from a 9-year Intensive Safety Surveillance Scheme (IS(3) ) in Miglustat (Zavesca(®) )-treated patients.
Pharmacoepidemiology and drug safety, 2015Co-Authors: Monika Brand, Audrey Muller, Bruno Bembi, Jonathan Alsop, Ivo N. Van Schaik, Derralynn HughesAbstract:Background Following approval in the EU in 2002 and the USA in 2003, an Intensive Safety Surveillance Scheme (IS3) was initiated to educate prescribers on the appropriate use of Miglustat for the treatment of type I Gaucher disease (GD1), and to actively solicit safety-relevant information. This report summarises data from all patients enrolled in IS3 between its initiation in 2003 and its closure in October 2012. Methods The IS3 was a prospective observational drug registry with a secure internet-based data capture system. All patients receiving Miglustat at participating sites received standard medical care according to routine medical practice. Data on patient and disease characteristics were collected at patient enrolment, subsequent follow-up visits and treatment discontinuation (if applicable). Data were summarised using descriptive statistics. Results During the 9 years of IS3, 407 patients were enrolled at 111 sites across 15 European countries. Approximately half (n = 202) had GD1, and half had other diseases (mainly Niemann–Pick disease type C (NP-C), for which Miglustat was approved in Europe in 2009). In total, 368 patients had data from at least one follow-up visit, 192 of whom had GD1. IS3 provided data from 798 patient-years exposure to Miglustat. Safety-relevant data were consistent with earlier published 5-year findings from IS3, the safety profile reported for Miglustat in GD1 clinical trials and other published information on GD1 manifestations. Conclusions Overall, the results of this long-term safety surveillance programme were in line with the well-known, documented safety profile of Miglustat. Copyright © 2015 John Wiley & Sons, Ltd.
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Efficacy of Miglustat in Niemann-Pick C disease: a single centre experience.
Molecular genetics and metabolism, 2013Co-Authors: Virginia Maria Ginocchio, Andrea Dardis, Bruno Bembi, Adele D'amico, Enrico Bertini, Ferdinando Ceravolo, Daniela Verrigni, Carlo Dionisi-vici, Federica DeodatoAbstract:Abstract Niemann–Pick disease type C (NPC) is a lysosomal storage disease characterized by progressive neurological degeneration. Miglustat is the first approved specific therapy and its efficacy in stabilizing or slowing disease progression has been demonstrated in previous studies. We evaluated data from 10 NPC patients treated with Miglustat in a single study centre. All disease manifestations were assessed and patients were stratified according to age at onset of neurological symptoms. Neurological data were recorded by using a modified version of the NP–C disability scale; a “composite score” and a “mean annual change” were calculated to evaluate disease progression. We observed a mean annual change of the composite score of 0.04 in our cohort, indicating slower progression of neurological symptoms if compared with the natural history of the disease. The evidence of slower disease evolution in patients treated with Miglustat suits with previous data and here it is also emphasized by the comparison between disease progression in two early-infantile onset patients receiving different Miglustat dosages. Evaluation of the mean annual change for individual subgroups of patients evidenced minor values in juvenile patients, highlighting better response in such class of patients. Among individual neurological parameters, swallowing showed the minor mean annual change (0.02), indicating better response to therapy. We underline the importance of using a standardized disability scale to quantify and compare neurological features and their evolution over time.
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Miglustat zavesca in type 1 gaucher disease 5 year results of a post authorisation safety surveillance programme
Pharmacoepidemiology and Drug Safety, 2009Co-Authors: Carla E. M. Hollak, Derralynn Hughes, Ivo N Van Schaik, B Schwierin, Bruno BembiAbstract:SUMMARY Purpose Miglustat (Zavesca 1 ) is an orally-available substrate reduction therapy (SRT) for treatment of mild-to-moderate type 1 Gaucher disease (GD1) in adult patients unsuitable for enzyme replacement therapy (ERT). Miglustat has not been evaluated inchildren with GD1, and isnot used during pregnancy and breast-feeding. A non-interventional, prospective, web-based safety surveillance programmewas initiated at the time of the European launch of Miglustat in 2003, and is ongoing. We report the first 5 years of collected data, focusing on neurological manifestations. Methods Data were collected on 122 GD1 patients between March 2003 and April 2008, representing 244 patient-years cumulative Miglustat post-authorisation experience. The electronically-captured data collected from participating physicians includes patient demographics, prior and current therapies, baseline disease manifestations and concurrent conditions, disease severity, duration of Miglustat exposure, and safety-relevant information. Results Mean (SD) age at baseline was 46.1 (16.5) years. At baseline, bone disease and neurological manifestations were reported in 55.6 and 28.6% of patients, respectively; the latter included peripheral neuropathy (7.2%) and a wide variety of neurological symptoms and signs. In addition, 23.2% had other health conditions relevant to neurological status. During the reporting period, new neurological manifestations were reported in 23 (18.9%) patients, principally tremor. Thirty-five (28.7%) patients discontinued treatment, predominantly for gastrointestinal (GI) disturbances (11.5%), two-thirds of which occurred during the first 6 months. Conclusion The safety profile of Miglustat in GD1 patients included in the safety surveillance programme is overall consistent with that reported in the registration and other clinical trials, and no new safety finding was identified. Copyright # 2009 John Wiley & Sons, Ltd. key words—Miglustat; type 1 Gaucher disease; neurological manifestations; post-authorisation safety surveillance programme
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Miglustat in patients with Niemann-Pick disease Type C (NP-C): A multicenter observational retrospective cohort study
Molecular genetics and metabolism, 2009Co-Authors: Mercedes Pineda, Mark Walterfang, Frédéric Sedel, James E. Wraith, Eugen Mengel, W. L. Hwu, Bruno Bembi, Marianne Rohrbach, G.c. Korenke, Thorsten MarquardtAbstract:Miglustat has been shown to stabilize disease progression in children, juveniles and adults with Niemann-Pick disease type C (NP-C), a rare genetic disorder characterized by progressive neurological deterioration. We report findings from a retrospective observational cohort study assessing the effects of Miglustat on neurological disease progression in patients treated in the clinical practice setting. Data from all NP-C patients prescribed Miglustat at 25 expert centers were evaluated using a disease disability scale. The scale analyzed four key parameters of neurological disease progression in NP-C (ambulation, manipulation, language, swallowing). Mean individual parameter scores and a composite score were calculated at baseline (time of diagnosis) and up to 4 follow-up visits. Overall, 66 patients were included (mean [SD] age at diagnosis, 9.7 [7.6] years, and at treatment start, 12.8 [9.5] years). The median (range) Miglustat exposure was 1.46 (0.05-4.51) years. Mean annual progression was +0.11 score units/year from diagnosis to treatment start, indicating disease progression prior to therapy, and decreasing to -0.01 score units/year from treatment start to last clinic visit, indicating stabilization. Stabilization of neurological disease on Miglustat was observed in all age groups, but the magnitude of the effect was greater in patients diagnosed in late childhood and in juveniles and adults. Stabilization of neurological disease was also observed in a subset of 19 patients with extended pre-treatment information. Overall, these data support previous clinical trial findings indicating clinically relevant beneficial effects of Miglustat on neurological disease progression in patients with NP-C.
Pilar Alfonso - One of the best experts on this subject based on the ideXlab platform.
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substrate reduction therapy with Miglustat in type 1 gaucher disease in spain nine years outcomes update on zagal study
Blood, 2013Co-Authors: Marcio M Andrade, Pilar Irún, Blanca Medrano, Koldo Atutxa, Angeles M Fernandezgalan, Abelardo Barez, Inmaculada Roig, Pilar Alfonso, Rafael Franco, Vicente GinerAbstract:Substrate reduction therapy (SRT) has showed as an useful therapy in type 1 GD patients with mild or moderate disease. The main limitation to use Miglustat has been the gastrointestinal adverse events. Since 2004 we have conducted the ZAGAL (Zavesca en Gaucher Leve) study for monitoring the real-life use of Miglustat in Spanish adult patients with mild-to moderate disease. The study included GD1 patient’s naive to therapy as well as patients who have previously been treated with ERT. For follow-up, the therapeutic goals for GD therapy by Pastores GM et al were applied. To date a total of 351 GD1 patients have been diagnosed in Spain (FEETEG unpublished. 2013); from 2004 until 2013, 53 of them have been exposed of Miglustat (15.1%). In 16 patients (30.2%) Miglustat was the first line of therapy and the remaining 38 switched from ERT. Currently 37 patients (mean age 43.6 y, range 22-83) 50.9% females, are on Miglustat therapy (20 at least for 5 years and 13 during more than 8 years). Related to efficacy, the therapy permit to achieve a stable hemoglobin concentration level and spleen reduced volume, but we recorded a decrease of absolute platelet count in 15 patients (28.3%) (mean: 35x109/L, range: 10-86x109/L). Related to biomarkers changes an increase in CT activity was observed in 56.6% of patients (mean: 2,448 nmol/mL.h, range 135-13,687) and 43.4 % for CCL18/PARC (mean: 250 ng/mL, range: 19-1016). Seventeen patients (32.1%) had transitory gastrointestinal disturbances. Sixteen patients (30.2%) discontinued therapy: one of them for pregnancy, two by bone crisis, two by weight loss, one for bad compliance and ten by gastrointestinal discomfort or intolerance (18.8%). 60% of patients has a fine tremor in first months on therapy. 4 died by non-related causes (2 cancer, 1 hearth attack, 1 liver failure), Conclusion The long term follow-up of GD patients treated with Miglustat shows that more than 69% had achieved and maintains the therapeutic goals. A high individual variability had been observed related to Miglustat gastrointestinal intolerance apparently no related with GBA genotype, gender and age, but possibly associated with disacaridases inhibition and food habits. Disclosures: No relevant conflicts of interest to declare.
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Real-world clinical experience with long-term Miglustat maintenance therapy in type 1 Gaucher disease: the ZAGAL project
Haematologica, 2009Co-Authors: Pilar Giraldo, Koldo Atutxa, Abelardo Barez, Pilar Alfonso, Rafael Franco, Dora Alonso, Alejandro Martín, Paz Latre, M.a. Fernandez-galan, Miguel PocoviAbstract:There are few published data from real-world clinical experience with Miglustat (Zavesca®), an oral inhibitor of glucosylceramide synthase, in type 1 Gaucher disease. We report data from a prospective, open-label investigational study that evaluated substrate reduction therapy with Miglustat 100 mg t.i.d. as a maintenance therapy in patients with Type 1 Gaucher disease who had been switched from previous enzyme replacement therapy. Long-term data on changes in organ size, blood counts, disease severity bio-markers, bone marrow infiltration, overall clinical status and safety/tolerability were analyzed from 28 patients with Type 1 Gaucher disease who were attending routine clinic visits. Assessments were performed at six, 12, 24, 36 and 48 months of therapy. Disease severity biomarkers improved up to 48 months after initiation of Miglustat, while other disease parameters remained stable. Miglustat showed an acceptable profile of safety and tolerability throughout treatment. In conclusion, Miglustat is an effective therapy for the long-term maintenance of patients with Type 1 Gaucher disease previously stabilized with enzyme replacement therapy.
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Real-World Clinical Experience with Long-Term Miglustat Therapy in Type 1 Gaucher Disease: The ZAGAL Project
Blood, 2008Co-Authors: Pilar Giraldo, Abelardo Barez, Pilar Alfonso, Rafael Franco, Mangeles Fernández-galán, Guillermo Martín-núñez, Dora Alonso, Antonio Acedo, Alejandro Martín, Elvira Martinez-estefanoAbstract:Background and objectives: Several reports describe the use of Miglustat (Zavesca ® ), an oral inhibitor of glucosylceramide synthase, for type 1 Gaucher disease (GD1) in clinical trials. There are few data on the use of Miglustat for GD1 in the real-world clinical experience. Here, we assess the long-term efficacy, tolerability and safety of Miglustat in a prospective, open-label, observational study of GD1 patients attending routine clinic visits. Design and Methods: 48 patients with mild-to-moderate GD1 received Miglustat 100 mg t.i.d. over 36 months. Patients were analysed in two groups: therapy-naive patients (n = 11) and those switched from previous treatment with enzyme replacement therapy (ERT; n = 37). Assessments of clinical status, haematological parameters, and organomegaly were performed before treatment and after 6, 12, 24 and 36 months of therapy. Data were compared with a historical reference cohort 29 GD1 patients treated for 36 months with ERT. Results: Nine treatment-naive patients completed 36 months of Miglustat therapy. Sustained improvements in haemoglobin were seen in all patients who had anaemia before treatment. Platelet counts improved in patients with initial thrombocytopenia, and were maintained in patients with normal counts at baseline. Plasma chitotriosidase activity decreased in treatment-naive patients during the first year on therapy and remained stable thereafter. S-MRI findings indicated improved bone status at 36 months. In patients switched from ERT, 15 completed 36 months of Miglustat therapy, and displayed maintained or improved clinical and haematological parameters, and surrogate disease severity markers. No statistically significant differences were observed at 36 months between treatmentnaive patients with similar baseline characteristics treated with either Miglustat or ERT. Overall, Miglustat was well tolerated. Interpretation and conclusions: Miglustat provided appreciable therapeutic responses on clinical, haematological, biomarker and S-MRI parameters at 36 months in patients with GD1, and was well tolerated. Therapeutic responses with Miglustat were comparable with those seen with ERT.
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neurologic improvement in a type 3 gaucher disease patient treated with imiglucerase Miglustat combination
Epilepsia, 2007Co-Authors: Jose Luis Capablo, Pilar Alfonso, Rafael Franco, Miguel Pocovi, Alicia Saenz De Cabezon, Pilar GiraldoAbstract:Summary: Purpose: Gaucher disease (GD) is an autosomal recessive lysosomal disorder caused by a deficiency of glucocerebrosidase. The neurologic manifestations of GD patients have to date been refractory to any treatment approach. We present a report of a neuronopathic GD patient whose myoclonic epilepsy improved after combination therapy with imiglucerase and Miglustat. Methods: In an adult type 3 GD patient who, despite good visceral and analytic response to ERT, developed progressive neurologic deterioration with marked myoclonic epilepsy and dystonia, we added Miglustat to the enzyme-replacement therapy. Results: After 2 years of combined Miglustat (200 mg, 3 t.i.d.) and imiglucerase (60 IU/kg every 2 weeks), generalized tonic–clonic seizures decreased, speech improved, and the general neurologic clinical picture improved markedly. The EEG showed a reduction in focal and generalized paroxysmal discharges. No significant adverse effects were observed. Conclusions: Combined imiglucerase and Miglustat therapy may be beneficial for some neuronopathic forms of GD.
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Neurologic improvement in a type 3 Gaucher disease patient treated with imiglucerase/Miglustat combination.
Epilepsia, 2007Co-Authors: Jose Luis Capablo, Pilar Alfonso, Rafael Franco, Miguel Pocovi, Alicia Saenz De Cabezon, Pilar GiraldoAbstract:Summary: Purpose: Gaucher disease (GD) is an autosomal recessive lysosomal disorder caused by a deficiency of glucocerebrosidase. The neurologic manifestations of GD patients have to date been refractory to any treatment approach. We present a report of a neuronopathic GD patient whose myoclonic epilepsy improved after combination therapy with imiglucerase and Miglustat. Methods: In an adult type 3 GD patient who, despite good visceral and analytic response to ERT, developed progressive neurologic deterioration with marked myoclonic epilepsy and dystonia, we added Miglustat to the enzyme-replacement therapy. Results: After 2 years of combined Miglustat (200 mg, 3 t.i.d.) and imiglucerase (60 IU/kg every 2 weeks), generalized tonic–clonic seizures decreased, speech improved, and the general neurologic clinical picture improved markedly. The EEG showed a reduction in focal and generalized paroxysmal discharges. No significant adverse effects were observed. Conclusions: Combined imiglucerase and Miglustat therapy may be beneficial for some neuronopathic forms of GD.
