INTRODUCTION: Gaucher disease type 1 (GD1) is caused by hereditary deficiency in activity of lysosomal acid β-glucosidase and lysosomal dysfunction due to abnormal recycling and storage of glycosphingolipids especially in tissue macrophages. Clinical manifestations can include anemia, thrombocytopenia, hepatosplenomegaly, and debilitating bone disease. Hematologists care for most patients with GD1 but may be unaware of the importance of plasma biomarkers not only as tissue response surrogates that are useful for monitoring treatment efficacy but also as pathogenic molecules that can directly contribute to disease manifestations. These biomarkers include chitotriosidase, macrophage inflammatory protein 1β (MIP-1β), glucosylceramide, glucosylsphingosine, and monosialodihexosyl ganglioside (GM3). Here we show differing changes in biomarker levels after inception of eliglustat therapy in treatment-naïve GD1 patients and in patients previously treated with enzyme replacement therapy (ERT). Eliglustat is an oral inhibitor of glucosylceramide biosynthesis approved by FDA as a first-line treatment of adults with GD1 who have extensive, intermediate, or poor CYP2D6 metabolizer phenotypes (>90% of patients). METHODS: We evaluated percent change from baseline in biomarker levels during time on eliglustat in the 4 completed clinical trials of oral eliglustat for GD1 adults (Sanofi Genzyme): Phase 2/NCT00358150 (treatment-naïve patients with moderate to severe baseline disease, N=26); Phase 3 ENGAGE/NCT00891202 (treatment-naïve patients with mild to moderate baseline disease, N=40); Phase 3 ENCORE/NCT00943111 (switch patients at prespecified therapeutic goals stabilized after a mean of 10 years of ERT], N=159); Phase 3 EDGE/NCT01074944 (mixture of treatment-naïve [N=22] and ERT-switch patients [N=148] with mild to moderate baseline disease and variable prior time on ERT). All percentages were calculated in the subset of patients with biomarkers measured at baseline and the reported timepoint. The attrition of patients with data at the longer-term time points is attributable primarily to a combination of 2-year enrollment periods, trial design, and protocol-mandated switches to commercial therapy for US patients. Most patients (81%) continued until eliglustat became commercially available or completion of their trial; 9 patients (2.3% overall) withdrew due to adverse events reported as drug-related. For Phase 2, ENGAGE, and ENCORE, chitotriosidase genotypes were obtained and values were normalized; patients homozygous for the CHIT null mutation were excluded and values for heterozygous patients were doubled. For EDGE patients, chitotriosidase genotype data were not obtained but patients with ≥4 zero values (n=12) were excluded. RESULTS: In treatment-naïve patients, all biomarkers were elevated at baseline. Median levels of glucosylceramide, GM3, and MIP-1β normalized within 1 year of starting eliglustat. Chitotriosidase and glucosylsphingosine levels markedly decreased but did not normalize. After 3-8 years on treatment, median percent reduction in chitotriosidase and glucosylsphingosine (Phase 2 and ENGAGE) was 85-92% (Table) but values did not normalize. In patients switching from ERT, median chitotriosidase was still modestly elevated at baseline. Median values for other biomarkers were normal or near normal. After 1 year of treatment, chitotriosidase decreased (Table). Median glucosylceramide, GM3, and MIP-1β remained normal or normalized. After 3-4 years, GM3 and MIP-1β remained normal. Median percent reduction in chitotriosidase from baseline was 60-63% but values did not normalize. Eliglustat was generally well-tolerated in all 4 trials; 97% of adverse events were mild/moderate and 86% considered unrelated to eliglustat by the investigator. CONCLUSIONS: Gaucher disease biomarkers decreased substantially in treatment-naïve patients after eliglustat treatment. In switch patients, including very stable patients after a mean of 10 years on ERT, chitotriosidase and MIP-1β also decreased substantively after eliglustat treatment. Future longitudinal follow-up of eliglustat-treated patients should indicate whether the biomarker and plasma glycosphingolipid responses reported here in stable patients at long-term therapeutic goals are associated with immunological and clinical improvements. Disclosures Weinreb: Shire HGT: Consultancy, Honoraria, Speakers Bureau; Sanofi Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cox:Sanofi Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Reimbursement, Research Funding. Mistry:Sanofi Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Reimbursement, Research Funding; NIH NIMS: Research Funding; Shire: Honoraria, Other: Travel Reimbursement, Research Funding; Pfizer: Honoraria, Other: Travel Reimbursement; Synageva: Honoraria, Other: Travel Reimbursement. Charrow:BioMarin: Research Funding; Shire: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amicus: Research Funding. Lukina:JSC GENERIUM: Research Funding; Sanofi Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Reimbursement, Research Funding; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Reimbursement. Foster:Sanofi Genzyme: Employment. Peterschmitt:Sanofi Genzyme: Employment.
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Open Access
Dec 23, 2023
Mona Alenezi + 1
