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Elena Lukina, MD, and colleagues have published 1-year results of a phase II trial of eliglustat tartrate in patients with type 1 Gaucher disease (GD1) in the peer-review journal Blood
. Lukina is from the Hematology Research Center at the Russian Academy of Medical Sciences in Moscow. In a press release from the American Society of Hematology, which publishes Blood, Lukina said, “Eliglustat tartrate provides promise for a safe, effective, and convenient oral therapy for patients with GD1.” Eliglustat tartrate is from a novel class of drugs known as glucosylceramide synthase inhibitors.
Patients with GD1 have an inherited gene mutation that causes insufficient activity of the glucocerebrosidase enzyme, resulting in an accumulation of glucosylceramide (a harmful lipid) in cells. At present, the primary treatment is intravenous enzyme replacement therapy (ERT). ERT replaces glucocerebrosidase, the enzyme needed to break down these lipids and prevent engorged Gaucher cells from infiltrating the liver, spleen, and bone marrow, where they can cause mild to severe complications. Common signs and symptoms of GD1 include hepatosplenomegaly, anemia, thrombocytopenia, and skeletal problems.
For many patients, weekly ERT is burdensome and they would likely welcome an oral treatment. Although miglustat (Zavesca) is an oral drug approved for GD1, it has a different mechanism of action than ERT and is approved only for adults unable to receive ERT. The novel drug Eliglustat tartrate also has a different mechanism of action from ERT, partially inhibiting the enzyme responsible for glucosylceramide production.
After phase I studies established the safe therapeutic dose, researchers initiated a phase II open-label, single-arm trial. Participants were required to have confirmed glucocerebrosidase deficiency and a spleen volume at least 10 times the normal volume. They also had to have a platelet count between 45,000 and 100,000/mm3 or a hemoglobin level from 8.0 to 10.0 g/dL for women and 8.0 to 11.0 g/dL for men. Patients who had a splenectomy or who had taken miglustat or imiglucerase (Cerezyme) during the past year or used a bisphosphonate during the prior 3 months were deemed ineligible. New bone crises or skeletal pathology during the previous 12 months or anemia that did not result from GD1 were among the other disqualifiers.
The study enrolled 26 men and women aged 18 to 60 years (mean, 34 y) at sites in 5 countries. Although people of Ashkenazi Jewish descent are at higher risk for Gaucher disease, the investigators reported that the majority (62%) of patients were non-Jewish Caucasian; in addition, 62% were women. Patients received 50 mg or 100 mg of eliglustat tartrate twice daily, with the dose dependent on plasma levels after a 20-day induction period using 50 mg twice daily.
The study’s primary efficacy endpoint encompassed 1-year improvement from baseline for at least 2 of 3 parameters: spleen volume, hemoglobin level, or platelet count. Improvement in spleen volume was defined as a 15% reduction measured by MRI or CT scanning; hemoglobin levels needed to increase at least 0.5 g/dL, and platelet counts needed to rise 15%. Some of the secondary endpoints were declines in liver volume and disease-related plasma biomarkers, such as chitotriosidase, believed to reflect the patient’s burden of Gaucher cells. Because skeletal complications are a serious concern with GD1, investigators monitored patients for bone crises or bone pain and any skeletal changes, such as fluctuations in bone mineral density (BMD). Quality of life (QOL) was also assessed.
There were 22 patients who completed all 52 weeks of treatment. Of the 4 discontinuations, 2 occurred on day 1 after detection of cardiac issues and 2 withdrew when they became pregnant. Most intent-to-treat patients (77%) met the composite primary efficacy endpoint (95% confidence interval [CI], 58%-89%); an even higher percentage of patients (91%) who completed all 52 weeks met this endpoint (95% CI, 72%-98%). At 1 year, mean hemoglobin levels increased 1.62 mg/dL (P <.001) and mean platelet count increased by 40.3% (P <.001). Spleen volume reduction was 38.5% (P <.001) and liver volume declined 17.0% (P <.001). No bone crises were reported nor were any clinically significant changes observed in skeletal assessments or bone pain. Patients for whom BMD data were available showed “striking” increases (+0.3) in mean Z-scores and T-scores for lumbar spine BMD. Chitotriosidase activity, commonly used to monitor response to treatment in patients with GD1, declined by ~50%. QOL assessments showed improvement in physical functioning and general health, along with a decline in fatigue.
At 1 year, 75 adverse events had been reported for 22 (85%) patients, with 43% occurring in the first 3 months. All were mild or moderate, except 1 case of thrombocytopenia and 1 spontaneous abortion, neither of which was treatment related. Only 7 (9%) adverse events were considered treatment-related; the authors said all were mild and transient and happened in the first 3 months.