Elivaldogene Autotemcel (Skysona)

Number: 1017

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses elivaldogene autotemcel (Skysona) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification: 

Precertification of elivaldogene autotemcel (Skysona) is required of all Aetna participating providers and members in applicable plan designs. For precertification of elivaldogene autotemcel, contact National Medical Excellence (NME) at 877-212-8811.  

Note: Site of Care Utilization Management Policy applies.  For information on site of service for elivaldogene autotemcel (Skysona), see Utilization Management Policy on Site of Care for Specialty Drug Infusions.

1. Exclusions

   Aetna considers any of the following as exclusion criteria:

   1. Skysona will be used to treat or prevent adrenal insufficiency; or
   2. Member has either of the following:
      
      
      1. Full deletions of the ABCD1 transgene; or
      2. Cerebral adrenoleukodystrophy (CALD) secondary to head trauma.

2. Prescriber Specialties

   This medication must be prescribed by or in consultation with a physician who specializes in the treatment of adrenoleukodystrophy (ALD).

3. Criteria for Initial Approval

   Aetna considers a one-time administration of elivaldogene autotemcel (Skysona) medically necessary for treatment of cerebral adrenoleukodystrophy (CALD) when all of the following criteria are met:

   1. Member must be a male between the ages of 4 and 17 years of age; and
   2. The member has a diagnosis of adrenoleukodystrophy confirmed by both of the following:
      
      
      1. The presence of a variant in the ABCD1 gene as detected by genetic testing, and
      2. Elevated very long chain fatty acids (VLCFA) values per reference range of the laboratory performing the test; and

   3. Member has early active disease as defined by all of the following:

      1. Central radiographic review of brain MRI demonstrating both of the following:

         1. Loes score between 0.5 and 9 (inclusive) on the 34-point scale, and
         2. Gadolinium enhancement on MRI of demyelinating lesions; and

      2. Neurologic function score (NFS) of less than or equal to 1; and

   4. Member is eligible for a hematopoietic stem cell transplant (HSCT) but is unable to find a matched sibling donor; and
   5. The member has not received Skysona or any other gene therapy previously; and
   6. The member has not received a prior allogeneic hematopoietic stem cell transplant (allo-HSCT).

   Aetna considers all other indications as experimental and investigational.

4. Related Policies 

   1. CPB 0202 - Magnetic Resonance Spectroscopy (MRS)
   2. CPB 0871 - Hematopoietic Cell Transplantation for Inherited Metabolic Disorders and Genetic Diseases

Dosage and Administration

Elivaldogene autotemcel is available as Skysona, a cell suspension for autologous use and administered as a single dose intravenous infusion. A single dose of Skysona contains a minimum of 5.0 × 10⁶ CD34+ cells/kg of body weight, suspended in a solution containing 5% dimethyl sulfoxide (DMSO).

• Individuals must undergo hematopoietic stem cell (HSC) mobilization and apheresis to obtain CD34+ cells for Skysona manufacturing.
• Dosing of Skysona is based on the number of CD34+ cells in the infusion bag(s) per kg of body weight. 
• The minimum recommended dose is 5.0 × 10⁶ CD34+ cells/kg. 
• Full myeloablative and lymphodepleting conditioning must be administered before infusion of Skysona. 
• Skysona is not to be sampled, altered, or irradiated. It is not for use in an in-line blood filter or an infusion pump.

Source: Bluebird bio, 2022b

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :
Other CPT codes related to the CPB:
38205	Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection; allogeneic
82726	Very long chain fatty acids
86367	Stem cells (ie, CD34), total count
96365 - 96368	Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug)
HCPCS codes covered if selection criteria are met:
Elivaldogene autotemcel (Skysona) –no specific code
Other HCPCS codes related to the CPB:
J1212	Injection, dmso, dimethyl sulfoxide, 50%, 50 ml
ICD-10 codes covered if selection criteria are met:
E71.520	Childhood cerebral X-linked adrenoleukodystrophy
E71.521	Adolescent X-linked adrenoleukodystrophy
E71.528	Other X-linked adrenoleukodystrophy
E71.529	X-linked adrenoleukodystrophy, unspecified type

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications 

• Skysona is indicated to slow the progression of neurologic dysfunction in boys 4-17 years of age with early, active cerebral adrenoleukodystrophy (CALD). Early, active cerebral adrenoleukodystrophy refers to asymptomatic or mildly symptomatic (neurologic function score, NFS ≤ 1) boys who have gadolinium enhancement on brain magnetic resonance imaging (MRI) and Loes scores of 0.5-9. 

  This indication is approved under accelerated approval based on 24-month Major Functional Disability (MFD)-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

  Limitations of Use:

  • Skysona does not treat or prevent adrenal insufficiency.
  • An immune response to Skysona may cause rapid loss of efficacy of Skysona in patients with full deletions of the human adenosine triphosphate binding cassette, sub family D, member 1 (ABCD1) gene.
  • Skysona has not been studied in CALD secondary to head trauma.
  • Given the risk of hematologic malignancy with Skysona, and unclear long-term durability of Skysona and human adrenoleukodystrophy protein (ALDP) expression, careful consideration should be given to the timing of treatment for each boy and treatment of boys with isolated pyramidal tract disease as clinical manifestations do not usually occur until adulthood. 

Elivaldogene autotemcel, also known as eli-cel, is available as Skysona (bluebird bio, Inc.). Skysona is an autologous hematopoietic stem cell (HSC)-based gene therapy prepared from the patient’s own HSCs, which are collected via apheresis procedure(s). The autologous cells are enriched for CD34+ cells, then transduced ex-vivo with Lenti-D lentiviral vector (LVV), and cultured with growth factors overnight. Lenti-D LVV is a replication-incompetent, self-inactivating LVV that adds functional copies of the ABCD1 gene into the patient's HSCs. The addition of the functional ABCD1 gene allows patients to produce the adrenoleukodystrophy (ALD) protein (ALDP), which can then participate in the local degradation of very long-chain fatty acids (VLCFAs). This degradation of VLCFAs is believed to slow or possibly prevent further inflammation and demyelination (bluebird bio, 2022a, 2022b).

Skysona carries a black box warning for hematologic malignancy. Hematologic malignancy, including life-threatening cases of myelodysplastic syndrome, has occurred in patients treated with Skysona. The cancers appear to be the result of the Skysona lentiviral vector, Lenti-D, integration in proto-oncogenes. Patients are to be monitored closely for evidence of malignancy through complete blood counts (CBCs) at least every 6 months and through assessments for evidence for clonal expansion or predominance at least twice in the first year and annually thereafter. Bone marrow evaluations are to be considered as clinically indicated.

Labeled warnings and precautions also include risk of serious infections (including life-threatening or fatal infection), prolonged cytopenias, delayed platelet engraftment, and risk of neutrophil engraftment failure. Opportunistic infections that have been diagnosed within the first 3 months after treatment include BK cystitis, cytomegalovirus reactivation, human herpesvirus-6 viremia, candidiasis, and bacteremias. Opportunistic infections after the first 3 months include an atypical mycobacterium vascular device infection, pseudomonas bacteremia, and Epstein-Barr virus (EBV) reactivations diagnosed as late as 18 months after treatment. Serious infections involving adenovirus include a case of transverse myelitis at 6 months that was attributed to adenovirus and entero/rhinovirus infection, and a fatal adenovirus infection at 21 months in a patient with CALD progression who developed multisystem organ failure. Grade 3 or higher infections occurred in 21% of all patients (12% bacterial, 3% viral, and 6% unspecified). The most common Grade 3 or higher infections were vascular device infections (7% of patients) diagnosed as late as 6 months after treatment, and bacteremias (6% of patients) diagnosed as late as 8 months after treatment. Febrile neutropenia developed within two weeks after infusion in 72% of patients. Skysona administration should be avoided in patients with active infections.

Patients may exhibit cytopenias, including pancytopenia, for greater than 1 year following conditioning and Skysona infusion. Grade 3 or higher cytopenias on or after Day 60 following infusion occurred in 47% of patients and included low platelet count (14%), low neutrophil count (22%), low lymphocyte count (27%), and low hemoglobin (2%). Grade 3 cytopenias persisted beyond Day 100 in 15% of patients and included low platelet count (7%), low neutrophil count (9%), and low lymphocyte count (6%). Serious adverse reactions of pancytopenia occurred in two patients who required support with blood and platelet transfusions as well as growth factors (G-CSF for up to 6 months and eltrombopag for up to 14 months) after administration. One patient had intercurrent parvovirus infection and his pancytopenia was ongoing at least two years after administration. Pancytopenia in the other patient was ongoing until he was diagnosed with myelodysplastic syndrome approximately two years after Skysona administration.

Delayed platelet engraftment has been observed with Skysona administration. Bleeding risk is increased prior to platelet engraftment and may continue after engraftment in patients with prolonged thrombocytopenia; 14% of patients had a platelet count ≤ 50 × 10⁹ /L beyond 60 days after treatment.

There is a potential risk of neutrophil engraftment failure after treatment with Skysona. Neutrophil engraftment failure was defined as failure to achieve 3 consecutive absolute neutrophil counts (ANC) greater than or equal to 0.5 × 10⁹ cells/L obtained on different days by Day 43 after infusion. 

Patients should not take anti-retroviral medications for at least one month prior to mobilization or the expected duration for elimination of the medications, and until all cycles of apheresis are completed. Anti-retroviral medications may interfere with manufacturing of the apheresed cells. If a patient requires anti-retrovirals for HIV prophylaxis, mobilization and apheresis of CD34+ cells should be delayed until HIV infection is adequately ruled out. Skysona has not been studied in patients with HIV-1, HIV-2, HTLV-1, or HTLV-2. A negative serology test
for HIV is necessary to ensure acceptance of apheresis material for Skysona manufacturing. Apheresis material from patients with a positive test for HIV will not be accepted for Skysona manufacturing.

Skysona affects polymerase chain reaction (PCR) assays for HIV due to LVV provirus insertion. A PCR-based assay should not be used to screen for HIV infection in patients treated with Skysona as a false-positive test result is likely.

The most common non-laboratory adverse reactions (20% or more) include mucositis, nausea, vomiting, febrile neutropenia, alopecia, decreased appetite, abdominal pain, constipation, pyrexia, diarrhea, headache, and rash. The most common Grade 3 or 4 laboratory abnormalities (40% or more) include leukopenia, lymphopenia, thrombocytopenia, neutropenia, anemia, and hypokalemia. 

The safety and efficacy of Skysona in children less than 4 years of age have not been established. No data are available. In the only patient in the Skysona clinical studies who had a full ABCD1 deletion, disease progression occurred. The patient experienced radiologic disease progression in the setting of declining peripheral blood vector copy number, suggesting loss of product efficacy which may have been immune mediated. The patient was subsequently treated with allogeneic hematopoietic stem cell transplant.

Skysona has not been studied in patients with renal or hepatic impairment.

Cerebral Adrenoleukodystrophy (CALD)

Cerebral adrenoleukodystrophy (CALD) is a rare, progressive and irreversible genetic neurodegenerative disease that is caused by mutations in the ABCD1 gene that affect the production of adrenoleukodystrophy protein (ALDP) and subsequently leads to buildup of very long-chain fatty acids (VLCFAs), primarily in the white matter of the brain and spinal cord. This buildup leads to cerebral inflammatory demyelination, the breakdown of the protective myelin sheath around the nerve cells responsible for brain function, especially for cognition and muscle control (Gupta et al, 2022; NORD, 2019; Wanders and Eichler, 2022). Irreversible neurological decline includes major functional disabilities such as loss of communication, cortical blindness, requirement for tube feeding, total incontinence, wheelchair dependence, or complete loss of voluntary movement (bluebird bio, 2022). Left untreated, 85–90% of males with symptomatic cerebral disease die or progress to a vegetative state within several years (Gupta et al, 2022).

Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disorder that is much more prominent in males with an incidence of 1 in 14-17,000 male births. By adulthood, approximately 40% of male patients develop CALD; however, the onset of symptoms of CALD typically occurs in childhood, with median age of 7 years (Gupta et al, 2022). According to Wanders and Eichler (2022), childhood ALD presents between 3 and 10 years of age, rarely presents after 15 years of age, and almost never occurs before 3 years of age. In the United States, newborn screening for X-linked ALD was added to the Recommended Uniform Screening Panel in 2016. At the beginning of 2022, approximately 27 states are now conducting newborn screening for ALD (Gupta et al, 2022). 

Affected females who are heterozygous for a pathogenic ABCD1 mutation typically present with an adrenomyeloneuropathy (AMN)-like phenotype, consisting of peripheral neuropathy and myelopathy, often with a gait disorder and fecal incontinence and sometimes with mild spastic paraparesis. The frequency of symptoms are less than 20 percent in females under age 40 to almost 90 percent in females older than 60. Adrenal insufficiency and cerebral involvement are rare in females. Per Wanders and Eichler (2022), there does not appear to be correlation between the pattern of X chromosome inactivation (also known as lyonization) and the risk for clinical symptoms based on the most rigorous analysis.

The diagnosis of cerebral ALD is established by magnetic resonance imaging (MRI). An MRI-based severity score was devised by Loes et al., utilizing a 0–34 point system related to the location and extent of involvement, and the presence of atrophy. The MRI severity score, or Loes scoring system, has been used since that time to compare the extent of involvement of patients with cerebral disease, and to define progression. It correlates with clinical findings, as patients with symptomatic disease are likely to have a Loes score of 10 or higher. The pattern of white matter involvement is varied, but often the splenium is the area where changes are first observed, and in about 70% of the cases the cerebral disease is primarily located in the occipital area (Gupta et al, 2022).

For asymptomatic males with ALD who have normal MRI, management consists of close monitoring. Routine MRI surveillance allows for early detection of onset of cerebral involvement and may facilitate optimal early treatment with hematopoietic cell transplantation (HCT), which has emerged as the treatment of choice for individuals with early stages of cerebral involvement in ALD. HCT should not be undertaken in males without MRI evidence of cerebral involvement, because approximately one-half of this group will remain free of cerebral disease. The most appropriate candidates for HCT are boys with evidence of central nervous system involvement on MRI who are early in their disease course (i.e., mild or no signs and symptoms). Boys who undergo successful HCT at an early stage of disease have a five-year survival greater than 90 percent. However, HCT is not curative and myelopathy symptoms may develop in adulthood. Gene therapy may be an option for patients with cerebral ALD who do not have a matched related donor for HCT (Wanders and Eichler, 2022).

On September 16, 2022, the U.S. FDA granted Accelerated Approval of Skysona (elivaldogene autotemcel) to slow the progression of neurologic dysfunction in boys 4-17 years of age with early, active CALD. Early, active CALD refers to asymptomatic or mildly symptomatic (neurologic function score, NFS less than or equal to 1) boys who have gadolinium enhancement on brain MRI and Loes scores of 0.5-9. 

The safety and efficacy of elivaldogene autotemcel were assessed in two 24-month, open-label, single-arm studies, the Phase 2/3 study ALD-102 (n=32) and Phase 3 ALD-104 (n=35) study. Patients enrolled in these studies were diagnosed with early, active CALD as defined by Loes score between 0.5 and 9 (inclusive) and gadolinium enhancement (GdE+) on MRI, as well as a neurologic function score (NFS) of less than or equal to 1, indicating limited changes in neurologic function. The NFS was used to evaluate 15 domains of neurological function with a maximum score of 25. A total NFS=0 indicates absence of neurologic dysfunction or asymptomatic disease. All patients had elevated very long chain fatty acid (VLCFA) levels and confirmed mutations in the ABCD1 gene. All patients were administered elivaldogene autotemcel as an intravenous infusion with a median (min, max) dose of 12 × 10⁶ (5, 38.2) CD34+ cells/kg (N=67). The efficacy of elivaldogene autotemcel was compared to an external untreated natural history control. The Accelerated Approval of Skysona is based on 24-month Major Functional Disability (MFD)-free survival. The MFDs are defined as: loss of communication, cortical blindness, requirement for tube feeding, total incontinence, wheelchair dependence, or complete loss of voluntary movement. To be included in the analysis, patients had to have symptoms at baseline (NFS=1) or be asymptomatic (NFS=0) at baseline and have developed symptoms (NFS ≥ 1) during the course of follow-up in the study. Additionally, they had to have at least 24 months of follow-up after initial NFS ≥ 1 or have had an event (MFD or death). A post-hoc enrichment analysis in symptomatic patients assessed MFD-free survival from onset of symptoms (NFS ≥ 1) in elivaldogene autotemcel treated (N=11) and untreated patients (N=7). Elivaldogene autotemcel treated patients had an estimated 72 percent likelihood of MFD-free survival at 24 months from time of first NFS ≥ 1, compared to untreated patients who had only an estimated 43 percent likelihood of MFD-free survival. Study 1 (ALD-102) is complete and Study 2 (ALD-104) is ongoing at the time of product approval. There was insufficient duration of follow-up to assess efficacy in elivaldogene autotemcel treated patients who remained asymptomatic. All patients who completed the 24 months of follow-up in studies ALD-102 or ALD-104 were encouraged to participate in a long-term follow-up study (LTF-304) to continue monitoring safety and efficacy outcomes in boys treated with elivaldogene autotemcel through 15 years post-treatment (bluebird bio, 2022a, 2022b).

There were insufficient data to compare relative efficacy of elivaldogene autotemcel to the standard of care, allogeneic hematopoietic stem cell transplant (allo-HSCT) in the treatment of CALD. However, while it does not inform the efficacy analysis, comparison of elivaldogene autotemcel with an external allo-HSCT control was performed for overall survival (OS) due to concerns about treatment-related toxicities. OS was analyzed as time-to-event Kaplan-Meier estimates comparing elivaldogene autotemcel (entire efficacy population, n=61) to early, active allo-HSCT subpopulations by donor type: human leukocyte antigen (HLA)-Matched allo-HSCT Subpopulation (n=34) and HLA-Mismatched allo-HSCT Subpopulation (n=17). There were insufficient long-term data to compare OS beyond Month 24. However, a distinct difference in OS in the first 9 months following treatment was seen for the subpopulation who received allo-HSCT from an HLA-mismatched donor as compared to elivaldogene autotemcel and allo-HSCT from an HLA-matched donor. While this analysis does not provide evidence of efficacy of elivaldogene autotemcel, it does demonstrate a survival advantage of elivaldogene autotemcel as compared to allo-HSCT from an HLA-mismatched donor, with early mortality in the HLA-mismatched allo-HSCT Subpopulation largely attributed to allo-HSCT-related toxicities. No patient experienced acute (Grade II or higher) or chronic graft versus host disease (GVHD) after elivaldogene autotemcel treatment (bluebird bio, 2022b).

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Appendix

Table 1: MRI Severity Scale Scoring (Loes Score)

Region	Maximum Score
Parieto-occipital white matter	4
Anterior temporal white matter	4
Frontal white matter Periventricular Central Subcortical Local atrophy	4
Corpus callosum Splenium Genu Body Splenium atrophy Genu atrophy	5
Global atrophy Mild Moderate Severe Brainstem	4
Basal ganglia	1
Visual pathway Optic radiation Meyer’s loop Lateral geniculate body Optic tract	4
Auditory pathway Medial geniculate body Brachium of inferior colliculus Lateral lemniscus Pons	4
Cerebellum White matter Atrophy	2
Projection fibers Internal capsule Brain stem	2
Total	34

Each region is given a score of 0 for normal, 0.5 for unilateral involvement, and 1 for bilateral involvement or atrophy. The maximum score is 34.

Source: Table adapted from Kumar et al (2021) and Loes et al (1994)

Table 2: Neurologic Function Score (NFS) for CALD

Symptom / Neuroexam	Score
Hearing / auditory processing problems	1
Aphasia / apraxia	1
Loss of communication	3
Vision impairment / field cut	1
Cortical blindness	2
Swallowing difficulty / other central nervous system dysfunction	2
Tube feeding	2
Running difficulties / hyperreflexia	1
Walking difficulties / spasticity / spastic gait (no assistance)	1
Spastic gait (needs assistance)	2
Wheelchair dependence	2
Complete loss of voluntary movement	3
Episodes of urinary or fecal incontinence	1
Total urinary or fecal incontinence	2
Nonfebrile seizures	1
Possible Total	25

A score of zero denotes absence of clinical signs of cerebral disease. Maximal signs within a domain score the total of all grades within that domain (for example, a patient with “total urinary or fecal incontinency” scores 3, for the sum of episodes of incontinency [n = 1] and total incontinency [n = 2]).

Source: Miller et al (2016)

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References