Recommendations for the use of eliglustat in the treatment of adults with Gaucher disease type 1 in the United States

Recommendations for the use of eliglustat in the treatment of adults with Gaucher disease type 1 in the United States

YMGME-05948; No. of pages: 9; 4C: Molecular Genetics and Metabolism xxx (2015) xxx–xxx Contents lists available at ScienceDirect Molecular Genetics ...

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YMGME-05948; No. of pages: 9; 4C: Molecular Genetics and Metabolism xxx (2015) xxx–xxx

Contents lists available at ScienceDirect

Molecular Genetics and Metabolism journal homepage: www.elsevier.com/locate/ymgme

Recommendations for the use of eliglustat in the treatment of adults with Gaucher disease type 1 in the United States Manisha Balwani a, Thomas Andrew Burrow b, Joel Charrow c, Ozlem Goker-Alpan d, Paige Kaplan e, Priya S. Kishnani f, Pramod Mistry g, Jeremy Ruskin h, Neal Weinreb i,⁎ a

Department of Genetics and Genomic Sciences, One Gustave L. Levy Place, Box 1497, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA Cincinnati Children's Hospital Medical Center, Division of Human Genetics, 3333 Burnet Avenue, MLC 4006, Cincinnati, OH 45229, USA Department of Pediatrics, Northwestern University Feinberg School of Medicine, Division of Genetics, Birth Defects and Metabolism, Ann and Robert H. Lurie Children's Hospital of Chicago, 225 East Chicago Avenue, Chicago, IL 60611, USA d Lysosomal Disorders Unit, O&O Alpan, LLC, 11212 Waples Mill Road, Fairfax, VA 22030, USA e Lysosomal Center, Division of Genetics, Children's Hospital of Philadelphia, Civic Center Blvd, Philadelphia, PA 19104, USA f Duke University School of Medicine, Department of Pediatrics, DUMC 103856, 595 Lasalle Street, GSRB 1, 4th Floor, Room 4010, Durham, NC 27710, USA g Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA h Massachusetts General Hospital, Electrophysiology Lab/Arrhythmia Service, 55 Fruit Street, Boston, MA 02114-2696, USA i University Research Foundation for Lysosomal Storage Diseases, Inc., 7367 Wexford Terrace, Boca Raton, FL 33433, USA b c

a r t i c l e

i n f o

Article history: Received 2 July 2015 Received in revised form 1 September 2015 Accepted 1 September 2015 Available online xxxx Keywords: Gaucher disease type 1 Eliglustat Substrate reduction therapy Enzyme replacement therapy

a b s t r a c t In Gaucher disease, deficient activity of acid β-glucosidase results in accumulation of its substrates, glucosylceramide and glucosylsphingosine, within the lysosomes of cells primarily in the spleen, liver, bone marrow, and occasionally the lung. The multisystem disease is predominantly characterized by hepatosplenomegaly, anemia, thrombocytopenia, and skeletal disease. Enzyme replacement therapy with recombinant human acid βglucosidase has been the first-line therapy for Gaucher disease type 1 for more than two decades. Eliglustat, a novel oral substrate reduction therapy, was recently approved in the United States and the European Union as a first-line treatment for adults with Gaucher disease type 1. Eliglustat inhibits glucosylceramide synthase, thereby decreasing production of the substrate glucosylceramide and reducing its accumulation. Although existing recommendations for the care of patients with Gaucher disease remain in effect, unique characteristics of eliglustat require additional investigation and monitoring. A panel of physicians with expertise in Gaucher disease and experience with eliglustat in the clinical trials provide guidance regarding the use of eliglustat, including considerations before starting therapy and monitoring of patients on eliglustat therapy. © 2015 Published by Elsevier Inc.

Contents 1. 2. 3.

4. 5. 6. 7.

Introduction . . . . . . . . . . . . . . Eliglustat dosing . . . . . . . . . . . . Recommendations for initial assessment . 3.1. CYP2D6 genotyping . . . . . . . 3.2. Concomitant medications . . . . . 3.3. Pregnancy and lactation . . . . . 3.4. Renal and hepatic status . . . . . 3.5. Medication adherence . . . . . . 3.6. Electrocardiogram (ECG) . . . . . Decision to treat and choice of therapy . . Recommendations for ongoing monitoring Managing patients on eliglustat . . . . . Directions for further research . . . . . .

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⁎ Corresponding author. E-mail addresses: [email protected] (M. Balwani), [email protected] (T.A. Burrow), [email protected] (J. Charrow), [email protected] (O. Goker-Alpan), [email protected] (P. Kaplan), [email protected] (P.S. Kishnani), [email protected] (P. Mistry), [email protected] (J. Ruskin), [email protected] (N. Weinreb).

http://dx.doi.org/10.1016/j.ymgme.2015.09.002 1096-7192/© 2015 Published by Elsevier Inc.

Please cite this article as: M. Balwani, et al., Recommendations for the use of eliglustat in the treatment of adults with Gaucher disease type 1 in the United States, Mol. Genet. Metab. (2015), http://dx.doi.org/10.1016/j.ymgme.2015.09.002

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M. Balwani et al. / Molecular Genetics and Metabolism xxx (2015) xxx–xxx

8. Summary. . . Author contributions Conflict of interest . Acknowledgments . References. . . . .

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1. Introduction Gaucher disease type 1 (GD1) is an autosomal recessive disorder arising from mutation of two alleles of the acid β-glucosidase gene, resulting in deficient activity of acid β-glucosidase and subsequent accumulation of its substrates, glucosylceramide and glucosylsphingosine, within the lysosomes of cells of the monocyte/macrophage lineage [1–3]. Substrate accumulation in the spleen, liver, bone marrow, and occasionally the lung, can lead to progressive and debilitating hepatosplenomegaly, anemia, thrombocytopenia, growth retardation, pulmonary disease, immune dysfunction, bone pain, osteoporosis, vertebral compression fractures, bone infarction, avascular necrosis, progressive joint destruction [1,2,4–10], and diminished quality of life [11–14]. Type 1 disease, which lacks the primary central nervous system involvement present in neuronopathic GD (type 2 and type 3) [2], is the most common form of GD in the United States and Europe, affecting approximately 1 in 40,000 to 1 in 60,000 individuals [15], and is especially prevalent among those of Ashkenazi Jewish ancestry [2]. For more than 20 years, enzyme replacement therapy (ERT) with recombinant human acid β-glucosidase (imiglucerase) has been the standard of care for GD1 because it reverses and prevents many of the visceral, hematological, and skeletal manifestations of the disease [9, 16–20]. More recently, two other ERTs (velaglucerase alfa and taliglucerase) have been introduced into clinical practice. ERT requires lifelong intravenous infusions, typically every other week. The infused enzyme targets cells of the monocyte/macrophage lineage; however, animal research has suggested that GD involvement beyond the monocyte/macrophage system may underlie unmet treatment needs with respect to skeletal, pulmonary, and immune manifestations of GD1 [21]. Furthermore, focal disease at sanctuary sites within the viscera and bone marrow persist in some patients, despite higher ERT doses of 60–120 U/kg/4 weeks (or 30–60 units/kg/2 weeks) [22,23]. An oral treatment could potentially address unmet needs and offer patients a convenient, needle-free treatment potentially available in regions where ERT is not accessible. Substrate reduction therapy (SRT) is an alternative treatment approach that seeks to balance glucosylceramide production with its impaired rate of degradation by partially inhibiting glucosylceramide synthase, the rate-limiting step for glycosphingolipid biosynthesis. This approach is feasible for GD because patients have some degree of residual enzyme activity. Eliglustat (Cerdelga, Genzyme, a Sanofi company, Cambridge, MA, USA) is a ceramide analog that potently and specifically inhibits glucosylceramide synthase, thereby reducing glucosylceramide accumulation [24,25]. Eliglustat does not inhibit intestinal enzymes, thereby avoiding the prevalent gastrointestinal side effects seen with the iminosugar glucosylceramide synthase inhibitor, miglustat, which is approved in the United States for treatment of adults with GD1 for whom ERT is unsuitable [24,26,27]. Both miglustat and eliglustat cross the blood–brain barrier; however, whereas miglustat achieves significant distribution into the brain, eliglustat is immediately transported back out of the CNS by the multidrug transporter Pgp-1 [28]. This suggests that eliglustat would have little utility for treating neuronopathic forms of GD and that neurologic side effects reported in some patients treated with miglustat would be less likely with eliglustat [24,26,27]. Eliglustat metabolism is heavily dependent on CYP2D6 and, to a lesser extent, on CYP3A of the cytochrome P450 pathway. The potential for drug interactions coupled with CYP2D6 metabolizer status is a significant

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determinant of both patient eligibility and recommended dose. With this caveat, in late August 2014, eliglustat was approved in the United States as a first-line treatment for adults (age ≥ 18 years) with GD1 who are CYP2D6 extensive, intermediate, or poor metabolizers, categories that encompass N90% of the general population [29]. Completed and ongoing clinical studies of eliglustat have involved nearly 400 patients with GD1. In previously untreated patients with GD1, 9 months of eliglustat therapy resulted in clinically meaningful improvements in platelet and hemoglobin levels, spleen and liver volumes, and bone outcomes (Table 1); these benefits continued or were maintained among the 19 Phase 2 study patients who have received 4 years of treatment [30–34]. In patients whose disease had been stabilized with ERT, hematological, visceral and bone parameters remained essentially unchanged for 12 months following a switch to eliglustat (Table 1) [35]. There are important pharmacotherapeutic differences between ERT and eliglustat that impact clinical management. Over the past 25 years, physicians have become familiar with ERT and published clinical guidelines for its effective use [9,36–38]. With the exception of participants in the clinical trials, most physicians who currently treat patients with GD1 are relatively unacquainted with eliglustat. Here we provide guidance regarding the use of eliglustat for physicians treating patients with GD1, including considerations before starting therapy and monitoring patients on eliglustat therapy. These recommendations were formulated during a 2-day meeting sponsored by Genzyme, a Sanofi company. Participants included invited physicians with expertise in GD who were site investigators in the eliglustat clinical trials and a cardiologist with expertise in cardiac arrhythmia, a potentially significant side effect of eliglustat. 2. Eliglustat dosing Because eliglustat is extensively metabolized by CYP2D6, and, to a lesser extent, CYP3A, eligibility and dosing are initially based on the patient's genetic CYP2D6 metabolizer status. Drugs that are inhibitors, inducers, or substrates in this pathway can affect eligibility and dosing. Four main phenotypes of CYP2D6 metabolizers have been identified: poor, intermediate, extensive, and ultra-rapid. In population pharmacokinetic analysis, CYP2D6 metabolizer phenotype was the most significant determinant of eliglustat blood concentrations. Table 2 provides recommendations for eliglustat dosing based on CYP2D6 metabolizer status and indicates where dose reduction or avoidance of eliglustat is required to avoid toxicity and/or potentially adverse drug-drug interactions when prescribed with drugs also metabolized by CYP2D6 and CYP3A [39]. In most cases, once eliglustat dose has been adjusted to account for concomitant medication use, no further adjustment of eliglustat dose is needed should the dose of the concomitant drug be modified (i.e., a patient's paroxetine dose is increased or decreased). Some medications exhibit dose-dependent inhibition of CYP2D6, and it is prudent to reevaluate if the dose of the concomitant medication has changed. If use of a concomitant medication will be short-term, such as a 5- to 10-day course of fluconazole, physicians should consider temporarily stopping eliglustat and restarting when the concomitant drug regimen is complete. A recommended dose has not been determined for ultra-rapid metabolizers as determined by CYP2D6 genotype analysis or for indeterminate metabolizers in whom testing has not been performed. Therefore, these patients are currently ineligible for eliglustat therapy. Eliglustat is also not recommended for

Please cite this article as: M. Balwani, et al., Recommendations for the use of eliglustat in the treatment of adults with Gaucher disease type 1 in the United States, Mol. Genet. Metab. (2015), http://dx.doi.org/10.1016/j.ymgme.2015.09.002

M. Balwani et al. / Molecular Genetics and Metabolism xxx (2015) xxx–xxx

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Table 1 Phase 2 and 3 clinical trials of eliglustat.

Baseline Characteristics Treatment history Age at study entry (years), mean (SD) Spleen volume (MN), mean (SD) Liver volume (MN), mean (SD) Hemoglobin (g/dL), mean (SD) Platelet count (x 109/L), mean (SD) Bone marrow burden score, mean (SD) Outcomes Primary endpoint

Primary endpoint met

Spleen volume Liver volume Hemoglobin Platelet count Bone marrow burden score

Phase 2 (NCT00358150) [31]

Phase 3 ENGAGE (NCT00891202) [34]

Phase 3 ENCORE (NCT00943111) [35]

Eliglustat (N = 26)

Eliglustat (N = 20)

Placebo (N = 20)

Eliglustat (N = 106)

Imiglucerase (N = 53)

Treatment naïve 34 (13) 20.0 (12.8) 1.8 (0.6) 11.1 (1.7) 66.4 (20.1) Not reported

Treatment naïve 31.6 (11.55) 13.89 (5.93) 1.44 (0.35) 12.1 (1.8) 75.05 (14.10) 10.9 (2.6)

32.1 (11.26) 12.50 (5.95) 1.36 (0.28) 12.8 (1.6) 78.48 (22.61) 9.8 (2.8)

Stable on ERT 37.6 (14.2) 3.17 (1.35) 0.94 (0.19) 13.6 (1.3) 203 (79) 8.22 (2·66)

37.5 (14.9) 2.74 (1.15) 0.92 (0.16) 13.9 (1.30) 188 (57) 8.12 (2·63)

Improvement from baseline to 12 months in at least 2 of the 3 main efficacy parameters (spleen volume, hemoglobin level, and platelet count)a Yes 91% (20 of 22) of completers Change: -38.5% Change: -17.0% Change: + 1.62 mg/dL Change: + 40.3% Not reported

Mean percentage change in spleen volume by MRI from baseline to 9 months Yes Treatment difference: -30% Change:d Change:d -27.8% + 2.3% Change:d Change:d -5.2% + 1.4% Change:d Change:d + 0.69 g/dL -0.54 g/dL Change:d Change:d + 32.0% -9.1% Baseline: 10.9 Baseline: 9.8 e 9 months: 9.8 9 months: 9.8

Percentage of patients whose hematological parameters and organ volumes remained stable after 12 monthsb Yesc Stable: Stable: 85% 94% Stable: Stable: 96% 100% Stable: Stable: 96% 94% Stable: Stable: 95% 100% Stable: Stable: 93% 100% Baseline: 8.25 Baseline: 8.28 12 months: 8.10 12 months: 8.06

MN: multiples of normal; MRI: magnetic resonance imaging; SD: standard deviation. a Improvements defined as: a reduction of at least 15% in spleen volume and increases of at least 0.5 g/dL in hemoglobin level and 15% in platelet count. b Stability defined as: hemoglobin concentration that did not decrease more than 1.5 g/dL, platelet count that did not decrease more than 25%, spleen volume (MN) that did not increase more than 25%, and liver volume (MN) that did not increase more than 20% from baseline. c In noninferiority analysis, the between groups difference was −8.8% (95% CI: -17.6, 4.2). The lower bound of the 95% CI for the difference in percentage (−17.6%) was within the prespecified threshold of −25%. d Data are least-square means. Analysis of covariance uses least-square mean linear regression to evaluate changes from baseline while adjusting for the covariates included in the model. e Decrease of 1.1 for eliglustat relative to placebo (P = 0.002).

any patient taking a strong CYP3A inducer because effective blood levels of eliglustat may not be achieved. Table 3 shows potential drug interactions that may occur when eliglustat is taken concomitantly with medications that are substrates of P-glycoprotein (P-gp) or CYP2D6, which could result in increased concentrations of the concomitant drug [39]. Physicians should monitor the concentration of the concomitant P-gp or CYP2D6 substrate drug and consider reducing the dosage and titrating to therapeutic effect. As concomitant medications are often prescribed by specialists other than the GD-treating physician, coordination of care is extremely important, a point that must be strongly emphasized when speaking with patients and their responsible caregivers.

Each eliglustat capsule contains 100 mg eliglustat tartrate, which is equivalent to 84 mg of eliglustat. The recommended CYP2D6 phenotype-based dosing differs from the dosing in the clinical studies of eliglustat, in which a dose-titration scheme was used to ensure plasma eliglustat steady-state pre-dose concentrations (Ctrough) above 5 ng/mL and minimize excessive eliglustat exposure [31,34,35]. In pharmacokinetic analysis from the clinical studies, an eliglustat Ctrough greater than 5 ng/mL target was not required for therapeutic efficacy and CYP2D6 phenotype was the most significant determinant of eliglustat exposure [40]. Furthermore, pharmacokinetic analyses of eliglustat concentration are difficult to interpret because the drug is cleared very rapidly from the body and drug concentrations fluctuate widely during each 12-h dosing interval, resulting in exquisite dependence on timing

Table 2 Recommended eliglustat dosing based on CYP2D6 metabolizer status and concomitant use of CYP2D6 and/or CYP3A inhibitors and CYP3A inducers. Recommended eliglustat dosage by CYP2D6 metabolizer status

Standard Dosing Concomitant Use of Eliglustat with: Strong or Moderate CYP2D6 Inhibitors plus Strong or Moderate CYP3A Inhibitors Strong CYP2D6 Inhibitors (e.g., paroxetine) Moderate CYP2D6 Inhibitors (e.g., terbinafine) Strong CYP3A Inhibitors (e.g., ketoconazole) Moderate CYP3A Inhibitors (e.g., fluconazole) Weak CYP3A Inhibitors (e.g., ranitidine) Strong CYP3A Inducers (e.g., rifampin, carbamazepine, phenobarbital, phenytoin, St. John's Wort, grapefruit)

Extensive metabolizer

Intermediate metabolizer

Poor metabolizer

84 mg twice daily

84 mg twice daily

84 mg once daily

Contraindicated 84 mg once daily 84 mg once daily 84 mg once daily 84 mg once daily 84 mg twice daily Not recommended

Contraindicated 84 mg once daily 84 mg once daily Contraindicated Not recommended 84 mg twice daily Not recommended

Contraindicated Contraindicated Contraindicated Contraindicated Not recommended Not recommended Not recommended

Please cite this article as: M. Balwani, et al., Recommendations for the use of eliglustat in the treatment of adults with Gaucher disease type 1 in the United States, Mol. Genet. Metab. (2015), http://dx.doi.org/10.1016/j.ymgme.2015.09.002

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M. Balwani et al. / Molecular Genetics and Metabolism xxx (2015) xxx–xxx

Table 3 Eliglustat drug interactions that result in increased concentrations of the concomitant drug. Drug class or drug name Digoxin (P-gp substrate)

Other P-gp substrates (e.g., phenytoin, colchicine, dabigatran etexilate) CYP2D6 substrates (e.g., metoprolol; tricyclic antidepressants [e.g., nortriptyline, amitriptyline, imipramine]; phenothiazines [e.g., perphenazine, chlorpromazine])

Clinical recommendations Measure serum digoxin concentrations before initiating eliglustat. Reduce digoxin dose by 30% and continue monitoring. Monitor therapeutic drug concentrations, as indicated, or consider reducing the dosage of the concomitant drug and titrate to clinical effect.

of dose in order to determine the need for dose escalation [40]. As a result, an individualized method of dosing according to the patient's CYP2D6 metabolizer status was instituted to eliminate the need for complex dose titration that would be difficult to implement in clinical practice.

3. Recommendations for initial assessment GD is diagnosed by demonstrating deficient acid β-glucosidase activity in leukocytes and/or by detection of mutations in each of the two alleles in the GBA1 gene [36,41]. As residual enzyme activity measured in leukocytes does not correlate with disease type or severity,

demonstration of two known mutant alleles in the GBA gene can provide additional diagnostic confirmation in the presence of residual enzyme activity [41]. The recommendations for the initial assessment and ongoing monitoring of adults with GD1 developed by the International Collaborative Gaucher Group (ICGG) in the context of treatment with ERT [38] continue to be the basis of care for Gaucher patients regardless of the type of therapy. The primary assessments at baseline include physical, hematological, biochemical, visceral, skeletal and pulmonary examinations and, pending development of a GD-specific patient-reported outcomes instrument, a generic patient-reported quality-of-life survey such as SF36 [38]. Table 4 provides updated recommendations that include additional assessments necessary for patients taking eliglustat (indicated with an asterisk). An algorithm for determining eligibility for eliglustat is provided in Fig. 1. Here we provide guidance on those assessments specific to consideration of eliglustat therapy. 3.1. CYP2D6 genotyping CYP2D6 genotyping is essential to determine the patient's eligibility and dosing regimen for eliglustat treatment based on the patient's CYP2D6 metabolizer status. Genotype testing using an FDA-cleared test is available at no cost to physicians and patients through a Genzyme-funded program with LabCorp (https://www.labcorp.com; phone: 919–474–4326). 3.2. Concomitant medications Physicians treating GD patients taking eliglustat should inquire about and track concomitant medication use at every visit. Likewise,

Table 4 Essential recommended assessments for Gaucher disease type 1 patients with asterisks indicating assessments specific to eliglustat. Baseline

Year 1

Long Term

History Cardiac, renal, and hepatic status

Yes

Pregnancy, intent to become pregnant, and lactation⁎

Yes

At each visit or with significant changes in disease status At each visit

At each visit or with significant changes in disease status At each visit

At each visit or with significant changes in disease status At each visit or with significant changes in disease status

At each visit or with significant changes in disease status At each visit or with significant changes in disease status

Blood Complete blood count (i.e., monitoring of hemoglobin and platelets) Yes

Every 3 months

Biomarkers (CCL18 if available, chitotriosidase, TRAP, ACE) CYP2D6 metabolizer profile⁎ Hepatic function (should include AST, ALT, AP, bilirubin, albumin) PT/PTT Renal function – should include BUN, creatinine, eGFR Electrolytes

Yes Yes Yes Yes Yes Yes

Every 3 months Not applicable Annually Annually Annually Annually

Every 6–12 months (or as clinically indicated) to assess against therapeutic goals Every 6–12 months or as clinically indicated Not applicable Annually Annually Annually Annually

Imaging Spleen and liver volumes (MRI preferred) MRI (coronal; T1- and T2-weighted) of the entire femora X-ray: AP of femora and lateral of spine DEXA (hip and spine) ECG

Yes Yes Yes Yes Yes

Annually Annually As clinically indicated NA As clinically indicated

Annually Annually As clinically indicated Every 2 years or as clinically indicated As clinically indicated

Medications Concomitant medications⁎ (including grapefruit) with regard to CYP2D6, CYP3A, and P-gp substrate metabolism Medication adherence⁎

Yes Yes (assess ability to adhere)

ACE: angiotensin converting enzyme; ALT: alanine aminotransferase; AST: aspartate aminotransferase; AP: alkaline phosphatase; BUN: blood urea nitrogen; CCL 18: chemokine (C-C motif) ligand 18; DEXA: dual-energy X-ray absorptiometry; ECG: electrocardiogram; GFR: glomerular filtration rate; MRI: magnetic resonance imaging; PT: prothrombin time; PTT: partial thromboplastin time; TRAP: tartrate resistant acid phosphatase. ⁎ These assessments are considered essential for monitoring patients with Gaucher disease type 1 on eliglustat therapy. Additional tests that may be useful in the care of patients with Gaucher disease type 1 are discussed in the text. Recommendations for comprehensive evaluation and monitoring of patients with Gaucher disease type 1 have been published elsewhere [38].

Please cite this article as: M. Balwani, et al., Recommendations for the use of eliglustat in the treatment of adults with Gaucher disease type 1 in the United States, Mol. Genet. Metab. (2015), http://dx.doi.org/10.1016/j.ymgme.2015.09.002

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Fig. 1. Algorithm to determine eligibility for eliglustat therapy in adults with Gaucher disease type 1.

patients should be instructed to inform other prescribers that they are taking eliglustat and alert them to the potential for drug interactions. Of special concern are medications that are inhibitors of CYP2D6 and CYP3A or inducers of CYP3A, as eliglustat is contraindicated, not recommended, or requires dose modification with concomitant use of these medications (Tables 2 and 3, see also above section on eliglustat dosing) [39]. The University of Washington Drug Interaction Database (http:// didb.druginteractioninfo.org) is one example of a subscription-based resource for information on potential drug interactions. Hospitalbased or academic center-based clinical pharmacologists can also serve as sources for this information. When the effect of a concomitant medication on CYP2D6 and/or CYP3A metabolism is in doubt, a clinical pharmacologist or pharmacist should be consulted. At higher than the usual therapeutic concentration, eliglustat is predicted to increase PR, QRS, and QTc (QT interval corrected for heart rate) intervals on ECG. Therefore, despite a generally wide safety margin, eliglustat is not recommended in patients with pre-existing cardiac disease (congestive heart failure, recent acute myocardial infarction, bradycardia, heart block, ventricular arrhythmia), long QT syndrome, or in combination with Class IA (e.g., quinidine, procainamide), Class IC (e.g., flecainide, propafenone), and Class III (e.g., amiodarone, dronedarone, dofetilide, ibutilide) antiarrhythmic medications [39]. For patients taking a short course of a QT-prolonging drug, such as an antibiotic or cold and flu medicine, physicians should consider temporarily discontinuing eliglustat until the QT-prolonging drug regimen is completed.

3.3. Pregnancy and lactation In the US Prescribing Information, eliglustat is classified as Pregnancy Category C (i.e., no adequate and well-controlled studies in humans)

and the drug is not contraindicated during pregnancy and breastfeeding [39]. However, given the absence of controlled studies of eliglustat in these populations and evidence supporting the safety of ERT during pregnancy and lactation [42–44], eliglustat should not be used in women who are pregnant or breastfeeding. Although it is not known whether eliglustat is excreted in breastmilk, being a small molecule, it is likely to be present in the milk of mothers taking eliglustat. 3.4. Renal and hepatic status Eliglustat has not been studied in patients with renal insufficiency, dialysis, post-kidney transplantation or those with hepatic impairment. Use of the drug is therefore not recommended in patients with moderate to severe renal impairment (GFR b 60 mL/min/1.73 m2) [39], patients on dialysis, patients post-kidney transplantation or those with hepatic impairment [39] (e.g., evidence of portal hypertension, ascites or varices). As acquired coagulopathy is a feature of GD, having disturbed international normalized ratio (INR) or prothrombin time/ partial thromboplastin time (PT/PTT) would not be a sufficient indicator of hepatic impairment in this population. 3.5. Medication adherence Physicians should evaluate and consider the patient's ability to comply with daily oral dosing to ensure optimal treatment of patients taking eliglustat. This differs from ERT, for which infusions are performed and monitored in a clinical setting. Patients should be advised to take eliglustat with plenty of water and never with grapefruit juice (a strong CYP3A inducer) and, if a dose is missed, to take the prescribed dose at the next scheduled time without doubling the next dose [39]. The capsules must be swallowed whole, as

Please cite this article as: M. Balwani, et al., Recommendations for the use of eliglustat in the treatment of adults with Gaucher disease type 1 in the United States, Mol. Genet. Metab. (2015), http://dx.doi.org/10.1016/j.ymgme.2015.09.002

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the biodistribution of eliglustat may be altered if the capsules are crushed, dissolved, or opened, or if the drug is compounded [39]. Although therapeutic drug monitoring is not a useful gauge of medication compliance, in unusual circumstances measurement of eliglustat blood levels may be indicated. Such testing is available from the drug's manufacturer (Genzyme, a Sanofi company) on a case-by-case basis.

GD severity score (DS3) and/or SF-36 or other health-related qualityof-life measure, especially to assess for fatigue and pain [38]. In addition to the recommendations for routine assessment of disease parameters, patients taking eliglustat should undergo additional specific assessments of concomitant medications, compliance with eliglustat therapy, and pregnancy and lactation (Table 4). Follow-up ECGs are warranted only as clinically indicated.

3.6. Electrocardiogram (ECG) Obtaining an ECG at the time of diagnosis is part of the current guidelines for all patients with GD [38]. In the US Prescribing Information, there is not a specific recommendation that providers obtain an ECG for patients who are starting treatment with eliglustat [39]. However, use of eliglustat in patients with pre-existing cardiac conditions has not been studied and eliglustat is not recommended for use in patients with underlying structural or electrical heart disease (see Section 3.2) [39]. Although eliglustat is predicted to cause increases in ECG intervals (PR, QTc, and QRS) at eliglustat plasma concentrations substantially above therapeutic levels, levels in the range predicted to cause clinically significant changes in cardiac conduction and repolarization (500 ng/ml) have not been observed in the clinical trials. However, patients with pre-existing cardiac abnormalities were excluded from the clinical trials, and it seems prudent to obtain an ECG prior to initiating eliglustat treatment, especially if a patient is on a medication known to prolong PR, QRS, and/or QT/QTc intervals. Additionally, there are rare individuals with congenital prolongation of the QT interval who may not be detected until an ECG is obtained. 4. Decision to treat and choice of therapy The decision to treat and choice of therapy should be based on the presence of GD symptoms, patient characteristics, individual patient's needs and/or preferences for therapy, and access to each type of therapy. Eliglustat is currently approved only for adults older than 18 years with GD1, whereas ERT is approved for both children and adults. Symptomatic children should be started on ERT and should not wait to start treatment until they are old enough for eliglustat. Early treatment of symptomatic patients has been shown to improve outcomes, including reversal of organomegaly, anemia, and thrombocytopenia, amelioration of bone pain and bone crises [18], reversal of osteopenia [8], prevention of avascular necrosis [6], acceleration of retarded growth in children [45], and better quality of life [14]. 5. Recommendations for ongoing monitoring The existing ICGG recommendations for evaluation and monitoring of adults with GD [38] include a comprehensive assessment on at least a yearly basis, although the frequency depends on clinical status and whether therapeutic goals [9] have been achieved [38]. Diseaserelated baseline and follow-up assessments are essential for all patients with GD, regardless of treatment modality to evaluate disease progression and treatment effects over time. As shown in Table 4, these assessments include measurement of liver and spleen volume by magnetic resonance imaging; assessment of hemoglobin, platelets, disease biomarkers, hepatic and renal function, prothrombin, and electrolytes; imaging of skeletal parameters; and assessment of quality of life [38]. In addition to the disease-related evaluations, a complete personal (including social) and family medical history and physical examination are important. Additional tests that may be helpful in monitoring patients with GD (although, as yet, the effect of eliglustat on these measures is unknown) include: serum protein electrophoresis and plasma free light chains as minimal routine myeloma screening particularly in patients older than 40 years with substitution of immunofixation for screening of gammopathy/myeloma in patients older than 60 years, iron panel, ferritin, vitamin B12, folate, 25-hydroxyvitamin D, D-dimer,

6. Managing patients on eliglustat Individualized, multidisciplinary care managed by or in consultation with a clinician who has expertise in GD is essential to ensure the best possible outcomes. Patient adherence to therapy is of utmost importance to minimize hepatosplenomegaly, anemia, thrombocytopenia, bone pain, and other skeletal disease manifestations [16–20]. As a daily oral therapy, eliglustat adherence will be outside the purview of clinic staff and must therefore be actively queried and addressed by clinicians at each visit. Although eliglustat has been well-tolerated by patients in the clinical studies, its newly approved status necessitates monitoring and reporting of adverse effects. In a combined safety analysis of 393 patients (535 patient-years of eliglustat exposure) who received at least one dose of eliglustat in the completed and ongoing clinical trials, 12 (3%) patients had adverse events that led to study withdrawal, of which 5 events were possibly or probably related to eliglustat treatment [46]. In this analysis, the most common adverse events reported in ≥ 10% of eliglustat-treated patients were: headache (17%), arthralgia (14%), nasopharyngitis (13%), upper respiratory infection (11%), diarrhea (10%), and dizziness (10%) [46]. Table 5 shows the most common adverse events reported more frequently in eliglustat-treated patients than patients receiving either placebo or imiglucerase in the completed Phase 3 trials

Table 5 Most commonly reported adverse events in the Phase 3 trials of eliglustat. ENGAGE trial (treatment-naïve patients): Adverse events occurring in ≥10% of patients and more frequently with eliglustat than placebo, n (%)

Arthralgia Headache Migraine Flatulence Nausea Oropharyngeal pain

Placebo (N = 20)

Eliglustat (N = 20)

2 (10) 6 (30) 0 (0) 1 (5) 1 (5) 1 (5)

9 (45) 8 (40) 2 (10) 2 (10) 2 (10) 2 (10)

ENCORE Trial (patients switching from ERT): Adverse events occurring in ≥5% of patients and more frequently with eliglustat than imiglucerase, n (%)

Fatigue Headache Nausea Diarrhea Back pain Pain in extremity Upper abdominal pain Dizziness Asthenia Cough Dyspepsia Gastroesophageal reflux disease Constipation Palpitations Rash

Imiglucerase (N = 53)

Eliglustat (N = 106)

1 (2) 1 (2) 0 (0) 2 (4) 3 (6) 1 (2) 0 (0) 0 (0) 0 (0) 2 (4) 1 (2) 0 (0) 0 (0) 0 (0) 0 (0)

15 (14) 14 (13) 13 (12) 13 (12) 13 (12) 12 (11) 11 (10) 9 (8) 9 (8) 7 (7) 7 (7) 7 (7) 5 (5) 5 (5) 5 (5)

Please cite this article as: M. Balwani, et al., Recommendations for the use of eliglustat in the treatment of adults with Gaucher disease type 1 in the United States, Mol. Genet. Metab. (2015), http://dx.doi.org/10.1016/j.ymgme.2015.09.002

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[39]. Most adverse events were mild to moderate in severity, nonserious, considered to be unrelated to eliglustat by the treating physician, and no adverse events led to study withdrawal [46]. Of note, high rates of diarrhea and tremor, which have been reported at rates of N 80% and ≈ 37%, respectively, in clinical studies of miglustat [26,47–49] have not been reported with eliglustat [50]. In the event that eliglustat-treated patients fail to achieve or maintain therapeutic targets for hematologic parameters or organ volumes within the time frames predicted by the clinical trials, a thorough assessment should be conducted including re-evaluation of pre-treatment status for indicators of response-limiting irreversible manifestations such as hepatic or splenic fibrosis [19], consideration of onset of a concurrent illness or pregnancy, and evaluation of possible non-compliant dosing and undisclosed concomitant medication use. The new onset of persistent bone pain or bone complications, such as avascular necrosis, as indicators of eliglustat refractoriness must also be judged in terms of pre-treatment splenectomy status and history of pre-treatment bone events, as such therapeutic “failures” are also known to occur in ERT-treated patients [51,52]. There are currently no data indicating that switching from eliglustat to ERT will result in improvement in patients who appear to be refractory on clinical grounds but, given the limited experience with eliglustat, such a strategy would seem to be reasonable. The effect, if any, of eliglustat on late-onset GD complications, such as multiple myeloma, other hematologic malignancies, hepatocellular carcinoma, Parkinsonism and peripheral neuropathy, is currently unknown.

7. Directions for further research Additional clinical studies are needed to better characterize the effects of eliglustat in patient populations not well-represented in the clinical studies. No differences in response to treatment were identified between the 10 (3%) patients aged 65 years and older and younger adults in the trials; however, this number is not sufficient to determine conclusively whether older adults respond differently to the drug than do younger adults. Similarly, with only 9 (2%) CYP2D6 ultrarapid metabolizers in the trials, additional research is needed to fully characterize the effects of eliglustat in this population. All of the ultrarapid metabolizers were titrated up to 84 mg (100 mg eliglustat tartrate) twice daily and two-thirds were titrated up to 126 mg (150 mg eliglustat tartrate) twice daily, with no serious adverse events reported in these patients. As children were excluded from the clinical trials and only two adolescents were enrolled, a pediatric trial is planned to assess the efficacy and safety of eliglustat use in children and adolescents. Additional research is also warranted to evaluate different doses and dosing strategies, as well as the use of eliglustat in patients with very severe thrombocytopenia (i.e., platelets below 40,000/mm3) and those with significant comorbidities that are not necessarily a contraindication for eliglustat, such as Parkinson's and other neurologic diseases, malignancies, and liver disease.

8. Summary Infusion of ERT has been the mainstay of GD care for more than 20 years and will continue to be the therapy of choice for many patients and physicians. With the approval of eliglustat as a first-line therapy, eligible GD1 patients now have the option of a daily oral therapy. It will be critical that physicians carefully assess individual patients to determine their appropriateness for eliglustat therapy. A summary of these additional considerations and assessments for eliglustat patients is provided in the inset.

7

Eliglustat-Specific Recommendations • Eliglustat is approved for adult patients with GD1 who are CYP2D6 extensive, intermediate or poor metabolizers. • Perform CYP2D6 genotyping to determine the patient's metabolizer status. • Determine eliglustat dose based on the patient's CYP2D6 metabolizer status. • Modify eliglustat dose with use of concomitant medications also metabolized by CYP2D6 and CYP3A (Table 2 and Table 3). • Consider eliglustat dose interruption for short-term use of concomitant medications also metabolized by CYP2D6 and CYP3A (Table 2 and Table 3). • Consider whether the patient is capable of complying with daily oral dosing. • Assess the following at each visit: concomitant medications, adherence to eliglustat therapy, pregnancy, and breastfeeding. • Eliglustat is not recommended in the presence of: o Pregnancy or breastfeeding o Pre-existing cardiac disease (congestive heart failure, recent acute myocardial infarction, bradycardia, heart block, ventricular arrhythmia) or long QT syndrome o In combination with Class IA, Class 1C and Class III antiarrhythmic medications o Moderate to severe renal impairment, end-stage renal disease, dialysis, or prior kidney transplantation o Hepatic impairment (e.g., evidence of portal hypertension, ascites or varices) • Consult a clinical pharmacologist, a pharmacist and/or tertiary care center with physician expertise in Gaucher disease if there are questions regarding use of concomitant medications.

Author contributions Authors are listed in alphabetical order. All authors contributed equally to the development of these guidelines. Conflict of interest Manisha Balwani has received honoraria and travel reimbursement from Genzyme, a Sanofi company, and is a member of the North American Advisory Board for the International Collaborative Gaucher Group (ICGG) Gaucher Registry. Thomas Andrew Burrow has received research/grant support, honoraria, and/or travel reimbursement from Genzyme, a Sanofi Company, and BioMarin Pharmaceutical. He is a member of the North American Advisory Board for the ICGG Gaucher Registry. Joel Charrow has received honoraria for consultation and advisory board participation from Genzyme, a Sanofi company, Shire, Pfizer/ Protalix, BioMarin, and Synageva. He has been an investigator in clinical trials sponsored by Genzyme, a Sanofi company, Shire, BioMarin, and Amicus. He has received honoraria for lectures from Genzyme, a Sanofi Company, the National Gaucher Foundation, the Fabry Support and Information Group, and the SIMD North American Metabolic Academy. He is a member of the North American Advisory Board for the ICGG Gaucher Registry. Ozlem Goker-Alpan has received honoraria and travel reimbursement from Genzyme, a Sanofi company. Paige Kaplan has received honoraria and/or grants from Genzyme, a Sanofi company, Pfizer and Synageva. She is a member of the North

Please cite this article as: M. Balwani, et al., Recommendations for the use of eliglustat in the treatment of adults with Gaucher disease type 1 in the United States, Mol. Genet. Metab. (2015), http://dx.doi.org/10.1016/j.ymgme.2015.09.002

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American and International Advisory Boards for the ICGG Gaucher Registry. Priya S. Kishnani has received honoraria from Genzyme, a Sanofi Company, Shire, Amicus, Roche and Synageva, and is a member of the North American Advisory Board for the ICGG Gaucher Registry. Pramod K. Mistry has received research/grant support, honoraria, and/or lecture fees from Genzyme, a Sanofi company, Shire, Pfizer, and Synageva. He is a member of the North American Advisory Board for the ICGG Gaucher Registry. Jeremy Ruskin has received honoraria for consultancy or participation on advisory boards for Genzyme, a Sanofi company. Neal Weinreb has received research support, consultation fees, honoraria and travel reimbursement for attending advisory boards or for speaking from Genzyme, a Sanofi Company, Shire HGT, and Pfizer Corporation. He is a member of the North American and International Advisory Boards for the ICCG Gaucher Registry. Acknowledgments Genzyme, a Sanofi company, facilitated the meeting of eliglustat advisory board members to discuss and develop these recommendations and paid for editorial work on the manuscript. The authors thank Raymond Mankoski, MD, PhD, Jennifer Ibrahim, MD, and Lisa Underhill, MS of Genzyme for critical review of the manuscript, and Laurie LaRusso, MS, ELS of Chestnut Medical Communications for medical writing support funded by Genzyme. All authors are members of the Eliglustat Advisory Board for Genzyme.

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Please cite this article as: M. Balwani, et al., Recommendations for the use of eliglustat in the treatment of adults with Gaucher disease type 1 in the United States, Mol. Genet. Metab. (2015), http://dx.doi.org/10.1016/j.ymgme.2015.09.002