Description
Elivaldogene autotemcel (Skysona®) is a one-time gene therapy indicated to slow the progression of neurologic dysfunction in pediatric males with early, active cerebral adrenoleukodystrophy (CALD) and for whom a human leukocyte antigen (HLA)-matched sibling hematopoietic stem cell (HSC) donor is not available.

Eli-celgene therapy adds functional copies of the human adenosine triphosphate binding cassette, sub family D, member 1 (ABCD1) gene into patients’ HSCs ex-vivo through transduction of autologous CD34+ cells with Lenti-D LVV. The addition of a functional gene allows patients to produce adrenoleukodystrophy protein (ALDP), which is thought to allow for the breakdown of very long chain fatty acids (VLCFAs) that otherwise accumulate to toxic levels in the brain causing inflammation and demyelination.

Policy
Skysona is considered Medically Necessary when the following criteria is met:

1. Diagnosis of early, active cerebral adrenoleukodystrophy (CALD) AND
2. Molecular genetic testing confirms mutation in the ABCD1 gene AND
3. ALL of the following: 
   • Patient has elevated very long chain fatty acid (VLCFA) levels 
   • Loes score between 0.5 and 9 (inclusive) based on brain MRI assessment [B, 4] 
   • Brain magnetic resonance imaging (MRI) utilizes Gadolinium enhancement (GdE +) and demonstrates demyelinating lesions [C, 5] 
   • Neurologic function score (NFS) less than or equal to 1 AND
4. BOTH of the following: 
   • Patient is male sex 
   • Patient is 4 to 17 years of age AND
5. Patient is not eligible for an allogeneic hematopoietic stem cell transplant with an HLA-matched sibling donor AND
6. Patient has obtained a negative test result for all of the following prior to cell collection: 
   • Hepatitis B virus (HBV) 
   • Hepatitis C virus (HCV) 
   • Human T-lymphotropic virus 1 and 2 (HTLV-1/HTLV-2) 
   • Human immunodeficiency virus (HIV) AND
7. Patient does not have CALD secondary to head trauma [A, 1] AND
8. Discontinue prophylactic anti-retroviral medications (e.g., Truvada, Descovy) for at least one month prior to initiating medications for stem cell mobilization and until all cycles of apheresis are completed AND
9. Prescribed by a stem cell transplant physician from a qualified treatment center [D, 6] AND
10. Patient has never received Skysona treatment in their lifetime 

Skysona is considered Not Medically Necessary for all other indications.

Rationale
Cerebral adrenoleukodystrophy (CALD) is a rare X-linked genetic disorder caused by mutations in the human adenosine triphosphate binding cassette, sub family D, member 1 (ABCD1) transgene. These mutations result in a reduction in adrenoleukodystrophy protein (ALDP) that transport very long-chain fatty acids (VLCFAs) to peroxisomes for metabolism. As a result VLCFAs accumulate within the adrenal gland and cerebral hemispheres of the central nervous system. Patients present with adrenal insufficiency and progressive neurodegenerative disease caused by demyelination. The ABCD1 gene mutation is estimated to occur in 1 in 17,000 births. Early CALD occurs in male patients age 2 to 10 years and can progress to complete disability within 2 years and death within 4 to 10 years if not treated. Female carriers of the ABCD1 mutation typically develop less severe symptoms of adrenoleukodystrophy during adulthood.

Glucocorticoids steroids are used for the management of adrenal insufficiency but have no impact on neurological abnormalities. Therefore, allogeneic hematopoietic stem cell transplantation (HSCT) should be considered to limit neurological progression for early-stage disease [e.g., magnetic resonance imaging (MRI) evidence of disease while asymptomatic or minimally symptomatic]. Limitations of HSCT include difficulty identifying a matched donor, as approximately 30% of children with CALD have an HLA-matched sibling donor, and complications of graft rejection and graft-versus-host disease (GvHD) can occur.

Elivaldogene autotemcel (Skysona) is an autologous HSC-based gene therapy that is prepared from the patient’s HSCs, which are collected via apheresis procedures. Elivaldogene autotemcel (Skysona) adds functional copies of the ABCD1 cDNA into patients’ HSCs through transduction of autologous CD34+ cells with Lenti-D lentiviral vectors (LVV). Following the elivaldogene autotemcel (Skysona) infusion, transduced CD34+ HSCs engraft in the bone marrow and differentiate into various cell types, including monocytes (CD14+) capable of producing functional ALDP to slow or possibly prevent further inflammation and demyelination.

According to the manufacturer prescribing information, elivaldogene autotemcel (Skysona) efficacy and safety was evaluated in two 24-month, open-label, single-arm studies in patients with early, active CALD as noted in the prescribing information. However, only one of these studies, STARBEAM ALD-102 (NCT01896102), is complete with interim data published in the literature and the remaining data published in the prescribing information. The STARBEAM ALD-102 study was a single-group, open-label, 
phase 2/3 study that assessed the efficacy and safety of elivaldogene autotemcel (Skysona) in male patients 17 years of age or younger who had early-stage CALD. The diagnosis of early-stage CALD was established with the following criteria: (1) Gadolinium enhancement on MRI due to CALD, (2) a score on the CALD-specific Neurologic Function Scale (which ranges from 0 to 25, with higher scores indicating more severe deficits) of 0 or 1, and (3) a Loes score (which ranges from 0 to 34, with higher scores
indicating an increased extent of lesions on MRI) of 0.5 to 9. Additionally, all patients had elevated VLCFAs levels and confirmed mutations in the ABCD1 gene. Patients with an HLA-matched sibling who could donate cells for transplantation were excluded. The primary outcome was the percentage of patients alive and having no major functional disability at 24 months following the elivaldogene autotemcel (Skysona) infusion. There were 32 male patients enrolled with a median age of 6 years and 53.1% of non-Hispanic or Latino race. The median Loes score was approximately 2 at baseline, and the NFS score was 0 to 1. Based on the primary endpoint, 90.6% of patients who received elivaldogene autotemcel (Skysona) met the efficacy outcome, maintaining a score on the NFS of 0 or 1. Of the three patients not meeting the primary endpoint, one died following rapid disease progression, and two withdrew at the investigator’s discretion to receive rescue allogeneic HSCT based on MRI evidence of disease progression; however, these situations were considered not to be treatment-related. No adverse effects related to elivaldogene autotemcel (Skysona) infusion, graft failure, GvHD, or 
transplantation-related death were observed. Most adverse events occurred in the conditioning phase or first two weeks after infusion and were considered to be consistent with myeloablative chemotherapy.

As outline in the elivaldogene autotemcel (Skysona) prescribing information, the most common non-laboratory adverse reactions ( ≥ 20%) include mucositis, nausea, vomiting, febrile neutropenia, alopecia, decreased appetite, abdominal pain, constipation, pyrexia, diarrhea, headache, and rash. Additionally, the most common Grade 3 or 4 laboratory abnormalities ( ≥ 40%) include leukopenia, lymphopenia, thrombocytopenia, neutropenia, anemia and hypokalemia.

References:

1. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2022. URL www.clinicalpharmacilogy-ip.com Accessed 09/29/22.
2. DynaMed [database online]. Ipswich, MA: EBSCO Information Services.; 2022. URL http://www.dynamed.com. Accessed 09/29/22.
3. Eichler F, Duncan C, Musolino PL, et al. Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy. N Engl J Med. 2017;377(17):1630-1638. doi:10.1056/NEJMoa1700554.
4. Micromedex Healthcare Series [Internet Database]. Greenwood Village, CO: Thomson Healthcare. Updated periodically. Accessed 09/29/22.
5. Skysona (elivaldogene autotemcel) [package insert]. Bluebird Bio, Inc. Somerville (MA): September 2022.

Coding

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each Policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community,  and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

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