Miglustat Therapy in Type 1 Gaucher Disease: Long-Term Treatment Experience From a Multicenter, Retrospective Cohort Study,
Authors: Kuter David J. , Mehta Atul , Hollak Carla , Giraldo Pilar , Hughes Derralynn , Belmatoug Nadia , Brand Monika , Muller Audrey , Schaaf Berthold , Giorgino Ruben , Zimran Ari 
Published: October 2019

Abstract
Abstract 3207

Introduction:
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.

Methods:
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 20th 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 31st 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.

Results:
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.

Conclusions:
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.

Disclosures:
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.