In Gaucher disease type 1 (GD1), deficient lysosomal acid β-glucosidase activity leads to accumulation of glucosylceramide and formation of lipid-laden macrophages known as Gaucher cells. Patients experience a range of disease manifestations including anemia, thrombocytopenia, hepatosplenomegaly, and debilitating bone complications that impair quality of life. Hematologists are central to disease recognition and management. Most patients, even those without overt symptoms of bone involvement, have radiologic evidence of bone disease. Eliglustat, an oral substrate-reduction therapy, is a first-line treatment for adults with GD1 who have extensive, intermediate or poor CYP2D6 metabolizer phenotypes (>90% of patients). Oral eliglustat partially inhibits glucosylceramide synthase, thereby reducing glucosylceramide accumulation, unlike enzyme replacement therapy (ERT), the historic standard of care for GD1, which augments acid β-glucosidase activity in mononuclear phagocytes and is administered in biweekly infusions.
We analyzed bone mineral density T- and Z-scores and occurrence of bone pain and bone crises in 4 completed clinical trials sponsored by Sanofi Genzyme that involved 393 GD1 patients treated with eliglustat for 4-8 years: Phase 2 (NCT00358150), Phase 3 ENGAGE (NCT00891202), Phase 3 ENCORE (NCT00943111), and Phase 3 EDGE (NCT01074944). Healthy reference scores are >-1 for T-scores and >-2 for Z-scores. Bone marrow burden (BMB) scores and changes in macrophage inflammatory protein 1β (MIP-1β) were also analyzed in the 3 Phase 3 trials. BMB, an MRI-based scoring system to evaluate marrow infiltration of both the lumbar spine and femur, and MIP-1β, a biomarker produced by inflammatory phagocytes surrounding Gaucher cells, are associated with active and evolving bone disease in GD1.
In treatment-naïve patients (Phase 2, N=26; ENGAGE, N=40), mean spine T-scores moved from the osteopenic range (>-2.5 to ≤ -1) at baseline to the healthy reference range after 2-3 years of eliglustat, with continued improvement thereafter in both trials. Mean±SEM spine T-score increased from -1.55±0.28 to -0.59±0.34 (n=14; mean±SEM increase from baseline: 0.96±0.32), after 8 years in Phase 2, and increased to -0.53±0.27 in ENGAGE patients with bone data at 4.5 years (n=9; mean±SEM increase from baseline: 0.53±0.16). Spine Z-scores for both trials showed similar improvements; femur T- and Z-scores in both trails remained in the normal range. In the ENCORE trial of patients stabilized after a mean of 10 years of ERT (N=157), T- and Z-scores (spine and femur) remained in the reference ranges for up to 4 years; least square mean spine Z-scores improved by 0.29 (P<0.0001). In EDGE (N=170, mostly ERT switch), randomized patients stabilized on eliglustat during a 6- to 18-month Lead-In Period maintained normal T- and Z-scores (spine and femur) through the dose regimen arm of the study and the succeeding extension period. Mean total BMB scores improved from 10 (in the marked to severe range) to 8 (moderate range) in ENGAGE (treatment-naive patients), and remained stable at 8 throughout ENCORE and EDGE (switch/mostly switch patients). The proportion of patients experiencing recent (≤4 weeks) bone pain decreased after treatment in all 4 trials, and reported pain became less severe. No patient in Phase 2 or ENGAGE had a bone crisis while on eliglustat. Bone crises were reported in 3/157 (1.9%) ENCORE patients over the trial duration. In EDGE, the only trial to enroll patients with active bone disease, 6/170 (3.5%) patients had bone crises during the trial, 3 of whom had bone crises during the 6 months prior to trial entry. Bone crises decreased with increasing time on eliglustat, with only 1 bone crisis reported during the 2- to 3-year trial extension. In ENGAGE (treatment-naïve), median MIP-1β levels elevated 3-fold at baseline normalized. In ENCORE and EDGE (switch/mostly switch), MIP-1β levels remained in the normal range. Across the 4 trials, most adverse events were mild/moderate (97%) and considered unrelated to eliglustat (86%); 9 (2.3% overall) patients withdrew due to adverse events considered drug-related.
Long-term eliglustat treatment induced continued improvement in bone parameters in treatment-naïve patients. These parameters remained stable in trials involving patients who had been previously treated. Eliglustat was generally well-tolerated.
Mistry:Sanofi Genzyme: Honoraria, Other: Principal Investigator for the eliglustat ENGAGE and ENCORE trials; ReceivedTravel Reimbursement; Member of the ICCG North American Advisory Board; , Research Funding. Charrow:Sanofi Genzyme: Honoraria, Other: Principal investigator, eliglustat EDGE trial; Member of advisory boards, Research Funding. Cox:Sanofi Genzyme: Honoraria, Other: Principal investigator for the eliglustat ENCORE trial; received travel reimbursement, Research Funding. Lukina:Sanofi Genzyme: Honoraria, Other: Principal investigator in the eliglustat Phase 2, ENGAGE, ENCORE, and EDGE trials; receives travel reimbursement; member of advisory boards, Research Funding. Marinakis:Sanofi Genzyme: Other: Principal investigator for the eliglustat EDGE trial, Research Funding. Foster:Sanofi Genzyme: Employment. Gaemers:Sanofi Genzyme: Employment. Peterschmitt:Sanofi Genzyme: Employment.
Asterisk with author names denotes non-ASH members.