PF428 GLUCOSYLSPHINGOSINE (LYSO-GL-1), A BIOMARKER OF GAUCHER DISEASE, CORRELATES WITH DISEASE SEVERITY AND RESPONSE TO ELIGLUSTAT IN 2 CLINICAL TRIALS OF TREATMENT-NAÏVE ADULTS WITH GAUCHER DISEASE TYPE 1
Authors: M.J. Peterschmitt, M. Foster, K. Zhang, C. Gerald
Journal: HemaSphere (2019)

Please indicate where the abstract has been published before: Special Issue of Molecular Genetics and Metabolism on The Lysosome Background: Gaucher disease type 1 (GD1) is caused by deficient activity of acid β-glucosidase, the enzyme that breaks down the major substrate glucosylceramide (GL-1) and the minor substrate glucosylsphingosine (lyso-GL-1), the deacylated form of GL-1, leading to the accumulation of these lipid substrates throughout the body, especially in cells of macrophage-monocyte origin. GD1 patients can experience progressive and debilitating hepatosplenomegaly, anemia, thrombocytopenia, and skeletal disease. Hematologists are central to diagnosis and management of Gaucher disease. Lyso-GL-1 is increasingly recognized as a key biomarker, as elevations are highly specific to the disease and in the causal pathway. Eliglustat (Cerdelga®, Sanofi Genzyme) is a first-line oral substrate reduction therapy approved for adults with GD1 with extensive, intermediate, or poor CYP2D6-metabolizer phenotypes (>90% of patients). Aims: We examined how lyso-GL-1 levels correlated with GD1 burden of disease as well as treatment response to eliglustat with respect to spleen volume, liver volume, hemoglobin level, and platelet count. Methods: Data were evaluated from an open-label Phase 2 trial (NCT00358150) of 26 treatment-naïve patients with moderate to severe disease with 8-year follow-up and a placebo-controlled Phase 3 trial (ENGAGE; NCT00891202) of 40 treatment-naïve patients with mild to moderate disease with up to 4.5-year follow-up. Baseline lyso-GL-1 measurements prior to eliglustat treatment were available in 24 Phase 2 patients and 38 ENGAGE patients, with follow-up measurements after 8 years of eliglustat for 16 Phase 2 patients and after 4.5 years of eliglustat for 10 ENGAGE patients. The upper limit of normal (ULN) for plasma lyso-GL-1 used in this analysis was determined by evaluating 100 healthy volunteers (50 female and 50 male). Results: At baseline, all patients in both trials had substantial elevations of lyso–GL-1 above the determined ULN of <5 ng/mL. In the Phase 2 trial (N = 24), the median baseline was 597 ng/mL, which is 119 times the ULN (range: 29–314 X ULN). The median baseline value in ENGAGE (N = 38) was 304 ng/mL, which is 61 times the ULN (range: 12–208 X ULN), reflecting the less severe baseline burden of disease in this placebo-controlled trial. Moderate-to-strong baseline correlations were observed for lyso-GL-1 with spleen volume, liver volume, and hemoglobin levels (spleen: r = 0.49 and r = 0.76; liver: r = 0.43 and r = 0.72; hemoglobin: r = −0.53 and r = −0.49; in Phase 2 and ENGAGE, respectively; all P < 0.05) but not with platelet count (r = −0.18, P = 0.40 [Phase 2]; r = −0.29, P = 0.08 [ENGAGE]). Lyso-GL-1 levels decreased in both trials, with a median percent change from baseline of −92% in Phase 2 after 8 years and −84% in ENGAGE after 4.5 years of eliglustat. Using mixed repeated measures modeling, change in lyso-GL-1 after eliglustat treatment correlated with improvements in clinical parameters in both trials (spleen: r = 0.72 and r = 0.63; liver: r = 0.28 and r = 0.57; hemoglobin: r = −0.65 and r = −0.34; and platelets: r = −0.26 and r = −0.18, in Phase 2 [N = 21–22] and ENGAGE [N = 38], respectively; all P < 0.05). Change in lyso-GL-1 also correlated with change in plasma chitotriosidase in both trials: r = 0.50 in Phase 2 and r = 0.38 in ENGAGE (both P < 0.0001). Summary/Conclusion: Our data showing marked elevations in lyso-GL-1 in all patients before eliglustat treatment, correlations with baseline disease, and correlations with improvements after eliglustat treatment, highlight the utility of lyso-GL-1 as a clinically useful biomarker for GD1.