ELIVALDOGENE AUTOTEMCEL (SKYSONA)
Elivaldogene autotemcel (Skysona), an autologous hematopoietic stem cell
–based gene therapy, is indicated to slow the progression of
neurologic dysfunction in boys 4 to 17 years of age with early, active cerebral adrenoleukodystrophy (CALD). In earlier stages, active CALD presents in asymptomatic or mildly symptomatic boys (neurologic function score
[NFS] ≤1) who have gadolinium enhancement on brain magnetic resonance imaging (MRI) and Loes
scores* of 0.5 to 9 points. This indication was approved under accelerated approval based on 24-month major functional disability (MFD)-free survival. Continued US Food and Drug Administration (FDA) approval for this indication may be contingent on
verification and description of clinical benefit in confirmatory trials.
Elivaldogene autotemcel (Skysona) is given as a single dose by
intravenous infusion; the minimum recommended dose is 5.0
× 106 CD34+ cells/kg.
*The Loes score is an adrenoleukodystrophy (ALD) MRI score, which rates the severity of white matter lesions and ranges from 0 (normal) to 34 (abnormal). Loes in 1994 developed an imaging-based scoring system for patients with X-ALD based on the neuroanatomical involvement and the presence or absence of total and/or global atrophy. This 34-point imaging-based severity scale was based on the location and extent of central nervous system involvement and presence of either focal or global atrophy.
CEREBRAL ADRENOLEUKODYSTROPHY (CALD)
CALD is a rare, neurodegenerative, X-linked genetic disease in young boys that mainly
affects the nervous system and adrenal glands. The estimated incidence of ALD is 1:20,000
to 1:30,000 males. It is caused by a defect in the adenosine triphosphate–binding cassette, subfamily D, member
1 (ABCD1) gene. Very-long-chain fatty acids accumulate, which causes inflammation in and damage to the brain;
other tissue types are also impacted. Around 40% of individuals with ALD will develop CALD, which is associated with rapid, progressive cerebral demyelination that usually occurs
when individuals are 3 to 12 years of age. Early stages of CALD are clinically
asymptomatic and are only detected by performing an MRI of the brain. Irreversible, devastating neurologic
decline can result, which include major functional disabilities (MFDs) such as loss of communication, cortical blindness, dependence on tube
feeding, total incontinence, use of a wheelchair for ambulation, or complete loss of voluntary movement. As the
disease progresses, individuals often develop profound disability. If an allogeneic hematopoietic stem cell
transplantation (HSCT) is not performed, almost one-half of impacted individuals will likely die within 5 years of
symptom onset.
CLINICAL EFFICACY
The efficacy of elivaldogene autotemcel (Skysona) was assessed in two 24-month, open-label, single arm, single-dose, multicenter,
multinational pivotal trials involving male individuals 17 years of age or younger, with early, active CALD as defined by its FDA-approved indication. STARBEAM (ALD-102) (published data in
17 individuals; n=32) was a Phase 2/3 investigation that is completed and involved individuals who did not have a
matched sibling donor for allogeneic HSCT. Study 2 (ALD-104) (unpublished; n=35) is an ongoing study in individuals with a matched sibling donor for allogeneic HSCT. Elivaldogene autotemcel (Skysona) was compared with a
natural history population, as well as individuals who underwent allogeneic HSCT. Individuals in both studies could
enroll in a long-term follow-up study (LTF-304). It should be noted that individuals involved in these two studies had
elevated very-long-chain fatty acid levels and confirmed mutations in the ABCD1 gene. In the published
STARBEAM study, at the time of the interim analysis (April 2017), 17 boys had received elivaldogene autotemcel (Skysona) with a
median follow-up of 29.4 months (range, 21.6 to 42.0 months). In total, 88% of individuals (n=15/17) who received
elivaldogene autotemcel (Skysona) were alive and free of an MFD; all maintained an NFS score of 0 to 1.5 In the symptomatic elivaldogene autotemcel (Skysona) subpopulation (n=11); slower progression to MFD or death (MFD-free survival) from time of symptom onset
(first NFS≥1) was observed compared with a similar natural history population (n=7). Data involving the
entire efficacy population (n=61) analyzed overall survival compared to early, active allogeneic HSCT
subpopulations by various donor type (human leukocyte antigen [HLA]-matched allogeneic HSCT subpopulation
[n = 34] and HLA-mismatched allogeneic HSCT subpopulation [n=17]). A reduced overall survival was noted in
the first 9 months after treatment among the subpopulation who received allogeneic HSCT from an HLA-mismatched donor compared with elivaldogene autotemcel (Skysona), as well as the group who received an allogeneic HSCT from an
HLA-matched donor. The earlier mortality in the HLA-mismatched allogeneic
HSCT subpopulation was mainly due to allogeneic HSCT-related toxicities.
In one individual involved in the elivaldogene autotemcel (Skysona) clinical trials
who had a full ABCD1 gene deletion, disease progression occurred. The individual experienced
radiologic disease progression, along with declining peripheral blood vector copy number, suggesting a
loss of product efficacy that may have been immune mediated. The individual eventually underwent
allogeneic HSCT. A noted limitation of use is that an immune response to elivaldogene autotemcel (Skysona) may
limit the persistence of descendent cells of Skysona, causing rapid loss of efficacy of Skysona in
individuals with full deletions of the ABCD1 transgene.
Allogeneic transplant was an exclusion criterion in
the pivotal studies.
Prior receipt of gene therapy was an exclusion criterion in the pivotal studies.
GUIDELINES
Elivaldogene autotemcel (Skysona) has not been addressed in guidelines post FDA-approval. Prior to FDA approval of elivaldogene autotemcel (Skysona) in September 2022, international
recommendations for the diagnosis and management of individuals with ALD (a consensus-based approach) were published. It was noted that allogeneic HSCT is the standard treatment for CALD and can halt progression. Genetically transduced autologous stem cell
transplantation (gene therapy [Skysona]) should be considered (if available) in boys if allogeneic donor options
are poor. Outcome is poor in individuals with advanced disease (Loes score greater than 9 and/or NFS greater than
1). Regarding gene therapy (elivaldogene autotemcel [Skysona]), the recommendation states that this therapy is not available for routine care; long-term
safety data are not yet available. Treatment for boys or men with advanced disease or progressive lesions
without gadolinium enhancement should only be considered after careful assessment in experienced centers.
SUMMARY
CALD is a rare, progressive and irreversible genetic neurodegenerative disease that is caused by mutations in the ABCD1 gene that affect the production of ADL protein (ALDP) and subsequently leads to build-up 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% to 90% of male individuals with symptomatic cerebral disease die or progress to a vegetative state within several years (Gupta et al., 2022).
ALD is an X-linked peroxisomal disorder that is much more prominent in male individuals, with an incidence of 1 in 14,000 to 17,000 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 female individuals 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% in females under age 40 to almost 90% 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 MRI. An MRI-based severity score was devised by Loes et al., utilizing a 0 to 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 results, 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 5-year survival greater than 90%. 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 FDA granted accelerated approval of elivaldogene autotemcel (Skysona) to slow the progression of neurologic dysfunction in boys 4 to 17 years of age with early, active CALD. Early, active CALD refers to asymptomatic or mildly symptomatic boys (NFS less than or equal to 1) who have gadolinium enhancement on brain MRI and Loes scores between 0.5 and 9.
The safety and efficacy of elivaldogene autotemcel (Skysona) 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. Individuals 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 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 of 0 indicates absence of neurologic dysfunction or asymptomatic disease. All individuals had elevated very-long-chain fatty acid (VLCFA) levels and confirmed mutations in the ABCD1 gene. All individuals were administered elivaldogene autotemcel (Skysona) as an intravenous infusion with a median (minimum, maximum) dose of 12 × 106 (5, 38.2) CD34+ cells/kg (N=67). The efficacy of elivaldogene autotemcel (Skysona) was compared to an external untreated natural history control. The accelerated approval of elivaldogene autotemce (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, individuals 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 individuals assessed MFD-free survival from onset of symptoms (NFS≥1) in elivaldogene autotemcel (Skysona)–treated (N=11) and untreated individuals (N=7). Elivaldogene autotemcel (Skysona)–treated individuals had an estimated 72% likelihood of MFD-free survival at 24 months from time of first NFS≥1, compared to untreated individuals who had only an estimated 43% 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 (Skysona)–treated individuals who remained asymptomatic. All individuals 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 (Skysona) through 15 years post-treatment (Bluebird bio, 2022a, 2022b).
There were insufficient data to compare relative efficacy of elivaldogene autotemcel (Skysona) to the standard of care, allo-HSCT, in the treatment of CALD. However, although it does not inform the efficacy analysis, comparison of elivaldogene autotemcel (Skysona) 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 (Skysona) (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 (Skysona) and allo-HSCT from an HLA-matched donor. Although this analysis does not provide evidence of efficacy of elivaldogene autotemcel (Skysona), it does demonstrate a survival advantage of elivaldogene autotemcel (Skysona) 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 individual experienced acute (Grade II or higher) or chronic graft-versus-host disease (GVHD) after elivaldogene autotemcel (Skysona) treatment (bluebird bio, 2022b).
