Impact of Long-Term Enzyme Replacement Therapy on Glucosylsphingosine (Lyso-Gb1) Values in Patients with Type 1 Gaucher Disease: Statistical Models for Comparing Three Enzymatic Formulations

Abstract

For three decades, enzyme replacement therapy (ERT), and more recently, substrate reduction therapy, have been the standard-of-care for type I Gaucher disease (GD1). Since 2012, three different ERTs have been available. No clinical trial or academic study has ever compared these ERTs beyond one year. Herein we compare the impact of the ERTs on repeated measurements of glucosylsphingosine (lyso-Gb1; the most sensitive and GD-specific biomarker). A total of 135 adult patients (77 (57%) female) with GD1, followed from July 2014 to March 2020 and treated with a single ERT (imiglucerase (n = 41, 30.4%), taliglucerase alfa (n = 21, 15.6%) and velaglucerase alfa (n = 73, 54.1%)), were included. Disease severity was defined by genotypes (mild: N370S (c.1226A>G) homozygous and N370S/R496H (c.1604G) compound heterozygous; severe: all other genotypes) and by the severity score index (SSI; mild: <7; severe: ≥7). Lyso-Gb1 testing was performed at Centogene™ on dry blood spot samples collected during routine visits. Patients treated with imiglucerase had higher lyso-Gb1 levels at different time points. A huge variation in lyso-Gb1 levels was noticeable both inter-individually and intra-individually for all three ERTs. A steeper and faster decrease of lyso-Gb1 levels was shown in velaglucerase alfa. Nevertheless, the differences between medications were not very large, and bigger numbers and more pretreatment data are required for more powerful conclusions.

Glucosylsphingosine (Lyso-Gb1): An Informative Biomarker in the Clinical Monitoring of Patients with Gaucher Disease

“…For these patients, lyso-Gb 1 levels while elevated, have settled into a ‘new-normal’ baseline for these patients and are a better reflection of the ongoing disease burden. These findings are consistent with previously published results that observed biomarker improvement or stability after ERT switch [ 18 , 41 ]; however, it should be noted that many other factors including dosing of ERT and periods of discontinuation, among others, may be contributing to this improvement following switch.…”

“…While the clinical benefits of treatment with ERT and/or SRT have been well documented in mouse models [ 33 ] and treatment naïve patients [ 13 , 34 , 35 , 36 , 37 ], considerable variation in the clinical response to treatment exists [ 32 ]. In one study, a comparison of lyso-Gb 1 levels in patients on long-term ERT showed considerable inter- and intra-individual variability with higher concentrations of lyso-Gb 1 observed in patients treated with imiglucerase in comparison to velaglucerase alfa [ 14 ] and with a steeper and faster decrease of lyso-Gb 1 levels in those treated with velaglucerase alfa [ 18 ]. In a subsequent study, comparison of patients treated with ERT (imiglucerase and velaglucerase alfa) was similar and with SRT, a better clinical response was observed secondary to treatment with eliglustat [ 22 , 36 ].…”

“…We posit that lyso-Gb 1 should be used as a tool in the clinical setting to monitor compliance. First, it has previously been published that changes in lyso-Gb 1 levels often precede changes in other clinical biomarkers, including platelet counts and organomegaly [ 18 , 42 ]. Trending lyso-Gb 1 levels in a monitoring plot may help clinicians identify potential cases of non-compliance before worsening of clinical symptoms and it may have clinical utility with regard to individualized therapeutic recommendations, allowing a conversation between patient and provider regarding which type of treatment would allow for the best compliance, and as a result, disease control.…”

“…In lysosomes, acid ceramidase actively converts glucosylceramide into lyso-Gb 1 , one of several adaptations in glucosylceramide metabolism [ 12 ]. Lyso-Gb 1 is sensitive and specific to GD, elevated in 100% of treatment-naïve patients and shown to be an effective biomarker in treatment monitoring with significant correlation to CHITO activity, liver and spleen volumes, and treatment mode [ 13 , 14 , 15 , 16 , 17 , 18 ], and not noted in other conditions.…”

Therapeutic Approaches in Lysosomal Storage Diseases

“…As an example, type 1 GD patients respond fairly well to ERT that can easily reach the macrophage to cleave glucosylceramide storage. Macrophages are responsible for the major clinical signs in this condition; nonetheless, ERT is not effective in neurological manifestations of type III GD and differentially distributed to tissues that are more difficult to target, such as the bone [ 18 ]. In FD, ERT reduces Gb3 levels in plasma and tissues, improves gastrointestinal symptoms and neuropathic pain and delays disease progression, by partially stabilizing heart and renal function [ 30 ].…”