Improvements in Skeletal Manifestations in Gaucher Disease Type 1 Patients After 3 Years of Treatment with Oral Eliglustat During a Phase 2 Trial,

In Gaucher disease type 1 (GD1), deficient lysosomal acid β-glucosidase leads to accumulation of undegraded glucosylceramide in lysosomes of tissue macrophages known as Gaucher cells. Skeletal complications are a major cause of morbidity and include bone marrow infiltration by Gaucher cells, osteopenia/osteoporosis, lytic lesions, fractures, avascular necrosis, and bone pain. Eliglustat, a novel, oral inhibitor of glucosylceramide synthase, is under investigation for the treatment of GD1.

To report skeletal changes after 3 years of eliglustat therapy.

This ongoing, open-label, uncontrolled, multicenter, Phase 2 clinical trial enrolled 26 adults with GD1 not on treatment for the previous 12 months, who had splenomegaly with thrombocytopenia and/or anemia. Study entry criteria also required that patients had no new pathologic bone involvement or bone crises within the preceding 12 months and not have used bisphosphonates during the previous 3 months. Changes from baseline were reported for centrally reviewed skeletal x-rays, dual-energy x-ray absorptiometry (DXA) and MRI assessments.

Of 26 enrolled patients, 19 completed 3 years of treatment. In 15 patients with evaluable DXA results at baseline and at 1, 2, and 3 years, mean lumbar spine BMD increased by 0.6±0.69 Z-score (baseline, −1.28), with greatest increases seen in osteoporotic patients. Mean femur BMD (T- and Z-score) remained normal through 3 years. Femur dark marrow on MRI, which reflects bone marrow infiltration by Gaucher cells, was reduced in 56% (10/18) or stable in 44% (8/18) of patients with findings at baseline. No bone crises or reductions in mobility occurred. On baseline radiographs, no patients had fractures, 42% (8/19 patients) had femoral lytic lesions, and 37% (7/19 patients) had bone infarcts. After 3 years, the lumbar spine and femurs showed no new lytic lesions, bone infarcts, fractures, or areas of osteonecrosis and no worsening of pre-existing lytic lesions or bone infarcts. One patient had worsening of asymptomatic osteonecrosis after 1 year noted retrospectively at baseline. Eliglustat was well-tolerated. Most adverse events (AEs) were mild and unrelated to treatment; the most common were viral infections (6 patients); urinary and upper respiratory tract infections (4 patients each); and headache, increased blood pressure, abdominal pain, diarrhea (3 patients each). Eight drug-related AEs, all mild, occurred in 6 patients.

During 3 years of eliglustat treatment, radiologic monitoring showed improvement or stabilization of GD1 bony manifestations with no noted safety-related trends, suggesting that eliglustat may be a promising treatment for skeletal complications of GD1. Ongoing Phase 3 studies will provide more information on the bone effects of eliglustat.

Peterschmitt:Genzyme: Employment. Kamath:Genzyme: Consultancy. Lukina:Genzyme: Honoraria. Watman:Genzyme: Membership on an entity's Board of Directors or advisory committees. Pastores:Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Actelion: Research Funding; Amicus: Research Funding; Biomarin: Research Funding; Shire HGT: Research Funding; Protalix: Research Funding. Arreguin:Genzyme: Research Funding. Aguzzi:Genzyme: Employment. Ross:Genzyme: Employment. Puga:Genzyme: Employment. Rosenthal:Genzyme: Consultancy.