Gene Therapy Treatments for Sickle Cell Disease - Medicare Advantage Form

Please refer to CMS website for the most current applicable CMS Online Manual System (IOMs)/National Coverage Determination (NCD)/ Local Coverage Determination (LCD)/Local Coverage Article (LCA)/ Transmittals.
There are no NCDs and/or LCDs for autologous gene therapy treatments for sickle cell disease.
Description Sickle cell disease (SCD) is a category of hereditary illnesses that affect the function of red blood cells (RBCs) and can be fatal. SCD diseases are caused by autosomal recessive mutations in the hemoglobin (Hb) subunit

Gene Therapy Treatments for Sickle Cell Disease Page: 2 of 7 beta gene. Hb clumping is the cause of erythrocytes' characteristic sickle shape. These cells can obstruct blood vessels, have a lower capacity for oxygen, raise blood viscosity, and have a rapid turnover rate because of enhanced hemolysis (breakdown of RBCs). Individuals differ significantly in terms of disease severity and clinical presentation. The effects of SCD include endothelial damage, anemia, severe pain, acute chest syndrome, stroke, retinopathy, infections, hypertension and substantially reduces life expectancy. The acute and long-term effects of ischemia-reperfusion harm organs, which can result in cerebral infarcts; heart, lung and kidney disease; excruciating pain and other complications, are the main causes of morbidity and death in SCD. The mainstays of treatment for SCD have been supportive care to manage complications and preventive measures to reduce the incidence of vaso-occlusive crises (VOCs). Treatment options primarily consist of hydroxyurea, pain management and transfusion, in those with SCD. Currently, the only potential cure is hematopoietic stem-cell transplantation (HSCT) using cells from a healthy donor. Allogeneic (donor) HSCT is the most successful potentially curative treatment for SCD, but its use is limited because of the lack of donors, concerns for transplant-related toxicities (including death), and preferences of the individual and family.4 The landscape of SCD treatment continues to evolve rapidly, with new disease-modifying therapies in development and potentially curative options now available. Gene therapy is rising to the forefront of the discussion as a potentially curative or highly disease-modifying option for abating the complications of the disease.9 Gene therapy is a technique that introduces a normal gene or alters the expression of a disease- causing gene. The goal of gene therapy is to provide a sustained therapeutic benefit via continual expression of the proteins that reduce the pathogenesis of the relevant disease.4 Casgevy (exagamglogene autotemcel) is an autologous, genome-edited, hematopoietic stem cell-based gene therapy indicated for the treatment of SCD in individuals 12 years of age and older with recurrent vaso-occlusive crises (VOCs).4 Casgevy uses CRISPR technology to edit blood stem cells to increase the production of fetal hemoglobin. Individuals are required to undergo hematopoietic stem cell (HSC) mobilization followed by apheresis to obtain CD34+ cells for CASGEVY manufacturing and is provided as a single dose infusion.15
Lyfgenia (lovotibeglogene autotemcel) is an autologous hematopoietic stem cell-based gene therapy indicated for the treatment of individuals 12 years of age or older with sickle cell disease and a history of vaso-occlusive events.14 Lyfgenia uses a lentiviral vector to introduce genetic modifications into the individual’s blood stem cells to produce a type of functional Hb A to fill in for dysfunctional ones. Individuals are required to undergo premobilization transfusions, hematopoietic stem cell (HSC) mobilization followed by apheresis to obtain CD34+ cells for LYFGENIA manufacturing.16 Requests for Casgevy (exagamglogene autotemcel) AND Lyfgenia (lovotibeglogene autotemcel) require review by a medical director. Coverage Determination

Gene Therapy Treatments for Sickle Cell Disease Page: 3 of 7 Humana follows the Medicare requirements that only allow coverage and payment for services that are reasonable and necessary for the diagnosis and treatment of illness or injury or to improve the functioning of a malformed body member except as specifically allowed by Medicare. In interpreting or supplementing the criteria above and in order to determine medical necessity consistently, Humana may consider the criteria contained in the following: Refer all requests or questions regarding Gene Therapy Treatments for Sickle Cell Disease to the Corporate Transplant Department.
Phone 1-866-421-5663 Fax 502-508-9300 Email transplant@humana.com Casgevy (exagamglogene autotemcel) AND Lyfgenia (lovotibeglogene autotemcel) will be considered medically reasonable and necessary when the following indications are met:
• Absence of an available 10/10 HLA matched related HSC donor; AND • Absence of limitations; AND • Individual has diagnosis of severe SCD, as indicated by BOTH: o Documented severe SCD genotype; AND o History of at least two severe vaso-occlusive crisis events per year for the previous two years.
Severe VOC is defined as an occurrence of at least one of the following events:  Acute chest syndrome; OR  Acute pain event requiring a visit to a medical facility and administration of pain medications (opioids, intravenous or non-steroidal anti-inflammatory drugs [NSAIDs]) or RBC transfusions; OR  Priapism lasting greater than 2 hours and requiring a visit to a medical facility; OR  Splenic sequestration • Individual is 12 through 65 years of age; AND
• Individual is eligible for an autologous stem cell transplant; AND • Failure or intolerance of hydroxyurea (HU); AND
• Karnofsky performance status of greater than or equal to 60 (greater than or equal to 16 years of age) OR a Lansky performance status of greater than or equal to 60 (less than 16 years of age)

Gene Therapy Treatments for Sickle Cell Disease Page: 4 of 7 The use of the criteria in this Medicare Advantage Medical Coverage Policy provides clinical benefits highly likely to outweigh any clinical harms. Services that do not meet the criteria above are not medically necessary and thus do not provide a clinical benefit. Medically unnecessary services carry risks of adverse outcomes and may interfere with the pursuit of other treatments which have demonstrated efficacy. Coverage Limitations US Government Publishing Office. Electronic code of federal regulations: part 411 – 42 CFR § 411.15 - Particular services excluded from coverage Casgevy (exagamglogene autotemcel) AND Lyfgenia (lovotibeglogene autotemcel) will not be considered medically reasonable and necessary if the following limitations are present 1,2,7,8,15,16:
• Clinically significant and active bacterial, fungal, parasitic or viral infection including hepatitis B or C (HBV, HCV), or human immunodeficiency virus (HIV); OR • Inadequate bone marrow function (defined by an absolute neutrophil count of less than 1000/µL (less than 500/µL for subjects on HU treatment) OR a platelet count less than 100,000/µL; OR • Individual has desire to become pregnant/reproduce OR unwilling to use effective contraception; OR • Individual is pregnant or breastfeeding; OR • Hepatic impairment; OR • Renal impairment (eg, estimated glomerular filtration rate less than 60 mL/min/1.73 m2); OR • Prior HSC transplant; OR
• Prior or current malignancy or immunodeficiency disorder (except previously treated, non-life threatening, cured tumors such as squamous cell carcinoma of the skin); OR • Prior receipt of ANY gene therapy *Following treatment with Lyfgenia (lovotibeglogene autotemcel), individuals with α-thalassemia trait may experience anemia with erythroid dysplasia that may require chronic RBC transfusions (Lyfgenia [lovotibeglogene autotemcel] has not been studied in individuals with more than two α-globin gene deletions).
A review of the current medical literature shows that the evidence is insufficient to determine that this service is standard medical treatment for an individual with any of the above indications. There remains an absence of randomized blinded clinical studies examining benefit and long-term clinical outcomes establishing the value of this service in clinical management for these indications.

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