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Positive Results Reported for Eliglustat (Cerdelga) in Treatment-Naïve Patients With Gaucher Disease Type 1

Treatment meets primary endpoint of improved spleen volume

Positive results from the ENGAGE registration study evaluating eliglustat (Cerdelga, Genzyme/Sanofi) in treatment-naïve patients with Gaucher disease type 1 have been published in JAMA.

The ENGAGE trial was a phase III, randomized, double-blinded, placebo-controlled study involving 40 treatment-naïve patients with Gaucher disease type 1 who had splenomegaly in addition to thrombocytopenia and/or anemia at study entry. Gaucher disease is a genetic disorder in which individuals fail to produce glucocerebrosidase, an important enzyme that breaks down the glycolipid glucocerebroside within lysosomes. In the absence of glucocerebrosidase, lipids accumulate in the bone marrow, lungs, spleen, liver, and brain –– causing spleen and liver enlargement, red and white blood-cell abnormalities, and bone deterioration; therefore, endpoints that specifically measured change in these symptoms were used in the study.

The patients were stratified by baseline spleen volume and were randomly assigned to receive eliglustat (50 or 100 mg twice daily) or placebo for 9 months. The study’s primary efficacy endpoint demonstrated a statistically significant mean reduction from baseline in spleen volume of 28% in the eliglustat-treated patients compared with a reduction of 2% in the placebo group, for an absolute difference of 30% (P < 0.0001).

Secondary endpoints were also statistically significant for eliglustat:

  • Hemoglobin levels increased from baseline by an absolute difference of 1.2 g/dL compared with placebo (P = 0.0006).
  • Liver volume decreased from baseline by an absolute difference of 6.6% compared with placebo (P = 0.0072).
  • Platelet counts increased from baseline by an absolute difference of 41% compared with placebo (P < 0.0001).

The most common adverse events associated with eliglustat included arthralgia, headache, migraine, flatulence, nausea, and oropharyngeal pain. No serious adverse events were observed in either treatment group.

Eliglustat, a first-line oral small molecule, was developed to expand the range of available treatment options for Gaucher disease type 1. Eliglustat is a ceramide analog that works by blocking the enzyme beta-glucosylceramide synthase, thereby slowing the production of glucocerebroside, the substance that builds up in patients’ lysosomes. Patients with Gaucher disease type 1 retain residual glucocerebrosidase enzyme activity, and eliglustat aims to slow the formation of the lipid to help balance the cell’s ability to clear it.

In August 2014, the FDA approved Cerdelga (eliglustat) capsules, the only first-line oral therapy for certain adults with Gaucher disease type 1. The FDA approval was based on efficacy data from two positive phase III studies of eliglustat: one in patients new to therapy (ENGAGE), and the other in patients switching from approved enzyme replacement therapies (ENCORE). The filing also incorporated 4 years of efficacy data from a phase II study of eliglustat.

Sources: Genzyme; February 17, 2015; and JAMA; February 17, 2015.


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