241 Form

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Medical Policy Gene Therapies for Cerebral Adrenoleukodystrophy Table of Contents • Policy: Commercial • Coding Information
• Information Pertaining to All Policies
• Policy: Medicare • Description
• References
• Authorization Information • Policy History

Policy Number: 241 BCBSA Reference Number: 5.01.45 (For Plan internal use only)

Related Policies Gene Therapy for Cerebral Adrenoleukodystrophy Skysona® (Elivaldogene autotemcel) Prior Authorization Request Form #242

Policy Commercial Members: Managed Care (HMO and POS), PPO, and Indemnity
Medicare HMO BlueSM and Medicare PPO BlueSM Members

Elivaldogene autotemcel is considered MEDICALLY NECESSARY for individuals if they meet criteria 1 through 5:

1. Individual is 4 to 17 years of age at the time of infusion of elivaldogene autotemcel.
2. Documented diagnosis of active cerebral X-linked adrenoleukodystrophy as defined by: a. Confirmed mutation in the ABCD1 gene; AND b. Elevated very-long-chain fatty acids (VLCFAs); AND c. Presence of active central nervous system (CNS) disease documented by: i. Loes score between 0.5 and 9 (inclusive) on the 34-point scale,]; AND ii. Gadolinium enhancement on MRI of demyelinating lesions.
3. Documented neurologic function score (NFS) score ≤1.
4. Individual DOES NOT have ANY of the following: a. History of receiving prior gene therapy or allogeneic hematopoietic stem cell transplant. b. Hematological compromise as evidenced by ANY of the following: i. Peripheral blood absolute neutrophil count (ANC) count <1500 cells/mm3;
   ii. Platelet count <100,000 cells/mm3 OR hemoglobin <10 g/Dl;
   iii. Uncorrected bleeding disorder. c. Hepatic compromise as evidenced by ANY of the following: i. Aspartate transaminase (AST) >2.5 × upper limit of normal (ULN); OR ii. Alanine transaminase (ALT) >2.5 × ULN; OR iii. Total bilirubin value >3.0 mg/dL, except if there is a diagnosis of Gilbert's Syndrome and the participant is otherwise stable. d. Cardiac compromise as evidenced by left ventricular ejection fraction <40%. e. Baseline estimated glomerular filtration rate <70 mL/min/1.73 m2 or actual or calculated creatinine clearance <50 mL/min.

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f. Any immediate family member (i.e., parent or siblings) with a known Familial Cancer Syndrome (Including but not limited to hereditary breast and ovarian cancer syndrome, hereditary nonpolyposis colorectal cancer syndrome and family adenomatous polyposis). g. Any clinically significant uncontrolled, active bacterial, viral, fungal, parasitic, or prion associated infection, including but not limited to positive human immunodeficiency virus (HIV- 1 or HIV-2), human T lymphotropic virus 1 (HTLV-1), active hepatitis B virus, and hepatitis C virus. h. Any condition(s) that are contraindicated for continued MRI studies. i. Absence of adequate contraception for fertile patients. j. Any contraindications to the use of granulocyte colony-stimulating factor (G-CSF) or plerixafor during the mobilization of hematopoietic stem cells, and any contraindications to use the use of busulfan or fludarabine, including known hypersensitivity to the active substances or to any of the excipients in their formulations.

Elivaldogene autotemcel is considered INVESTIGATIONAL when the above criteria are not met.

Elivaldogene autotemcel is considered INVESTIGATIONAL for all other indications.

Repeat treatment of elivaldogene autotemcel is considered INVESTIGATIONAL.

Policy Guidelines Recommended Dose The minimum recommended dose is 5.0 × 106 CD34+ cells/kg of body weight.

Dosing Limits One injection per lifetime.

Other Considerations • Elivaldogene autotemcel was not studied in combination with statins, Lorenzo's Oil, or dietary regimens used to lower VLFCA levels.
• Prescriber’s discretion is advised regarding the continuation of VLFCA lowering treatments after elivaldogene autotemcel administration. • Where feasible, the individual’s vaccination should be up to date with all age-appropriate vaccinations before elivaldogene autotemcel administration. • Where feasible, the individual should receive periodic monitoring for hematological malignancies, including Myelodysplastic Syndrome (MDS). • Final administration of elivaldogene autotemcel may be limited based on the myeloablative and lymphodepleting conditioning requirements. Prior Authorization Information Inpatient • For services described in this policy, precertification/preauthorization IS REQUIRED for all products if the procedure is performed inpatient.
Outpatient • For services described in this policy, see below for products where prior authorization might be required if the procedure is performed outpatient.

Outpatient Commercial Managed Care (HMO and POS) Prior authorization is required. Commercial PPO and Indemnity Prior authorization is required. Medicare HMO BlueSM Prior authorization is required. Medicare PPO BlueSM Prior authorization is required.

Requesting Prior Authorization Using Authorization Manager Providers will need to use Authorization Manager to submit initial authorization requests for services. Authorization Manager, available 24/7, is the quickest way to review authorization requirements, request

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authorizations, submit clinical documentation, check existing case status, and view/print the decision letter. For commercial members, the requests must meet medical policy guidelines.

To ensure the request is processed accurately and quickly: • Enter the facility’s NPI or provider ID for where services are being performed. • Enter the appropriate surgeon’s NPI or provider ID as the servicing provider, not the billing group.

Authorization Manager Resources Refer to our Authorization Manager page for tips, guides, and video demonstrations.

Complete Prior Authorization Request Form for Cerebral Adrenoleukodystrophy Skysona® (Elivaldogene autotemcel) (242) using Authorization Manager.

For out of network providers: Requests should still be faxed to 888-973-0726. CPT Codes / HCPCS Codes / ICD Codes
Inclusion or exclusion of a code does not constitute or imply member coverage or provider reimbursement. Please refer to the member’s contract benefits in effect at the time of service to determine coverage or non-coverage as it applies to an individual member.

Providers should report all services using the most up-to-date industry-standard procedure, revenue, and diagnosis codes, including modifiers where applicable. The following codes are included below for informational purposes only; this is not an all-inclusive list.

The above medical necessity criteria MUST be met for the following codes to be covered for Commercial Members: Managed Care (HMO and POS), PPO, Indemnity, Medicare HMO Blue and Medicare PPO Blue:

HCPCS Codes HCPCS codes:

Code Description C9399 Unclassified drugs or biologicals J3387 Injection, elivaldogene autotemcel, per treatment
J3490 Unclassified drugs
J3590 Unclassified biologics
ICD-10 Procedure Codes ICD-10- PCS procedure codes: Code Description XW043F3 Introduction of Other New Technology Therapeutic Substance into Central Vein, Percutaneous Approach, New Technology Group 3 (no specific code for this drug) XW043F5 Introduction of Other New Technology Therapeutic Substance into Central Vein, Percutaneous Approach, New Technology Group 5 Description Cerebral adrenoleukodystrophy (CALD) is an X-linked genetic neurodegenerative disease that most severely affects individuals assigned male at birth. The genetic mutation leads to impaired or loss of adrenoleukodystrophy protein (ALDP) expression.

X-linked adrenoleukodystrophy is established in a male (assigned male at birth or AMAB) with suggestive clinical findings and elevated very long chain fatty acids (VLCFA), with the majority having inherited a pathogenic variant in the ABCD1 gene. While female (assigned female at birth or AFAB) carriers can

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develop spastic paraparesis most often in adulthood, adrenal function is generally not impaired. CALD typically only affects AMAB in childhood and AFAB with CALD are very rare. Defective function of ALDP leads to the accumulation of very long-chain fatty acids (VLCFAs), which occurs in plasma and all tissue types but most prominently in the adrenal cortex and white matter of the brain and spinal cord. VLCFAs initiate an inflammatory cascade ultimately leading to inflammatory cerebral demyelination. In general, once clinical symptoms appear, the clinical course is rapid with progressive cognitive and neurologic deficits leading to major disability including cortical blindness, incontinence, requirement for tube feeding, loss of communication, loss of ambulation, loss of voluntary movement, and ultimately premature death. Prior to the approval of elivaldogene autotemcel, there were no approved treatments for CALD in the US. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered the standard of care and has been shown to stabilize neurologic function, with better outcomes observed in patients treated at the early stages of cerebral involvement and among those who receive human leukocyte antigen (HLA)-matched transplant versus HLA-mismatched transplant. Challenges associated with HSCT include serious immunologic complications, including transplant-related mortality, graft rejection, and graft-versus-host disease. Elivaldogene autotemcel is an autologous hematopoietic stem cell (HSC)-based gene therapy which adds functional copies of the ABCD1 cDNA into patients’ HSCs through transduction of autologous CD34+ cells with Lenti-D lentiviral vector. After infusion, transduced CD34+ HSCs engraft in the bone marrow and differentiate into various cell types, including monocytes (CD14+) capable of producing functional ALDP. Functional ALDP can then participate in the local degradation of VLCFAs, which is believed to slow or possibly prevent further inflammation and demyelination.

Summary For individuals who are assigned male at birth and 4 to 17 years of age with early, active cerebral adrenoleukodystrophy (CALD) who receive elivaldogene autotemcel, the evidence includes a single post- hoc analysis from 2 single-arm interventional studies and 2 non-concurrent historical control studies. The interventional studies enrolled patients with early, active CALD as defined by Loes score between 0.5 and 9 (inclusive) and gadolinium enhancement on magnetic resonance imaging (MRI), as well as a neurologic function score (NFS) of ≤1, indicating limited changes in neurologic function. The post-hoc analysis in an enriched sample of symptomatic study participants compared time from onset of symptoms (NFS ≥1) to time to first major functional disability (MFD) or death (i.e., MFD-free survival) in treated (n=11) and natural history untreated (n=7) individuals. Relevant outcomes of interest are overall survival, disease- specific survival, change in disease status, functional outcomes, quality of life, treatment-related morbidity and treatment-related mortality. The estimated MFD-free survival at month 24 from time of first NFS ≥1 were 72% (95% CI, 35%-90%) for the symptomatic elivaldogene autotemcel treated subpopulation and 43% (95% CI, 10%-73%) for the natural history subpopulation. Notable limitations include post-hoc analysis using a historical control with a limited sample size and known differences in the baseline prognostic variables such as age at enrollment, age at first NFS ≥1, Loes score, and distribution of brain MRI pattern of disease between the 2 groups. As a result, it is difficult to determine whether the observed effect was due to a treatment effect or due to treatment at an early stage of disease with insufficient duration of follow-up to detect progression to MFD or death. In addition to the significant uncertainty about efficacy, 3 cases of myelodysplastic syndrome mediated by Lenti-D lentiviral vector integration into proto- oncogenes were reported. Given that 1 of the 3 cases of hematological malignancy occurred 7.5 years after administration of gene therapy, long-term follow-up (>15 years) is required to establish precision around durability of the treatment effect as well as side effects. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Policy History Date Action 1/2026 Clarified coding information 1/2024 Clarified coverage and updated IC to align with 118E MGL § 51A. 7/2023 Reformatted Policy. 02/2023 New medical policy describing medically necessary indications. Policy created with literature review through October 24, 2022. The use of elivaldogene autotemcel is considered medically appropriate for individuals with childhood cerebral X-linked adrenoleukodystrophy when certain conditions are met. Effective 02/01/2023.

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Information Pertaining to All Blue Cross Blue Shield Medical Policies Click on any of the following terms to access the relevant information: Medical Policy Terms of Use Managed Care Guidelines Indemnity/PPO Guidelines Clinical Exception Process Medical Technology Assessment Guidelines References

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23. Prescribing Label: Skysona (elivaldogene autotemcel) suspension for intravenous infusion. Initial U.S. Approval: 2022. Available at https://https://www.fda.gov/media/161640/download
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