Journal of Inherited Metabolic Disease

, Volume 27, Issue 6, pp 757–766 | Cite as

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

  • D. Elstein
  • C. Hollak
  • J. M. F. G. Aerts
  • S. van Weely
  • M. Maas
  • T. M. Cox
  • R. H. Lachmann
  • M. Hrebicek
  • F. M. Platt
  • T. D. Butters
  • R. A. Dwek
  • A. Zimran
Article

Abstract

Summary: It has been shown that treatment with miglustat (Zavesca, N-butyldeoxynojirimycin, OGT 918) improves key clinical features of type I Gaucher disease after 1 year of treatment. This study reports longer-term efficacy and safety data. Patients who had completed 12 months of treatment with open-label miglustat (100-300 mg three times daily) were enrolled to continue with therapy in an extension study. Data are presented up to month 36. Liver and spleen volumes measured by CT or MRI were scheduled every 6 months. Biochemical and haematological parameters, including chitotriosidase activity (a sensitive marker of Gaucher disease activity) were monitored every 3 months. Safety data were also collected every 3 months. Eighteen of 22 eligible patients at four centres entered the extension phase and 14 of these completed 36 months of treatment with miglustat. After 36 months, there were statistically significant improvements in all major efficacy endpoints. Liver and spleen organ volumes were reduced by 18% and 30%, respectively. In patients whose haemoglobin value had been below 11.5 g/dl at baseline, mean haemoglobin increased progressively from baseline by 0.55 g/dl at month 12 (NS), 1.28 g/dl at month 24 (p=0.007), and 1.30 g/dl at month 36 (p=0.013). The mean platelet count at month 36 increased from baseline by 22×109/L. No new cases of peripheral neuropathy occurred since previously reported. Diarrhoea and weight loss, which were frequently reported during the initial 12-month study, decreased in magnitude and prevalence during the second and third years. Patients treated with miglustat for 3 years show significant improvements in organ volumes and haematological parameters. In conclusion, miglustat was increasingly effective over time and showed acceptable tolerability in patients who continued with treatment for 3 years.

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REFERENCES

  1. Cox TM, Schofield JP (1997)Gaucher 's disease:clinical features a d natural history. In:Zimra A,ed.Baillie're 's Clinical Haematology:Gaucher 's Disease.London: Baille're-Tindall,657-689.Google Scholar
  2. Cox TM, Lachma R, Hollak C,et al (2000)Novel oral treatment of Gaucher 's disease with N-butyldeoxynojirimyci (OGT 918)to decrease substrate biosynthesis.Lancet 355(9214): 1481-1485.Google Scholar
  3. Cox TM, Aerts JMFG, Andria G,et al (2003)The role of the iminosugar N-butyl-deoxy ojirimyci (miglustat)i the management of type 1 (non-neuronopathic)Gaucher disease:a positio statement.J Inherit Metab Dis 26:513-526.Google Scholar
  4. Elstein D, Hadas-Halpern I, Itzchaki M,et al (1996)Effect of low-dose ERT on bones in Gaucher disease patients with severe skeletal involvement.Blood Cells Mol Dis 22:104-111.Google Scholar
  5. Hollak C, van Weely S, van Oers MH, Aerts J (1994)Marked elevation of plasma chitotriosidase activity:a novel hallmark of Gaucher disease.J lin Invest 93:1288-1292.Google Scholar
  6. Hollak CEM, Maas JM, Aerts JM (2001)Clinically relevant therapeutic endpoints intype 1 Gaucher disease.J Inherit Metab Dis 24 (supplement 2):97-105.Google Scholar
  7. Johnson LA, Hoppel BE, Gerard EL,et al (1992)Quantitative chemical shift imaging of vertebral bone marrow in patients with Gaucher disease.Radiology 182 (2):451-455.Google Scholar
  8. Maas M, Akkerman EM, Venema HW, Stoker J, De Heeten GJ (2001)Dixon qua titative chemical shift MRI for bone marrow evaluation in the lumbar spine:a reproducibility study in healthy volunteers.J Comput Assist Tomogr 25:691-697.Google Scholar
  9. Maas M, Hollak CE, Akkerma EM, Aerts JM, Stoker J, De Heete GJ (2002)Quanti-fication of skeletal involvement in adults with type I Gaucher 's disease:fat fraction measured by Dixon quantitative chemical shift imaging as a valid parameter.Am J Roentgenol 179 (4):961-965.Google Scholar
  10. Miller SP, Zirzow GC, Doppelt SH, Brady RO, Barton NW (1996)Analysis of the lipids of normal and Gaucher bone marrow.J Lab Clin Med 127 (4):353-358.Google Scholar
  11. Platt F, Neises GR, Dwek R, Butters T (1994)N-Butyldeoxy ojirimycin is a novel inhibitor of glycolipid synthesis.JBiol Chem 269 (11):8362-8365.Google Scholar
  12. Platt F, Neises GR, Reinkensmeier G,et al (1997)Prevention of lysosomal storage inTaySachs mice treated with N-butyldeoxynojirimycin.Science 276:428-431.Google Scholar
  13. Platt F, Jeyakumar M, Andersson U,et al (2003)Substrate reduction therapy in mouse models of the glycosphingolipidoses.Phil Trans R Soc Lond B 358:947-954.Google Scholar
  14. Vellodi A, Bembi B, de Villemeur TB,et al (2001)Management of euronopathic Gaucher disease:a European consensus.J Inherit Metab Dis 24(3):319-327.Google Scholar

Copyright information

© Kluwer Academic Publishers 2004

Authors and Affiliations

  • D. Elstein
    • 1
  • C. Hollak
    • 2
  • J. M. F. G. Aerts
    • 2
  • S. van Weely
    • 2
  • M. Maas
    • 2
  • T. M. Cox
    • 3
  • R. H. Lachmann
    • 3
  • M. Hrebicek
    • 4
  • F. M. Platt
    • 5
  • T. D. Butters
    • 5
  • R. A. Dwek
    • 5
  • A. Zimran
    • 1
  1. 1.Shaare Zedek Medical CentreJerusalemIsrael
  2. 2.Academic Medical CentreUniversity of AmsterdamAmsterdamThe Netherlands
  3. 3.Department of MedicineUniversity of Cambridge, Addenbrooke's HospitalCambridgeUK
  4. 4.Institute of Inherited Metabolic DisordersPragueCzech Republic
  5. 5.Oxford Glycobiology Institute, Department of BiochemistryUniversity of OxfordOxfordUK

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