Miglustat Therapy in Type 1 Gaucher Disease: Long-Term Treatment Experience From a Multicenter, Retrospective Cohort Study,

Miglustat (Zavesca^®) was approved for the treatment of adults with mild-to-moderate type 1 Gaucher disease (GD1) for whom enzyme replacement therapy (ERT) is either unsuitable or not a therapeutic option in the EU in 2002 and in the USA in 2003. However, data from real-world clinical experience with miglustat remain limited.

Medical chart data were collected from consecutive adult GD1 patients who initiated commercial miglustat therapy at centers in 9 EU countries or the US after 20^th November 2002. Both ERT-naïve and ERT-pretreated patients were included. Follow-up data were collected from miglustat initiation to the end of the observation period (i.e. last information/visit before the end of the study on 31^st December 2008, death or loss to follow up). Data on patient demographics, medical history and disease characteristics were collected. Outcome assessments included hematological and biochemical parameters, liver/spleen volumes, gastrointestinal signs/symptoms and neurological manifestations.

115 patients (55% female; mean±SD age at miglustat initiation 45±14 years) were enrolled, among whom 34 (30%) were ERT-naïve and 81 (70%) were ERT-pretreated. The median (range) miglustat exposure was 15 (1 – 53) months in ERT-naïve and 15 (0 – 62) months in ERT-pretreated patients. At the time of miglustat initiation the median (range) hemoglobin concentration in ERT-naïve patients (n=24) was 12.8 (10.2 – 16.4) g/dl, and in ERT-pretreated patients (n=65) it was 13.6 (7.3 – 17.4) g/dl; 5 patients in each group had anemia. The median (range) change in hemoglobin from miglustat initiation to last assessment in ERT-naïve patients was 0.3 (−2.5 – 3.6) g/dl, and in ERT-pretreated patients it was −0.3 (−4 – 4.6) g/dl. In the subgroup of patients with anemia the median (range) change was 1.3 (0.1 – 3.6) g/dl in the 5 ERT-naïve patients and 2.6 (−2.7 – 4.6) in the 5 ERT-pretreated patients. At the time of miglustat initiation the median (range) platelet count in ERT-naïve patients (n=25) was 101 (37 – 730) ×10⁹/l, and in ERT-pretreated patients (n=65) it was 173 (43 – 382) ×10⁹/l; 12 patients in the ERT-naïve and 9 in the ERT-pretreated group had thrombocytopenia. The median (range) change in platelet count was 8 (−77 – 145) ×10⁹/l in ERT-naïve patients and −10 (−144 – 434) ×10⁹/l in ERT-pretreated patients. In the subgroup of patients with thrombocytopenia, the median (range) change was 31 (−29 – 145) ×10⁹/l in the 12 ERT-naïve patients and 14 (−32 – 434) ×10⁹/l in the 9 ERT-pretreated patients. Plasma chitotriosidase was highly variable. Substantial median (range) reductions were seen in 20 evaluable ERT-naïve patients [−1365 (−13216 – 3477) nmol/ml/h] but not in the 43 evaluable ERT-pretreated patients [20 (−2700 – 12431) nmol/ml/h]. Few patients had spleen and liver organ volume data recorded. Forty-nine patients (43%) discontinued miglustat during the observation period. Tolerability issues, primarily gastrointestinal, were the most frequent reason for discontinuation, accounting for 32 (28%) of all 115 patients. Other reasons included: non-medical (n=7), insufficient efficacy (n=5), switch to ERT (n=4), and patient death (n=1). Tremor was observed in 3/115 (3%) patients before, and in 18/115 (16%) after miglustat initiation.

Based on hematological parameters, we observed that miglustat can maintain disease stability in GD1 patients, irrespective of previous ERT therapy. Although based on a limited number of patients, benefits appeared more pronounced in analyses of anemic and thrombocytopenic patients. Gastrointestinal manifestations remain a concern, leading to discontinuation in around one-third of patients. The safety profile of miglustat was similar to that in previous clinical trials.

Kuter:Actelion: Consultancy. Mehta:Actelion: Consultancy. Hollak:Actelion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hughes:Actelion: Consultancy. Belmatoug:Actelion: Consultancy, Research Funding. Brand:Actelion: Employment. Muller:Actelion: Employment. Schaaf:Factum Gmbh: Consultancy. Giorgino:Actelion: Employment. Zimran:Actelion: Honoraria.