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

Abstract

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 x 10(9)/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.

Putative Biological Mechanisms of Efficiency of Substrate Reduction Therapies for Mucopolysaccharidoses

“…Since it slows down the production of glycosphingolipids, it should be effective in reducing storage of these compounds. Although positive effects of such treatment in clinical trials were reported (Elstein et al 2004;Pastores et al 2005), its efficacy in Gaucher disease has recently been questioned (Tylki-Szymanska et al 2011;Machaczka et al 2012).…”

Selective action of the iminosugar isofagomine, a pharmacological chaperone for mutant forms of acid-β-glucosidase

“…While effective in managing the visceral symptoms of the disease, enzyme replacement therapy is expensive and cannot address the neurological defects because the replacement enzyme is unable to cross the blood-brain barrier [4]. Treatment with the iminosugar N-butyldeoxynojirimycin (NB-DNJ, Miglustat), an inhibitor of glucosylceramide synthase, has been shown to improve liver and spleen volume and hematological parameters in type 1 Gaucher patients [5]. However, the administration of NB-DNJ is observed to cause several significant side effects including peripheral neuropathy and gastrointestinal complications [6][7][8].…”

Isofagomine Induced Stabilization of Glucocerebrosidase

“…The standard treatment for individuals with GCase deficiencies involves either enzyme replacement therapy with imiglucerase (Cerezyme, Genzyme Corp.) [3] or less frequently, substrate reduction therapy with mi-glustat (Zavesca, Actelion Ltd.). [4,5] Recently a third therapeutic approach, enzyme enhancement therapy (EET), utilizing small molecule pharmacological chaperone (PC) has been proposed. Currently, isofagomine (IFG), an iminosugar and potent competitive inhibitor of GCase (Plicera, Amicus Therapeutics Inc.) is being evaluated clinically as a PC for EET.…”