Effects of oral eliglustat on skeletal manifestations in patients with type 1 Gaucher disease: Results from four completed clinical trials after long-term treatment

Debilitating bone complications are common among patients with Gaucher disease type 1 (GD1). We analyzed changes in bone parameters among 393 GD1 patients treated with oral eliglustat for 4–8 years in 4 Sanofi Genzyme-sponsored clinical trials (Phase 2/NCT00358150 [N=26]; Phase 3: ENGAGE/NCT00891202 [N=40]; ENCORE/NCT00943111 [N=157]; EDGE/NCT01074944 [N=170]. In treatment-naïve patients (Phase 2/ ENGAGE), mean spine T-scores moved from the osteopenic range at baseline to the healthy range after 2–3 years. Mean±SEM spine T score increased from 1.55±0.28 to 0.59±0.34 (n=14) after 8 years in Phase 2, and increased to 0.53±0.27 in ENGAGE after 4.5 years (n=9). In both trials, spine Z-scores improved and femur T- and Z-scores remained normal. In ENCORE (patients stabilized after a mean of 10 years of enzyme replacement therapy [ERT]), T- and Z-scores remained in reference ranges for up to 4 years; least-square mean spine Z-scores improved by 0.29 (P<0.0001). In EDGE (mostly ERT switch), patients stabilized during the Lead-In maintained normal T- and Z-scores through the dose-regimen arm and extension period. Mean total bone marrow burden scores improved from marked-to-severe to moderate in ENGAGE and remained stable (moderate) throughout ENCORE and EDGE. Proportions of patients experiencing bone pain decreased after treatment in all trials; reported pain became less severe. Bone crises were infrequent, with none in Phase 2 or ENGAGE patients and in 3/157 (1.9%) patients in ENCORE and 6/170 (3.5%) in EDGE (3 of whom had bone crises before trial entry). Median macrophage inflammatory protein-1β levels normalized in ENGAGE and remained normal in ENCORE and EDGE. Eliglustat was generally well-tolerated. Overall, 97% of adverse events were mild/moderate (97%) and 86% considered unrelated to eliglustat; 9 (2.3% overall) patients withdrew due to adverse events considered drug-related. In summary, bone-related parameters showed improvement in treatment-naïve patients and stability or improvement in switch patients.Sanofi Genzym