General Information

Cerdelga (eliglustat) is a small molecule inhibitor of glucosylceramide synthase. Glucosylceramide synthase is an enzyme that results in reduced production of glucocerebroside, a fatty substance that abnormally accumulates in the cells and tissues of those with Gaucher's disease.

Cerdelga is specifically indicated for the long-term treatment of adult patients with Gaucher disease type 1 (GD1) who are CYP2D6 extensive metabolizers (EMs), intermediate metabolizers (IMs), or poor metabolizers (PMs) as detected by an FDA-cleared test.

Cerdelga is supplied as capsules for oral administration. Once patients have been selected using an FDA-cleared test for determining CYP2D6
genotype, the recommended dose is as follows:

CYP2D6 EMs or IMs: 84 mg orally twice daily

CYP2D6 PMs: 84 mg orally once daily

Swallow capsules whole, do not crush, dissolve or open capsules. Avoid eating grapefruit or drinking grapefruit juice.

Mechanism of Action

Gaucher disease is caused by a deficiency of the lysosomal enzyme acid β-glucosidase. Acid β-glucosidase catalyzes the conversion of the sphingolipid glucocerebroside into glucose and ceramide. The enzymatic deficiency causes an accumulation of glucosylceramide (GL-1) primarily in the lysosomal compartment of macrophages, giving rise to foam cells or "Gaucher cells". Cerdelga is a specific inhibitor of glucosylceramide synthase and acts as a substrate reduction therapy for GD1.

Clinical Trial Results

The FDA approval of Cerdelga was based on two trials:

Treatment-Naïve GD1 Patients – Trial 1

This randomized, double-blind, placebo-controlled, multicenter clinical study evaluated the efficacy and safety of Cerdelga in 40 treatment-naïve GD1 patients 16 years of age or older with pre-existing splenomegaly and hematological abnormalities. Patients were stratified according to baseline spleen volume (≤ 20 or > 20 multiples of normal [MN]) 400 and randomized to receive Cerdelga or placebo for the duration of the 9-month blinded primary analysis period. The Cerdelga treatment group was comprised of IM (5%), EM (90%) and URM (5%) patients. Patients randomized to Cerdelga treatment received a starting dose of 42 mg twice daily, with a dose increase to 84 mg twice daily possible at Week 4 based on the plasma trough concentration at Week 2. The majority of patients (17 [85%]) received a dose escalation to 84 mg twice daily at Week 4, and 3 (15%) continued to receive 42 mg twice daily for
the duration of the 9-month blinded primary analysis period. The primary endpoint was the percentage change in spleen volume (in MN) from baseline to 9 months as compared to placebo. At baseline, mean spleen volumes were 12.5 and 13.9 MN in the placebo and Cerdelga groups, respectively. During the 9-month primary analysis period, Cerdelga demonstrated statistically significant improvements in the primary endpoint. Percentage Change in Spleen Volume MN (%): placebo: 2.3 versus Cerdelga: -27.8; difference between Cerdelga and placebo: -30.0 (p <0.0001).

Patients Switching from Enzyme Replacement Therapy to Cerdelga - Trial 2

This randomized, open-label, active-controlled, non-inferiority, multicenter clinical study evaluated the efficacy and safety of Cerdelga compared with imiglucerase in 159 treated GD1 patients previously treated with enzyme replacement therapy who met pre-specified therapeutic goals at baseline. Patients were randomized to receive Cerdelga or imiglucerase for the duration of the 12-month primary analysis period. Seventy-five percent of patients randomized to Cerdelga were previously treated with imiglucerase; 21% with velaglucerase alfa and 4% were unreported. Patients randomized to Cerdelga treatment received a starting dose of 42 mg twice daily, with dose increases to 84 mg twice daily and 127 mg twice daily possible at Weeks 4 and 8 based on plasma trough concentrations of Cerdelga at Weeks 2 and 6, respectively. The percentage of patients receiving the 3 possible Cerdelga doses was: 42 mg twice daily (20%), 84 mg twice daily (32%) and 127 mg twice daily (48%). The Cerdelga treatment group was comprised of PM (4%), IM 446 (10%), EM (80%) and URM (4%) patients. The primary composite endpoint required stability in all four component domains (hemoglobin level, platelet count, liver volume, and spleen volume) based on changes between baseline and 12 months. Stability was defined by the following pre-specified thresholds of change: hemoglobin level <1.5 g/dL decrease, platelet count < 25% decrease, liver volume <20% increase and spleen volume <25% increase. Cerdelga met the criteria to be declared non-inferior to imiglucerase in maintaining patient stability. After 12 months of treatment, the percentage of patients meeting the primary composite endpoint was 84.8% for the Cerdelga group compared to 93.6% for the imiglucerase group.