Subject: Kanuma (sebelipase alfa) Original Effective Date: 11/21/2016 04/24 Policy Number: MCP-289 Revision Date(s):

Review Date(s): 12/15/2016; 9/19/2017, 9/13/2018 MCPC Approval Date: 9/13/2018

DISCLAIMER This Molina Clinical Policy (MCP) is intended to facilitate the Utilization Management process. It expresses Molina's determination as to whether certain services or supplies are medically necessary, experimental, investigational, or cosmetic for purposes of determining appropriateness of payment. The conclusion that a particular service or supply is medically necessary does not constitute a representation or warranty that this service or supply is covered (i.e., will be paid for by Molina) for a particular member. The member's benefit plan determines coverage. Each benefit plan defines which services are covered, which are excluded, and which are subject to dollar caps or other limits. Members and their providers will need to consult the member's benefit plan to determine if there are any exclusion(s) or other benefit limitations applicable to this service or supply. If there is a discrepancy between this policy and a member's plan of benefits, the benefits plan will govern. In addition, coverage may be mandated by applicable legal requirements of a State, the Federal government or CMS for Medicare and Medicaid members. CMS's Coverage Database can be found on the CMS website. The coverage directive(s) and criteria from an existing National Coverage Determination (NCD) or Local Coverage Determination (LCD) will supersede the contents of this MCP document and provide the directive for all Medicare members.

SUMMARY OF EVIDENCE/POSITION

This policy addresses the coverage of Kanuma (sebelipase alfa), a hydrolytic lysosomal cholesteryl ester and triacylglycerol-specific enzyme administered intravenously for the treatment of the rare disease lysosomal acid lipase deficiency (LAL-D), also known as Wolman disease (WD) and cholesteryl ester storage disease (CESD).

The intent of the drug policy is to ensure appropriate selection of patients for therapy based on product labeling, clinical guidelines, and clinical studies. Molina Healthcare reserves the right to update this Policy and revise coverage criteria to include or omit any off-label condition(s) as necessary based on medical literature and clinical studies that may become available.

 Kanuma (sebelipase alfa), an enzyme replacement therapy, is the first treatment approved by the Food and Drug Administration (FDA) that addresses the underlying cause of Lysosomal Acid Lipase Deficiency (LAL-D), a rare, serious, life-threatening lysosomal storage disease. Kanuma was granted orphan drug designation since it treatment of a rare disease affecting fewer than 200,000 patients in the United States.

 Sebelipase alfa is a hydrolytic lysosomal cholesteryl ester and triacylglycerol-specific enzyme. Sebelipase alfa binds to cell surface receptors via glycans expressed on the protein and is subsequently internalized into lysosomes. Sebelipase alfa catalyzes the lysosomal hydrolysis of cholesteryl esters and to free , glycerol, and free fatty acids. In patients with LAL deficiency, replacement with sebelipase alfa, a recombinant form of LAL, results in improvement in disease-related hepatic and lipid parameters.a

 Lysosomal Acid Lipase Deficiency (LAL-D) is an autosomal recessive lysosomal storage disorder caused by a genetic defect that leads to a marked decrease or loss in the activity of the LAL enzyme. 4,5,6 The deficiency leads to the accumulation of cholesteryl esters and triglycerides in multiple organs, including the liver, spleen, intestine, and walls of blood vessels. The accumulation of lipids leads to increased liver fat content and progression of liver disease, which includes fibrosis and cirrhosis. LAL-D is associated with significant morbidity including , cardiovascular disease, and liver damage. It may lead to liver failure and, in the most severe form, death. Lipid

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accumulation in the intestinal wall leads to malabsorption and growth failure. Sebelipase alfa binds to cell surface receptors via glycans and is then internalized into lysosomes. LAL-D is caused by mutations affecting the LIPA gene—resulting in a deficiency of LAL enzyme activity in the lysosomes. Manifesting frequently in childhood, LAL-D was historically referred to as 2 separate disorders.1 The

disease was previously known as Wolman’s disease in infants, and as cholesteryl ester storage disease in children and adults. However, it is now known that these conditions are both manifestations of the same disease13 and both presentations have come to be known as LAL-D. Wolman disease (WD) is an early onset form of LAL-D that is seen in infants and cholesteryl ester storage disease (CESD) another form of LAL-D with a later onset, seen in early childhood or later in life.

 WD: Wolman disease often presents during infancy (around 2 to 4 months of age) and is a rapidly progressive disease. Patients with Wolman disease rarely survive beyond the first year of life. A complete deficiency of the enzyme (estimated prevalence 1:500,000 live births) causes malabsorption, growth failure, , adrenal cortical insufficiency, and death within the first year of life.9,10

 CESD: CESD is a milder, later-onset form of LAL deficiency and presents in early childhood or later. Life expectancy of patients with CESD depends on the severity of the disease and associated complications. Partial LAL deficiency (estimated prevalence 1:40,000), which can present later in childhood or in adulthood, is associated with gastrointestinal symptoms, hepatosplenomegaly, elevated transaminase levels, and dyslipidemia, often progressing to hepatic fibrosis and cirrhosis and a need for liver transplantation. 9,10

 Sebelipase alfa is currently the only treatment option that addresses the underlying pathophysiology of the disease. Previous treatments focused on management of symptoms caused by the disease and included supportive options such as dietary modifications, use of lipid-lowering agents (e.g. HMG-CoA reductase inhibitors, cholestyramine) such as alone or in combination with other modalities and medications (e.g., ezetimibe)6,13 liver transplantation,13 and hematopoietic stem cell transplantation (HSCT).13 However, no well-controlled studies have proven that any of these treatments are safe or effective in patients with LAL-D13,14 and do not address the underlying cause of disease.  At present, there is limited information in the medical literature on the long-term outcomes of liver transplantation in patients with LAL-D. Liver transplantation itself also carries inherent significant risks, and requires concomitant immunosuppression. Furthermore, cells of hematopoietic lineage which will repopulate the transplanted liver will remain enzyme deficient in transplanted patients; hence, other disease complications may persist even if transplants are successful.

 Sebelipase alfa is administered intravenously as a 2-hour infusion every other week, or weekly for patients with rapidly progressive LAL-D presenting within the first 6 months of life.

 Sebelipase alfa appears to be a relatively safe and effective treatment for LAL deficiency. Treatment options for LAL­ D are limited, and the availability of this agent will be helpful in the management of this rare genetic disease. The evaluated studies suggest that sebelipase alfa therapy is associated with decreases in markers of the severity of LAL­ D, but findings have only been reported to 52 weeks. Although the number of patients exposed to sebelipase alfa in clinical trials was relatively low, the safety profile and efficacy analysis appear to be positive. Neutralizing antibodies to sebelipase alfa have developed and did not appear to compromise safety and efficacy; however findings over a longer duration of exposure are of interest. Therefore, a concern with this agent is the development of antidrug antibodies in some patients and the longer-term effect regarding the compromise of safety and efficacy. The effect of Kanuma on long‐term liver disease progression, potential reversal or stabilization of liver fibrosis, cardiovascular morbidity, and mortality has not been established.

CLASSIFICATION: Recombinant Enzyme Replacement Agents

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FDA INDICATIONS

 Lysosomal Acid Lipase Deficiency: Treatment of patients with lysosomal acid lipase deficiency (LAL-D).a

Available as: 20 mg per 10 mL (2 mg/mL) solution in single-use vials for intravenous infusion

FDA Approved: December 8, 2015 Sebelipase alfa was granted priority review by the FDA and received breakthrough therapy designation on December 8, 2015 as the first enzyme replacement therapy (ERT) for the treatment of patients of all ages with a diagnosis of LAL-D. Kanuma was also granted breakthrough therapy designation as it is the first and only treatment available for Wolman disease, the very severe infant form of the disease.

Black Box Warnings: None at the time of this writing

REMS: No REMS is required for sebelipase alfa at the time of this writing

RECOMMENDATIONS/COVERAGE CRITERIA

Kanuma (sebelipase alfa) may be authorized for members who meet ALL of the following criteria [ALL]

1. Prescriber specialty [ONE]

 Prescribed by, or in consultation with, a board-certified endocrinologist, clinical geneticist or specialist experienced in the treatment of inborn errors of metabolism. Submit consultation notes if applicable.

NOTE: Consultation notes must be submitted for initial request and for continuation of treatment requests at least ONCE annually.

2. Diagnosis/Indication [ALL]

 Clinical documented diagnosis of Lysosomal Acid Lipase Deficiency (LAL-D) (may include clinical notes from the member’s medical records including any applicable labs and/or tests, supporting the diagnosis): [ONE]

 Wolman Disease

 Cholesteryl Ester Storage Disease (CESD) AND elevated alanine aminotransferase (ALT) greater than or equal to 1.5 times the upper limit of normal (ULN) (based on the age- and gender-specific normal ranges)

 Diagnosis of LAL-D confirmed by ONE (1) of the following: [ONE]

 Documented decreased lysosomal acid lipase (LAL) activity relative enzyme activity in ONE (1) of the following: [ONE] o Dried Blood Spot (DBS) test o Leucocyte testing

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 Molecular genetic testing: Lysosomal acid lipase (LIPA) gene mutation detected [mutations in lipase A, LIPA gene; biallelic pathogenic variants in LIPA] 4,5  Due to similar clinical presentations, LAL-D is often misdiagnosed as familial defective apolipoprotein B (ApoB) deficiency, Wilson disease, non-alcoholic fatty liver disease/nonalcoholic steatohepatitis, metabolic syndrome, familial combined hyperlipidemia2heterozygous familial hypercholesterolemia (HeFH), familial combined hyperlipidemia (FCH), or polygenic hypercholesterolaemia.4,5,10  A diagnosis of LAL-D can be confirmed by identification of a LIPA mutation or a deficient LAL enzyme in peripheral blood leukocytes, fibroblasts, or dried blood spots. A biopsy and/or radiographic findings may help support a LAL-D diagnosis, however these are not considered diagnostic.

3. Age/Gender/Restrictions [ALL]

 1 month of age and older  The safety and effectiveness of sebelipase alfa has been evaluated in pediatric patients 1 month and older.a  Clinical trials did not include patients aged 65 years old and older.a,E

 Member’s current weight (rounded to the nearest kg)

4. Conventional Therapy/Concurrent Therapy/Other Requirements [ALL]

 No prior allergic response to Kanuma [applicable to new members to Molina Healthcare and who were (or have been) on previous therapy]  There are no formal recommendations for regular monitoring of patients receiving sebelipase alfa. However, due to the risk of hypersensitivity reactions such as anaphylaxis, patients should be monitored during and after every infusion; patients and caregivers should be informed of the signs and symptoms of anaphylaxis and hypersensitivity reactions and instructed to seek immediate medical care if signs or symptoms occur. Due to the potential for immunogenicity, patients who do not respond as anticipated to sebelipase alfa can be tested for neutralizing antibodies.a

 Baseline Assessments of ALL of the following: [ALL]

 Growth (IF APPLICABLE)  Following initiation of treatment with Kanuma 1 mg/kg once weekly, weight-for-age z-scores improved in 3 of 5 surviving patients with growth failure, and all 6 surviving patients demonstrated improvements in weight-for-age z-scores following dose escalation to 3 mg/kg once weekly.

 Lipid profile levels (ALT, AST, LDL-c, TG, non-HDL-c, HDL-c)  Common manifestations of LAL deficiency include elevations in serum transaminase levels, hepatomegaly, lipid accumulation within the hepatocytes, and dyslipidemia.  In children and adults, Kanuma provided reductions in ALT values and liver fat content compared to placebo. In pediatric and adult patients with LAL-D (ages included 4 to 58 years), Kanuma therapy resulted in larger reductions from baseline in ALT values and liver fat content, as measured by MRI, compared with placebo. Reduced ALT values were generally seen within 2 weeks. Treated patients also had significant improvements in lipid parameters, including LDL-C, HDL-C, non-HDL-C, and triglycerides, compared to placebo. Continued improvements in ALT, LDL-C, and HDL-C were seen in patients treated with sebelipase alfa for up to 36 weeks. (Balwani et al., 2013; Valayannopoulos et al., 2014; Burton et al., 2015).  With prolonged therapy, these changes are sustained; however, follow-up is limited to 52 weeks. The significance of these findings is unknown with respect to morbidity or mortality.

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 Organ volumes (liver or spleen volume) and hepatic fat content as measured by magnetic resonance imaging (MRI) scan. Prescriber submit MRI.  Organ volumes: There was a greater reduction in liver volume in patients receiving sebelipase alfa compared to those receiving placebo. Spleen volumes were also reduced in the sebelipase alfa arm compared to the placebo arm.2,3  It is reasonable to request for a baseline MRI scan to survey treatment progression of a lysosomal acid lipase deficiency (LAL-D) case. Such scans/liver imaging can be useful to determine if there is poor response to treatment as implied in the provided policy and to screen for hepatocellular carcinoma which can arise in settings of advanced cirrhosis. However, radiographic findings are not considered diagnostic of the disease. Furthermore, there is no standard set of guidelines developed for the surveillance of individuals with LAL-D.E

5. Contraindications*/Exclusions/Discontinuations *Food and Drug Administration (FDA)–approved labeling lists no contraindications to therapy with Kanuma (sebelipase alfa).a Authorization will not be granted if ANY of the following conditions apply [ANY]  Non-FDA approved indications  Hypersensitivity to Kanuma (sebelipase alfa) or any of its components  Allergy to egg or egg products (not an absolute contraindication; however consideration warranted)  Sebelipase alfa is produced in egg whites of genetically engineered chickens; it has not been studied in patients with a history of egg allergy. Consider the risks and benefits in patients with known systemic hypersensitivity reactions to eggs or egg products.a  Antibody formation (not an absolute contraindication; however consideration warranted)  Patients have developed anti-drug antibodies (ADA) to sebelipase alfa and may be more likely to experience hypersensitivity reactions. Some patients with neutralizing antibodies experienced decreased growth velocity. No clear association exists between the development of ADA and decreased efficacy in patients.a Exclusions  Previous hematopoietic stem cell or liver transplant7,8  Severe hepatic dysfunction (Child-Pugh Class C)2,3  Serological evidence of hepatitis B and/or hepatitis C virus infection1,E  Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) elevations greater than 3 times the upper limit of normal (ULN)1,E  Chronic liver disease attributed to a cause other than cholesteryl ester storage disease1,E  A score of 8 or higher on the Alcohol Use Disorders Identification Test screening tool1,E  Previous hematopoietic bone marrow or liver transplant1,E  Exposure to an investigational therapy for another indication within the previous 30 days1,E  Any potential or identification of a compliance issue1,E

6. Labs/Reports/Documentation required [ALL] All documentation for determination of medical necessity must be submitted for review. Prescriber to submit documentation as indicated in the criteria above, including but not limited to chart notes, applicable lab values and/or tests, adverse outcomes, treatment failures, or any other additional clinical information or clinical notes from the member’s medical records supporting the diagnosis. Letters of support and/or explanation are often useful, but are not sufficient documentation unless ALL specific information required by this MCP is included. NOTE: Additional documentation, rationale, and/or supporting evidence may be requested for review as deemed necessary or appropriate by Molina Medical/Pharmacy staff.

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CONTINUATION OF THERAPY

Kanuma (sebelipase alfa) may be authorized for continuation of therapy if meet ALL of the following criteria are met: [ALL]

1. Initial Coverage Criteria [ALL]

 Member currently meets ALL initial coverage criteria

 Consultation notes (if applicable) must for continuation of treatment requests at least ONCE annually

2. Compliance

N/A

3. Labs/Reports/Documentation required [ALL APPLICABLE] Kanuma (sebelipase alfa) may be reauthorized with documentation that the markers of the disease are improved by therapy as compared to baseline.

 Wolman disease: Survival7,8 OR other clinically significant improvement in symptoms and/or lab values has been achieved or sustained from baseline  The primary efficacy endpoint was the percentage of subjects (%) in the Primary Efficacy Analysis Set (PES) who survived to at least 12 months of age.7,8

 CESD: Evidence of treatment efficacy/clinical benefit as documented by ONE (1) or more of the following, including but not limited to: [ALL APPLICABLE]

 Weight-for-age z-scores (IF APPLICABLE): Improvements in weight-for-age z-scores  Following initiation of treatment with Kanuma 1 mg/kg once weekly, weight-for-age z-scores improved in 3 of 5 surviving patients with growth failure, and all 6 surviving patients demonstrated improvements in weight-for-age z-scores following dose escalation to 3 mg/kg once weekly. 7,8 Available at: http://www.who.int/childgrowth/standards/weight_for_age/en/

 Lipid profile levels (ALT, AST, LDL-c, TG, non-HDL-c, HDL-c):2,3 Improvement in lipid profile levels†  Common manifestations of LAL-D include elevations in serum transaminase levels, hepatomegaly, lipid accumulation within the hepatocytes, and dyslipidemia.  † In children and adults, Kanuma provided reductions in ALT values and liver fat content compared to placebo. Study findings suggest that sebelipase alfa therapy is associated with statistically significant decreases in transaminases, total cholesterol, non-HDL cholesterol, LDL, triglycerides, ferritin, liver volume, and hepatic fat content; and is associated with increases in HDL (Balwani et al., 2013; Valayannopoulos et al., 2014; Burton et al., 2015). With prolonged therapy, these changes are sustained; however, follow-up is limited to 52 weeks. The significance of these findings is unknown with respect to morbidity or mortality.

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 Organ volumes (liver or spleen volume) and hepatic fat content (reduction in hepatic fat content): Improvement (reduction in liver/spleen volume) as compared to baseline MRI. Prescriber submit MRI at 20 weeks and annually thereafter.  Organ volumes: There was a greater reduction in liver volume in patients receiving sebelipase alfa compared to those receiving placebo. Spleen volumes were also reduced in the sebelipase alfa arm compared to the placebo arm.  Reduction in steatosis. Multi- and gradient-echo MRI showed a significant reduction in hepatic fat content in patients receiving sebelipase alfa compared to those receiving placebo. Reductions in steatosis occurred more frequently in the sebelipase alfa group compared to the placebo group.

MOLINA CLINICAL REVIEWER: Baseline levels of growth (if applicable), lipid levels (ALT, AST, LDL-c, TG, non-HDL-c, HDL-c), organ volumes (Liver or spleen volume) and hepatic fat content in member’s profile as submitted on review of ‘Initial Therapy’ request.

NOTES: In children and adults, Kanuma provided reductions in ALT values and liver fat content compared to placebo. Study findings suggest that sebelipase alfa therapy is associated with statistically significant decreases in transaminases, total cholesterol, non-HDL cholesterol, LDL, triglycerides, ferritin, liver volume, and hepatic fat content; and is associated with increases in HDL (Balwani et al., 2013; Valayannopoulos et al., 2014; Burton et al., 2015). With prolonged therapy, these changes are sustained; however, follow-up is limited to 52 weeks. The significance of these findings is unknown with respect to morbidity or mortality.

4. Discontinuation of Treatment [ANY] Discontinue treatment if ANY of the following conditions applies: [ANY]  Intolerable adverse effects or drug toxicity (e.g., , vomiting, fever, rhinitis, anemia, cough, nasopharyngitis, urticaria, headache, oropharyngeal pain, asthenia, constipation, nausea)  Persistent and uncorrectable problems with adherence to treatment  Poor response to treatment as evidenced by physical findings and/or clinical symptoms

Contraindications/Exclusions to therapy [ANY] *FDA–approved labeling lists no contraindications to therapy with Kanuma (sebelipase alfa)a Authorization will not be granted if ANY of the following conditions apply [ANY]  Non-FDA approved indications  Hypersensitivity to Kanuma (sebelipase alfa) or any of its components  Allergy to egg or egg products (not an absolute contraindication; however consideration warranted)  Sebelipase alfa is produced in egg whites of genetically engineered chickens; it has not been studied in patients with a history of egg allergy. Consider the risks and benefits in patients with known systemic hypersensitivity reactions to eggs or egg products.a  Antibody formation (not an absolute contraindication; however consideration warranted)  Patients have developed anti-drug antibodies (ADA) to sebelipase alfa and may be more likely to experience hypersensitivity reactions. Some patients with neutralizing antibodies experienced decreased growth velocity. No clear association exists between the development of ADA and decreased efficacy in patients.a Exclusions  Previous hematopoietic stem cell or liver transplant7,8  Severe hepatic dysfunction (Child-Pugh Class C)2,3  Serological evidence of hepatitis B and/or hepatitis C virus infection1,E  Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) elevations greater than 3 times the upper limit of normal (ULN)1,E  Chronic liver disease attributed to a cause other than cholesteryl ester storage disease1,E  A score of 8 or higher on the Alcohol Use Disorders Identification Test screening tool1,E

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 Previous hematopoietic bone marrow or liver transplant1,E  Exposure to an investigational therapy for another indication within the previous 30 days1,E  Any potential or identification of a compliance issue1,E

ADMINISTRATION, QUANTITY LIMITATIONS, AND AUTHORIZATION PERIOD

1. Recommended Dosage [AS APPLICABLE]

 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: [AS APPLICABLE]

 1 to 12 months (initial dosage): 1 mg/kg once weekly as an IV infusiona

 Dosage adjustment: If response not optimal, may increase to 3 mg/kg once weeklya

 Pediatric and Adult Patients with LAL Deficiency: 1 mg/kg once every other week as an intravenous infusion

NOTE: To determine the number of vials needed based on patient weight and the recommended dose of 1 mg/kg or 3 mg/kg:  Total dose (mg) = Patient’s weight (kg) × recommended dose (mg/kg)  Total number of vials = Total dose (mg) divided by 20 mg/vial  Round up to the next whole vial number

2. Authorization Limit [ALL]

 Quantity limit: [ONE]  Infants 1-6 months of age: 3mg/kg weekly  4 years of age and older: 1mg/kg every other week

NOTE: Member’s current weight must be provided at time of request

 Duration of initial authorization: 3 months

 Continuation of treatment: Re-authorization for continuation of treatment is required every 6 months to determine continued need based on documented positive clinical response

3. Route of Administration [ALL]

 Kanuma (sebelipase alfa) is considered a provider-administered medication IV infusion only in a physician's office, at the member's home or at an infusion center (not affiliated with a hospital).  There are no formal recommendations for regular monitoring of patients receiving sebelipase alfa. However, due to the risk of hypersensitivity reactions such as anaphylaxis, patients should be monitored during and after every infusion;patients and caregivers should be informed of the signs and symptoms of anaphylaxis and hypersensitivity reactions and instructed to seek immediate medical care if signs or symptoms occur. Due to the potential for immunogenicity, patients who do not respond as anticipated to sebelipase alfa can be tested for neutralizing antibodies.a

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COVERAGE EXCLUSIONS

This policy addresses Kanuma (sebelipase alfa) for the treatment of the rare disease lysosomal acid lipase deficiency (LAL-D), also known as Wolman disease (WD) and cholesteryl ester storage disease (CESD) when appropriate criteria are met. All other uses of Kanuma (sebelipase alfa) that are not an FDA-approved indication or not included in the ‘Coverage Criteria’ section of this policy are considered experimental/investigational or not a covered benefit of this policy. This subject to change based on research and medical literature, or at the discretion of Molina Healthcare.

*Pharmaceutical samples: The use of pharmaceutical samples (from the prescriber or manufacturer assistance program) will not be considered when evaluating the medical condition, prior prescription history, or as continuation of therapy.

SUMMARY OF EVIDENCE/POSITION

PIVOTAL TRIALS The FDA approval for Kanuma was based on the results obtained from two phase III clinical trials. The efficacy of Kanuma is based on data from 75 patients (including infant, pediatric, and adult patients) with Lysosomal Acid Lipase Deficiency (LAL-D) who were treated with Kanuma in two clinical studies and one supporting open-label extension study.1  Adults and children with lysosomal acid lipase deficiency (ARISE trial; N=66) achieved normalization of ALT and AST and other parameters with sebelipase alfa compared with placebo (Burton et al., 2015)  In infants with evidence of rapidly progressive disease prior to 6 months of age, survival occurred in 6 of 9 sebelipase alfa-treated patients compared with 0 of 21 untreated historical cohort patients.a,7,8

SurVival of Lysosomal Acid Lipase Deficiency (LAL-D) Infants Treated With SebelipAse aLfa (VITAL)7,8 Jones SA, et al, 2015 (LAL-CL03 trial)

Effect of sebelipase alfa on survival and liver function in infants with rapidly progressive lysosomal acid lipase deficiency

A multicenter, open-label, single-arm clinical study on the efficacy of sebelipase alfa (Kanuma) was conducted in 9 infants with LAL-D who had growth failure or other rapidly progressive disease prior to 6 months of age.

 9 children (5 boys and 4 girls) younger than 24 months of age with documented cases of LAL activity below the normal range of the laboratory performing the test, or with at least 2 mutations determined via genetic testing. Children were required to have growth failure, with onset before 6 months of age. Key exclusion criteria included clinically important concurrent disease, known hypersensitivity to eggs, previous hematopoietic stem cell or liver transplantation, or preparation for a transplant.

 Sebelipase alfa 0.35 mg/kg once weekly was administered for the first 2 weeks, followed by 1 mg/kg once weekly thereafter. In 6 patients, the dose was increased to 3 mg/kg/week between weeks 4 and 88 due to suboptimal response. In 1 patient, the dose was increased to 5 mg/kg/week at week 88 due to the presence of medication-neutralizing antibodies and a decreased velocity of growth.

 Efficacy was assessed by comparing the survival of infants treated with sebelipase alfa (Kanuma) to 21 historical cohort infants with a similar age at disease presentation and clinical characteristics who were not treated with sebelipase alfa. Of the 9 Kanuma-treated infants, 6 patients survived beyond 12 months of age, compared to 0 of 21 patients in the historical cohort, all of whom died by 8 months of age. The median age of the 6 surviving Kanuma­ treated patients was 18.1 months (range 12 to 42.2 months). Following initiation of treatment with Kanuma 1 mg/kg once weekly, weight-for-age z-scores improved in 3 of 5 surviving patients with growth failure, and all 6 surviving patients demonstrated improvements in weight-for-age z-scores following dose escalation to 3 mg/kg once weekly.

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 Primary End Point(s): The primary efficacy endpoint was the percentage of subjects (%) in the Primary Efficacy Analysis Set (PES) who survived to at least 12 months of age. Result: Survival at 12 months of age. 6 of the 9 patients met the primary end point and were still alive at 12 months of age. The 3 subjects who died had received 4 or fewer doses of medication, and the causes of death were deemed

unrelated to study medication.

 Summary:  In the trial in infants with Wolman disease, six of nine infants (67 percent) treated with Kanuma were alive at 12 months of age, whereas none of the 21 infants in the historical control group survived. In the trial in CESD patients, there was a statistically significant improvement in LDL-cholesterol levels and other disease-related parameters in those treated with Kanuma versus placebo after 20 weeks of treatment.  The results suggest that sebelipase alfa is associated with mostly mild AEs, including nausea, headache, and diarrhea. During the extension study, mild AEs included headache, cold, sore throat, abdominal pain/cramping, nausea, diarrhea, and back pain. In addition, during the dose-escalation study, decreases in transaminases, triglycerides, and total cholesterol; increases in HDL; and no antidrug antibodies were observed. Study limitations include small sample size, lack of a control group, exclusion of children, lack of long-term follow-up, and lack of histologic confirmation with liver biopsies.A  All deaths were deemed unrelated to the study medication. One adverse event consisting of malaise with tachycardia and fever during infusion was thought to be caused by sebelipase alfa. Other adverse events were minor and consisted of fever, diarrhea, or vomiting.

A Multicenter Study of SBC-102 (Sebelipase Alfa) in Patients with Lysosomal Acid Lipase Deficiency/ARISE (Acid Lipase Replacement Investigating Safety and Efficacy)2,3 Sebelipase alfa vs Placebo

The ARISE study, a double-blind RCT, compared sebelipase alfa with placebo in patients with LAL-D (Burton et al., 2015).2 The results suggest that, compared with placebo, sebelipase alfa was associated with decreases in transaminases, triglycerides, and total cholesterol, and increases in HDL. Study limitations noted were the small sample size, lack of histologic confirmation with liver biopsies, and lack of long-term follow-up.A

 Patients: 66 patients at least 4 years or older with a confirmed enzyme activity–based diagnosis of LAL deficiency and ALT level at least 1.5 times the ULN. Patients taking lipid-lowering medications had to have been on a stable dose for at least 6 weeks before screening and were required to continue taking the same stable dose throughout the study. Patients who had undergone transplantation or had severe hepatic dysfunction were excluded.  Inclusion: male and female patients aged ≥4 years if they had confirmed enzyme activity-based diagnosis of LAL-D using the dried-blood spot assay. Patients were also required to have an alanine aminotransferase (ALT) ≥ 1.5 times the upper limit of normal (ULN); and any patients using lipid-lowering medications were required to use them at a stable dose for at least 6 weeks before screening, and to continue on this dose during the study.  Exclusion: Patients who had undergone transplantation or had severe hepatic dysfunction were excluded.

 Patients were randomized to placebo versus 1 mg/kg of sebelipase alfa every other week for 20 weeks (11 infusions). The trial included a screening period, a 20-week double-blind period, and an open-label extension period that was ongoing at the time of this publication. Patients were stratified by age (< 12 versus ≥ 12 years of age), ALT level (< 3 versus ≥ 3 times ULN), and use or non-use of lipid-lowering medications at baseline. Liver volume was assessed with magnetic resonance imaging (MRI) in units of multiples of normal (MN). Secondary endpoints were tested statistically in a hierarchical fashion.

Following the double-blind portion of the trial, there was an open-label extension period during which all patients received IV infusions of sebelipase alfa.

 Primary outcome measure

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 Normalization of ALT level: More patients in the sebelipase alfa group (31%) experienced ALT normalization than with placebo (7%; P = 0.03); the number needed to treat (NNT) was 4.2. The mean reduction from baseline in ALT level was −58 units/L in the sebelipase arm compared to −7 units/L in the

placebo arm (P < 0.001). Additional analysis using the recently applied criteria in studies of non-alcoholic fatty liver disease showed a response rate of 67% in the sebelipase alfa arm compared to a 7% response rate with placebo.

 Results (sebelipase alfa group versus placebo group)2,3  Aspartate aminotransferase (AST) levels: Normalization of AST. More patients in the sebelipase arm (42%) experienced normalized AST levels than with placebo (3%; P < 0.001); the NNT was 2.6.  Levels of other biochemical markers of liver function: Normalization of gamma-glutamyltransferase occurred in 62% of those randomized to sebelipase alfa compared to 8% administered placebo.  Serum lipid levels: Greater mean reductions in LDL-C, non–HDL-C, and triglycerides from baseline occurred in patients receiving sebelipase alfa compared with those receiving placebo, while there was a greater increase in HDL-C. Reductions in LDL-C occurred in all patients randomized to sebelipase alfa regardless of baseline status and use of concurrent lipid-lowering medication.  Hepatic fat content: Reduction in steatosis. Multi- and gradient-echo MRI showed a significant reduction in hepatic fat content in patients receiving sebelipase alfa compared to those receiving placebo. Reductions in steatosis occurred more frequently in the sebelipase alfa group compared to the placebo group.  Organ volumes: There was a greater reduction in liver volume in patients receiving sebelipase alfa compared to those receiving placebo. Spleen volumes were also reduced in the sebelipase alfa arm compared to the placebo arm (P < 0.001).  Apolipoprotein AI levels: Apolipoprotein AI levels were increased in the sebelipase alfa group compared to placebo.  Apolipoprotein B levels: Apolipoprotein B levels were decreased in the sebelipase alfa arm.

 Adverse Events9  Diarrhea, vomiting, fever, and rhinitis occurred in ≥50% of infants treated with sebelipase alfa. In clinical trials, symptoms consistent with anaphylaxis occurred in 3 of 106 patients treated with the drug; hypersensitivity reactions occurred in 21 of 106 patients, including 9 of 14 infants. Neutralizing antibodies to sebelipase alfa have developed; whether they reduce the efficacy of the drug is unknown. Sebelipase alfa is prepared from eggs produced by genetically engineered chickens; it has not been studied in patients with a history of egg allergy.  Most common AEs (sebelipase alfa group versus placebo group): Headache (28% versus 20%); pyrexia (19% versus 20%); diarrhea (17% versus 17%); oropharyngeal pain (17% versus 3%); upper respiratory tract infection (17% versus 20%); epistaxis (11% versus 20%); nasopharyngitis (11% versus 10%); AEs related to the study drug (14% versus 20%); infusion-associated reactions (6% versus 13%).  Serious adverse events (SAEs) in the active treatment group included infusion-associated reaction and gastritis. One SAE related to the study drug occurred in the treatment group (infusion-associated reaction).

Summary In a double-blind trial, 66 patients ≥ 4 years old with LAL deficiency were randomized to receive sebelipase alfa (1 mg/kg IV every other week) or placebo for 20 weeks.2 The alanine aminotransferase (ALT) level, the primary endpoint, was normal at 20 weeks in 11 of 36 (31%) patients who received sebelipase alfa and in 2 of 30 (7%) who received placebo. The mean reduction from baseline in ALT levels was 58 U/L with sebelipase alfa and 7 U/L with placebo. Both of these differences were statistically significant. Lipid levels improved and reductions in hepatic fat content were reported in patients receiving the drug. In an open-label extension of the trial, further reductions in LDL and non-HDL cholesterol were reported with sebelipase alfa.

The study was stratified according to patient age (younger than 12 years and 12 years and older), ALT level (less than 3 times the ULN and 3 times the ULN and above), and use or non-use of lipid-lowering agents. The analysis included all randomized patients who received at least 1 dose of study medication, which were all 66 subjects. A positive correlation was noted between decreases in LDL-C and in ALT in patients randomized to sebelipase alfa. Infusion-associated

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reactions were uncommon and while 5 patients had positive antidrug antibody tests during the study period, no effect on safety or efficacy variables was observed. The efficacy of sebelipase alfa was further confirmed during the open-label extension period, with further reductions in LDL-C and non–HDL-C; in patients randomized to placebo in the double- blind period, reductions in ALT and LDL-C were also observed following a switch to sebelipase alfa in the extension period.

Non-randomized, open-label, phase 1/2, multicenter, multinational, dose-escalation study (LAL-CL01) and extension study (LAL-CL04) Drug: Sebelipase alfa Balwani M, et al, 2013 (LAL-CL01 and LAL-CL04 trials)

Patients: 9 patients between 18 and 65 years of age with deficient LAL enzyme activity confirmed by a central laboratory.  Inclusion criteria: All patients were required to have hepatomegaly on physical exam or elevated transaminases 1.5 to 3 times the upper limit of normal (ULN), confirmed via clinical laboratory testing. Patients receiving statins or ezetimibe were eligible provided the doses had been stable for at least 4 weeks prior to screening. Female patients of childbearing potential were required to use a medically acceptable form of contraception.  Exclusion criteria: Severe hepatic dysfunction (Child-Pugh class C), AST and/or ALT elevations greater than 3 times the ULN, chronic liver disease attributed to a cause other than cholesteryl ester storage disease, serological evidence of hepatitis B and/or hepatitis C virus infection, a score of 8 or higher on the Alcohol Use Disorders Identification Test screening tool, previous hematopoietic bone marrow or liver transplant, hypersensitivity to eggs, or exposure to an investigational therapy for another indication within the previous 30 days. The 9 patients meeting eligibility were sequentially enrolled in 1 of 3 dosing groups. All 9 patients received 4 weekly infusions of sebelipase alfa; 7 of the patients continued with the extension trial (LAL-CL04).

Patients were treated using a sequential dose cohort strategy. Cohort 1 was treated with 0.35 mg/kg, cohort 2 was treated with 1 mg/kg, and cohort 3 was treated with 3 mg/kg; all doses were administered via once-weekly intravenous (IV) infusions of sebelipase alfa on days 0, 7, 14, and 21. Dose escalations to 1 mg/kg in cohort 1 and to 3 mg/kg in cohort 2 were based on review of safety data by an independent safety committee. Patients on stable doses of lipid-lowering medications remained on their stable prestudy dosage. After completion of the initial study (LAL-CL01), all patients were eligible to enter an extension trial (LAL-CL04) to evaluate the long-term safety and efficacy of sebelipase alfa. During the extension trial, patients resumed treatment with 4 once-weekly infusions of sebelipase alfa 0.35, 1, or 3 mg/kg before transitioning to once-every-other-week infusions of 1 or 3 mg/kg; patients receiving 0.35 mg/kg injections were increased to 1 mg/kg, while those receiving 1 or 3 mg/kg remained on their respective dosages.

Results: End Point(s)  Liver transaminases: After initiation with sebelipase alfa, ALT and AST levels decreased rapidly in 8 of the 9 treated patients, regardless of whether their baseline levels were within or above the normal range. No obvious differences in response were seen among the different dosage cohorts. Reductions were apparent within 2 weeks of the first infusion, and levels continued to decrease through day 28; improvements were evident for up to 2 weeks after the last dose, but had partially reversed 3 weeks later. By day 28, roughly 1 week after the fourth infusion, transaminases had normalized in all 6 patients with abnormal baseline ALT and in 4 of the 6 patients with abnormal AST. Treatment was associated with decreases in AST and ALT from baseline through day 28 (P < 0.05). The mean decrease in ALT was 39 units/L, equating to a 41% reduction, and the mean decrease in AST was 18 units/L, which equated to a 32% decrease.  Serum lipids: Total cholesterol, triglycerides, and low-density lipoprotein cholesterol (LDL-C) increased in most subjects between the first infusion and day 28. Total cholesterol increased by an average of 140 mg/dL (70%), triglycerides increased by 82 mg/dL (69%), and LDL-C increased by 113 mg/dL (87%); the increase in lipid parameters was similar in the 0.35 and 1 mg/kg dosage groups, but more pronounced in the 3 mg/kg group.

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Summary: No serious adverse events occurred during the study period, and there was no need for premedication with antipyretics or antihistamines, or modifications to the infusion rate of sebelipase alfa. No anti-sebelipase alfa antibodies were found during testing. There was no evidence of a dose effect on reductions in AST and/or ALT or in the maintenance of the effect after the medication had been discontinued. The article describes limited data through week 12 of the LAL- CL04 extension trial; complete data for the LAL-CL04 trial are described in the following reference section.1

Limitations: There was no comparator group in this small, non-randomized study.

HAYES At the time of this writing, a Health Technology Brief ‘Sebelipase Alfa (Kanuma) for Treatment of Lysosomal Acid Lipase Deficiency’ is available and published on May 26, 2016.A

A rating of “C” has been assigned for the use of sebelipase alfa for lysosomal acid lipase deficiency (LAL-D).  This Hayes Rating indicates a low-quality body of evidence indicating that sebelipase alfa favorably affects markers of disease activity in patients with lysosomal acid lipase deficiency.  Sebelipase alfa is currently the only FDA-approved treatment for LAL-D, a rare disorder that is associated with significant morbidity and mortality. Follow-up from these studies were limited to 1 year and the effect of sebelipase alfa on survival and quality of life have not been studied.  Significant uncertainty about safety remains due to the lack of long-term studies and the appearance of neutralizing antibodies to sebelipase alfa and whether these antibodies reduce the efficacy of the drug.

PRACTICE GUIDELINES/PROFESSIONAL SOCIETIES

There is no standard set of guidelines developed for the surveillance of individuals with lysosomal acid lipase deficiency (LAL-D).5,E

National Institute for Health and Care Excellence (NICE)D NICE offered preliminary recommendations in an evaluation consultation document regarding sebelipase alfa; NICE noted that this document is not a final practice guideline and is currently undergoing consultation and revision (NICE, 2016).  Sebelipase alfa is not recommended for treating LAL-D in patients who present with rapidly progressive LAL-D before 6 months of age, except as part of a clinical trial.

 Sebelipase alfa is not recommended for children and adults who do not present with rapidly progressive LAL-D before 6 months of age due to high cost and uncertain long-term benefits.

 Research should be designed to provide evidence about benefits of long-term treatment with sebelipase alfa compared with shorter-term treatment followed by HSCT with curative intent.

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DEFINITIONS

Serum alanine aminotransferase (ALT) is a valid laboratory parameter for evaluation and follow-up of liver diseases and hepatocellular damage. The upper limit of the normal range (ULN) varies in different laboratories according to the commercial kit used and the reference population chosen by each manufacturer to establish the normal range.

Z-score: in a standard normal distribution, the z-score represents the number of standard deviations away from the population mean. In other words, it indicates the degree to which an individual’s measurement deviates from what is expected for that individual.

Z-score (or SD-score) = (observed value - median value of the reference population) / standard deviation value of reference population

Available at: http://www.who.int/childgrowth/standards/weight_for_age/en/

APPENDIX

N/A

CODING INFORMATION: THE CODES LISTED IN THIS CLINICAL POLICY ARE FOR INFORMATIONAL PURPOSES ONLY. LISTING OF A SERVICE OR DEVICE CODE IN THIS POLICY DOES NOT IMPLY THAT THE SERVICE DESCRIBED BY THIS CODE IS A COVERED OR NON­ COVERED. COVERAGE IS DETERMINED BY THE BENEFIT DOCUMENT. THIS LIST OF CODES MAY NOT BE ALL INCLUSIVE AND INCLUSION OR EXCLUSION OF ANY CODES DOES NOT GUARANTEE COVERAGE. PROVIDERS SHOULD REFERENCE THE MOST UP-TO-DATE SOURCES OF PROFESSIONAL CODING GUIDANCE PRIOR TO THE SUBMISSION OF CLAIMS FOR REIMBURSEMENT OF COVERED SERVICES. CPT Description NA

HCPCS Description C9478 Injection, sebelipase alfa, 1mg J3590 Unclassified biologics J3490 Unclassified drugs [when specified as sebelipase alfa, KANUMA]

REFERENCES

Package Insert, FDA, Drug Compendia a. Kanuma (sebelipase alfa) [prescribing information]. Cheshire, CT: Alexion Pharmaceuticals; December 2015.Available at: http://www.kanuma.com/docs/full-prescribing-information.pdf. Accessed November 2016. b. U.S. Food and Drug Administration. (2015, December). Center for Drug Evaluation and Research. Kanuma (sebelipase alfa). Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125561s000lbl.pdf. Accessed on November 2016. c. Drug Facts and Comparisons. Facts and Comparisons eAnswers [online]. Kanuma (sebelipase alfa). Clinical Drug Information LLC, 2016. Available from Wolters Kluwer Health, Inc. [via subscription only] a. Clinical Pharmacology [database online]. Kanuma (sebelipase alfa). Tampa, FL: Gold Standard, Inc.; 2016. URL: http://www.clinicalpharmacology.com. [via subscription only] Accessed November 2016. b. American Hospital Formulary Service (AHFS). Drug Information 2016. [STAT!Ref Web site]. Sebelipase alfa (systemic). Available at: http://online.statref.com. [via subscription only]. Accessed on November 2016. c. Micromedex Healthcare Series [Internet database]. DRUGDEX Evaluations. Sebelipase alfa (Kanuma). Greenwood Village, CO: Thomson Micromedex. [via subscription only]. Available at: http://www.micromedexsolutions.com/micromedex2/librarian. Accessed November 2016. d. Clinical Pharmacology [Internet]. Sebelipase alfa. Available from: http://www.clinicalpharmacology.com/ [via subscription only]. Accessed on November 2016.

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e. Sebelipase alfa Monograph. Lexicomp Online, American Hospital Formulary Services (AHFS) Online, Hudson, Ohio, Lexi-Comp., Inc. [via subscription only] Accessed on November 2016. f. FDA approves first drug to treat a rare enzyme disorder in pediatric and adult patients. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm476013.htm. Accessed November 2016. g. LAL Deficiency Registry. Available at: https://www.laldeficiencyregistry.com/PhysicianLandingPage.aspx. Accessed November 2016. h. National Organization for Rare Diseases. Available at: https://rarediseases.org/for-patients-and-families/information­ resources/rare-disease-information/. Accessed on November 2016. i. Alexion Pharmaceuticals. Trial in children with growth failure due to early onset lysosomal acid lipase (LAL) deficiency/Wolman disease. ClinicalTrials.gov website. Available at: https://clinicaltrials.gov/ct2/show/study/NCT01371825?term=01371825&rank=1 . Updated March 6, 2015. NLM Identifier: NCT01371825.

Clinical Trials, Definitions, Peer-Reviewed Publications 1. Balwani M, Breen C, Enns GM, et al. Clinical effect and safety profile of recombinant human lysosomal acid lipase in patients with cholesteryl ester storage disease. Hepatology. 2013;58(3):950-957. PubMed 2. Burton BK, Balwani M, Feillet F, et al. A phase 3 trial of sebelipase alfa in lysosomal acid lipase deficiency. N Engl J Med. 2015;373(11):1010-1020. PubMed 3. Rader, DJ. Lysosomal acid lipase deficiency: a new therapy for a genetic lipid disease. N Engl J Med 2015; 373:1071. 4. Reiner, Guardamagna, Nair, et al. Lysosomal acid lipase deficiency - an under-recognized cause of dyslipidaemia and liver dysfunction. Atherosclerosis. 2014; 235(1): 21-30. Available at: http://www.atherosclerosis­ journal.com/article/S0021-9150(14)00202-0/abstract Accessed on November 2016. 5. Hoffman EP, Barr ML, Giovanni MA, et al. Lysosomal Acid Lipase Deficiency. 2015 Jul 30. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993­ 2015. Available at: http://www.ncbi.nlm.nih.gov/books/NBK305870/ Accessed on November 2016. 6. Porto AF. Lysosomal acid lipase deficiency: diagnosis and treatment of Wolman and cholesteryl ester storage diseases. Pediatr Endocrinol Rev. 2014;12(suppl 1):125-132. PubMed 7. Jones SA et al. Effect of sebelipase alfa on survival and liver function in infants with rapidly progressive lysosomal acid lipase deficiency. Mol Genet Metab. 2015;114(2):S59. 8. FDA. Medical review: sebelipase alfa. Available at: www.accessdata.fda.gov. Accessed on November 2016. 9. Med Lett Drugs Ther. 2016 Sebelipase Alfa (Kanuma) for Lysosomal Acid Lipase Deficiency (online only). Sep 26;58(1504):e126-127 10. Bernstein DL, et al. J Hepatol. 2013;58:1230-43. doi:10.1016/j.jhep.2013.02.014. 2. Reiner Ž, et al. Atherosclerosis. 2014;235:21-30. doi:10.1016/j.atherosclerosis.2014.04.003. 3. Roberts EA, et al. Hepatology. 2008;47:2089-111. doi:10.1002/hep.22261. 11. Sutton VR, Hahn S. Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features. In: UpToDate, Waltham, MA: Walters Kluwer Health; 2016. Available at UpToDate.com. Accessed November 2016. 12. Valayannopoulos V, Malinova V, Honzík T, et al. Sebelipase alfa over 52 weeks reduces serum transaminases, liver volume and improves serum lipids in patients with lysosomal acid lipase deficiency. J Hepatol. 2014;61(5):1135­ 1142. 13. Reiner Z et al. Lysosomal acid lipase deficiency--an under-recognized cause of dyslipidaemia and liver dysfunction. Atherosclerosis. 2014;235(1):21-30. 14. Rader DJ. Lysosomal Acid Lipase Deficiency: A New Therapy for a Genetic Lipid Disease. N Engl J Med. 2015;373(11):1071-3.

Government Agencies, Professional Societies, and Other Authoritative Publications A. Hayes, Inc. Hayes Health Technology Brief. Sebelipase Alfa (Kanuma) for Treatment of Lysosomal Acid Lipase Deficiency. Lansdale, PA: Hayes Inc.; May 26 2016. Accessed November 2016. B. National Institute of Neurological Disorders and Stroke. NINDS acid lipase disease information page. Last updated February 23, 2016. Available at: http://www.ninds.nih.gov/disorders/acid_lipase/acid_lipase.htm. Accessed November 2016. C. National Organization for Rare Diseases. Available at: https://rarediseases.org/for-patients-and­ families/information-resources/rare-disease-information/. Accessed November 2016.

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D. National Institute for Health and Care Excellence (NICE). Evaluation consultation document – Sebelipase alfa for treating lysosomal acid lipase deficiency. February 2016. Available at: https://www.nice.org.uk/guidance/gid­ lysosomalacidlipasedeficiencysebelipasealfaid737/documents/evaluation-consultation-document. Accessed November 2016. E. AMR Peer Review Network. Peer Reviewer: Board certified in Clinical Molecular Genetics. 11/17/2016. AMR Tracking Num: 762535

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