Cigna Drug and Biologic Coverage Policy

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1 Cigna Drug and Biologic Coverage Policy Subject Lysosomal Storage Disorders Therapy Effective Date... 11/15/2017 Next Review Date... 11/15/2018 Coverage Policy Number Table of Contents Coverage Policy... 1 General Background... 9 Coding/Billing Information References Related Coverage Resources Pharmacogenetic Testing INSTRUCTIONS FOR USE The following Coverage Policy applies to health benefit plans administered by Cigna companies. Coverage Policies are intended to provide guidance in interpreting certain standard Cigna benefit plans. 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. Proprietary information of Cigna. Copyright 2017 Cigna Coverage Policy Lysosomal Storage Disorder therapies include the following products: agalsidase beta (Fabrazyme ) alglucosidase alfa (Lumizyme ) asfotase alfa (Strensiq ) eliglustat (Cerdelga ) elosulfase alfa (Vimizim ) galsulfase (Naglazyme ) idursulfase (Elaprase ) imiglucerase (Cerezyme ) laronidase (Aldurazyme ) miglustat (Zavesca ) pegademase bovine (Adagen ) sebelipase alfa (Kanuma ) taliglucerase alfa (Elelyso ) velaglucerase alfa (VPRIV ) Cigna covers lysosomal storage disorders therapies as medically necessary when the following criteria are met: Product Criteria for Use Adagen All of the following are met: (pegademase bovine) Documented diagnosis of adenosine deaminase (ADA) deficiency (in hemolysates or in other cells if recent transfusion) Presence of severe combined immunodeficiency (SCID) Page 1 of 14

2 Aldurazyme (laronidase) Cerdelga (eliglustat) Cerezyme (imiglucerase) Elaprase (idursulfase) Elelyso (taliglucerase Fabrazyme (agalsidase beta) Kanuma (sebelipase Lumizyme (alglucosidase Criteria for Use Not a suitable candidate for or has failed bone marrow transplantation (BMT) Both of the following are met: Mucopolysaccharidosis I (MPS I) with diagnosis documented by either of the following: o Demonstrated deficiency of alpha-l-iduronidase (for example, in peripheral blood leukocytes, plasma, or cultured fibroblasts) o Genetic testing One of the following forms: o Hurler form o Hurler-Scheie form o Scheie form with moderate to severe symptoms Individual is an adult and meets both of the following: 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 Genetic testing One of the following: o CYP2D6 extensive metabolizer (EM) o CYP2D6 intermediate metabolizer (IM) o CYP2D6 poor metabolizer (PM) Cigna does NOT cover the use of eliglustat (Cerdelga) for any other indication because it is considered experimental, investigational or unproven. This includes but is NOT limited to the following: CYP2D6 ultra-rapid metabolizers CYP2D6 indeterminate metabolizers Concomitant use with Zavesca or other treatments approved for Gaucher disease Gaucher disease type 1 or type 3 (with systemic involvement) with diagnosis documented by either of the following: Deficiency of glucosylceramidase [also known as acid β-glucosidase or glucocerebrosidase] in peripheral blood leukocytes or other nucleated cells Hunter syndrome [Mucopolysaccharidosis II (MPS II)] with diagnosis documented by 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 Gaucher disease type 1 or type 3 (with systemic involvement) with diagnosis documented by either of the following: Deficiency of glucosylceramidase [also known as acid β-glucosidase or glucocerebrosidase] in peripheral blood leukocytes or other nucleated cells Fabry disease with diagnosis documented by either of the following: Deficiency of alpha-galactosidase A in plasma or peripheral leukocytes Lysosomal Acid Lipase (LAL) Deficiency (Wolman disease, cholesteryl ester storage disease [CESD]) with diagnosis documented by either of the following: Deficiency of LAL in peripheral blood leukocytes, fibroblasts, or dried blood spots Pompe disease with diagnosis documented by either of the following: Deficiency of acid alpha-glucosidase in leukocytes or skin fibroblasts Page 2 of 14

3 Naglazyme (galsulfase) Strensiq (asfotase Vimizim (elosulfase VPRIV (velaglucerase Zavesca (miglustat) Criteria for Use Mucopolysaccharidosis VI (MPS VI, Maroteaux-4 Lamy syndrome) with diagnosis documented by either of the following: Deficiency of N-acetylgalactosamine 4-sulfatase [ARSB] in leukocytes, fibroblasts, and dried blood spots All of the following are met: 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 Mucopolysaccharidosis IVA (MPS IVA, Morquio A syndrome) with diagnosis documented by either of the following: Deficiency of N-acetylgalactosamine-6-sulphatase (GLANS) in cultured fibroblasts or leukocytes Gaucher disease type 1 or type 3 (with systemic involvement) with diagnosis documented by either of the following: Deficiency of glucosylceramidase [also known as acid β-glucosidase or glucocerebrosidase] in peripheral blood leukocytes or other nucleated cells Mild to moderate Gaucher disease type 1 in an adult and all of the following: Documented deficiency of glucosylceramidase (also known as acid β-glucosidase or glucocerebrosidase) in peripheral blood leukocytes or other nucleated cells or genetic testing Will be used as monotherapy Not a candidate for enzyme replacement therapy 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 Cigna does not cover the use of any Lysosomal Storage Disorders Therapy product for any other indication because it is considered experimental, investigational or unproven. 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 Lysosomal Storage Disorders therapy. Note: Receipt of sample product does not satisfy any criteria requirements for coverage FDA Approved Indications Product Adagen (pegademase bovine) FDA Approved Indication Adagen (pegademase bovine) Injection is indicated for enzyme replacement therapy for adenosine deaminase (ADA) deficiency in patients with severe combined immunodeficiency disease (SCID) who are not suitable candidates for or who have failed bone marrow transplantation. Adagen (pegademase bovine) Injection is recommended for use in infants from birth or in children of any age at the time of diagnosis. Adagen (pegademase bovine) Injection is not intended as a replacement for HLA identical bone marrow transplant therapy. Adagen (pegademase bovine) Injection is also not intended to replace continued close medical supervision and the initiation of Page 3 of 14

4 Aldurazyme (laronidase) Cerdelga (eliglustat) Cerezyme (imiglucerase) Elaprase (idursulfase) FDA Approved Indication appropriate diagnostic tests and therapy (e.g., antibiotics, nutrition, oxygen, gamma globulin) as indicated for intercurrent illnesses. Aldurazyme (laronidase) is indicated for patients with Hurler and Hurler-Scheie forms of 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 is indicated for the long-term treatment of adult patients with Gaucher disease type 1 (GD1) who are CYP2D6 extensive metabolizers (EMs), intermediate metabolizers (IMs), or poor metabolizers (PMs) as detected by an FDA-cleared test. 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)]. Cerezyme (imiglucerase for injection) is indicated for long-term enzyme replacement therapy for pediatric and adult patients with a confirmed diagnosis of Type 1 Gaucher disease that results in one or more of the following conditions: a. anemia b. thrombocytopenia c. bone disease d. hepatomegaly or splenomegaly Elaprase is indicated for patients with Hunter syndrome (Mucopolysaccharidosis II, MPS II). Elaprase has been shown to improve walking capacity in patients 5 years and older. 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. Elelyso (taliglucerase Fabrazyme (agalsidase beta) Kanuma (sebelipase Lumizyme (alglucosidase Naglazyme (galsulfase) Strensiq (asfotase Vimizim (elosulfase VPRIV (velaglucerase Zavesca 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)]. Elelyso is indicated for the treatment of patients with a confirmed diagnosis of Type 1 Gaucher disease. Fabrazyme (agalsidase beta) is indicated for use in patients with Fabry disease. Fabrazyme reduces globotriaosylceramide (GL-3) deposition in capillary endothelium of the kidney and certain other cell types. Kanuma is indicated for the treatment of patients with a diagnosis of Lysosomal Acid Lipase (LAL) deficiency. Lumizyme (alglucosidase is a hydrolytic lysosomal glycogen-specific enzyme indicated for patients with Pompe disease (acid α-glucosidase (GAA) deficiency). Naglazyme (galsulfase) is indicated for patients with Mucopolysaccharidosis VI (MPS VI, Maroteaux-Lamy syndrome). Naglazyme has been shown to improve walking and stair-climbing capacity. Strensiq is indicated for the treatment of patients with perinatal/infantile- and juvenile-onset hypophosphatasia (HPP). Vimizim (elosulfase is indicated for patients with Mucopolysaccharidosis type IVA (MPS IVA; Morquio A syndrome). VPRIV is indicated for long-term enzyme replacement therapy (ERT) for patients with type 1 Gaucher disease. Zavesca is a glucosylceramide synthase inhibitor indicated as monotherapy for the treatment of Page 4 of 14

5 (miglustat) FDA Approved Indication 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). FDA Recommended Dosing Product Adagen (pegademase bovine) Recommended Dosing Adagen (pegademase bovine) Injection is recommended for use in infants from birth or in children of any age at the time of diagnosis. Adagen (pegademase bovine) Injection should be administered every 7 days as an intramuscular injection. The dosage of Adagen (pegademase bovine) Injection should be individualized. The recommended dosing schedule is 10 U/kg for the first dose, 15 U/kg for the second dose, and 20 U/kg for the third dose. The usual maintenance dose is 20 U/kg per week. Further increases of 5 U/kg/week may be necessary, but a maximum single dose of 30 U/kg should not be exceeded. Plasma levels of ADA more than twice the upper limit of 35 μmol/hr/ml have occurred on occasion in several patients, and have been maintained for several weeks in one patient who received twice weekly injections (20 U/kg per dose) of Adagen (pegademase bovine) Injection. No adverse effects have been observed at these higher levels; there is no evidence that maintaining pre-injection plasma ADA above 35 μmol/hr/ml produces any additional clinical benefits. Dose proportionality has not been established and patients should be closely monitored when the dosage is increased. Adagen (pegademase bovine) Injection is not recommended for intravenous administration. Aldurazyme (laronidase) Cerdelga (eliglustat) The optimal dosage and schedule of administration should be established for each patient based on monitoring of plasma ADA activity levels (trough levels before maintenance injection) and biochemical markers of ADA deficiency (primarily red cell datp content). Since improvement in immune function follows correction of metabolic abnormalities, maintenance dosage in individual patients should be aimed at achieving the following biochemical goals: 1) maintain plasma ADA activity (trough levels before maintenance injection) in the range of μmol/hr/ml (assayed at 37 C); and 2) decline in erythrocyte datp to μmol/ml packed erythrocytes, or 1% of the total erythrocyte adenine nucleotide (ATP + datp) content, with a normal ATP level, as measured in a pre-injection sample. In addition, continued monitoring of immune function and clinical status is essential in any patient with a primary immunodeficiency disease and should be continued in patients undergoing treatment with Adagen (pegademase bovine) Injection. The recommended dosage regimen of Aldurazyme is 0.58 mg/kg of body weight 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)]. 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)]. Patient Selection 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 Page 5 of 14

6 Recommended Dosing 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)]. Cerezyme (imiglucerase) Elaprase (idursulfase) Elelyso (taliglucerase Fabrazyme (agalsidase beta) 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 Cerezyme (imiglucerase for injection) is administered by intravenous infusion over 1-2 hours. Dosage should be individualized to each patient. Initial dosages range from 2.5 U/kg of body weight 3 times a week to 60 U/kg once every 2 weeks. 60 U/kg every 2 weeks is the dosage for which the most data are available. Disease severity may dictate that treatment be initiated at a relatively high dose or relatively frequent administration. Dosage adjustments should be made on an individual basis and may increase or decrease, based on achievement of therapeutic goals as assessed by routine comprehensive evaluations of the patient s clinical manifestations. The recommended dosage regimen of Elaprase is 0.5 mg per kg of body weight administered once weekly as an intravenous infusion. Recommended Dosage in Patients 4 Years and Older Treatment-naïve patients: The recommended dosage of Elelyso for long-term treatment is 60 units/kg of body weight administered every other week as a 60 to 120 minute intravenous infusion. Patients switching from imiglucerase: Patients currently being treated with imiglucerase for Type 1 Gaucher disease can be switched to Elelyso. Patients previously treated on a stable dosage of imiglucerase are recommended to begin treatment with Elelyso at that same units/kg dosage when they switch from imiglucerase to Elelyso. Administer Elelyso for long-term treatment every other week as a 60 to 120 minute intravenous infusion. Dosage adjustments can be made based on achievement and maintenance of each patient's therapeutic goals [see Clinical Studies (14.2)]. The recommended dosage of Fabrazyme is 1 mg/kg body weight infused every two weeks 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). Kanuma (sebelipase 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 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. Patients with Rapidly Progressive LAL Deficiency Presenting within the First 6 Months of 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. Page 6 of 14

7 Lumizyme (alglucosidase Naglazyme (galsulfase) Recommended Dosing Pediatric and Adult Patients with LAL Deficiency: The recommended dosage is 1 mg/kg administered once every other week as an intravenous infusion. The recommended dosage of alglucosidase alfa is 20 mg/kg body weight administered every 2 weeks as an intravenous infusion. The recommended dosage regimen of Naglazyme is 1 mg per kg of body weight 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. Strensiq (asfotase 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. Dosage for Perinatal/Infantile-Onset HPP 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. Vimizim (elosulfase VPRIV (velaglucerase 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)]. The recommended dose is 2 mg per kg given intravenously over a minimum range of 3.5 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)]. Recommended Starting Dosage in Patients Naïve to Enzyme Replacement Therapy VPRIV should be administered under the supervision of a healthcare professional. The recommended starting VPRIV dosage in naïve adults and naïve pediatric patients 4 years of age and older is 60 Units/kg administered every other week as a 60-minute intravenous infusion. The dosage can be adjusted based on achievement and maintenance of each patient s therapeutic goals. Switching from Imiglucerase to VPRIV Adults and pediatric patients 4 years of age and older currently being treated on a stable dosage of imiglucerase for type 1 Gaucher disease may be switched to VPRIV by starting treatment with VPRIV at the previous imiglucerase dosage two weeks after the last imiglucerase dose. VPRIV should be administered under the supervision of a healthcare professional as a 60-minute Page 7 of 14

8 Zavesca (miglustat) Recommended Dosing intravenous infusion. The dosage can be adjusted based on achievement and maintenance of each patient s therapeutic goals. Premedication to Reduce Risk of Subsequent Hypersensitivity Reactions Consider pre-treatment with antihistamines and/or corticosteroids in patients who exhibited symptoms of hypersensitivity associated with prior VPRIV infusions. Appropriate medical support should be readily available when VPRIV is administered [see Warnings and Precautions (5.1)]. Therapy should be directed by physicians who are knowledgeable in the management of 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 Adagen Adagen is supplied in single-use vials containing 375 units per 1.5 ml solution (pegademase bovine) 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) Cerezyme Cerezyme is available in 200 Units per Vial or 400 Units per Vial. (imiglucerase) Elaprase Elaprase is supplied in single-use vials of 6 mg/3 ml (2 mg/ml). (idursulfase) Elelyso Elelyso is available in single-use vials of 200 Units per vial. (taliglucerase Fabrazyme Fabrazyme is supplied as single-use vials of 35 mg and 5 mg reconstituted to yield a concentration (agalsidase beta) of 5 mg/ml. Kanuma Kanuma is supplied as single-use vials of 20 mg/10 ml (2 mg/ml) solution. (sebelipase Lumizyme Lumizyme is supplied as single-use vials containing 50 mg of alglucosidase alfa reconstituted to a (alglucosidase resultant solution concentration of 5 mg/ml. Naglazyme Naglazyme is supplied as 5 ml vials (5 mg per 5 ml). (galsulfase) Strensiq Strensiq is supplied in single-use vials of solution in the following strengths: 18 mg/0.45 ml; 28 (asfotase 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 VPRIV (velaglucerase Zavesca (miglustat) VPRIV is available in single-use vials of 400 Units for reconstitution to yield a final concentration of 100 Units/mL. Zavesca is supplied in hard gelatin capsules containing 100 mg miglustat. Page 8 of 14

9 General Background Disease Overview 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 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 Page 9 of 14

10 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 o 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 [ARSB]) should also be evaluated to rule out multiple sulfatase deficiencies. Genetic testing is available for confirmation. (Wang, 2011) 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) 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. 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) Page 10 of 14

11 Pharmacology Product Pharmacology Adagen Pegademase is a modified enzyme of ADA attached to numerous strands of (pegademase monomethoxypolyethylene glycol (PEG), which permits prolonged circulation of ADA in the blood. bovine) The ADA enzyme is derived from bovine intestines. In the absence of ADA, purine substrates and their metabolites, adenosine and 2 deoxyadenosine, accumulate. These are toxic to lymphocytes, causing severe immunodeficiency. Replacing the ADA corrects the metabolic abnormality, leading to improved immune function, decreased frequency of opportunistic infections and fewer complications of infections. After treatment with pegademase, onset of metabolic deficiency correction and initial improvement in immune function is within 2 6 months. Improvement in overall clinical function is usually seen after the completion of one year of therapy. Aldurazyme (laronidase) Cerdelga (eliglustat) Cerezyme (imiglucerase) Elaprase (idursulfase) Elelyso (taliglucerase Fabrazyme (agalsidase beta) Kanuma (sebelipase Lumizyme (alglucosidase Naglazyme (galsulfase) Strensiq (asfotase The rationale of Aldurazyme therapy in MPS I is to provide exogenous enzyme for uptake 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. Cerdelga is a specific inhibitor of glucosylceramide synthase (IC50 = 10 ng/ml), and acts as a substrate reduction therapy for GD1. In clinical trials Cerdelga reduced spleen and liver size, and improved anemia and thrombocytopenia. Cerezyme (imiglucerase) for injection is an analogue of human enzyme β-glucocerebrosidase. It is produced by recombinant deoxyribonucleic acid (DNA) technology using mammalian cell culture (i.e., Chinese hamster ovary). Gaucher disease is characterized by a genetic lipid storage disorder, and patients with the disease have a functional enzyme deficiency of β- glucocerebrosidase activity that leads to the accumulation of glucocerebroside within macrophages in the liver, spleen, lymph nodes, and bone marrow. Cerezyme replaces the enzyme activity of β-glucocerebrosidase that catalyzes the hydrolysis of glucocerebroside to glucose and ceramide. Elaprase (idursulfase) replaces the enzyme iduronate-2-sulphatase (I2S), which 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. Elelyso (taliglucerase is a recombinant form of glucocerebrosidase and is produced by a novel, carrot-cell based process, which uses no animal tissues. Similar to other enzyme replacement therapies, taliglucerase alfa works as a catalyst for the hydrolysis of glucocerebroside to ceramide and glucose. Fabrazyme (agalsidase beta) reduces globotriasylceramide (GL-3) deposition in the 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. Sebelipase alfa replaces the deficient enzyme, lysosomal acid lipase, to restore lysosomal lipid metabolism. Lumizyme (alglucosidase replaces the deficient alpha-glucosidase enzyme and degrades glycogen in lysosomes. Naglazyme (galsulfase) provides an exogenous enzyme to increase the catabolism of dermatan sulfate. HPP is caused by a deficiency in TNSALP enzyme activity, which leads to elevations in 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. Page 11 of 14

12 Vimizim (elosulfase VPRIV (velaglucerase Zavesca (miglustat) Pharmacology Vimizim is intended to provide the exogenous enzyme N-acetylgalactosamine-6-sulfatase 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-phosphateterminated oligosaccharide chains of elosulfase alfa to mannose-6-phosphate receptors VPRIV (velaglucerase) is an analogue of the human enzyme glucocerebrosidase. Patients with Gaucher disease are deficient in this enzyme. Velaglucerase is given to replace this enzyme deficiency and aid with the breakdown of glycolipid glucocerebroside. Zavesca (miglustat) is a competitive and reversible inhibitor of the enzyme glucosylceramide synthase, the initial enzyme in a series of reactions which results in the 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. Guidelines 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. (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 multidisciplinary teams familiar with managing these disease states. (Wang, 2011) 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) Clinical Efficacy 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 Page 12 of 14

13 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 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 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 C9399 C9478 J0180 J0221 J1322 J1458 J1743 J1786 J1931 J2504 J3060 J3385 J8499 Description Unclassified drugs or biologicals Injection, sebelipase alfa, 1 mg Injection, agalsidase beta, 1 mg Injection, alglucosidase alfa (lumizyme), 10 mg Injection, elosulfase alfa, 1 mg Injection, galsulfase, 1 mg Injection, idursulfase, 1 mg Injection, imiglucerase, 10 units Injection, laronidase, 0.1 mg Injection, pegademase bovine, 25 IU Injection, taliglucerase alfa, 10 units Injection, velaglucerase alfa, 100 units 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 Alexion Pharmaceuticals Inc. Kanuma (sebelipase injection, for intravenous use [product information]. Cheshire, CT: Alexion Pharmaceuticals Inc. December Alexion Pharmaceuticals Inc. Strensiq (asfotase injection, for subcutaneous use [product information]. Cheshire CT: Alexion Pharmaceuticals Inc. October Algahim MF, Almassi GH. Current and emerging management options for patients with Morquio A syndrome. Ther Clin Risk Manag. 2013; 9: Page 13 of 14

14 5. Bennett LL, Mohan D. Gaucher disease and its treatment options. Ann Pharmacother. Sep 2013; 47 (9): BioMarin Pharmaceutical Inc. Naglazyme (galsulfase) injection for intravenous use [product information]. Novato, CA: BioMarin Pharmaceutical Inc. April BioMarin Pharmaceutical Inc. Vimizim (elosulfase injection, for intravenous use [product information]. Novato, CA: BioMarin Pharmaceutical Inc. February 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, noninteriority trial. Lancet 2015; 385: Crunkhorn S. Trial watch: enzyme replacement success in Phase III trial for rare metabolic disorder. Nat Rev Drug Discov. Jan 2013; 12 (1): 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): Genzyme Corporation. Aldurazyme (laronidase) [product information]. Cambridge, MA: Genzyme Corporation. April Genzyme Corporation. Cerezyme (imiglucerase for injection) [product information]. Cambridge, MA: Genzyme Corporation. December Genzyme Corporation. Fabrazyme (agalsidase beta) [product information]. Cambridge, MA: Genzyme Corporation. May Genzyme Corporation. Lumizyme (alglucosidase, for injection, for intravenous use [product information]. Cambridge, MA: Genzyme Corporation. August Genzyme Ireland, Ltd. Cerdelga (eliglustat) capsules, for oral use [product information]. Waterford, Ireland: Genzyme Ireland, Ltd. August Hoffman EP, Barr ML, Giovanni MA, et al. Lysosomal Acid Lipase Deficiency Jul 30 [Updated 2016 Sep 1]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; Mornet E, Nunes ME. Hypophosphatasia. In: Pagon RA, Adam MP, Ardinger HH, et al, editors. SourceGeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; Nov 20 [updated 2016 Feb 4]. 18. Pfizer Labs. Elelyso (taliglucerase for injection, for intravenous use [product information]. New York, NY: Pfizer Labs. December 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: Reiner Z, Guardamagna O, Nair D, et al. Lysosomal acid lipase deficiency an under-recognized cause of dyslipidaemia and liver dysfunction. Atherosclerosis 2014; 235: Shemesh E, Deroma L, Bembi B et al. Enzyme replacement and substrate reduction therapy for Gaucher disease (Review). Cochrane Database Syst Rev Mar 27; Shire Human Genetic Therapies, Inc. Elaprase (idursulfase) injection, for intravenous use [product information]. Lexington, MA: Shire Human Genetic Therapies, Inc. June Shire Human Genetic Therapies, Inc. VPRIV (velaglucerase alfa for injection), for intravenous use [product information]. Lexington, MA: Shire Human Genetic Therapies, Inc. April Sigma-Tau Pharmasource, Inc. Adagen (pegademase bovine) Injection [product information]. Indianapolis, IN: Sigma-Tau Pharmasource, Inc. June Vellodi A, Tylki-Szymanska A, Davies EH, et al. Management of neuronopathic Gaucher disease: Revised recommendations. J Inherit Metab Dis 2009; 32: Wang R, Bodamer O, Watson, et al. Lysosomal storage diseases: Diagnostic confirmation and management of presymptomatic individuals. Genet Med May; 13 (5): 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: 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): Yogalingam G. Aryplase (Biomarin). Curr Opin Investig Drugs. Oct 2004; 5 (10): The registered marks "Cigna" and the "Tree of Life" logo are owned by Cigna Intellectual Property, Inc., licensed for use by Cigna Corporation and its operating subsidiaries. All products and services are provided by or through such operating subsidiaries and not by Cigna Corporation. Such operating subsidiaries include Connecticut General Life Insurance Company, Cigna Health and Life Insurance Company, Cigna Behavioral Health, Inc., Cigna Health Management, Inc., and HMO or service company subsidiaries of Cigna Health Corporation. Page 14 of 14