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 triglycerides to free cholesterol, 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 hypercholesterolemia, cardiovascular disease, and liver damage. It may lead to liver failure and, in the most severe form, death. Lipid Page 1 of 16 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, hepatomegaly, 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 statins 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 Page 2 of 16 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