Skeletal improvement in patients with Gaucher disease type 1: a phase 2 trial of oral eliglustat

Abstract

Objective: Eliglustat is an investigational oral substrate reduction therapy for Gaucher disease type 1 (GD1). Its skeletal effects were evaluated by prospective monitoring of bone mineral density (BMD), fractures, marrow infiltration by Gaucher cells, focal bone lesions, and infarcts during an open-label, multi-site, single-arm phase 2 trial (NCT00358150).

Materials and methods: Institutional review board approval and patient informed consent were obtained. Eliglustat (50 or 100 mg) was self-administered by mouth twice daily; 19 patients completed 4 years of treatment. All were skeletally mature (age range, 18-55 years). DXA and MRI assessments were conducted at baseline and annually thereafter. X-rays were obtained annually until month 24, and then every other year.

Results: Lumbar spine BMD increased significantly (p = 0.02; n = 15) by a mean (SD) of 9.9% (14.2%) from baseline to year 4; corresponding T-scores increased significantly (p = 0.01) from a mean (SD) of -1.6 (1.1) to -0.9 (1.3). Mean femur T-score remained normal through 4 years. Femur MRI showed that 10/18 (56%) patients had decreased Gaucher cell infiltration compared to baseline; one patient with early improvement had transient worsening at year 4. There were no lumbar spine or femoral fractures and no reported bone crises during the study. At baseline, 8/19 (42%) patients had focal bone lesions, which remained stable, and 7/19 (37%) patients had bone infarctions, which improved in one patient by year 2. At year 4, one new asymptomatic, indeterminate bone lesion was discovered that subsequently resolved.

Conclusions: Eliglustat may be a therapeutic option for treating the skeletal manifestations of GD1.

Figures

Fig. 1

Improvements in femur dark marrow during 4 years of eliglustat treatment. The six zones of the femur are numbered according to the original method [1]

Fig. 2

Dark marrow improvement in two patients after 4 years of eliglustat therapy. Top Coronal T1-weighted MR images of the proximal right femur of a 55-year-old female patient at baseline (a) and at 48 months (b) demonstrate decreased but persistent dark marrow in the femoral head epiphysis, greater trochanteric apophysis, and intertrochanteric region of the proximal femur. Dark marrow has also largely disappeared from the proximal femoral diaphysis. Coronal T1-weighted MR images of the distal left femur at baseline (c) and at 36 months (d) demonstrate substantially decreased dark marrow in the distal femoral diaphysis and metaphysis. Bottom Coronal T1-weighted MR images of the proximal right femur of a 30-year-old male patient at baseline (e) and at 48 months (f) demonstrate decreased dark marrow in the intertrochanteric region and proximal diaphysis of the femur. Coronal T1-weighted MR images of the distal right femur at baseline (g) and at 48 months (h) in the same patient demonstrate complete resolution of dark marrow in the distal femoral diaphysis and metaphysis with residual normal fatty marrow

Fig. 3

Changes in lumbar spine bone mineral density with eliglustat treatment. Each point represents the T-score for a given patient, with age at treatment initiation shown adjacent to the symbol

Fig. 4

Resolution of indeterminate lesion and continued dark marrow improvement in one patient. Coronal T1-weighted MR images of the distal right femur of a 55-year-old female patient at 36 months (a) and 48 months (b) demonstrate an interval increase in dark marrow in the distal femoral diaphysis and metaphysis with a new indeterminate metaphyseal bone lesion at 48 months. At 60 months (c), the bone lesion resolved and dark marrow continued to improve, even as compared to 36 months, with near-complete resolution of dark marrow in the distal femoral diaphysis and metaphysis