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Treatment with Eliglustat maintains hematological and organ volume stability in adults with Gaucher disease type 1 previously stabilized with intravenous enzyme replacement therapy


The results from the ENCORE study exploring Cerdelga ( Eliglustat ) as a maintenance therapy suitable for adult patients who had reached pre-specific treatment goals on enzyme replacement therapy ( ERT ) were published in The Lancet.

ENCORE is a randomized, multinational, phase 3, open-label, non-inferiority study designed to determine whether patients with Gaucher disease type 1 who had been stabilized after 3 or more years of ERT infusions would remain stable after switching to Eliglustat, a novel, oral, selective inhibitor of glucosylceramide synthase.
Eligible patients were randomized 2:1 to receive either oral Eliglustat ( n=106 ) or ERT with Imiglucerase ( Cerezyme ) ( n=53 ) over a period of 12 months.

The composite primary efficacy endpoint was the percentage of patients whose hematologic parameters and organ volumes remained stable, using the following stability criteria established for patients with Gaucher disease type 1 on maintenance therapy with Eliglustat: a) hemoglobin concentration that did not decrease more than 1.5 g/dL; b) platelet count that did not decrease more than 25%; c) spleen volume that did not increase more than 25%; d) liver volume that did not increase more than 20%.

After 12 months, 85% of patients receiving Eliglustat and 94% of patients receiving Imiglucerase met the composite endpoint of stability in all four of these measures.
The difference between the two treatments was within the pre-specified margins.

The principal secondary endpoints were stability with respect to the individual components of the primary endpoint.
At least 93% of patients on Eliglustat remained stable with respect to hemoglobin concentration, platelet count, spleen volume, and liver volume after 12 months of treatment.

Additional endpoints evaluated bone disease, Gaucher disease severity, quality-of-life and Gaucher-disease associated biomarkers. Baseline values for these measures reflected the clinical stability of this population, and no significant changes were seen after the switch to Eliglustat, with the exception of decreases in levels of the plasma biomarkers glucosylceramide and GM3. Given the mechanism of action of Eliglustat, these were expected and all values remained within the healthy reference range.

A treatment preference survey done at the beginning of the trial found that 94% of patients in both treatment groups had a preference for oral treatment.
After 12 months of treatment, all patients on Eliglustat who responded to the survey ( 94% ) confirmed this treatment preference, with the most frequent reasons cited being its convenience, capsule formulation, availability at home and feeling better after treatment.

Most adverse events were non-serious and mild or moderate in severity. The most common side effects considered related to Eliglustat were diarrhea ( 5% of patients ), arthralgia ( 4% ), fatigue ( 4% ) and headache ( 4% ).
Two patients on Eliglustat and one patient on Imiglucerase ( 2% of each treatment arm ) discontinued treatment. Discontinuations in the Eliglustat group were due to palpitations without clinically relevant ECG findings, deemed possibly treatment-related and myocardial infarction, deemed unrelated to treatment.
The patient on Imiglucerase discontinued due to psychotic disorder, deemed unrelated to treatment.

In Gaucher disease type 1, a deficiency of lysosomal acid beta-glucosidase leads to glucosylceramide accumulation in macrophages. This results in symptoms including hepatosplenomegaly, anemia, thrombocytopenia and skeletal disease.
Eliglustat is a ceramide analog that works by partially inhibiting the enzyme UDP-glucosylceramide transferase, slowing the production of beta-glucosylceramide, the substance that builds up in the lysosomes of affected patients.
Patients with Gaucher disease type 1 retain residual acid beta-glucosidase enzyme activity and Cerdelga aims to reduce the rate at which the lipid is made so that the residual function is able to clear the excess and re-establish a healthy equilibrium. ( Xagena )

Source: Genzyme, 2015

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