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

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.