Miglustat therapy in type 1 Gaucher disease: Clinical and safety outcomes in a multicenter retrospective cohort study

doi:10.1016/j.bcmd.2013.04.005

Blood Cells, Molecules, and Diseases

Volume 51, Issue 2, August 2013, Pages 116-124

https://doi.org/10.1016/j.bcmd.2013.04.005 Get rights and content

Abstract

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-naïve (‘naïve’) 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 naïve 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) × 10⁹/l in naïve patients and 173 (43–382) × 10⁹/l in pretreated patients; median (range) changes in platelet count were 8 (− 77–145) × 10⁹/l and − 10 (− 144–434) × 10⁹/l, respectively. Plasma chitotriosidase was substantially reduced in naïve 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 naïve 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.

Introduction

Gaucher disease type 1 (GD1) is an inherited lysosomal disorder caused by impaired activity of β-glucocerebrosidase [1], and is characterized by a range of systemic and skeletal manifestations including hepatosplenomegaly, anemia, thrombocytopenia, osteopenia, bone pain and fractures [2], [3].

While enzyme replacement therapy (ERT) forms the mainstay of treatment for GD1, the iminosugar, miglustat (Zavesca®; Actelion Pharmaceuticals Ltd.) represents an alternative treatment strategy — substrate reduction therapy (SRT). Based on clinical trial data [4], [5], [6], miglustat was approved in the EU in 2002 and in the USA in 2003 for the treatment of adults with mild-to-moderate GD1 for whom ERT is either unsuitable or not a therapeutic option [7].

In clinical trials in ERT-naïve adults with GD1, miglustat treatment was effective in reducing liver and spleen volume and increasing hemoglobin concentration and platelet count during 12–36 months of treatment [4], [5], [6], [8], [9]. Miglustat has also been shown to improve bone mineral density in both trabecular and cortical bones [10]. Data also indicate that miglustat may serve as maintenance therapy in some patients previously stabilized on ERT [9], [11], [12].

The safety and tolerability profile of miglustat has been well established based on data from clinical trials and post-marketing surveillance [4], [9], [13], [14]. Gastrointestinal disturbances (primarily diarrhea and flatulence) represent the main tolerability issue during miglustat therapy and remain the most frequent reason for discontinuation among those who stop treatment [15]. Studies have shown that dietary alterations before initiation and/or during the early weeks of miglustat treatment may reduce gastrointestinal disturbances [15].

A Spanish prospective, open-label investigational study of miglustat in GD1 patients has suggested that the long-term efficacy and safety profiles of miglustat during up to 6 years of use in clinical practice are consistent with findings from clinical trials [11], [16]. Nevertheless, data from clinical experience with miglustat remain relatively limited. In particular, there is a lack of data from ERT-naïve patients compared with those who have previously received ERT.

Here we describe clinical outcomes and safety-relevant information from an observational cohort study in ERT-naïve and ERT-pretreated GD1 patients receiving miglustat therapy in clinical practice settings in the EU and USA.

Section snippets

Study design and patients

This was an observational, retrospective, longitudinal cohort study conducted at multiple centers across the EU and USA. At each participating center, consecutive patients aged ≥ 18 years who had a confirmed diagnosis of GD1 and who were treated with commercial miglustat between 20th November 2002 and 31st December 2008 were included.

Ethical approval or waivers for the study protocol were obtained from the Ethics Committees or Independent Review Boards of all participating centers. Where

Patients and treatment

A total of 115 patients were included from 31 centers across 9 EU countries (Austria, Czech Republic, France, Germany, Italy, The Netherlands, Slovak Republic, Spain, United Kingdom) and the USA. Sixty-three (55%) patients were females. GD1 diagnosis was confirmed through both enzymatic and genotyping analyses in the majority (72/115 [63%]) of patients. Demographic, diagnostic and disease characteristics data in the ≥ 2-year miglustat group (N = 39) were comparable with those in the all-patients

Discussion

This cohort of 115 adult patients with mild-to-moderate GD1 is considered representative of the GD1 population receiving miglustat in clinical practice. Hemoglobin and platelet count were maintained within normal ranges in most patients treated with miglustat for a median of 1.3 years. Based on analyses of median (range) and mean (95% CI) changes between miglustat initiation and last assessment as well as changes in individual patient levels over time, both parameters tended to increase in

Conclusions

The use of miglustat in everyday clinical practice was associated with increased hemoglobin and platelet count in ERT-naïve patients, and that these parameters tended to remain stable or decrease slightly among patients who previously received ERT. It was not possible to assess hepatosplenomegaly in this study as organ volumes are not routinely monitored in clinical practice. The safety profile of miglustat was consistent with previous clinical trial and post-marketing surveillance data, with

Conflict of interest/financial disclosures

D.J.K. has received research support from, and has provided consultancy to, Actelion Pharmaceuticals Ltd. and Genzyme Corporation. A.Me and D.H. have received honoraria from, and participated on advisory boards for, Actelion Pharmaceuticals Ltd. C.E.M.H. has undertaken consultancy roles for, and received research funding from, Actelion Pharmaceuticals Ltd.; all honoraria are donated to the Gaucher Stichting — a national foundation that supports research in the field of lysosomal storage

Contributors

D.J.K., A.Me, C.E.M.H., P.G., D.H., N.B. and A.Z. were participating clinical investigators; D.J.K., C.E.M.H., A.Me and A.Z. also participated on the Study Advisory Committee. All clinical investigators were involved in the recruitment and treatment of patients and the provision of raw clinical data. M.B. was the scientific study leader at Actelion and provided oversight on all aspects of study conduct and data analyses. A.Mu was the study epidemiologist and contributed to all methodological

Role of the funding source

This study was sponsored by the Actelion Pharmaceuticals Ltd. All authors were involved in the interpretation of the data and the decision to submit the manuscript for publication.

Acknowledgments

The authors would like to thank all participating physicians for their valuable contributions to these data, and Harbajan Chadha-Boreham PhD, Senior Statistician at Actelion for providing support on the Statistical Analysis Plan. We would also like to thank Matthew Reilly PhD, associated with InTouch Medical Ltd., for medical writing assistance in the preparation of this manuscript. This study was funded by the Actelion Pharmaceuticals Ltd.

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Recommendations for oral treatment for adult patients with type 1 Gaucher disease
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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.
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.
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Citation Excerpt :
In this Spanish cohort, adverse events were mild-to-moderate, including gastrointestinal disturbance (40%), reversible fine-hand tremor (60%) and weight loss (4.7%) (Giraldo et al., 2018). Gastrointestinal tolerability should be identified as an important clinical management issue, because high percent of patients with GD1 discontinued treatment with miglustat due to it (Hollak et al., 2009; Kuter et al., 2013). Eliglustat is the second SRT that was approved in 2014 for GD1 patients, who are not CYP2D6 ultra-rapid metabolisers (Sanofi/Genzyme, 2021).
Gaucher disease (GD), the most common lysosomal disorders, is a rare autosomal recessive hereditary disease that is caused by deficiency of glucosylceramidase. For now, there are five approved therapies for GD, which are used to treat thousands of patients with GD. Despite success of approved therapies, many unresolved issues attract academic institutions and industry to develop potential therapies to resolve them. This paper updated the latest information about approved therapies and potential curative therapies.
Application of carbohydrates in approved small molecule drugs: A review
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Carbohydrates are an important energy source and play numerous key roles in all living organisms. Carbohydrates chemistry involved in diagnosis and treatment of diseases has been attracting increasing attention. Carbohydrates could be one of the major focuses of new drug discovery. Currently, however, carbohydrate-containing drugs account for only a small percentage of all drugs in clinical use, which does not match the important roles of carbohydrates in the organism. In other words, carbohydrates are a relatively untapped source of new drugs and therefore may offer exciting novel therapeutic opportunities. Here, we presented an overview of the application of carbohydrates in approved small molecule drugs and emphasized and evaluated the roles of carbohydrates in those drugs. The potential development direction of carbohydrate-containing drugs was presented after summarizing the advantages and challenges of carbohydrates in the development of new drugs.
Metabolizing profile of the cytochrome pathway CYP2D6, CYP3A4 and the ABCB 1 transporter in Spanish patients affected by Gaucher disease
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Several therapeutic options are available for type 1 Gaucher disease (GD1), including enzymatic replacement therapy (ERT) and substrate reduction therapy (SRT). Eliglustat is a selective inhibitor of glucosylceramide synthase that is extensively metabolized by CYP2D6 and, to a lesser extent by CYP3A4; it is also an inhibitor of the P-gp transporter. The aim of this study is to evaluate the metabolizer profile of these cytochrome isoforms in 61 GD1 patients, and to analyze interferences with concomitant therapies. Patients were selected from the Spanish Gaucher Disease Registry considering clinical data, GBA genotype, severity score index, comorbidities, concomitant drugs, type and response to therapy and adverse effects. The polymorphisms of CYP2D6, CYP3A4 and three ABCB1 transporter variants were analyzed by Polymerase Chain Reaction (PCR). The most frequent metabolizer profile was extensive or intermediate for CYP2D6, extensive for CYP3A4*1B and CYP3A4*22 and normal activity for ABCB1. Correlations between metabolizer profile and other variables were analyzed by multiple regression study. Twenty-eight patients received ERT, 17 eliglustat and seven miglustat. Forty-two patients (68.8%) had associated diseases and 54.5% were taking daily concomitant medication. Nine patients under eliglustat therapy received concomitant drugs that interact with the CYPs and/or ABCB1, five of these did not reach therapeutic goals and three presented mild or moderate adverse effects (headache and gastrointestinal disorders). Detailed analysis in four patients with TTT haplotype, corresponding to lack of activity of the transporter, was performed. In order to apply personalized medicine and avoid interferences and adverse effects, the individual CYP metabolizer profile and transporter must be considered when choosing the concomitant medication and/or making dose adjustments.
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Citation Excerpt :
Patients who were stable on ERT and were switched to SRT (miglustat) showed no change in bone pain [104]. Up to now, miglustat efficacy on bone symptoms remains poorly evaluated [105] and long term data for eliglustat is needed to fully evaluate its effects on bone disease. Another SRT drug, ibiglustat, is in clinical trials [106].
Gaucher disease (GD) is caused by pathogenic mutations in GBA1, the gene that encodes the lysosomal enzyme β-glucocerebrosidase. Despite the existence of a variety of specific treatments for GD, they cannot completely reverse bone complications. Many studies have evidenced the impairment in bone tissue of GD, and molecular mechanisms of bone density alterations in GD are being studied during the last years and different reports emphasized its efforts trying to unravel why and how bone tissue is affected. The cause of skeletal density affection in GD is a matter of debates between research groups. and there are two opposing hypotheses trying to explain reduced bone mineral density in GD: increased bone resorption versus impaired bone formation. In this review, we discuss the diverse mechanisms of bone alterations implicated in GD revealed until the present, along with a presentation of normal bone physiology and its regulation. With this information in mind, we discuss effectiveness of specific therapies, introduce possible adjunctive therapies and present a novel model for GD-associated bone density pathogenesis. Under the exposed evidence, we may conclude that both sides of the balance of remodeling process are altered. In GD the observed osteopenia/osteoporosis may be the result of contribution of both reduced bone formation and increased bone resorption.

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Miglustat therapy in type 1 Gaucher disease: Clinical and safety outcomes in a multicenter retrospective cohort study

Abstract

Introduction

Section snippets

Study design and patients

Patients and treatment

Discussion

Conclusions

Conflict of interest/financial disclosures

Contributors

Role of the funding source

Acknowledgments

Baillieres Clin. Haematol.

Lancet

Blood Cells Mol. Dis.

Blood

Clin. Ther.

Clin. Ther.

Semin. Hematol.

Blood Cells Mol. Dis.

Gaucher disease

The Gaucher registry: demographics and disease characteristics of 1698 patients with Gaucher disease

Arch. Intern. Med.

Sustained therapeutic effects of oral miglustat (Zavesca, N-butyldeoxynojirimycin, OGT 918) in type I Gaucher disease

J. Inherit. Metab. Dis.

Miglustat (Zavesca) Summary of Product Characteristics

Goal-oriented therapy with miglustat in Gaucher disease

Curr. Med. Res. Opin.