An observational study to investigate the relationship between plasma glucosylsphingosine (lyso-Gb1) concentration and treatment outcomes of patients with Gaucher disease in Japan

This is the first observational cohort study to report the plasma lyso-Gb1 concentrations in Japanese patients with GD treated with velaglucerase alfa, and to investigate the relationship of lyso-Gb1 concentration with treatment outcomes, evaluated by achievement rate of multiple GD therapeutic goals. In this study, 70% of patients with GD receiving velaglucerase alfa achieved all 6 therapeutic goals (hepatomegaly, splenomegaly, anemia, thrombocytopenia, bone pain, and bone crisis). The proportion of patients achieving each therapeutic goal was also high, ranging from 85 to 100%, and low plasma lyso-Gb1 concentration correlated with achievement of all 6 therapeutic goals. Furthermore, lyso-Gb1 concentration in this patient cohort was lower compared with that reported in a previous study of non-Japanese patients with type 1 GD receiving ERT. These results suggest that Japanese patients with GD are treated effectively with velaglucerase alfa, and that lyso-Gb1 concentration may be a useful biomarker to predict achievement of the treatment goals, which may ultimately be useful to also evaluate treatment efficacy for GD.

This study demonstrated that plasma lyso-Gb1 concentration in Japanese patients with GD treated with velaglucerase alfa is low, and although not statistically significant, low plasma lyso-Gb1 concentration correlates with a higher achievement rate of therapeutic goals for GD. Lower lyso-Gb1 concentration was observed in patients who had achieved all 6 therapeutic goals, assessed by the extent of hepatomegaly, splenomegaly, anemia (hemoglobin level), thrombocytopenia (platelet count), bone pain, and bone crisis, than in those who had not achieved all 6 therapeutic goals. Similarly, in a retrospective, exploratory analysis of data from phase 3 clinical trials of patients with type 1 GD treated with velaglucerase alfa, decreasing lyso-Gb1 concentrations had a statistically significant correlation with increasing platelet count and decreasing spleen volume in the treatment-naive group at some timepoints during treatment [21]. A previous cohort study of treated and untreated children with type 1 or 3 GD also reported that lyso-Gb1 significantly correlated with platelet count (p < 0.0001, r = − 0.42) and hemoglobin level (p = 0.003, r = − 0.35) [22]. Further, in a retrospective, multicenter observational study, 25 patients with GD who received an ERT (velaglucerase alfa [n = 17], imiglucerase [n = 4], or taliglucerase alfa [n = 4]) had decreased lyso-Gb1 levels and spleen and liver volumes, and increased platelet counts and hemoglobin levels [24]. Collectively, those results and the results of this study may further indicate that lyso-Gb1 is a useful biomarker to evaluate treatment response in patients with GD receiving ERT treatment. However, a target plasma lyso-Gb1 concentration to indicate treatment effectiveness has not yet been determined. Therefore, future studies to establish a target may be beneficial in guiding physicians when monitoring lyso-Gb1.

Lyso-Gb1 concentrations are expected to be high in Japanese patients with GD compared with non-Japanese patients with GD, as Japanese patients commonly have the L444P mutation [7, 8, 25], which is associated with a higher lyso-Gb1 level [19, 20], and a more severe phenotype of GD than other phenotypes [2, 19, 26, 27]. Baseline lyso-Gb1 concentrations were not available in this study, which is a limitation; however, in this study the median plasma lyso-Gb1 concentration observed in Japanese patients treated with velaglucerase alfa for a median duration of 49.5 months (~ 215.1 weeks) was 24.3 ng/mL, which was lower compared with those previously reported in non-Japanese patients [3, 21]. Results from a retrospective, exploratory analysis of patients with type 1 GD treated with velaglucerase alfa indicated that the median lyso-Gb1 concentration was 43.6 ng/mL at treatment week 209 for the treatment-naive patients, and 26.6 ng/mL at treatment week 161 for the switch-treatment patients [21]. In another study, the lyso-Gb1 concentration was 89 ng/mL, a reduction of 49% from 180.9 ng/mL, after a mean of 3.6 years (~ 187.7 weeks) of treatment with imiglucerase [3]. Possible reasons for the observation of lower lyso-Gb1 in this study of Japanese patients compared with the previous studies [3, 21] are that patients in this study were treated with velaglucerase alfa for a longer duration and possibly at a higher dose (60 U/kg every other week [approved dose in Japan] [28] versus 52.4 U/kg [treatment-naive patients] and 28.9 U/kg [switch-treatment patients] [21]). Furthermore, a previous study has reported a reduction in lyso-Gb1 concentration in 2 patients with type 3 GD treated with ambroxol chaperone therapy in combination with ERT [29]; given that the present study included 5 patients receiving ambroxol, the possibility of the effects of ambroxol in lowering lyso-Gb1 concentrations should not be excluded. Nonetheless, these findings demonstrate that lyso-Gb1 concentrations of ERT-treated patients are lower in Japanese patients with GD than non-Japanese patients with GD. Although patients’ baseline lyso-Gb1 concentrations were not available in this study, long-term treatment with velaglucerase alfa at a dose of 60 U/kg every other week may be effective in reducing lyso-Gb1 levels in Japanese patients with GD.

In this study, achievement rate of GD therapeutic goals was high (70%) in Japanese patients with GD who were treated with velaglucerase alfa, most likely at a dose of 60 U/kg every other week. A previous benchmark analysis of patients with type 1 GD treated with imiglucerase reported that the proportion of patients achieving all 6 GD therapeutic goals increased with higher doses of imiglucerase (achieved 1–3 goals: 37.6 U/kg/4 weeks; achieved 4 goals: 56.9 U/kg/4 weeks; 5 goals: 70.7 U/kg/4 weeks; all goals: 74.2 U/kg/4 weeks) [30]. Therefore, given that the dose of velaglucerase alfa was higher in this study (i.e., 120 U/kg/4 weeks), this may explain the high achievement rate of GD therapeutic goals observed in this study, further suggesting that higher doses of velaglucerase alfa treatment may be associated with a greater achievement rate of therapeutic goals.

In this study, although most patients had low plasma lyso-Gb1 concentrations, a plasma lyso-Gb1 concentration ≥ 100 ng/mL was observed in 2 patients. These results may be explained by the fact that 1 patient, who had type 1 GD, was treated with velaglucerase alfa for only 3 months, which is also reflected by the low treatment achievement rate (33.3%). The second patient had type 2 GD, was experiencing neurological and bone symptoms, and had developed immunoglobulin G and immunoglobulin E antibodies against both imiglucerase and velaglucerase alfa. The patient experienced serious infusion-associated reactions requiring treatment with antihistamines, corticosteroids, and analgesics prior to velaglucerase alfa administration. Nonetheless, results from this study suggest that velaglucerase alfa may be effective in achieving therapeutic goals for GD in Japanese patients, who generally have more severe disease compared with non-Japanese patients [9, 27].

In this study, the sample size was limited because the number of patients with GD is limited in Japan. The velaglucerase alfa dose used in this study and in previous studies varied; the approved dose of velaglucerase alfa in Japan is 60 U/kg every other week, which was higher than the dose used in previous studies conducted outside of Japan. Pre-treatment plasma lyso-Gb1 concentration was unavailable because the number of patients newly starting treatment was very small, and it is almost impossible to prospectively measure lyso-Gb1 concentration prior to treatment initiation in patients with GD in Japan. Therefore, the change in plasma lyso-Gb1 concentration from pre-treatment to post-treatment could not be evaluated. Furthermore, the study population was heterogeneous (included patients with type 1, 2, and 3 GD), making it difficult to distinguish whether higher levels of lyso-Gb1 reflect disease severity or low treatment response, and the study did not control for ambroxol use. Therefore, treatment-naive patients with GD should be enrolled in future studies to evaluate the correlation between the change in lyso-Gb1 concentration from pre-treatment phase and clinical parameters, including those 6 therapeutic goals selected in this study. Furthermore, patients treated with velaglucerase alfa for ≥ 3 months were included in this study based on our clinical experience that the effects of ERT stabilize at around 3–6 months; however, the results from this study indicated that ERT treatment with velaglucerase alfa for ≤ 3 months may be insufficient to stabilize lyso-Gb1 concentrations.

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