Drug and Biologic Coverage Policy

Effective Date ...... 8/1/2021 Next Review Date… ...... 8/1/2022 Coverage Policy Number ...... 1319

Enzyme Related Therapies

Table of Contents Related Coverage Resources

Coverage Policy ...... 1 Pharmacogenetic Testing FDA Approved Indications ...... 4 Recommended Dosing ...... 5 General Background ...... 9 Coding/Billing Information ...... 15 References ...... 15

INSTRUCTIONS FOR USE The following Coverage Policy applies to health benefit plans administered by Cigna Companies. Certain Cigna Companies and/or lines of business only provide utilization review services to clients and do not make coverage determinations. References to standard benefit plan language and coverage determinations do not apply to those clients. Coverage Policies are intended to provide guidance in interpreting certain standard benefit plans administered by Cigna Companies. Please note, the terms of a customer’s particular benefit plan document [Group Service Agreement, Evidence of Coverage, Certificate of Coverage, Summary Plan Description (SPD) or similar plan document] may differ significantly from the standard benefit plans upon which these Coverage Policies are based. For example, a customer’s benefit plan document may contain a specific exclusion related to a topic addressed in a Coverage Policy. In the event of a conflict, a customer’s benefit plan document always supersedes the information in the Coverage Policies. In the absence of a controlling federal or state coverage mandate, benefits are ultimately determined by the terms of the applicable benefit plan document. Coverage determinations in each specific instance require consideration of 1) the terms of the applicable benefit plan document in effect on the date of service; 2) any applicable laws/regulations; 3) any relevant collateral source materials including Coverage Policies and; 4) the specific facts of the particular situation. Coverage Policies relate exclusively to the administration of health benefit plans. Coverage Policies are not recommendations for treatment and should never be used as treatment guidelines. In certain markets, delegated vendor guidelines may be used to support medical necessity and other coverage determinations.

Coverage Policy

Enzyme related therapies include the following products: • agalsidase beta (Fabrazyme®) • alglucosidase alfa (Lumizyme®) • asfotase alfa (Strensiq®) • elapegademase-lvlr (Revcovi™) • eliglustat (Cerdelga®) • elosulfase alfa (Vimizim®) • galsulfase (Naglazyme®) • idursulfase (Elaprase®) • laronidase (Aldurazyme®) • migalastat (Galafold™) • miglustat (Zavesca®) • sacrosidase (Sucraid®) • sebelipase alfa (Kanuma®) • vestronidase alfa-vjbk (Mepsevii™)

Enzyme related therapies are considered medically necessary when the following criteria are met: Page 1 of 16 Coverage Policy Number: 1319 Product Criteria for Use Aldurazyme Both of the following are met: (laronidase) • Mucopolysaccharidosis I (MPS I) with one of the following forms: o Severe mucopolysaccharidosis I (MPS I) o Attenuated mucopolysaccharidosis I (MPS I) with moderate to severe symptoms • Diagnosis documented by either of the following: o Demonstrated deficiency of alpha-L-iduronidase (for example, in peripheral blood leukocytes, plasma, or cultured fibroblasts) in the absence of a pseudodeficiency allele o Confirmation of biallelic pathogenic or likely pathogenic variants in the IDUA gene Cerdelga Individual is an adult and meets both of the following: (eliglustat) • Gaucher disease type 1 with diagnosis documented by either of the following: o Deficiency of glucosylceramidase [also known as acid β-glucosidase or glucocerebrosidase] in peripheral blood leukocytes or other nucleated cells o Confirmation of biallelic pathogenic variants in the GBA gene • One of the following: o CYP2D6 extensive metabolizer (EM) o CYP2D6 intermediate metabolizer (IM) o CYP2D6 poor metabolizer (PM)

Eliglustat (Cerdelga) is considered experimental, investigational or unproven for ANY other use including the following: • CYP2D6 ultra-rapid metabolizers • CYP2D6 indeterminate metabolizers • Concomitant use with Zavesca or other treatments approved for Gaucher disease Elaprase Hunter syndrome [Mucopolysaccharidosis II (MPS II)] with diagnosis documented by (idursulfase) either of the following: • Deficiency of iduronidate 2-sulfatase in leukocytes, fibroblasts, or plasma and documentation of normal enzymatic activity of at least one other sulfatase in the same tissue type • Confirmation of a hemizygous pathogenic variant in the IDS gene Fabrazyme Fabry disease with diagnosis documented by ALL of the following: (agalsidase beta) • ONE of the following: o Deficiency of alpha-galactosidase A in plasma or peripheral leukocytes o Confirmation of a hemizygous pathogenic variant in the GLA gene • No concomitant use of Galafold (migalastat) Galafold All of the following are met: (migalastat) • Documented diagnosis of Fabry disease in an adult • Confirmed pathogenic or likely pathogenic variant in the GLA gene known to cause Fabry disease AND • Amenable mutation identified in GLA for use with Galafold • No concomitant use of Fabrazyme (agalsidase) Kanuma Lysosomal Acid Lipase (LAL) Deficiency (Wolman disease, cholesteryl ester storage (sebelipase alfa) disease [CESD]) with diagnosis documented by either of the following: • Deficiency of LAL in peripheral blood leukocytes, fibroblasts, or dried blood spots • Confirmation of biallelic pathogenic variants in the LIPA gene Lumizyme Pompe disease with diagnosis documented by either of the following: (alglucosidase alfa) • Deficiency of acid alpha-glucosidase in leukocytes or skin fibroblasts in the absence of a pseudodeficiency allele • Confirmation of biallelic pathogenic or likely pathogenic variants in the GAA gene

Page 2 of 16 Coverage Policy Number: 1319 Product Criteria for Use Mepsevii Mucopolysaccharidosis VII (MPS VII, Sly syndrome) with diagnosis documented by (vestronidase alfa- either of the following: vjbk) • Deficiency of beta-glucuronidase in peripheral blood leukocytes or cultured fibroblasts • Genetic testing confirming mutations in the GUSB gene Naglazyme Mucopolysaccharidosis VI (MPS VI, Maroteaux-4 Lamy syndrome) with diagnosis (galsulfase) documented by either of the following: • Deficiency of N-acetylgalactosamine 4-sulfatase [ARSB] in leukocytes, fibroblasts, and dried blood spots • Confirmation of biallelic pathogenic variants in the ARSB gene Revcovi Adenosine deaminase severe combined immune deficiency (ADA-SCID) with (elapegademase-lvlr) diagnosis documented by either of the following: • Documented adenosine deaminase (ADA) deficiency (in hemolysates or in other cells if recent transfusion) consistent with the diagnosis of ADA-SCID • Confirmation of biallelic pathogenic variants or likely pathogenic in the ADA gene Strensiq All of the following are met: (asfotase alfa) • Documented diagnosis of perinatal/infantile-onset or juvenile-onset hypophosphatasia (HPP) • Total serum alkaline phosphatase (ALP) activity level below the lower limit of normal for age • Elevated serum pyridoxal 5’-phosphate (PLP) level • Radiologic evidence and clinical features of hypophosphatasia present • Confirmation of either a monoallelic or biallelic pathogenic variant(s) in the ALPL gene Sucraid BOTH of the following criteria are met: (sacrosidase) • Documentation of symptomatic congenital sucrose-isomaltase deficiency (CSID) (for example, diarrhea, bloating, abdominal cramping) • Diagnosis is confirmed by ONE of the following: o Endoscopic biopsy of the small bowel with disaccharidase levels consistent with CSID as evidenced by ALL of the following*: . Decreased (usually absent) sucrose (normal reference: greater than 25U/g protein) . Decreased to normal isomaltase (palatinase) (normal reference: greater than 5U/g protein) . Decreased maltase (normal reference: greater than 100 U/g protein) . Decreased to normal lactase (normal reference: greater than 15 U/g protein) o Documentation of homozygous or compound heterozygous pathogenic or likely pathogenic mutations in the sucrose-isomaltase (SI) gene *OR below the reporting lab’s normal reference range, if noted.

Initial approval duration is 6 months. Reauthorization of Sucraid for 12 months requires evidence of beneficial clinical response. Vimizim Mucopolysaccharidosis IVA (MPS IVA, Morquio A syndrome) with diagnosis (elosulfase alfa) documented by either of the following: • Deficiency of N-acetylgalactosamine-6-sulphatase (GALNS) in cultured fibroblasts or leukocytes • Confirmation of biallelic pathogenic variants in the GALNS gene Zavesca Mild to moderate Gaucher disease type 1 in an adult and ALL of the following: (miglustat) • ONE of the following o Documented deficiency of glucosylceramidase (also known as acid β- glucosidase or glucocerebrosidase) in peripheral blood leukocytes or other nucleated

Page 3 of 16 Coverage Policy Number: 1319 Product Criteria for Use o Confirmation of biallelic pathogenic variants in the GBA gene • Will be used as monotherapy • Not a candidate for enzyme replacement therapy AND • ONE of the following o History of beneficial clinical response to Zavesca o Documented failure/inadequate response, contraindication per FDA label, intolerance to, or not a candidate for Cerdelga

Cigna does NOT cover the use of miglustat (Zavesca) for any other indication because it is considered experimental, investigational or unproven. This includes but is NOT limited to the following: • Concomitant use with Cerdelga or other treatments approved for Gaucher disease

Initial and reauthorization is up to 12 months unless otherwise stated.

Enzyme Related Therapies are considered medically necessary for continued use when the initial criteria are met unless otherwise stated.

When coverage is available and medically necessary, the dosage, frequency, duration of therapy, and site of care should be reasonable, clinically appropriate, and supported by evidence-based literature and adjusted based upon severity, alternative available treatments, and previous response to therapy.

Enzyme Related Therapies are considered experimental, investigational or unproven for ANY other use.

Note: Receipt of sample product does not satisfy any criteria requirements for coverage

FDA Approved Indications

FDA Approved Indication

Product FDA Approved Indication Aldurazyme Aldurazyme (laronidase) is indicated for patients with Hurler and Hurler-Scheie forms of (laronidase) Mucopolysaccharidosis I (MPS I) and for patients with the Scheie form who have moderate to severe symptoms. The risks and benefits of treating mildly affected patients with the Scheie form have not been established.

Aldurazyme has been shown to improve pulmonary function and walking capacity. Aldurazyme has not been evaluated for effects on the central nervous system manifestations of the disorder. Cerdelga Cerdelga is indicated for the long-term treatment of adult patients with Gaucher disease (eliglustat) type 1 (GD1) who are CYP2D6 extensive metabolizers (EMs), intermediate metabolizers (IMs), or poor metabolizers (PMs) as detected by an FDA-cleared test.

Limitations of Use: • Patients who are CYP2D6 ultra-rapid metabolizers (URMs) may not achieve adequate concentrations of Cerdelga to achieve a therapeutic effect [see Clinical Studies (14)]. • A specific dosage cannot be recommended for those patients whose CYP2D6 genotype cannot be determined (indeterminate metabolizers) [see Clinical Studies (14)]. Elaprase Elaprase is indicated for patients with Hunter syndrome (Mucopolysaccharidosis II, MPS (idursulfase) II). Elaprase has been shown to improve walking capacity in patients 5 years and older.

Page 4 of 16 Coverage Policy Number: 1319 Product FDA Approved Indication In patients 16 months to 5 years of age, no data are available to demonstrate improvement in disease-related symptoms or long term clinical outcome; however, treatment with Elaprase has reduced spleen volume similarly to that of adults and children 5 years of age and older.

The safety and efficacy of Elaprase have not been established in pediatric patients less than 16 months of age [see Use in Specific Populations (8.4)]. Fabrazyme Fabrazyme (agalsidase beta) is indicated for use in patients with Fabry disease. (agalsidase beta) Fabrazyme reduces globotriaosylceramide (GL-3) deposition in capillary endothelium of the kidney and certain other cell types. Galafold Galafold is indicated for the treatment of adults with a confirmed diagnosis of Fabry (migalastat) disease and an amenable galactosidase alpha gene (GLA) variant based on in vitro assay data Kanuma Kanuma is indicated for the treatment of patients with a diagnosis of Lysosomal Acid (sebelipase alfa) Lipase (LAL) deficiency. Lumizyme Lumizyme (alglucosidase alfa) is a hydrolytic lysosomal glycogen-specific enzyme (alglucosidase indicated for patients with Pompe disease (acid α-glucosidase (GAA) deficiency). alfa) Mepsevii Mepsevii is indicated in pediatric and adult patients for the treatment of (vestronidase Mucopolysaccharidosis VII alfa-vjbk) (MPS VII, Sly syndrome). Limitations of Use: The effect of Mepsevii on the central nervous system manifestations of MPS VII has not been determined. Naglazyme Naglazyme (galsulfase) is indicated for patients with Mucopolysaccharidosis VI (MPS VI, (galsulfase) Maroteaux-Lamy syndrome). Naglazyme has been shown to improve walking and stair- climbing capacity. Revcovi Revcovi is a recombinant adenosine deaminase indicated for the treatment of adenosine (elapegademase- deaminase severe combined immune deficiency (ADA-SCID) in pediatric and adult lvlr) patients. Strensiq Strensiq is indicated for the treatment of patients with perinatal/infantile- and juvenile- (asfotase alfa) onset hypophosphatasia (HPP). Sucraid Sucraid (sacrosidase) indicated as oral replacement therapy of the genetically (sacrosidase) determined sucrase deficiency, which is part of congenital sucrase-isomaltase deficiency (CSID). Vimizim Vimizim (elosulfase alfa) is indicated for patients with Mucopolysaccharidosis type IVA (elosulfase alfa) (MPS IVA; Morquio A syndrome). Zavesca Zavesca is a glucosylceramide synthase inhibitor indicated as monotherapy for the (miglustat) treatment of adult patients with mild to moderate type 1 Gaucher disease for whom enzyme replacement therapy is not a therapeutic option (e.g., due to constraints such as allergy hypersensitivity, or poor venous access).

Recommended Dosing

FDA Recommended Dosing

Product Recommended Dosing Aldurazyme The recommended dosage regimen of Aldurazyme is 0.58 mg/kg of body weight (laronidase) administered once weekly as an intravenous (IV) infusion. Pretreatment is recommended 60 minutes prior to the start of the infusion and may include antihistamines, antipyretics, or both [see Warnings and Precautions (5)].

Page 5 of 16 Coverage Policy Number: 1319 Product Recommended Dosing

Each vial of Aldurazyme provides 2.9 milligrams (mg) of laronidase in 5.0 milliliters (mL) of solution and is intended for single use only. Do not use the vial more than one time. The concentrated solution for infusion must be diluted with 0.9% Sodium Chloride Injection, USP, to a final volume of 100 mL or 250 mL, using aseptic techniques. The final volume of the infusion is determined by the patient’s body weight. Patients with a body weight of 20 kg or less should receive a total volume of 100 mL. Patients with a body weight greater than 20 kg should receive a total volume of 250 mL [see Dosage and Administration (2.2)]. For patients with underlying cardiac or respiratory compromise and weighing up to 30 kg, physicians may consider diluting Aldurazyme in a volume of 100 mL and administering at a decreased infusion rate [see Dosage and Administration (2.2), Warnings and Precautions (5.3) and Adverse Reactions (6.3)]. Cerdelga Patient Selection (eliglustat) Select patients with Gaucher disease type 1 based on their CYP2D6 metabolizer status. It is recommended patient genotypes be established using an FDA-cleared test for determining CYP2D6 genotype [see Indications and Usage (1)].

Recommended Adult Dosage The recommended dosage of Cerdelga is 84 mg twice daily in CYP2D6 EMs and IMs. The recommended dosage in CYP2D6 PMs is 84 mg once daily; appropriate adverse event monitoring is recommended [see Adverse Reactions (6.1)]. The predicted exposures with 84 mg once daily in patients who are CYP2D6 PMs are expected to be similar to exposures observed with 84 mg twice daily in CYP2D6 IMs [see Clinical Pharmacology (12.3)].

Some inhibitors of CYP2D6 and CYP3A are contraindicated with Cerdelga depending on the patient's metabolizer status [see Contraindications (4)]. Co-administration of Cerdelga with other CYP2D6 and CYP3A inhibitors may require dosage adjustment depending on the patient's CYP2D6 metabolizer status to reduce the risk of potentially significant adverse reactions [see Table 3 and Table 4 in Drug Interactions (7.1)].

Reduce the dosage of Cerdelga to 84 mg once daily for: • CYP2D6 EMs and IMs taking strong or moderate CYP2D6 inhibitors • CYP2D6 EMs taking strong or moderate CYP3A inhibitors Elaprase The recommended dosage regimen of Elaprase is 0.5 mg per kg of body weight (idursulfase) administered once weekly as an intravenous infusion. Fabrazyme The recommended dosage of Fabrazyme is 1 mg/kg body weight infused every two weeks (agalsidase beta) as an intravenous (IV) infusion. Patients should receive antipyretics prior to infusion [see Warnings and Precautions (5.2)].

The initial IV infusion rate should be no more than 0.25 mg/min (15 mg/hr). The infusion rate may be slowed in the event of infusion reactions. After patient tolerance to the infusion is well established, the infusion rate may be increased in increments of 0.05 to 0.08 mg/min (increments of 3 to 5 mg/hr) with each subsequent infusion. For patients weighing < 30 kg, the maximum infusion rate should remain at 0.25 mg/min (15 mg/hr). For patients weighing ≥ 30 kg, the administration duration should not be less than 1.5 hours (based on individual patient tolerability).

Patients who have had a positive skin test to Fabrazyme or who have tested positive for anti-Fabrazyme IgE may be successfully re-challenged with Fabrazyme. The initial re- challenge administration should be a low dose at a lower infusion rate, e.g., 1/2 the therapeutic dose (0.5 mg/kg) at 1/25 the initial standard recommended rate (0.01 mg/min). Once a patient tolerates the infusion, the dose may be increased to reach the approved

Page 6 of 16 Coverage Policy Number: 1319 Product Recommended Dosing dose of 1 mg/kg and the infusion rate may be increased by slowly titrating upwards (doubled every 30 minutes up to a maximum rate of 0.25 mg/min), as tolerated. Galafold The recommended dosage regimen of Galafold is 123 mg orally once every other day at (migalastat) the same time of day. Kanuma Patients with Rapidly Progressive LAL Deficiency Presenting within the First 6 Months of (sebelipase alfa) Life: The recommended starting dosage is 1 mg/kg administered once weekly as an intravenous infusion. For patients who do not achieve an optimal clinical response, increase to 3 mg/kg once weekly.

Pediatric and Adult Patients with LAL Deficiency: The recommended dosage is 1 mg/kg administered once every other week as an intravenous infusion. Lumizyme The recommended dosage of alglucosidase alfa is 20 mg/kg body weight administered (alglucosidase every 2 weeks as an intravenous infusion. alfa) Mepsevii The recommended dosage of Mepsevii is 4 mg/kg administered by intravenous infusion (vestronidase every two weeks. alfa-vjbk) Naglazyme The recommended dosage regimen of Naglazyme is 1 mg per kg of body weight (galsulfase) administered once weekly as an intravenous infusion.

Pretreatment with antihistamines with or without antipyretics is recommended 30 to 60 minutes prior to the start of the infusion [see Warnings and Precautions (5.2)].

The total volume of the infusion should be delivered over a period of time of no less than 4 hours. Naglazyme should be diluted with 0.9% Sodium Chloride Injection, USP, to a final volume of 250 mL and delivered by controlled intravenous infusion using an infusion pump. The initial infusion rate should be 6 mL per hour for the first hour. If the infusion is well tolerated, the rate of infusion may be increased to 80 mL per hour for the remaining 3 hours. The infusion time can be extended up to 20 hours if infusion reactions occur.

For patients 20 kg and under or those who are susceptible to fluid volume overload, physicians may consider diluting Naglazyme in a volume of 100 mL [see Warnings and Precautions (5.1) and Adverse Reactions (6.3)]. The infusion rate (mL per hour) should be decreased so that the total infusion duration remains no less than 4 hours. Revcovi Adagen-naïve patients (elapegademase- The starting weekly dose of REVCOVI is 0.4 mg/kg based on ideal body weight, divided lvlr) into two doses (0.2 mg/kg twice a week), intramuscularly, for a minimum of 12 to 24 weeks until immune reconstitution is achieved. After that, the dose may be gradually adjusted down to maintain trough

ADA activity over 30 mmol/hr/L, trough dAXP level under 0.02 mmol/L, and/or to maintain adequate immune reconstitution based on clinical assessment of the patient. The optimal long-term dose and schedule of administration should be established by the treating physician for each patient individually and may be adjusted based on the laboratory values for trough

ADA activity, trough dAXP level, and/or on the treating physician’s medical assessment of the

Page 7 of 16 Coverage Policy Number: 1319 Product Recommended Dosing patient’s clinical status Sucraid The recommended dosage is: (sacrosidase) • 1 mL (8,500 I.U.) (one full measuring scoop or 28 drops) per meal or snack for patients up to 15 kg in body weight. • 2 mL (17,000 I.U.) (two full measuring scoops or 56 drops) per meal or snack for patients over 15 kg in body weight. Strensiq Dosage for Perinatal/Infantile-Onset HPP (asfotase alfa) The recommended dosage regimen of Strensiq for the treatment of perinatal/infantile- onset HPP is 6 mg/kg per week administered subcutaneously as either: • 2 mg/kg three times per week, or • 1 mg/kg six times per week. Injection site reactions may limit the tolerability of the six times per week regimen [see Adverse Reactions (6.1)].

The dose of Strensiq may be increased for lack of efficacy (e.g., no improvement in respiratory status, growth, or radiographic findings) up to 9 mg/kg per week administered subcutaneously as 3 mg/kg three times per week.

Dosage for Juvenile-Onset HPP The recommended dosage regimen of Strensiq for the treatment of juvenile-onset HPP is 6 mg/kg per week administered subcutaneously as either: • 2 mg/kg three times per week, or • 1 mg/kg six times per week. Injection site reactions may limit the tolerability of the six times per week regimen [see Adverse Reactions (6.1)]. Vimizim The recommended dose is 2 mg per kg given intravenously over a minimum range of 3.5 (elosulfase alfa) to 4.5 hours, based on infusion volume, once every week. Pre-treatment with antihistamines with or without antipyretics is recommended 30 to 60 minutes prior to the start of the infusion [see Warnings and Precautions (5.1)]. Zavesca Therapy should be directed by physicians who are knowledgeable in the management of (miglustat) Gaucher disease.

The recommended dose for the treatment of adult patients with type 1 Gaucher disease is one 100 mg capsule administered orally three times a day at regular intervals. If a dose is missed, the next Zavesca capsule should be taken at the next scheduled time.

It may be necessary to reduce the dose to one 100 mg capsule once or twice a day in some patients due to adverse reactions, such as tremor or diarrhea.

Drug Availability

Product Drug Availability Aldurazyme Aldurazyme is supplied in single-use vials containing 2.9 mg laronidase per 5 mL. (laronidase) Cerdelga Cerdelga is supplied as 84 mg hard gelatin capsules, (eliglustat) Elaprase Elaprase is supplied in single-use vials of 6 mg/3 mL (2 mg/mL). (idursulfase) Fabrazyme For injection: 5 mg or 35 mg of agalsidase beta as a white to off-white, lyophilized cake or (agalsidase beta) powder in a single-dose vial for reconstitution. Galafold Galafold capsules are supplied as 123 mg migalastat capsules. (migalastat) Galafold capsules are packaged as two 7-count capsules blister strips with aluminum foil lidding encased in cardboard blister cards providing 14 capsules per wallet pack that supplies the drug product for 4 weeks (28 days). Kanuma Kanuma is supplied as single-use vials of 20 mg/10 mL (2 mg/mL) solution. (sebelipase alfa)

Page 8 of 16 Coverage Policy Number: 1319 Product Drug Availability Lumizyme Lumizyme is supplied as single-use vials containing 50 mg of alglucosidase alfa (alglucosidase reconstituted to a resultant solution concentration of 5 mg/mL. alfa) Mepsevii MEPSEVII (vestronidase alfa-vjbk) injection is supplied as a carton containing one 10 (vestronidase mg/5 mL (2 mg/mL) single-dose vial alfa-vjbk) Naglazyme Naglazyme is supplied as 5 mL vials (5 mg per 5 mL). (galsulfase) Revcovi Revcovi injection, 2.4 mg/1.5 mL (1.6 mg/mL), is a sterile, preservative free, (elapegademase- clear, colorless solution for intramuscular use available as one single-dose vial per carton lvlr) The vial stopper is not made with natural rubber latex. Sucraid Sucraid Oral Solution is available in 118 mL (4 fluid ounces) bottles, packaged two bottles (sacrosidase) per box. Each mL of solution contains 8,500 International Units (I.U.) of sacrosidase. Strensiq Strensiq is supplied in single-use vials of solution in the following strengths: 18 mg/0.45 (asfotase alfa) mL; 28 mg/0.7 mL; 40 mg/mL, or 80 mg/0.8 mL. Vimizim Vimizim is available in single-use vials of 5 mg/5 mL (1 mg/mL). (elosulfase alfa) Zavesca Zavesca is supplied in hard gelatin capsules containing 100 mg miglustat. (miglustat)

General Background

Disease Overview

Congenital sucrase-isomaltase deficiency (CSID) Congenital sucrase-isomaltase deficiency (CSID) is a chronic, autosomal recessive, inherited, phenotypically heterogeneous disease with very variable enzyme activity. CSID is usually characterized by a complete or almost complete lack of endogenous sucrase activity, a very marked reduction in isomaltase activity, a moderate decrease in maltase activity, and normal lactase levels.

Currently, the primary method for diagnosing CSID is biopsy of the small intestine with assays for lactase, sucrose, isomaltase (palatinase) and maltase activity. A sucrose breath hydrogen test provides a less invasive way to diagnose CSID. This test, however, is not particularly reliable owing to substantial contamination because of false-positives from secondary sucrose deficiencies (for example dumping syndrome, bacterial overgrowth) as well as false negatives (for example nonhydrogen producers, effects of antibiotics). This test requires the individual to ingest a large quantity of sucrose, which can exacerbate CSID symptoms. (Treem, 2012)

Genetic testing is another method of diagnosing CSID. Four mutations in the SI (sucrose-isomaltase) gene have been identified in the majority of symptoms in this disease. A study by Uhrich and colleagues demonstrated that 83% of children of European ancestry with symptoms and suspected CSID could be diagnosed solely by genetic testing. (Uhrich 2012). Considering the high rate of diagnosis with genetic testing, it has recently been suggested that genetic testing be the first line method for diagnosis of CSID, as individuals are identified in a timely manner, allowing appropriate treatments to be initiated. (Lombardo 2017)

Fabry Disease Fabry disease is an X-linked disorder caused by a deficiency of the alpha-galactosidase A (α-gal A) enzyme. Because affected females may have indeterminate enzyme levels, genetic testing may be required for a diagnosis. In a male, low or absent levels of the α-gal A enzyme is sufficient for diagnosis. (Desnick, 2003) The mean age of presentation is 6-8 years and is generally an acute, episodic pain crisis. (Wang, 2011)

Gaucher Disease Gaucher disease is an autosomal recessive, lysosomal storage disease categorized as types 1, 2, or 3. Gaucher disease type 1 occurs most often in adults and accounts for 95% of Gaucher disease cases. Type 1 disease is associated with visceral complications and does not involve the central nervous system. Gaucher disease types

Page 9 of 16 Coverage Policy Number: 1319 2 and 3 are neuronopathic variants. Gaucher disease type 2 generally affects infants, and results in substantial brain damage and early death. Gaucher disease type 3 usually affects children, but can also affect adults.

Gaucher disease is caused by an insufficiency of glucosylceramidase (also known as acid β-glucosidase or glucocerebrosidase). Glucosylceramidase is an enzyme that metabolizes glucosylceramide to glucose and ceramide. (Bennett, 2013) Excess glucosylceramide in the lysosomal compartments of macrophages forms Gaucher cells. Gaucher cells accumulate in the bone marrow, liver, spleen, and other organs potentially causing skeletal disease, organomegaly, and significant anemia, leukopenia, and thrombocytopenia. (Bennett, 2013) Gaucher disease is diagnosed through a demonstration of deficient glucocerebrosidase (glucosylceramidase) enzyme activity in peripheral blood leukocytes or other nucleated cells.

Hypophosphatasia (HPP) HPP is a rare genetic disorder with mutations in the ALPL gene resulting in defective mineralization of bone and/or teeth and reduced serum alkaline phosphatase (ALP) activity. Infantile-HPP has an onset between birth and six months of age and is characterized by rickets without an elevated serum ALP activity. Childhood or juvenile-onset HPP is characterized by low bone mineral density for age with unexplained fractures to rickets and dental manifestations include premature loss of primary teeth with intact roots. (Mornet, 2016)

The diagnosis is made through a combination of clinical (e.g., prenatal long-bone bowing, infantile rickets without elevated serum ALP activity, hypercalcemia and hypercalciuria, pathologic fractures, premature loss of deciduous teeth, family history); biochemical (e.g., low total serum ALP activity, elevated urine concentration of phosphoethanolamine [PEA], elevated serum concentration of pyridoxal 5’-phosphate [PLP], normal serum concentration of calcium, ionized calcium, and inorganic phosphate, normal serum concentration of vitamin D and parathyroid hormone with elevated urine inorganic pyrophosphate); and radiographic features (e.g., osteopenia, osteoporosis, or low bone mineral content for age; infantile rickets; alveolar bone loss; focal bony defects of the metaphyses; metatarsal stress fractures; osteomalacia with lateral pseudofractures). Genetic testing is available, although not required, for diagnosis (except for prenatal diagnosis). (Mornet, 2016)

Lysosomal Acid Lipase (LAL) Deficiency LAL deficiency is also referred to as Wolman disease or cholesteryl ester storage disease [CESD]. The deficiency of the LAL enzyme is caused by a mutation in the LIPA gene. (Reiner, 2014) While genetic testing is available, the diagnosis is typically made by identifying deficient LAL enzyme activity in peripheral blood leukocytes, fibroblasts, or dried blood spots. (Hoffman, 2016) The deficiency results in elevated low-density lipoprotein (LDL) cholesterol and decreased high-density lipoprotein (HDL) cholesterol levels and affected individuals may have childhood cardiovascular disease. (Reiner, 2014)

Mucopolysaccharidosis (MPS) Mucopolysaccharidoses are rare inherited disorders affecting lysosomal storage and metabolism of glycosaminoglycans (GAGs; also called mucopolysaccharides). There are 4 different types of GAGs, including chondroitin-6- sulfate, dermatan sulfate, heparin sulfate, and keratan sulfate. Normally, GAGs are broken down in lysosomes through enzyme catabolism. However, in mucopolysaccharidoses, a specific lysosomal enzyme is absent or deficient, leading to reduced catabolism of GAGs. As GAGs accumulate within the body, cellular physiology and organ function are disrupted, with disease signs and symptoms worsening throughout the patient’s life. A single lysosomal enzyme is deficient in each MPS disorder, and the specific manifestations of the disorder vary based on which lysosomal enzyme is lacking.

o Mucopolysaccharidosis Type I (MPS I) MPS I is caused by a deficiency of alpha-L-iduronidase. It is subdivided into 3 syndromes: Scheie syndrome (MPS IS), which is a mild form; Hurler-Scheie Syndrome (MPS IH/S), which is an intermediate form; and Hurler Syndrome (MPS IH), which is the most severe form. The diagnosis is typically made through biochemical analysis (reduced or undetectable alpha-L-iduronidase activity). Molecular analysis is available for confirmation. (Wang, 2011)

o Mucopolysaccharidosis Type II (MPS II; Hunter Syndrome) Hunter syndrome is caused by a deficiency of iduronidate 2-sulfatase (IDS). Low levels of IDS is sufficient for diagnosis of MPS II. Other sulfatase enzymes (arylsulfatase A [ARSA] or arylsulfatase B

Page 10 of 16 Coverage Policy Number: 1319 [ARSB]) should also be evaluated to rule out multiple sulfatase deficiencies. Genetic testing is available for confirmation. (Wang, 2011)

o Mucopolysaccharidosis Type IVA (MPS IVA; Morquio A syndrome) In Morquio A syndrome, the deficient enzyme is N-acetylgalactosamine-6-sulphatase (GALNS), which is normally responsible for breakdown of keratan sulfate and chondroitin-6-sulfate in bone, cartilage, and corneal tissue. (Algahim, 2013; Crunkhorn, 2013; Pyeritz, 2011) Deficiency of GALNS leads to severe bone disorders (e.g., skeletal dysplasia, short stature) and impaired mobility (e.g., motor dysfunction, joint stiffness, joint degeneration). Many patients also develop heart disease (e.g., aortic aneurysm, coronary artery intimal sclerosis, valvular disease), corneal clouding, hearing loss, and restrictive or obstructive airway disease. Symptoms of Morquio A typically present after the first year of life, although many patients require multiple surgical interventions before 10 years of age. (Algahim, 2013) The initial diagnosis of any MPS may be based on presence of key clinical signs, followed by testing to confirm the specific enzyme deficiency. Morquio A syndrome may be diagnosed initially based on abnormally high urinary concentrations of keratan sulfate, followed by additional testing to confirm GALNS deficiency. (Pyeritz, 2011)

o Mucopolysaccharidosis Type VI (MPS VI, Maroteaux-Lamy syndrome) Mucopolysaccharidosis VI is an inherited autosomal recessive metabolic disorder. Patients with MPS VI have a deficiency in N-acetylgalactosamine 4-sulfatase activity (ARSB), resulting in the accumulation of dermatan sulfate (DS), a glycosoaminoglycans (GAG) substrate, which can lead to the loss of cellular, tissue, and organ function. Patients with MPS VI excrete an excessive amount of DS. (Yogalingam, 2004) Confirmatory genetic testing is available.

o Mucopolysaccharidosis Type VII (MPS VII, Sly syndrome) Mucopolysaccharidosis VII is an inherited autosomal recessive metabolic disorder. Patients with MPS VII have a deficiency of β-glucuronidase (GUS). This enzyme takes part in the degradation of glycosaminoglycans (GAGs) such as chondroitin sulfate, dermatan sulfate and heparin sulfate. This leads to accumulation of partially degraded GAGs in tissue lysosomes, ultimately resulting in loss of cellular and organ function. (Montano, 2016)

Pompe Disease Pompe disease, also known as type II glycogen storage disease, is an inherited, autosomal recessive disorder caused by acid alpha-glucosidase enzyme deficiency. (Weinstein, 2003) Acid alpha-glucosidase is the enzyme responsible for the degradation of glycogen in lysosomes. Patients with Pompe disease accumulate glycogen in lysosomes throughout the body, however accumulation is most pronounced in the skeletal muscle and cardiac tissue. (Weinstein, 2003) Skin fibroblast studies are the gold standard for diagnosis and deficiency of the enzyme in leukocytes or dried blood spots can also be used. (Winchester, 2008) The Pompe Disease Diagnostic Working Group recommends a confirmatory test if dried blood spots are used. (Winchester, 2008) Genetic testing is also available. Pompe disease is classified as either infantile-onset or late-onset based on the age when symptoms begin. Infantile-onset generally has symptoms present around 3 months of age. (Wang, 2011)

Pharmacology

Product Pharmacology Aldurazyme The rationale of Aldurazyme therapy in MPS I is to provide exogenous enzyme for uptake (laronidase) into lysosomes and increase the catabolism of GAG. Aldurazyme uptake by cells into lysosomes is most likely mediated by the mannose-6-phosphate-terminated oligosaccharide chains of laronidase binding to specific mannose-6-phosphate receptors. Because many proteins in the blood are restricted from entry into the central nervous system (CNS) by the blood brain barrier, effects of intravenously administered Aldurazyme on cells within the CNS cannot be inferred from activity in sites outside the CNS. The ability of Aldurazyme to cross the blood brain barrier has not been evaluated in animal models or in clinical studies.

Page 11 of 16 Coverage Policy Number: 1319 Product Pharmacology Cerdelga Cerdelga is a specific inhibitor of glucosylceramide synthase (IC50 = 10 ng/mL), and acts (eliglustat) as a substrate reduction therapy for GD1. In clinical trials Cerdelga reduced spleen and liver size, and improved anemia and thrombocytopenia. Elaprase Elaprase (idursulfase) replaces the enzyme iduronate-2-sulphatase (I2S), which (idursulfase) catalyses the breakdown of the glycosaminoglycans (GAGs) dermatan sulfate and heparin sulfate in lysosomes. A deficiency of I2S leads to an accumulation of dermatan sulfate and heparin sulfate in lysosomes, and the build-up of these cellular waste products in tissues and organs ultimately results in the inability of tissues and organs to function properly. Fabrazyme Fabrazyme (agalsidase beta) reduces globotriasylceramide (GL-3) deposition in the (agalsidase beta) capillary endothelium of the kidney, heart and skin. It is a recombinant form of the defective enzyme, ά-galactosidase, and is intended to provide an exogenous source of ά- galactosidase in Fabry disease patients. Galafold Migalastat is a pharmacological chaperone that reversibly binds to the active site of the (migalastat) alpha-galactosidase A (alpha-Gal A) protein (encoded by the galactosidase alpha gene, GLA), which is deficient in Fabry disease. Kanuma Sebelipase alfa replaces the deficient enzyme, lysosomal acid lipase, to restore (sebelipase alfa) lysosomal lipid metabolism. Lumizyme Lumizyme (alglucosidase alfa) replaces the deficient alpha-glucosidase enzyme and (alglucosidase degrades glycogen in lysosomes. alfa) Mepsevii Vestronidase alfa-vjbk is a recombinant form of human GUS and is intended to provide (vestronidase exogenous alfa-vjbk) GUS enzyme for uptake into cellular lysosomes. Mannose-6-phosphate (M6P) residues on the oligosaccharide chains allow binding of the enzyme to cell surface receptors, leading to cellular uptake of the enzyme, targeting to lysosomes and subsequent catabolism of accumulated GAGs in affected tissues. Naglazyme Naglazyme (galsulfase) provides an exogenous enzyme to increase the catabolism of (galsulfase) dermatan sulfate. Revcovi Elapegademase-lvlr provides an exogenous source of ADA enzyme that is associated (elapegademase- with a lvlr) decrease in toxic adenosine and deoxyadenosine nucleotides levels as well as an increase in lymphocyte number. Sucraid Sucrase is naturally produced in the brush border of the small intestine, primarily the (sacrosidase) distal duodenum and jejunum. Sucrase hydrolyzes the disaccharide sucrose into its component monosaccharides, glucose and fructose. Isomaltase breaks down disaccharides from starch into simple sugars. Sucraid does not contain isomaltase. Strensiq HPP is caused by a deficiency in TNSALP enzyme activity, which leads to elevations in (asfotase alfa) several TNSALP substrates, including inorganic pyrophosphate (PPi). Elevated extracellular levels of PPi block hydroxyapatite crystal growth which inhibits bone mineralization and causes an accumulation of unmineralized bone matrix which manifests as rickets and bone deformation in infants and children and as osteomalacia (softening of bones) once growth plates close, along with muscle weakness. Replacement of the TNSALP enzyme upon Strensiq treatment reduces the enzyme substrate levels. Vimizim Vimizim is intended to provide the exogenous enzyme N-acetylgalactosamine-6-sulfatase (elosulfase alfa) that will be taken up into the lysosomes and increase the catabolism of the GAGs KS and C6S. Elosulfase alfa uptake by cells into lysosomes is mediated by the binding of mannose-6-phosphate-terminated oligosaccharide chains of elosulfase alfa to mannose- 6-phosphate receptors Zavesca Zavesca (miglustat) is a competitive and reversible inhibitor of the enzyme (miglustat) glucosylceramide synthase, the initial enzyme in a series of reactions which results in the

Page 12 of 16 Coverage Policy Number: 1319 Product Pharmacology synthesis of most glycosphingolipids. Miglustat works to reduce the rate of glycosphingolipid biosynthesis so the amount of glycosphingolipid substrate is reduced to a level which allows the activity of the deficient glucocerebrosidase enzyme to be more effective.

Professional Societies/Organizations American College of Medical Genetics The American College of Medical Genetics (ACMG) publication on the diagnosis and management of lysosomal storage diseases addresses several specific diseases. Disorders with clear ACMG recommendations are: • Pompe disease: The group comments that alglucosidase has shown benefit in both the early and late forms of the disease and advocate for the timely initiation of intervention with ERT in the scenario of infantile disease. • Fabry disease: Agalsidase beta is suggested as the standard of care for individuals with symptoms of disease. ERT in this disease state has shown improvements in the rate of renal dysfunction, pulmonary and GI symptoms. It is also noted that ERT decreases renal, cardiac and CNS incidents. • Gaucher, Type I: ERT demonstrates improvements in peripheral symptoms during the first year of treatment, however, bone effects lag behind and may take several years to realize improvement. Substrate reduction therapy (SRT, e.g., Cerdelga, Zavesca) is effective in hepatosplenomegaly and hematologic parameters, but bone effects are modest and also lag behind. ACMG suggests using SRT as second line treatment in adults who experience severe side effects with ERT or who refuse ERT and have a milder form of the disease. The ACMG recommends immediate treatment with ERT for individuals diagnosed with Gaucher type 3. The guidelines do not mention preference for one drug over another. (Wang, 2011)

ACMG recognizes that data is sparse in these conditions and evidence can be disorganized and not robust. As screening in newborns diagnoses more cases of these disorders, there will be an increased need for multi- disciplinary teams familiar with managing these disease states. (Wang, 2011)

Consensus approach for the management of severe combined immune deficiency caused by adenosine deaminase deficiency A consensus statement for management of ADA-SCID was recently updated (2018). Diagnosis is usually established by demonstrating absent or very low (< 1 % of normal) ADA catalytic activity, accompanied by elevated Ado or dAdo in plasma, urine, or dried blood spots. This should be followed by genetic testing to confirm bi-allelic mutations in the ADA gene. Enzyme replacement therapy (ERT) is recommended by the consensus panel for all patients newly diagnosed with ADA-SCID as an immediate stabilizing measure. The ideal duration of ERT has not been established. The consensus recommends that most patients use ERT as a “bridge” for a few months to approximately 2 years prior to undergoing curative therapy with a hematopoietic stem cell transplant (HSCT) or hematopoietic stem cell gene therapy (HSC-GT). Long-term use of ERT has declined in the past 30 years and has not been systematically studied. Lymphocyte counts and function may deteriorate over time, contributing to increased risk of infections and malignancy. Therefore, ERT longer than 5 to 8 years should be avoided, and employed on a continuous basis only when neither HSCT nor HSC-GT have been available or effective. The consensus also suggests ERT use for patients with later onset phenotypes who may not be ideal candidates for curative processes. (Kohn, 2018)

European Working Group on Gaucher Disease Task The European Working Group on Gaucher Disease Task Force provides recommendations for the management of neuronopathic (e.g., type 3) Gaucher disease. Their treatment recommendations note that enzyme replacement therapy (ERT) has an excellent safety profile and that ERT enhances quality of life by ameliorating systemic involvement (skeletal deterioration, visceromegaly, hematological abnormalities) in non-neuronopathic and neuronopathic Gaucher disease. The recommendations also note that evidence is not available demonstrating that ERT reverses, stabilizes, or slows progression of neurological symptoms. (Vellodi, 2009) The treatment guidelines advocate starting ERT as soon as possible after diagnosis. At the time the recommendations were authored, Cerezyme was the treatment of choice. (Vellodi, 2009)

Page 13 of 16 Coverage Policy Number: 1319 Clinical Efficacy

Congenital sucrose-isomaltase deficiency (CSID) A two-phase (dose response preceded by a breath hydrogen phase) double-blind, multi-site, crossover trial was conducted in 28 patients (aged 4 months to 11.5 years) with confirmed CSID. During the dose response phase, the patients were challenged with an ordinary sucrose-containing diet while receiving each of four doses of sacrosidase: full strength (9000 I.U./mL) and three dilutions (1:10 [900 I.U./mL], 1:100 [90 I.U./mL], and 1:1000 [9 I.U./mL]) in random order for a period of 10 days. Patients who weighed no more than 15 kg received 1 mL per meal; those weighing more than 15 kg received 2 mL per meal. The dose did not vary with age or sucrose intake. A dose-response relationship was shown between the two higher and the two lower doses. The two higher doses of sacrosidase were associated with significantly fewer total stools and higher proportions of patients having lower total symptom scores, the primary efficacy end-points. In addition, higher doses of sacrosidase were associated with a significantly greater number of hard and formed stools as well as with fewer watery and soft stools, the secondary efficacy end-points.

Analysis of the overall symptomatic response as a function of age indicated that in CSID patients up to 3 years of age, 86% became asymptomatic. In patients over 3 years of age, 77% became asymptomatic. Thus, the therapeutic response did not differ significantly according to age.

A second study of similar design and execution as the first used 4 different dilutions of sacrosidase: 1:100 (90 I.U./mL), 1:1000 (9 I.U./mL), 1:10,000 (0.9 I.U./mL), and 1:100,000 (0.09 I.U./mL). There were inconsistent results with regards to the primary efficacy parameters.

In both trials, however, patients showed a marked decrease in breath hydrogen output when they received sacrosidase in comparison to placebo. (QOL Medical LLC,2018)

Gaucher Disease A recent Cochrane systematic review of ERT and SRT in Gaucher disease assessed eight randomized controlled trials, including 300 individuals, and note there are limitations in reviewing data solely from randomized controlled trials for chronic rare diseases. The authors report that in treatment-naïve individuals, or in the scenario of a year-long drug holiday prior to starting ERT, the three marketed ERT products seem to be non-inferior to each other and demonstrate improvements in the first year of therapy in hepatosplenomegaly, hematologic parameters and specific biomarkers. Safety appears to be similar among the three compounds. There is no evidence to support the use of one ERT over another in treatment-naïve individuals. The Cochrane authors cite two small, short-term miglustat studies that demonstrate its potential as maintenance therapy for ERT in individuals whose disorder is well controlled. However, because the studies were short in duration, switching from intravenous therapy and oral miglustat should be accompanied by judicious monitoring of these patients for disease progression. As analyzed here, the approved indication for miglustat in those who are intolerant to or refuse intravenous ERT treatment is not based on evidence of superiority over ERT, and comes with a significant level of side effects. (Shemesh, 2015)

In a non-inferiority trial, eliglustat was compared with imiglucerase in 160 individuals who were stable for at least 3 years on therapy for type 1 Gaucher’s disease. The composite primary end point was the percentage of patients who had hematologic lab values and organ volumes remain stable for 12 months. The non-inferiority margin was 25% for eliglustat relative to imiglucerase. Eighty-five percent in the eliglustat arm and 94% in the imiglucerase arm met the primary end point (between group difference -8.8%; 95% CI -17.6 to 4.2), and the lower margin of the CI fell within the pre-determined threshold for non-inferiority. The study team concluded that oral eliglustat was able to sustain hematological and organ volume stability in individuals who were previously well controlled on intravenous treatment and it can be considered as a therapeutic option in this population. (Cox, 2015)

Juvenile-Onset Hypophosphatasia Asfotase alfa (Strensiq) 6 mg/kg per week or 9 mg/kg per week was evaluated in an open-label, 24-week trial including 8 patients with juvenile-onset hypophosphatasia (HPP). At study entry, patients were 6-12 years of age. All of the patients entered the extension study and received treatment for at least 48 months (initially

Page 14 of 16 Coverage Policy Number: 1319 asfotase alfa was dosed at 3 mg/kg per week with dosing increased to 6 mg/kg per week). Improvements in growth, skeletal manifestations (substantial healing of rickets), and gait were observed. (Alexion Pharmaceuticals Inc., 2016)

Coding/Billing Information

Note: 1) This list of codes may not be all-inclusive. 2) Deleted codes and codes which are not effective at the time the service is rendered may not be eligible for reimbursement.

Covered when medically necessary:

HCPCS Codes Description C9399 Unclassified drugs or biologicals J0180 Injection, agalsidase beta, 1 mg J0221 Injection, alglucosidase alfa (lumizyme), 10 mg J1322 Injection, elosulfase alfa, 1 mg J1458 Injection, galsulfase, 1 mg J1743 Injection, idursulfase, 1 mg J1931 Injection, laronidase, 0.1 mg J2840 Injection, sebelipase alfa, 1 mg J3397 Injection, vestronidase alfa-vjbk, 1 mg J3590 Unclassified biologics J8499 Prescription drug, oral, non-chemotherapeutic, NOS

References

1. Actelion Pharmaceuticals US, Inc. Zavesca (miglustat) capsules, for oral use [product information]. South San Francisco, CA: Actelion Pharmaceuticals US, Inc. February 2016. 2. Alexion Pharmaceuticals Inc. Kanuma (sebelipase alfa) injection, for intravenous use [product information]. Cheshire, CT: Alexion Pharmaceuticals Inc. December 2015. 3. Alexion Pharmaceuticals Inc. Strensiq (asfotase alfa) injection, for subcutaneous use [product information]. Cheshire CT: Alexion Pharmaceuticals Inc. October 2016. 4. Algahim MF, Almassi GH. Current and emerging management options for patients with Morquio A syndrome. Ther Clin Risk Manag. 2013; 9: 45-53. 5. Amicus Therapeutics U.S., Inc. Galafold (migalastat) capsules, for oral use [product information]. Cranbury, NJ. Amicus Therapeutics U.S., Inc. August 2018. 6. Bennett LL, Mohan D. Gaucher disease and its treatment options. Ann Pharmacother. Sep 2013; 47 (9): 1182-1193. 7. BioMarin Pharmaceutical Inc. Naglazyme (galsulfase) injection for intravenous use [product information]. Novato, CA: BioMarin Pharmaceutical Inc. April 2013. 8. BioMarin Pharmaceutical Inc. Vimizim (elosulfase alfa) injection, for intravenous use [product information]. Novato, CA: BioMarin Pharmaceutical Inc. February 2014. 9. Cox T, Drelichman G, Cravo R et al. Eliglustat compared with imiglucerase in patients with Gaucher’s disease type 1 stabilised on enzyme replacement therapy: a phase 3, randomized, open-label, non-interiority trial. Lancet 2015; 385: 2355-62. 10. Crunkhorn S. Trial watch: enzyme replacement success in Phase III trial for rare metabolic disorder. Nat Rev Drug Discov. Jan 2013; 12 (1): 12. 11. Desnick RJ, Brady R, Barranger J, et al. Fabry Disease, an under-recognized multisystemic disorder: expert recommendations for diagnosis, management, and enzyme replacement therapy. Ann Intern Med. 2003; 138 (4): 338346. 12. Genzyme Corporation. Aldurazyme (laronidase) [product information]. Cambridge, MA: Genzyme Corporation. April 2013.

Page 15 of 16 Coverage Policy Number: 1319 13. Genzyme Corporation. Fabrazyme (agalsidase beta) [product information]. Cambridge, MA: Genzyme Corporation. May 2010. 14. Genzyme Corporation. Lumizyme (alglucosidase alfa), for injection, for intravenous use [product information]. Cambridge, MA: Genzyme Corporation. August 2014. 15. Genzyme Ireland, Ltd. Cerdelga (eliglustat) capsules, for oral use [product information]. Waterford, Ireland: Genzyme Ireland, Ltd. August 2014. 16. Hoffman EP, Barr ML, Giovanni MA, et al. Lysosomal Acid Lipase Deficiency. 2015 Jul 30 [Updated 2016 Sep 1]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 19932016. 17. Kohn DB, Hershfield MS, Puck JM, et al. Consensus approach for the management of severe combined immune deficiency caused by adenosine deaminase deficiency. J Allergy Clin Immunol. 2018 September 5 [Epub ahead of print] 18. Leadiant Biosciences Inc. Revcovi (elapegademase-lvlr) injection, for intramuscular use [product information]. Gaithersburg, MD: Leadiant Biosciences Inc. October 2018. 19. Lombardo RC, Hopkin R, Maisam A. Impact of Genetic Testing in the Diagnosis and Management of Sucrase-Isomaltase Deficiency. J Gastroenterol Res 2017;1(1):30-33. 20. Montano AM, Lock-Hock N, Graham BH, et al. Clinical course of Sly Syndrome (Mucopolysaccharidosis type VII). J Med Genet. 2016;0:1-16. 21. Mornet E, Nunes ME. Hypophosphatasia. In: Pagon RA, Adam MP, Ardinger HH, et al, editors. SourceGeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. 2007 Nov 20 [updated 2016 Feb 4]. 22. Pyeritz RE. Inherited diseases of connective tissue. In: Goldman L, Schafer AI, eds. Goldman's Cecil Medicine. 24th ed. Maryland Heights, MO: W.B. Saunders; 2011:1662-1667. 23. QOL Medical, LLC. Sucrase (sacrosidase) oral solution [product information]. Vero Beach, FL. QOL Medical, LLC. April 2018. 24. Reiner Z, Guardamagna O, Nair D, et al. Lysosomal acid lipase deficiency – an under-recognized cause of dyslipidaemia and liver dysfunction. Atherosclerosis 2014; 235: 21-30. 25. Shemesh E, Deroma L, Bembi B et al. Enzyme replacement and substrate reduction therapy for Gaucher disease (Review). Cochrane Database Syst Rev. 2015 Mar 27;3. 26. Shire Human Genetic Therapies, Inc. Elaprase (idursulfase) injection, for intravenous use [product information]. Lexington, MA: Shire Human Genetic Therapies, Inc. June 2013. 27. Treem WR. Clinical Aspects and Treatment of Congenital Sucrase-Isomaltase Deficiency.J Pediatr Gastroenterol Nutr. 2012;Nov 55 Suppl 2:S7-S13. 28. Uhrich S, Wu Z, Huang JY, et al. Four mutations in the SI gene are responsible for the majority of clinical symptoms of CSID. J Pediatr Gastroenterol Nutr 2012;55:S34-S35. 29. Ultragenyx Pharmaceutical Inc. Mepsevii (vestronidase alfa-vjbk) injection, for intravenous use [product information]. Novato, CA. Ultragenyx Pharmaceutical, Inc. November 2017. 30. Vellodi A, Tylki-Szymanska A, Davies EH, et al. Management of neuronopathic Gaucher disease: Revised recommendations. J Inherit Metab Dis 2009; 32: 660-4. 31. Wang R, Bodamer O, Watson, et al. Lysosomal storage diseases: Diagnostic confirmation and management of presymptomatic individuals. Genet Med. 2011 May; 13 (5): 457-84. 32. Weinstein DA, Koeberl DD, Wolfsdorf JI. Type II Glycogen Storage Disease. In: National Organization for Rare Disorders, ed. NORD Guide to Rare Disorders. Philadelphia: Lippincott Williams & Wilkins; 2003:452. 33. Winchester B, Bali D, Bodamer OA, et al; Pompe Disease Diagnostic Working Group. Methods for a prompt and reliable laboratory diagnosis of Pompe disease: report from an international consensus meeting. Mol Genet Metab 2008; 93 (3): 275-81. 34. Yogalingam G. Aryplase (Biomarin). Curr Opin Investig Drugs. Oct 2004; 5 (10): 1111-1120.

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