Michael R. Page, PharmD, RPh
Gaucher disease type 1 (GD1) is a lysosomal storage disease resulting from deficient activity of the beta-glucosidase enzyme, which leads to building of glucosylceramide (GL-1) within tissue macrophages. This buildup of GL-1 may result in a variety of sequelae including hepatosplenomegaly, anemia, and thrombocytopenia, as well as bone disease.
Treatments for GD1 work in 1 of 2 ways, either by degrading existing GL-1 or by reducing synthesis of existing GL-1. Treatments of the first type include enzyme replacement therapies (ERTs), and treatments of the second type are generally known as substrate reduction therapies (SRTs). SRTs, such as Cerdegla (eliglustat), inhibit the enzyme glucosylceramide synthase (GCS) to slow production of GL-1.
Eliglustat is an orally bioavailable treatment was approved by the FDA in 2014, and is indicated for use in patients with GD1 and CYP2D6 phenotypes compatible with treatment. Of patients with GD1, more than 90% of patients have the requisite CYP2D6 phenotype to qualify for treatment.
Previous phase 2 and 3 studies demonstrate the efficacy of eliglustat in improving platelet and hemoglobin levels, reducing the volume of the spleen and the liver, and improving bone disease outcomes.
The initial trials reported outcomes after 9 to 12 months of follow-up, but further investigation showed sustained efficacy over 18 months of therapy. At the WorldSYMPOSUM 2016 meeting in San Diego, California, researchers reported robust 4-year efficacy data with eliglustat in a follow-up study of patients participating in the ENCORE clinical trial.
Of the 157 patients who entered the original extension, 4-year follow-up data was available for 46 patients, including 20 males and 26 females. The average age of these patients upon entry in the original trial was 34.0 years (SD: 14.4 years), and patients had an average age of first diagnosis of 14.4 years (SD: 11.9 years). Prior to receiving eliglustat, patients had received an average of 9.4 years (SD: 4.5 years) of ERT therapy.
Adverse events over 507 patient-years of exposure to eliglustat occurring in at least 5% of patients included upper abdominal pain (7%), arthralgia (6%), dyspepsia (6%), fatigue, gastritis, and abnormal findings in nerve conductions studies (5% each).
Patients were assessed based on several stability parameters related to hemoglobin, platelet, spleen, and liver outcomes. Patients were considered stable on the hemoglobin parameter if their hemoglobin concentration did not decrease more than 1.5 g/dL from baseline. Stability in the platelet domain was defined as a platelet count that did not decrease more than 25% from baseline, whereas stability on spleen and liver volume parameters were defined as increases in volume of no more than 25% from baseline, and no more than 20% from baseline, respectively.
After 4 years of therapy, all patients achieved stability of hemoglobin levels, and 96% of patients achieved platelet count stability. Spleen and liver volume stability was achieved and 94% and 96% of patients, respectively. The vast majority (91%) of patients receiving eliglustat for 4 years met stability outcomes for all 4 measures.
Researchers also assessed disease stability on hemoglobin, platelet, spleen, and liver outcomes based on therapeutic goals after 1 to 2 years of ERT. These included having hemoglobin levels >11.0 g/dL (in women in children) or >12 g/dL (in men), or having a platelet count of 100,000 per mm3
or higher. Spleen volumes ≤8 multiples of normal (MN) and liver volume ≤5 MN defined stable patient status on these domains.
In the 4-year analysis of patient stability based on therapeutic goals, all patients achieved normal parameters in hemoglobin, spleen and liver outcomes, and 96% of patients met criteria for stable platelet counts. Nearly all patients (96%) achieved stability on all 4 parameters, with stability assessed by goal levels.
In this 4-year follow-up study of the ENCORE trial, researchers identified high rates of clinical stability on both composite and individual measures. Additionally, with 507 patient-years of follow-up data, researchers identified no new safety signals. For the treatment of patients with GD1, long-term data in this follow-up study confirm both the efficacy and safety of oral eliglustat.
1. Cox TM, Drelichman G, Cravo R, et al. Eliglustat compared with imiglucerase in patients with Gaucher disease type 1 stabilised on enzyme replacement therapy: a phase 3, randomised, open-label, non-inferiority trial. Lancet
2. Cox TM, Drelichman G, Balwani M, et al. Four-year follow-up from the ENCORE trial: a randomized, controlled, open-label non-inferiority study comparing eliglustat to imiglucerase in Gaucher disease type 1 patients stabilized on enzyme replacement therapy: 24-month results. Mol Genet Metabol