Medical Drug Criteria (MDC)

Policy Num:       P1.002.024
Policy Name:     Elivaldogene autotemcel (Skysona) Suspension for Intravenous Infusion
Policy ID:          [P1.002.024][Ac L M+ P+ ][5.01.45]

Last Review:       September 22, 2025
Next Review:      September 20. 2026
 

Related Policies: None

Elivaldogene autotemcel (Skysona) Suspension for Intravenous Infusion

Summary

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 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.

Policy Statements

Elivaldogene autotemcel is considered medically necessary for individuals if they meet criteria 1 through 4 :

1. 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:

   1. Confirmed mutation in the ABCD1 gene, AND

   2. Elevated very-long-chain fatty acids (VLCFAs), AND

   3. Presence of active central nervous system (CNS) disease documented by:

      1. Loes score between 0.5 and 9 (inclusive) on the 34-point scale, AND

      2. Gadolinium enhancement on MRI of demyelinating lesions.

3. Documented neurologic function score (NFS) score ≤1.

4. Does not have the following:

   1. History of receiving prior gene therapy or allogeneic hematopoietic stem cell transplant.

   2. Hematological compromise as evidenced by ALL the following:

      1. Peripheral blood absolute neutrophil count (ANC) count <1500 cells/mm³, AND

      2. Platelet count <100,000 cells/mm³ OR hemoglobin <10 g/dL, AND

      3. Uncorrected bleeding disorder.

   3. Hepatic compromise as evidenced by:

      1. Aspartate transaminase (AST) >2.5 × upper limit of normal (ULN), AND

      2. Alanine transaminase (ALT) >2.5 × ULN, AND

      3. Total bilirubin value >3.0 mg/dL, except if there is a diagnosis of Gilbert's Syndrome and the participant is otherwise stable.

   4. Cardiac compromise as evidenced by left ventricular ejection fraction <40%.

   5. Baseline estimated glomerular filtration rate <70 mL/min/1.73 m² or actual or calculated creatinine clearance <50 mL/min.

   6. Any immediate family member (i.e., parent or siblings) with a known history of hematological malignancy, including myelodysplastic syndrome.

   7. 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.

   8. Any condition(s) that are contraindicated for continued MRI studies.

   9. Absence of adequate contraception for fertile patients.

   10. 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

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.

DOSAGE/ADMINISTRATION

Recommended Dose

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

Dosing Limits

One injection per lifetime.

REQUIRED MEDICAL INFORMATION

See policy statement

EXCLUSION CRITERIA

None

BENEFIT APPLICATION

BlueCard/National Account Issues
State or federal mandates (eg, Federal Employee Program) may dictate that certain U.S. Food and Drug Administration-approved devices, drugs, or biologics may not be considered investigational, and thus thesedevices may be assessed only by their medical necessity.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered. Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

OTHER CRITERIA

None

Practice Guidelines and Position Statements

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in 'Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

International Recommendations for the Diagnosis and Management of Patients With Adrenoleukodystrophy

Three international centers of excellence for adrenoleukodystrophy (ALD; Amsterdam UMC, Massachusetts General Hospital, and Kennedy Krieger Institute) aided by health consultancy agency Adelphi Values constituted a multi-disciplinary panel comprising of pediatric neurologists, endocrinologists, metabolic specialists, hematopoietic cell transplant experts, radiologists, laboratory scientists and patient advocacy groups to develop best-practice recommendations for diagnosis, clinical surveillance, and treatment of ALD using a consensus-based modified Delphi approach.^26, The panel received financial support of Bluebird Bio, SwanBio Therapeutics, and Minoryx. The panel recommendations for treatment of cerebral adrenoleukodystrophy (CALD) are as follows:

• "Transplantation eligibility should be determined by an ALD transplantation expert.

• Eligibility criteria are not exclusive. In general, boys are considered eligible for transplantation when they have demyelination with gadolinium enhancement (MR severity score (Loes score) ≤9) and a neurological function score of 0 or 1; adult men when they have demyelinating lesions with gadolinium enhancement and no or few neurocognitive impairment.

• Genetically transduced autologous stem cell transplantation (gene therapy) should be considered (if available) in boys if allogeneic donor options are poor."

U.S. Preventive Services Task Force Recommendations

Not applicable

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

No unpublished or ongoing trials that might influence this review were identified. FDA has requested Bluebird Bio to conduct 2 post-marketing studies to verify the clinical benefit. These are

• Study 1: Follow all subjects who received elivaldogene autotemcel in Studies ALD-102 and ALD-104 to assess event-free survival (i.e., alive without major functional disability (MFD) or need for hematopoietic stem cell transplant [HSCT]) for a minimum of 10 years following administration of elivaldogene autotemcel. Timeline for final protocol submission is January 31, 2023, for interim clinical study report submission: July 31, 2027 and final study report submission: July 31, 2032.

• Study 2: Investigate event-free survival for at least five years post-treatment in 24 boys with more advanced early active, CALD [(based on baseline Loes scores and Neurologic Function Score (NFS)] who will be newly treated with elivaldogene autotemcel. Timeli

References

1. Moser HW. Adrenoleukodystrophy: phenotype, genetics, pathogenesis and therapy. Brain. Aug 1997; 120 ( Pt 8): 1485-508. PMID 9278636
2. Moser HW, Mahmood A, Raymond GV. X-linked adrenoleukodystrophy. Nat Clin Pract Neurol. Mar 2007; 3(3): 140-51. PMID 17342190
3. Loes DJ, Hite S, Moser H, et al. Adrenoleukodystrophy: a scoring method for brain MR observations. AJNR Am J Neuroradiol. Oct 1994; 15(9): 1761-6. PMID 7847225
4. Moser HW, Loes DJ, Melhem ER, et al. X-Linked adrenoleukodystrophy: overview and prognosis as a function of age and brain magnetic resonance imaging abnormality. A study involving 372 patients. Neuropediatrics. Oct 2000; 31(5): 227-39. PMID 11204280
5. Moser HW, Raymond GV, Dubey P. Adrenoleukodystrophy: new approaches to a neurodegenerative disease. JAMA. Dec 28 2005; 294(24): 3131-4. PMID 16380594
6. Mallack EJ, Turk BR, Yan H, et al. MRI surveillance of boys with X-linked adrenoleukodystrophy identified by newborn screening: Meta-analysis and consensus guidelines. J Inherit Metab Dis. May 2021; 44(3): 728-739. PMID 33373467
7. Loes DJ, Fatemi A, Melhem ER, et al. Analysis of MRI patterns aids prediction of progression in X-linked adrenoleukodystrophy. Neurology. Aug 12 2003; 61(3): 369-74. PMID 12913200
8. Melhem ER, Loes DJ, Georgiades CS, et al. X-linked adrenoleukodystrophy: the role of contrast-enhanced MR imaging in predicting disease progression. AJNR Am J Neuroradiol. May 2000; 21(5): 839-44. PMID 10815658
9. Peters C, Charnas LR, Tan Y, et al. Cerebral X-linked adrenoleukodystrophy: the international hematopoietic cell transplantation experience from 1982 to 1999. Blood. Aug 01 2004; 104(3): 881-8. PMID 15073029
10. Shapiro E, Krivit W, Lockman L, et al. Long-term effect of bone-marrow transplantation for childhood-onset cerebral X-linked adrenoleukodystrophy. Lancet. Aug 26 2000; 356(9231): 713-8. PMID 11085690
11. Mosser J, Douar AM, Sarde CO, et al. Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters. Nature. Feb 25 1993; 361(6414): 726-30. PMID 8441467
12. Executive Summary: X-linked adrenoleukodystrophy (X-ALD) to the Recommended Uniform Screening Panel. Available at https://www.hrsa.gov/sites/default/files/hrsa/advisory-committees/heritable-disorders/rusp/x-ald-exsum.pdf. Last accessed Sep 11, 2023.
13. Hubbard WC, Moser AB, Liu AC, et al. Newborn screening for X-linked adrenoleukodystrophy (X-ALD): validation of a combined liquid chromatography-tandem mass spectrometric (LC-MS/MS) method. Mol Genet Metab. Jul 2009; 97(3): 212-20. PMID 19423374
14. Raymond GV, Jones RO, Moser AB. Newborn screening for adrenoleukodystrophy: implications for therapy. Mol Diagn Ther. 2007; 11(6): 381-4. PMID 18078355
15. Kemper AR, Brosco J, Comeau AM, et al. Newborn screening for X-linked adrenoleukodystrophy: evidence summary and advisory committee recommendation. Genet Med. Jan 2017; 19(1): 121-126. PMID 27337030
16. Miller WP, Rothman SM, Nascene D, et al. Outcomes after allogeneic hematopoietic cell transplantation for childhood cerebral adrenoleukodystrophy: the largest single-institution cohort report. Blood. Aug 18 2011; 118(7): 1971-8. PMID 21586746
17. Aubourg P, Blanche S, Jambaqué I, et al. Reversal of early neurologic and neuroradiologic manifestations of X-linked adrenoleukodystrophy by bone marrow transplantation. N Engl J Med. Jun 28 1990; 322(26): 1860-6. PMID 2348839
18. Engelen M, Kemp S, de Visser M, et al. X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management. Orphanet J Rare Dis. Aug 13 2012; 7: 51. PMID 22889154
19. Raymond GV, Aubourg P, Paker A, et al. Survival and Functional Outcomes in Boys with Cerebral Adrenoleukodystrophy with and without Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant. Mar 2019; 25(3): 538-548. PMID 30292747
20. Summary Basis for Regulatory Action for Elivaldogene Autotemcel. Available at https://www.fda.gov/media/162098/download. Accessed September 11, 2023.
21. Mahmood A, Dubey P, Moser HW, et al. X-linked adrenoleukodystrophy: therapeutic approaches to distinct phenotypes. Pediatr Transplant. Dec 2005; 9 Suppl 7: 55-62. PMID 16305618
22. Kühl JS, Kupper J, Baqué H, et al. Potential Risks to Stable Long-term Outcome of Allogeneic Hematopoietic Stem Cell Transplantation for Children With Cerebral X-linked Adrenoleukodystrophy. JAMA Netw Open. Jul 06 2018; 1(3): e180769. PMID 30646031
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. Accessed on September 11, 2023.
24. Chiesa R, Boelens JJ, Duncan CN, et al. Variables affecting outcomes after allogeneic hematopoietic stem cell transplant for cerebral adrenoleukodystrophy. Blood Adv. Mar 08 2022; 6(5): 1512-1524. PMID 34781360
25. Eichler F, Duncan C, Musolino PL, et al. Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy. N Engl J Med. Oct 26 2017; 377(17): 1630-1638. PMID 28976817
26. Engelen M, van Ballegoij WJC, Mallack EJ, et al. International Recommendations for the Diagnosis and Management of Patients With Adrenoleukodystrophy: A Consensus-Based Approach. Neurology. Nov 22 2022; 99(21): 940-951. PMID 36175155

Codes

Policy History