1. Reductions in glucosylsphingosine (lyso-Gb1) in treatment-naïve and previously treated patients receiving velaglucerase alfa for type 1 Gaucher disease

Reductions in glucosylsphingosine (lyso-Gb1) in treatment-naïve and previously treated patients receiving velaglucerase alfa for type 1 Gaucher disease

Deborah Elstein 1 Björn Mellgard, PhD MD 1 Quinn Dinh, MD 1 Yongchang Qiu, PhD 1 Claudia Cozma, MD 2 Sabrina Eichler, PhD 2 Tobias Böttcher, PhD 2 Ari Zimran, MD 3 Lan Lan 1
1 Shire 2 CENTOGENE AG 3 Shaare Zedek Medical Center (SZMC), Jerusalem
August 19, 2017

Molecular Genetics and Metabolism (2017), dx.doi.org/10.1016/j.ymgme.2017.08.005

Abstract:

Gaucher disease (GD), an autosomal recessive lipid storage disorder, arises from mutations in the GBA1 (β- glucocerebrosidase) gene, resulting in glucosylceramide accumulation in tissue macrophages. Lyso-Gb1 (glucosylsphingosine, lyso-GL1), a downstream metabolic product of glucosylceramide, has been identified as a promising biomarker for the diagnosis and monitoring of patients with GD. This retrospective, exploratory analysis of data from phase 3 clinical trials of velaglucerase alfa in patients with type 1 GD evaluated the potential of lyso-Gb1 as a specific and sensitive biomarker for GD. A total of 22 treatment-naïve patients and 21 patients previously treated with imiglucerase (switch patients) were included in the analysis. Overall, demographics between the two groups were similar. Mean lyso-Gb1 concentrations were reduced by 302.2 ng/mL from baseline to week 209 in treatment-naïve patients and by 57.3 ng/mL from baseline to week 161 in switch patients, corresponding to relative reductions of 82.7% and 52.0%, respectively. In both the treatment-naïve and switch groups, baseline mean lyso-Gb1 was higher for patients with at least one N370S mutation (363.9 ng/mL and 90.7 ng/mL, respectively) than for patients with non-N370S mutations (184.6 ng/mL and 28.3 ng/mL, respectively). Moderate correlations between decreasing lyso-Gb1 levels and increasing platelet counts, and with decreasing spleen volumes, were observed at some time points in the treatment-naïve group but not in the switch group. These findings support the utility of lyso-Gb1 as a sensitive and reliable biomarker for GD, and suggest that quantitation of this biomarker could serve as an indicator of disease burden and response to treatment.