Eliglustat tartrate for the treatment of adults with type 1 Gaucher disease

Figures & data

Figure 1 Synthesis of glycosphingolipids. In Gaucher disease, glucosylceramide accumulates due to a decrease or loss of activity of β-glucocerebrosidase. Eliglustat tartrate blocks the enzyme glucosylceramide synthase. Glucosylceramide synthase is localized in the cis/medial Golgi membrane which plays an important role in catalyzing the formation of glucosylceramide from ceramide and UDP-glucose. Glucosylceramide is further metabolized to other glycosphingolipids (not shown).

Table 1 Features and properties of eliglustat

Class	2-ring-heterocyclic compound, amides, pyrrolidines, small molecules.
Chemical name	Octanamide, N-((1R,2R)-1-(2,3-dihydrobenzo [b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl) propan-2-yl) octanamide (2R,3R)-2,3-dihydroxysuccinate. Molecular weight 479.59.
Pharmacodynamics	IC50 of 10 ng/mL for inhibition of GLC synthase.
Pharmacokinetics	Exposure depends on CYP2D6 phenotype; linear and time-dependent pharmacokinetics and greater than dose-dependent exposure in CYP2D6 EMs and IMs.
	Non-time-dependent pharmacokinetics expected in PMs.
	Accumulation of drug in PMs was 300%, 400%, and 2,300% for 50, 200, and 350 mg doses, respectively.
	tmax (hours): 1.5 (EMs); 3 (PMs).
	t1/2 (hours): 6.5 (EMs); 8.9 (PMs).
	Cmax: 12.1–25 ng/mL (EMs); 113–137 ng/mL (PMs).
	AUC: 76.3–143 h*ng/mL (EMs); 956 h*ng/mL (PMs).
	Protein bound: 76%–83%; mainly distributed in plasma, not in red blood cells.
	Widely distributed to tissue: 835 L after intravenous administration.
	Low oral bioavailability due to significant first-pass metabolism.
Metabolism	Mainly CYP2D6, less with CY3A4. No active metabolites have been identified.
	Excretion: fecal 51.4% and urine 41.8%.
Drug–drug interaction,	Eliglustat is a CYP2D6 and CYP3A substrate.
Drug–food interaction	Use with CYP3A inducers such as rifampin, carbamazepine, phenobarbital, St John’s wort and phenytoin decreases eliglustat levels.
	Use with CYP3A inhibitors such as ketoconazole, fluconazole, and ranitidine causes prolongation of PR, QT, and/or QRS intervals, which can cause cardiac arrhythmias. Eliglustat may be contraindicated in some patients depending on their CYP2D6 metabolizer status.
	Inhibits P-gp and CYP2D6 drugs such as digoxin, colchicine, dabigatran, metoprolol, TCA, and phenothiazines.
	May interact with grapefruit juice.
	Food does not affect the pharmacokinetics of eliglustat.
Renal, hepatic impairment	No dose adjustment in mild renal impairment.
	Use of eliglustat is not recommended in patients with moderate to severe impairment, or end-stage renal disease, or any degree of hepatic impairment or cirrhosis.
Formulation, dosing	Hard gelatin capsule, 100 mg eliglustat tartrate (equivalent of 84 mg eliglustat). The inactive ingredients are microcrystalline cellulose, lactose monohydrate, hypromellose, glyceryl behenate, gelatin, candurin silver fine, yellow iron oxide, and FD&C blue 2.
	Take one capsule twice daily for EMs and IMs, take one capsule once daily for PMs.

Abbreviations: EMs, extensive metabolizers; IMs, intermediate metabolizers; PMs, poor metabolizers; AUC, area under curve; P-gp, P-glycoprotein; CYP, cytochrome P450; TCA, tricyclic antidepressants; IC₅₀, concentration at which the drug achieves 50% enzyme inhibition; GLC, glucosylceramide.

Table 2 Comparison characteristics of miglustat and eliglustat

Miglustat (Zavesca^®)	Eliglustat (Cardelga^®)
Manufacturer: Actelion Pharmaceuticals, Allschwil, Switzerland.	Manufacturer: Genzyme Corporation, Cambridge, MA, USA.
Mechanism of action: GLC synthase inhibitor.	Mechanism of action: GLC synthase inhibitor.
Structure: imino sugar N-butyl-deoxynojirimycin.	Structure: d-threo-1-phenyl-2 decanoylamino-3-morpholino-1-propanol.
Adverse effects: tremor (30%), diarrhea (85%)*, weight loss (65%), reduced platelet counts, numbness, and feeling of burning on hands and feet.	Adverse effects (≥10%): arthralgia, headache, nausea, fatigue, back pain, pain in extremities. Adverse effects (occasional): upper abdominal pain, diarrhea, migraine, flatulence, oropharyngeal pain, dizziness, asthenia, reflux disease, constipation, palpitation, rash.
Pregnancy category: X.	Pregnancy category: C.
Dosage: 100 mg capsule taken three times daily or twice daily if patients experience tremor or diarrhea. In moderate renal impairment, start at once-daily dosing. Not recommended in severe renal impairment.	Dosage: 84 mg capsules taken twice daily or once daily depending on CYP2D6 genotypes: IMs, EMs, or PMs as detected by a test cleared by the US Food and Drug Administration.
Passes blood–brain barrier, intended to treat neuronopathic GD (GD3), but not showing effectiveness in clinical trials.	Does not pass blood–brain barrier.
Approved for patients who cannot take ERTs due to anaphylactic reactions.	Approved for GD1 patients.
Contraindication: none.	Contraindications: CYP2D6 EMs and IMs taking a strong or moderate CYP2D6 inhibitor with a strong or moderate CYP3A4 inhibitor. CYP2D6 IMs and PMs taking a strong CYP3A inhibitor.
Warning and precautions: need to evaluate at baseline and do follow-up neurological testing every 6 months for peripheral neuropathy. Reduce dose if tremor or discontinue treatment if tremor does not resolve after dosage is reduced. Evaluate underlying diarrhea and weight loss after the dose is reduced.	Warning and precautions: electrocardiographic changes and potential cardiac arrhythmias. Not recommended in patients with pre-existing cardiac disease, long QT syndrome, and concomitant use of class Ia and class III antiarrhythmics.

Note:

* Due to inhibition of intestinal α-disaccharides.

Abbreviations: EMs, extensive metabolizers; IMs, intermediate metabolizers; PMs, poor metabolizers; GD, Gaucher disease; ERT, enzyme replacement therapy; CYP, cytochrome P450; GLC, glucosylceramide.

Table 3 Summary of eliglustat in Phase III clinical trials

Study	Patients	Study design	Outcomes	Results
Cox et al^Citation73 ENCORE trial NCT00943111	160 GD1 adults who received 3 years of imiglucerase. Only 146 patients completed the trial.	R, MN, OL, NIT trial. Eliglustat group (n=106) given 50 mg or 100 mg twice daily for 4 weeks, then 50 mg, 100 mg, or 150 mg at weeks 2 and 6, depending on their plasma eliglustat. Imiglucerase group (n=54) at patient’s normal dose every 2 weeks.	Primary: % change in hematological variable and organ volumes after 12 months.	Eliglustat group showed 85% versus imiglucerase group 94% were stable % in hemoglobin concentrations, platelet count, and spleen and liver volumes. Differences between groups were −8.8% (95% CI −17.6, 4.2).
Mistry et al^Citation72 ENGAGE trial NCT00891202	40 GD1 patients with splenomegaly, thrombocytopenia, and/or anemia. All completed the trial.	R, DB, PCT trial. Patients received eliglustat based on their spleen volumes. Eliglustat (n=20) received 50 mg or 100 mg twice daily or placebo (n=20) for 9 months.	Primary: % change in spleen volume from baseline after 9 months. Secondary: % change in liver volume, platelet count, and hemoglobin level.	Eliglustat reduced spleen volume by 27.77% (95% CI −32.57, −22.97) versus placebo increase of 2.26% (95% CI −2.54, 7.06); an absolute treatment difference of −30.03% (95% CI −36.82, −23.24; P<0.001). Eliglustat caused reduction in liver volume by 6.64% (95% CI −11.37, −1.91; P=0.007), increase in hemoglobin by 1.22 g/dL (95% CI 0.57–1.88 g/dL; P<0.01), and increase in platelet count by 41.06% (95% CI 23.95–58.17; P<0.01), respectively, versus placebo.
EDGE trial^Citation74 NCT01074944	171 GD1 adults (older than 18 years).	R, MC, MN, DB trial. Eliglustat twice-daily dosing of 50 mg or 100 mg; or once-daily dosing of 100 mg or 200 mg.	Primary: number of patients who remain stable after twice-daily versus once-daily dosing.	Ongoing Results expected August 2015.

Abbreviations: GD1, Gaucher disease type 1; R, randomized; MN, multinational; OL, open-label; NIT, non-inferiority trial; DB, double-blind; PCT, placebo-controlled trial; MC, multicultural; CI, confidence interval.

CoxTMDrelichmanGCravoREliglustat compared with imiglucerase in patients with Gaucher’s disease type 1 stabilized on enzyme replacement therapy: a Phase 3, randomised, open-label non-inferiority trialLancet20153852355236225819691

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MistryPKLukinaETurkiaHBEffect of oral eliglustat on splenomegaly in patients with Gaucher disease type 1JAMA201531369570625688781

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Genzyme A, Sanofi CompanyA study of eliglustat tartrate (Genz-112638) in patients with Gaucher disease (ENGAGE) Available from: http://www.clinicaltrials.gov/ct2/eliglusatAccessed June 23, 2015

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