An open-label, noncomparative study of miglustat in type I Gaucher disease: efficacy and tolerability over 24 months of treatment.

Abstract Background: The substrate synthesis inhibitor miglustat ( N -butyldeoxynojirimycin) is the first oral agent to receive regulatory approval for the treatment of type I Gaucher disease (GD). Objectives: The aims of this study were to further assess previous observations of the effects of miglustat in adult patients with mild to moderate type I GD and to evaluate the tolerability and safety profile of this drug. Methods: This was a noncomparative, open-label study in adult patients with type I GD (confirmed by genotyping and glucocerebrosidase assay) who were unwilling or unable to receive enzyme replacement therapy (ERT) or who had discontinued ERT for at least 3 months. Patients received miglustat 100 mg TID for 12 months, with the option of continuing treatment for a further 12 months. The primary end point was the percentage change in liver volume. Secondary end points included the percentage change in spleen volume and changes in hematologic parameters (hemoglobin, platelets), chitotriosidase activity (a surrogate marker of disease burden), and bone assessments (dual-energy X-ray absorptiometry, magnetic resonance imaging, and radiography). Clinical safety was monitored, including assessment of neurologic status at baseline and throughout the study using a comprehensive battery of standardized neurologic tests (eg, Purdue Pegboard Test, Mini-Mental State Examination, nerve conduction studies) and neuropsychological tests. Results: Of the 10 patients (7 men, 3 women) who received at least 1 dose of miglustat, 7 completed 24 months of treatment. Patients were aged between 32 and 62 years (mean, 46.3 years) and weighed between 55 and 88 kg (mean, 72.4 kg). All patients had at least 1 manifestation of GD, including 10 with splenomegaly (mean size, 8.1 times normal; range, 3.9–15.9 times normal), 9 with thrombocytopenia, and 8 with hepatomegaly (mean size, 1.5 times normal; range, 1.0–2.0 times normal). At baseline, hemoglobin concentrations ranged from 11.5 to 15.1 g/dL (mean, 13.2 g/dL), platelet counts from 55 to 161 × 10 9 /L (mean, 83.8 × 10 9 /L), and chitotriosidase activity from 526 to 29636 nmol/mL · h (mean, 8143.7 nmol/mL · h). In the 8 patients comprising the efficacy set, significant mean percentage changes from baseline in liver volume were seen at 6 months (−8.4%; P = 0.036; 95% CI, −16.1 to −0.7) and 18 months (−15.1%; P = 0.022; 95% CI, −27.1 to −3.0). Although not statistically significant, the 95% CIs for the percentage changes in liver volume at 12 months (−9.4%; 95% CI, −19.5 to 0.6) and 24 months (−5.6%; 95% CI, −12.1 to 1.0) were similar to those at 6 and 18 months, supporting a consistent clinical effect. Significant mean percentage reductions in spleen volume were observed at 6 months (−19.0%; P = 0.006; 95% CI, −30.4 to −7.6) and 18 months (−24.3%; P = 0.001; 95% CI, −33.6 to −15.1). Mean hemoglobin concentrations, which were normal at baseline, remained stable over the course of the study. There were no significant changes in bone status. There was a significant mean increase in absolute platelet count at 12 months (by 13.9 × 10 9 /L; P = 0.030; 95% CI, 1.8 to 26.0); at 24 months, the mean percentage increase from baseline (23.0%) was not statistically significant. The mean percentage reduction from baseline in chitotriosidase activity at 24 months was 25.3%. Treatment was well tolerated, and the incidence of most adverse events decreased with time. Gastrointestinal and central nervous system adverse events reported during 3-month periods at the beginning (0–3 months) and end (>21–24 months) of the study were flatulence (10 and 2 patients, respectively), diarrhea (9 and 0), abdominal pain (7 and 1), tremor (4 and 1), paresthesia (3 and 0), headache (2 and 3), and abdominal distention (2 and 0). No evidence of clinically significant adverse effects on neurologic or neuropsychological function was found during the study. Conclusions: In this small study in symptomatic adult patients with type I GD, miglustat treatment resulted in a significant decrease in liver and spleen volume at 6 and 18 months, with clinical improvement noted over 24 months. Bone involvement and platelet and hemoglobin values remained stable, with no significant changes noted during the observation period. The effects of treatment were consistent with those of earlier studies of miglustat in type I GD.