Low-Dose N-Butyldeoxynojirimycin (OGT 918) for Type I Gaucher Disease

doi:10.1006/bcmd.2002.0497

Blood Cells, Molecules, and Diseases

Volume 28, Issue 2, March 2002, Pages 127-133

https://doi.org/10.1006/bcmd.2002.0497 Get rights and content

Abstract

ABSTRACT

The objective of this study was to evaluate the efficacy and safety of low-dose substrate balance therapy with OGT 918 for the treatment of adults with Gaucher disease. Eighteen patients with Gaucher disease from two centers were enrolled in an open-label 6-month study of OGT 918, 50 mg taken three times daily (TID), followed by an optional extended-use phase. Changes in liver and spleen volume at 6 and 12 months, as well as routine hematological and biochemical parameters on a monthly basis, were evaluated. During the extension, dosage was increased to 100 mg TID in patients in one center to improve the response. Seventeen patients completed 6 months; of 16 patients in the extension phase, 13 were evaluable at 12 months. Percentage changes in liver (−5.9%, P = 0.007) and spleen (−4.5%, P = 0.025) volumes and in chitotriosidase levels (−4.6%, P = 0.039) at 6 months were commensurately lower than those reported previously in an open-label trial using 100 mg TID; hemoglobin and platelet counts were not boosted. At 12 months there were further mean decreases from baseline in liver volume (−6.2%, P = 0.037), spleen volume (−10.1%, P < 0.05), and chitotriosidase levels (−15.3%, P < 0.05) as well as mean changes of −2.27 and +14.7% in hemoglobin and platelet concentrations, respectively. There were no serious adverse effects throughout the 6-month study period; common side effects were diarrhea (94%) and weight loss (67%), comparable to the incidence in the original trial. We conclude that OGT 918 was safe and effective at 50 mg TID, but shows dose dependency in ameliorating parameters of Gaucher disease relative to the results noted in the seminal trial; there was no improvement in the rate of hematological response and no reduction in side effects. Results from the extension wherein some patients were dose increased suggest that 100 mg TID should be the preferred starting regimen for patients with symptomatic type I Gaucher disease.

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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).
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Gaucher disease and Fabry disease: New markers and insights in pathophysiology for two distinct glycosphingolipidoses
2014, Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
Citation Excerpt :
Several hydrophobic iminosugars inhibit GCS [100–102]. One of them, N-butyldeoxynojirimycin (Zavesca, Actelion), is already a registered drug for oral treatment of Gaucher disease and shown to reverse organomegaly and hematological symptoms in mildly affected type 1 GD patients [103–108]. More potent and specific iminosugar-type inhibitors of GCS, like AMP-DNM (N-(5-adamantane-1-yl-methoxy-pentyl)-deoxynojirimycin) [109], have been designed, as well as ceramide-analogues inhibiting the enzyme [110].
Gaucher disease (GD) and Fabry disease (FD) are two relatively common inherited glycosphingolipidoses caused by deficiencies in the lysosomal glycosidases glucocerebrosidase and alpha-galactosidase A, respectively. For both diseases enzyme supplementation is presently used as therapy. Cells and tissues of GD and FD patients are uniformly deficient in enzyme activity, but the two diseases markedly differ in cell types showing lysosomal accumulation of the glycosphingolipid substrates glucosylceramide and globotriaosylceramide, respectively. The clinical manifestation of Gaucher disease and Fabry disease is consequently entirely different and the response to enzyme therapy is only impressive in the case of GD patients. This review compares both glycosphingolipid storage disorders with respect to similarities and differences. Presented is an update on insights regarding pathophysiological mechanisms as well as recently available biochemical markers and diagnostic tools for both disorders. Special attention is paid to sphingoid bases of the primary storage lipids in both diseases. The value of elevated glucosylsphingosine in Gaucher disease and globotriaosylsphingosine in Fabry disease for diagnosis and monitoring of disease is discussed as well as the possible contribution of the sphingoid bases to (patho)physiology. This article is part of a Special Issue entitled New Frontiers in Sphingolipid Biology.
Miglustat therapy in type 1 Gaucher disease: Clinical and safety outcomes in a multicenter retrospective cohort study
2013, Blood Cells, Molecules, and Diseases
Citation Excerpt :
Head-to-head clinical trials or comparative effectiveness studies would be needed for such a comparison, and to date no such studies have been reported. Previous clinical trials assessing the efficacy of miglustat in GD1 have primarily been based on changes in liver volume [5,6,9,12], which is viewed as a consistent clinical indicator of disease course and treatment effects [20]. However, in our study only a small number of patients underwent consistent spleen and liver volume assessments, reflecting the fact that organ volumes are not routinely measured in GD1 patients in clinical practice.
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.
Pilot study using ambroxol as a pharmacological chaperone in type 1 Gaucher disease
2013, Blood Cells, Molecules, and Diseases
Citation Excerpt :
Although outcome measures were globally unchanged after the initial 6 months, there were individual improvements in disease-specific parameters. The concept of a dose-dependency as was seen in the SRT low-dose miglustat trial [31] may also be applicable to PCs. In the low-dose miglustat trial [31] in patients with type 1 Gaucher disease, halving the dose from that which proved to be effective in the seminal trial [32] resulted in halving the efficacy (but the rate and intensity of adverse events were not halved).
The purpose of this pilot was to assess the tolerability and efficacy of ambroxol as a pharmacological chaperone in patients with symptomatic, type 1 Gaucher disease who present with measurable disease parameters but are not receiving enzyme replacement therapy (ERT) in order to provide proof of concept and/or ascertain the suitability of ambroxol for a larger clinical trial. The Israeli Ministry of Health Form 29c was employed to prescribe ambroxol for off-label use. Twelve patients were dispensed 2 capsules of 75 mg of ambroxol daily for 6 months. There were 8 females (66.7%). Mean age at entry was 41.1 (range: 24–63) years. Mean body weight at entry was 66.4 (range: 46.5–100) kg. One patient withdrew because of a hypersensitivity reaction, one because of elective splenectomy. No patient experienced clinically relevant deterioration in disease parameters measured. One patient achieved a robust response relative to baseline: + 16.2% hemoglobin; + 32.9% platelets; − 2.8% liver volume; and − 14.4% spleen volume. Three patients, including the above one, elected to continue on ambroxol for a further 6 months: hemoglobin levels and liver volumes were relatively stable, but platelet counts further increased in the above patient (+ 52.6% from baseline) and spleen volumes decreased further in all three patients (− 6.4%, − 18.6%, and − 23.4% from baseline). Thus, ambroxol may be a safe option for Gaucher disease patients with potential disease-specific efficacy and should be expanded into a clinical trial using higher doses and placebo-controlled design.

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^☆: Communicated by E. Beutler, M.D., 02/08/02

^f1: Correspondence and reprint requests to: Deborah Elstein, Gaucher Clinic, Shaare Zedek Medical Center, P.O. Box 3235, Jerusalem 91031, Israel. Fax: +972-2-651-7979. E-mail: [email protected].

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Regular ArticleLow-Dose N-Butyldeoxynojirimycin (OGT 918) for Type I Gaucher Disease☆

Abstract

Lancet

Glucosylceramide lipidoses

Regular Article
Low-Dose N-Butyldeoxynojirimycin (OGT 918) for Type I Gaucher Disease☆