Mechanism of Action

Cerdelga (eliglustat) is indicated for the long-term treatment of adult patients with Gaucher disease type 1 who are CYP2D6 extensive metabolizers, intermediate metabolizers, or poor metabolizers as detected by an FDA-cleared test. Patients who are CYP2D6 ultra-rapid metabolizers may not achieve adequate concentrations of Cerdelga to achieve a therapeutic effect. A specific dosage cannot be recommended for those patients whose CYP2D6 genotype cannot be determined.

Gaucher disease type 1, the most common lysosomal storage disease, is a rare, autosomal recessive disease in which the accumulation of glucosylceramide results in progressive multi-organ dysfunction.

Glucosylceramide is synthesized in the Golgi by the enzyme glucosylceramide synthase, or GCS, and plays an essential role in cellular function.

Lysosomes are also involved in various cellular processes including intracellular digestion of macromolecules. When cells age or become damaged, their components are degraded and digested in the lysosome and recycled into new cellular components.

Glucosylceramide is metabolized by the lysosomal enzyme glucocerebrosidase. This process helps to maintain homeostasis within the cells.

In patients with Gaucher disease type 1, the rate of glucosylceramide production may exceed its rate of degradation. Deficient glucocerebrosidase enzyme activity causes glucosylceramide to accumulate in the lysosomes. Immune system responses to this buildup of glucosylceramide may contribute to an increase in GCS activity and further glucosylceramide production.

Residual enzyme activity is most likely not sufficient to counterbalance the increased production of glucosylceramide, which accumulates primarily in cells of the monocyte/macrophage lineage. The accumulation of Gaucher cells…

…in the liver, spleen, bone marrow, and other organs results in the signs and symptoms of Gaucher disease.

Treatments are available to help manage the signs and symptoms of Gaucher disease type 1, including oral therapies. Substrate reduction therapy, or SRT, is a class of medication that contains oral options. Cerdelga (eliglustat) is the only first line oral SRT treatment for most adults with Gaucher disease type 1 who are treatment naïve or want to switch from ERT infusions.

Cerdelga is an oral, noninvasive therapy that partially inhibits GCS, thereby slowing down the production and accumulation of glucosylceramide.

Cerdelga specifically inhibits glucosylceramide synthase, which slows the production of glucosylceramide substrate to a level that can be effectively cleared in the lysosomes with residual glucocerebrosidase enzyme activity.

By limiting the production of glucosylceramide substrate, Cerdelga aims to restore balance on the substrate pathway within the cells and reduce accumulation in the liver, spleen, and bone marrow.

Patient eligibility for Cerdelga is partly determined by CYP2D6 metabolizer status since Cerdelga is primarily metabolized by CYP2D6. CYP2D6 enzyme activity can vary among individuals, altering their response to drugs that are CYP2D6 substrates. A patient’s CYP2D6 metabolizer status will impact the bioavailability and effectiveness of Cerdelga in inhibiting GCS and glucosylceramide production.

Therefore, Cerdelga dosing is based on a patient’s CYP2D6 metabolizer status.

Important Safety Information

CONTRAINDICATIONS

CERDELGA is contraindicated in the following patients based on CYP2D6 metabolizer status due to the risk of cardiac arrhythmias from prolongation of the PR, QTc, and/or QRS cardiac intervals:

• Extensive Metabolizers (EMs) taking a strong or moderate CYP2D6 inhibitor concomitantly with a strong or moderate CYP3A inhibitor, EMs with moderate or severe hepatic impairment, or EMs with mild hepatic impairment and taking a strong or moderate CYP2D6 inhibitor.

• Intermediate Metabolizers (IMs) taking a strong or moderate CYP2D6 inhibitor concomitantly with a strong or moderate CYP3A inhibitor, IMs taking a strong CYP3A inhibitor, or IMs with any degree of hepatic impairment.

• Poor Metabolizers (PMs) taking a strong CYP3A inhibitor, or PMs with any degree of hepatic impairment.

WARNINGS AND PRECAUTIONS

CERDELGA is predicted to cause increases in ECG intervals (PR, QTc, and QRS) at substantially elevated plasma concentrations and may increase risk of cardiac arrhythmias. Use of CERDELGA is contraindicated, to be avoided, or requires dosage adjustment in patients taking CYP2D6 or CYP3A inhibitors, depending CYP2D6 metabolizer status, type of inhibitor, or degree of hepatic impairment. Avoid use of CERDELGA in patients with pre-existing cardiac disease, long QT syndrome, or in combination with Class IA or Class III antiarrhythmic medications.

ADVERSE REACTIONS

The most common adverse reactions (≥10%) to CERDELGA include: fatigue, headache, nausea, diarrhea, back pain, pain in extremities, and upper abdominal pain.

DRUG INTERACTIONS

Coadministration of CERDELGA with CYP2D6 or CYP3A inhibitors may increase eliglustat concentrations, which may increase the risk of cardiac arrhythmias from prolongations of the PR, QTc, and/or QRS cardiac interval. Use of CERDELGA is contraindicated, to be avoided, or may require dosage adjustment depending on the concomitant drug and CYP2D6 metabolizer status. See section 7 of the full Prescribing Information for more details and other potentially significant drug interactions.

USE IN SPECIFIC POPULATIONS

Available data on the use of CERDELGA in pregnant women is not sufficient to assess drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CERDELGA and any potential adverse effects on the breastfed child from CERDELGA or from the underlying maternal condition.

Use of CERDELGA in patients with renal impairment is based on the patient’s CYP2D6 metabolizer status. Avoid use of CERDELGA in EMs with end-stage renal disease (ESRD), and IMs and PMs with any degree of renal impairment.

Use of CERDELGA is contraindicated or may require dosage adjustment in patients with hepatic impairment based on CYP2D6 metabolizer status, concomitant use of CYP2D6 or CYP3A inhibitors, and degree of hepatic impairment.

Please see accompanying full Prescribing Information.

For more information on Cerdelga for your eligible patients with Gaucher disease type 1, speak to your local Sanofi representative for more information.