Reductions in glucosylsphingosine (lyso-Gb1) in treatment-naïve and previously treated patients receiving velaglucerase alfa for type 1 Gaucher disease: Data from phase 3 clinical trials

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 302.2ng/mL from baseline to week 209 in treatment-naïve patients and by 57.3ng/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 (363.9ng/mL and 90.7ng/mL, respectively) than for patients with non-N370S mutations (184.6ng/mL and 28.3ng/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.

Value of Glucosylsphingosine (Lyso-Gb1) as a Biomarker in Gaucher Disease: A Systematic Literature Review

“…Using the NICE STA method, risk of bias in the sole randomized controlled trial was deemed low, although bias regarding the allocation concealment process and between-group baseline similarities was unclear ( Table S1 ) [ 36 ]. Thirty non-randomized clinical trials and observational studies with full-study reporting were assessed using the Newcastle–Ottawa scoring tool [ 3 , 26 , 33 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 ], of which 19 were deemed to have a high risk of bias (score 0–3; Table S2 ). Thirty-two animal studies were assessed using the SYRCLE risk of bias tool [ 45 , 53 , 58 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , …”

“…Eleven studies provided information relevant to the diagnosis of GD [ 3 , 26 , 33 , 38 , 40 , 41 , 44 , 46 , 47 , 49 , 50 ]. Normally, lyso-Gb1 is undetectable or found at trace levels in plasma (i.e., <4.9 ng/mL (10.61 nmol/L)) and tissue [ 39 , 114 ]. Data from five prospective observational studies indicated consistently that lyso-Gb1 in plasma and red blood cell (RBC) membranes were higher in untreated patients with GD than in control subjects ( Table 4 ) [ 3 , 26 , 40 , 44 , 46 ].…”

“…Four studies provided information on lyso-Gb1 as a prognostic biomarker of GD ( Table 5 ) [ 26 , 33 , 39 , 50 ].…”

“…Patients with N370S displayed lower concentrations of lyso-Gb1 than those with L444P (c.1448T > C), which is known to be more frequent in patients with a more fatal course of disease [ 50 , 115 ]. An exploratory pooled analysis of phase III clinical trials revealed that mean plasma lyso-Gb1 was twice as high for 17 patients with ≥1 allele with the N370S variant (N370S/N370S or N370S/other) than for five patients with non-N370S mutations [ 39 ].…”

“…In 17 studies, cross-sectional and longitudinal data on lyso-Gb1 in treated and untreated patients with GD were compared [ 33 , 36 , 37 , 38 , 39 , 40 , 41 , 43 , 44 , 45 , 47 , 48 , 49 , 50 , 51 , 52 , 53 ]. Results from 16 of the 17 studies showed that treatment with enzyme replacement therapy (ERT) and substrate reduction therapy (SRT) either alone or in combination produced marked reductions in lyso-Gb1 concentrations in plasma, cerebrospinal fluid (CSF), and urine relative to baseline or control ( Table S6 ).…”