Clinical experience with substrate reduction therapy in type 1 Gaucher disease

Objective: Substrate reduction therapy was first described as a new potential therapeutic option to treat glycosphingolipid disorders (GSLD) in the early 80ies. Only recently the first commercially available drug (Zavesca®, miglustat) has been launched for treatment of mild to moderate forms of type 1 Gaucher disease and long-term follow up data from clinical trials became available.

Methods: Zavesca® has been studied in three clinical trials. The main trial (OGT 918–001) was a multicenter, non-comparative study of 28 patients who were unable or unwilling to have ERT. The dosage regimen in this study was 100mg t.i.d. A second study of low-dose miglustat (50mg t.i.d) included 18 patients (OGT 918–003). In a third study (OGT 918–004) 36 patients who had previously been treated with ERT for at least two years were randomised to continue ERT, to switch to treatment with miglustat (100mg t.i.d.) or to receive both treatments. For all three studies, patient data have been collected in an extended-use protocol of up to 36 month.

Results: Organ volume response after 36 months of treatment was a mean reduction of 17.5% in liver and 29.6% in spleen volume resp. (p<0.001 for all values). For hemoglobin concentration and platelet count a mean increase from baseline of 0.95g/dl (p<0.05) and 22.2×10⁹/l (p<0.001) resp. was demonstrated. In a treatment evaluation survey (comparison vs. ERT) 78% of miglustat treated patients reported significant improvements in convenience and overall satisfaction (vs. 33% in ERT patients).

Conclusion: Miglustat is an effective inhibitor of glycosphingolipid synthesis and a long-term clinical evaluation has demonstrated clinical improvement in patients with mild to moderate type 1 Gaucher disease.

Keywords: Gaucher disease, substrate reduction therapy, Zavesca