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Stability is maintained in adults with Gaucher disease type 1 switched from velaglucerase alfa to eliglustat or imiglucerase: A sub-analysis of the eliglustat ENCORE trial.

ABSTRACT: Gaucher disease type 1 is an autosomal recessive disorder caused by deficient activity of the lysosomal enzyme acid ?-glucosidase resulting in accumulation of glucosylceramide and clinical manifestations of anemia, thrombocytopenia, hepatosplenomegaly, and skeletal disease. The historic standard of care is intravenous recombinant enzyme therapy with imiglucerase. Eliglustat, an oral substrate reduction therapy, is a first-line treatment for adults with Gaucher disease type 1 who have a compatible CYP2D6-metabolizer phenotype (? 95% of patients). The 12-month ENCORE trial (NCT00943111) found eliglustat non-inferior to imiglucerase in maintaining stability in adult Gaucher patients previously stabilized after ? 3 years of enzyme therapy (imiglucerase or velaglucerase alfa). This post-hoc analysis examined safety and efficacy in the 30 ENCORE patients who were receiving velaglucerase alfa at study entry and were randomized to eliglustat (n = 22) or imiglucerase (n = 8). Efficacy and safety in velaglucerase alfa-transitioned patients were consistent with the full ENCORE trial population; 90% of patients switched to eliglustat and 88% of patients switched to imiglucerase met the composite endpoint (stable hemoglobin concentration, platelet count, spleen volume, and liver volume). Clinical stability was maintained for 12 months in Gaucher disease type 1 patients in the ENCORE trial who switched from velaglucerase alfa to either eliglustat or imiglucerase.

SUBMITTER: Pleat R

PROVIDER: S-EPMC5050260 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Stability is maintained in adults with Gaucher disease type 1 switched from velaglucerase alfa to eliglustat or imiglucerase: A sub-analysis of the eliglustat ENCORE trial.

Pleat Rebecca R Cox Timothy M TM Burrow T Andrew TA Giraldo Pilar P Goker-Alpan Ozlem O Rosenbloom Barry E BE Croal Laura R LR Underhill Lisa H LH Gaemers Sebastiaan J M SJ Peterschmitt M Judith MJ

Molecular genetics and metabolism reports 20160930

Gaucher disease type 1 is an autosomal recessive disorder caused by deficient activity of the lysosomal enzyme acid β-glucosidase resulting in accumulation of glucosylceramide and clinical manifestations of anemia, thrombocytopenia, hepatosplenomegaly, and skeletal disease. The historic standard of care is intravenous recombinant enzyme therapy with imiglucerase. Eliglustat, an oral substrate reduction therapy, is a first-line treatment for adults with Gaucher disease type 1 who have a compatibl ...[more]

PMID: 27722092

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Project description:Gaucher disease type 1, an inherited lysosomal storage disorder, is caused by mutations in GBA1 leading to defective glucocerebrosidase (GCase) function and consequent excess accumulation of glucosylceramide/glucosylsphingosine in visceral organs. Enzyme replacement therapy (ERT) with the biosimilars, imiglucerase (imig) or velaglucerase alfa (vela) improves/reverses the visceral disease. Comparative transcriptomic effects (microarray and mRNA-Seq) of no ERT and ERT (imig or vela) were done with liver, lung, and spleen from mice having Gba1 mutant alleles, termed D409V/null. Disease-related molecular effects, dynamic ranges, and sensitivities were compared between mRNA-Seq and microarrays and their respective analytic tools, i.e. Mixed Model ANOVA (microarray), and DESeq and edgeR (mRNA-Seq). While similar gene expression patterns were observed with both platforms, mRNA-Seq identified more differentially expressed genes (DEGs) (?3-fold) than the microarrays. Among the three analytic tools, DESeq identified the maximum number of DEGs for all tissues and treatments. DESeq and edgeR comparisons revealed differences in DEGs identified. In 9V/null liver, spleen and lung, post-therapy transcriptomes approximated WT, were partially reverted, and had little change, respectively, and were concordant with the corresponding histological and biochemical findings. DEG overlaps were only 8-20% between mRNA-Seq and microarray, but the biological pathways were similar. Cell growth and proliferation, cell cycle, heme metabolism, and mitochondrial dysfunction were most altered with the Gaucher disease process. Imig and vela differentially affected specific disease pathways. Differential molecular responses were observed in direct transcriptome comparisons from imig- and vela-treated tissues. These results provide cross-validation for the mRNA-Seq and microarray platforms, and show differences between the molecular effects of two highly structurally similar ERT biopharmaceuticals.

Dataset Information

Stability is maintained in adults with Gaucher disease type 1 switched from velaglucerase alfa to eliglustat or imiglucerase: A sub-analysis of the eliglustat ENCORE trial.

Publications

Stability is maintained in adults with Gaucher disease type 1 switched from velaglucerase alfa to eliglustat or imiglucerase: A sub-analysis of the eliglustat ENCORE trial.

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