Eliglustat for Gaucher Disease Type 1

David Green, MD, PhD reviewing Mistry PK et al. JAMA 2015 Feb 17.

This new glucosylceramide synthase inhibitor was well tolerated and significantly more effective than placebo.

Gaucher disease is a liposomal storage disorder characterized by accumulation of glucosyl-ceramide in monocytes and macrophages, resulting in hepatosplenomegaly, anemia, thrombocytopenia, and bone disease. Most patients are deficient in glucocerebrosidase and require replacement of this enzyme; the recombinant enzyme is given intravenously every 2 weeks and is expensive. Enzyme treatment can be supplemented with miglustat, an oral inhibitor of glucosylceramide synthase (GCS), but diarrhea, weight loss, and peripheral neuropathy limit the usefulness of this drug.

To assess the safety and effectiveness of a new oral GCS inhibitor, eliglustat, investigators conducted an industry-funded, multicenter, randomized, double-blind, placebo-controlled trial involving 40 treatment-naive patients with Gaucher disease type 1. Patients were randomized to 9 months of treatment with placebo or eliglustat (50 mg twice daily for 4 weeks and then dose adjustments based on trough plasma concentrations).

Results were as follows:

• Mean spleen volume (the primary endpoint) decreased with eliglustat and increased with placebo (-27.8% vs. 2.3%; P<0.001).
• Liver volume decreased with eliglustat and increased with placebo (-5.2% vs. 1.4%; P=0.007).
• Hemoglobin increased with eliglustat but decreased with placebo (0.69 g/dL vs. -0.54 g/dL; P<0.001).
• Platelet count increased with eliglustat but decreased with placebo (32.0% vs. -9.1%; P<0.001).
• Bone marrow burden score decreased more with eliglustat than with placebo (-1.7 vs. -0.4; P=0.002); various biomarkers of Gaucher cells and inflammation also decreased with eliglustat.
• Adverse effects — including arthralgia, nasopharyngitis, headache, nasal obstruction, and fever — occurred more often with eliglustat but were not severe and did not result in patient withdrawals from the study.

Citation(s):

Mistry PK et al. Effect of oral eliglustat on splenomegaly in patients with Gaucher disease type 1: The ENGAGE randomized clinical trial. JAMA 2015 Feb 17; 313:695.