Biochemical response to substrate reduction therapy versus enzyme replacement therapy in Gaucher disease type 1 patients.

Bouwien E Smid,Patrick Wisse,Johannes M Aerts,Herman S Overkleeft,Carla E Hollak,Maria J Ferraz,Mina Mirzaian,Marri Verhoek

doi:10.1186/s13023-016-0413-3

Bouwien E Smid, Patrick Wisse + Show 6 more

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https://doi.org/10.1186/s13023-016-0413-3

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Abstract

BackgroundWe retrospectively compared biochemical responses in type 1 Gaucher disease patients to treatment with glycosphingolipid synthesis inhibitors miglustat and eliglustat and ERT.MethodsSeventeen GD1 patients were included (n = 6 eliglustat, (two switched from ERT), n = 9 miglustat (seven switchers), n = 4 ERT (median dose 60U/kg/m). Plasma protein markers reflecting disease burden (chitotriosidase, CCL18) and lipids reflecting substrate accumulation (glucosylsphingosine, glucosylceramide) were determined. Also, liver and spleen volumes, hemoglobin, platelets, and fat fraction were measured.ResultsIn patients naïve to treatment, chitotriosidase, CCL18 and glucosylsphingosine decreased comparably upon eliglustat and ERT treatment, while the response to miglustat was less. After 2 years, median decrease of chitotriosidase was 89 % (range 77–98), 88 % (78–92) and 37 % (29–46) for eliglustat, ERT and miglustat naïve patients respectively; decrease of CCL18 was 73 % (63–78), 54 % (43–86), and 10 % (3–18); decrease of glucosylsphingosine was 86 % (78–93), 78 % (65–91), 48 % (46–50). Plasma glucosylceramide in eliglustat treated patients (n = 4) reached values below the normal range (n = 20 healthy controls). Biochemical markers decreased or stabilized in switchers from ERT to eliglustat (n = 2), but less in miglustat switchers (n = 7). Clinical parameters responded comparably upon eliglustat and ERT treatment.ConclusionsOur explorative study provides evidence that biochemical markers respond comparably in patients receiving eliglustat treatment and ERT, while the corresponding response to miglustat treatment is less.

Highlights

We retrospectively compared biochemical responses in type 1 Gaucher disease patients to treatment with glycosphingolipid synthesis inhibitors miglustat and eliglustat and Enzyme replacement therapy (ERT)
Patients Of the included patients six were treated with eliglustat: four were naïve to treatment (‘naïve patients’) and two had been treated with ERT for 18 or more years (‘switch patients’)
One switch patient (Table 1, no. 12), severely affected at initiation of ERT, interrupted eliglustat treatment after 17 weeks because of an AE possibly related to eliglustat use

Summary

Introduction

We retrospectively compared biochemical responses in type 1 Gaucher disease patients to treatment with glycosphingolipid synthesis inhibitors miglustat and eliglustat and ERT. Gaucher disease type I (GD1, OMIM230800) results from a deficiency of glucocerebrosidase (GBA1), a lysosomal enzyme responsible for the degradation of glucocerebroside (GlcCer) and glucosylsphingosine (GlcSph) [1, 2]. GlcCer and GlcSph accumulate, Smid et al Orphanet Journal of Rare Diseases (2016) 11:28 demonstrate remarkable improvement of cytopenias and hepatosplenomegaly [3,4,5,6,7,8]. In particular patients with bone disease at start of therapy can experience despite treatment additional bone complications, the frequency of such events seems reduced [10]. It has been suggested that a systemic therapy targeting macrophages might be more beneficial, as aspects of GD’s symptomatology (malignancies, pulmonary hypertension, Parkinson’s disease and osteoporosis) are insufficiently explained by macrophage involvement solely [11]

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