Skysona (elivaldogene autotemcel) is a gene therapy indicated to treat cerebral adrenoleukodystrophy.
In mid-September 2022, the U.S. Food and Drug Administration (FDA) approved Skysona to slow the progression of neurological dysfunction in boys 4–17 years old with early, active cerebral adrenoleukodystrophy (CALD). Approval is conditional, meaning the drug has yet to be definitively validated for efficacy.
Early, active cerebral adrenoleukodystrophy is defined as a disease characterized by an asymptomatic course or with mild symptoms (neurological function score, NFS ≤ 1), the presence of gadolinium enhancement on brain MRI imaging and a Loes score ranging from 0.5 to 9.
Skysona, developed by Bluebird Bio, is used once.
The cost of Skysona in the United States is set at $3 million.
What Is Cerebral Adrenoleukodystrophy
Adrenoleukodystrophy (ALD) is an X-linked metabolic disorder characterized by elevated toxic levels of very long chain fatty acids (VLCFAs) that accumulate in body tissues, leading to adrenal insufficiency and neurodegeneration.
Adrenoleukodystrophy develops due to loss-of-function mutations (over 750 different mutations have been identified) in the ABCD1 gene located on the X chromosome. The ABCD1 gene codes for the protein ALDP, which is present on peroxisome membranes and is responsible for the transport and degradation of VLCFAs.
ALDP deficiency determines a high concentration of VLCFAs, which leads to their pathological accumulation in the plasma and tissues, including the white matter of the brain, spinal cord, and adrenal cortex. This is reflected by endocrine disorders (adrenal insufficiency, testicular insufficiency), progressive myelopathy, peripheral neuropathy, leukodystrophy.
Cerebral adrenoleukodystrophy (CALD), being the most severe form of ALD, is characterized by demyelinating lesions affecting the cerebral hemispheres. The most common phenotype is CALD with early onset, that is, developing in childhood.
Cerebral adrenoleukodystrophy, which manifests at the age of 3–10 years and progresses rapidly, leads to visual and hearing impairment, gait difficulties, seizures, cognitive impairment, limb weakness and rigidity with eventual loss of voluntary movements, loss of communication ability, incontinence, deafness and cortical blindness. Complete neurodegeneration to a vegetative state is noted within two years; death occurs within four years of onset.
Adrenoleukodystrophy, also known as Addison–Schilder disease and Siemerling–Creutzfeldt disease, is a rare genetic pathology: 1 case per 5,000–17,000 newborns (boys and girls) and 1 case per 20,000–30,000 newborn boys. The cerebral form of adrenoleukodystrophy develops in 35%–40% of boys with ALD.
Healing treatment for cerebral adrenoleukodystrophy involves allogeneic hematopoietic stem cell transplantation (allo-HSCT), but the procedure is done only in the early stages of the disease, is associated with limited availability of HLA-matched related donors (they are not available in more than 70% of cases) and is characterized by risks of graft rejection and graft-versus-host disease (GvHD).
Otherwise, treatment of CALD is limited to supportive symptomatic therapy, including dietary restrictions and administration of a dietary supplement, Lorenzo’s oil (a 4:1 mixture of glycerol trioleate and glycerol trierucate), which inhibits elongation of saturated fatty acids in the body.
How Skysona Works
Elivaldogene autotemcel is a lentiviral vector (Lenti-D LVV) encoding DNA complementary to ABCD1 gene. 
Patients undergo hematopoietic stem cell mobilization with granulocyte colony-stimulating factor (GCSF) followed by apheresis to extract peripheral blood mononuclear cells (PBMCs) and immunomagnetic procedure to separate CD34+ cells, which are then ex vivo pre-activated with cytokine set and transduced with Lenti-D LVV to add functional copies of ABCD1 complementary DNA.
Patients then undergo full myeloablative and lymphodepleting chemotherapeutic conditioning with busulfan and cyclophosphamide (for successful autograft engraftment), followed by a single intravenous infusion of modified CD34+ cells. The latter take root in the bone marrow, where they differentiate into various cell types, including monocytes (CD14+) that migrate to the brain, where they differentiate into macrophages and microglia expressing ALDP protein. It is used to locally breakdown very long chain fatty acids (VLCFAs) that accumulate toxically in cerebral adrenoleukodystrophy. The result is stabilization of the disease with slowing down and prevention of inflammation and demyelination.
The beneficial effect of Skysona lasts for life.
No other beneficial therapeutic effects associated with the manifestations of the disease, including adrenal insufficiency and adrenomyeloneuropathy, should be expected from Skysona.
Efficacy and Safety of Skysona Gene Therapy
Clinical trials (non-randomized, open-label, multicenter, international) completed STARBEAM/ALD-102 (NCT01896102) phase 2/3 and ongoing ALD-104 (NCT03852498) phase 3 invited male patients (n=67) under 17 years of age with cerebral adrenoleukodystrophy.
Among the main participation criteria: cerebral adrenoleukodystrophy with early onset; disease in active form (Loes score between 0.5 to 9 and gadolinium enhancement on MRI imaging of demyelinating lesions), neurological function score (NFS) ≤ 1, indicating limited neurological deterioration.
Subjects received a single intravenous infusion of elivaldogene autotemcel at a median dose of 11.8×106 cells/kg (5.0–38.2).
After 2 years of follow-up after undergoing gene therapy for early, cerebral adrenoleukodystrophy with Skysona, 91.1% (95% CI: 78.8 to 97.5) of patients had an event-free survival (EFS): remained alive, had none of the six major functional disability (loss of communication, cortical blindness, tube feeding, total incontinence, wheelchair dependence, complete loss of voluntary movement), did not require an allogeneic hematopoietic stem cell transplantation, and had not experienced myelodysplastic syndrome.
After 3, 4, and 5 years, EFS was fair for 90.6% (95% CI: 75.0 to 98.0), 87.0% (95% CI: 66.4 to 97.2), and 82.4% (95% CI: 56.6 to 96.2) of patients who fell within the relevant follow-up period (n=32, n=23, and n=17).
According to the LTF-304 (NCT02698579) long-term clinical trial, at 7 years after administration of elivaldogene autotemcel, EFS was reported for 86.8% (95% CI: 72.7 to 93.9) of patients.
- By comparison, EFS at 2 and 7 years after diagnosis of cerebral adrenoleukodystrophy left untreated is 57.1% (95% CI: 17.2 to 83.7) and 38.1% (95% CI: 6.1 to 71.6).
- By comparison, EFS after 2 years after undergoing autologous hematopoietic stem cell transplantation is 87.1% (95% CI: 69.2 to 95.0), 70.6% (95% CI: 43.1 to 86.6), 90.0% (95% CI: 47.3 to 98.5), and 42.9% (95% CI: 9.8 to 73.4) for HLA-matched related donor, HLA-unmatched related donor, HLA-matched unrelated donor, and HLA-unmatched unrelated donor, respectively.
At 2 and 5 years after administration of Skysona, most patients (82.8% and 85.7%) retained their pre-treatment neurological function performance, and most had normal intelligence quotient (median IQ of 96.0 and 97.0).
Thus, Skysona is a gene therapy that can completely cure cerebral adrenoleukodystrophy.
The prescribing information for Skysona is marked with a boxed warning about the risk of hematologic malignancies, including life-threatening myelodysplastic syndrome (MDS). It was encountered in 4% of patients (n=3/67) and was diagnosed 1.2, 2.1, and 7.5 years after administration of Skysona, respectively, and allogeneic hematopoietic stem cell transplantation had to be resorted to for treatment. Such complications of elivaldogene autotemcel appear to be related to the integration of the lentiviral vector into proto-oncogenes (e.g., MECOM, PRDM16). Periodic monitoring of patients for signs of hematologic malignancy with a complete blood count every six months is recommended.
The FDA also expressed concern about the potential development of MDS in four other children who had an increased relative frequency of integration into proto-oncogenes.
No cases of acute or chronic graft-versus-host disease have been reported.
Skysona made its debut in mid-July 2021, when the European Medicines Agency (EMA) authorized it for the treatment of early cerebral adrenoleukodystrophy in patients under 18 with an ABCD1 genetic mutation for whom HLA-matched related donor of hematopoietic stem cells is not available.
However, very soon, in mid-November 2021, Bluebird withdrew Skysona’s marketing authorization due to the final realization that costly gene therapy is unlikely to catch on among the frugal European countries, whose governments are not adequately aware of the long-term economic benefits of such medical techniques that dramatically alter the course of severe and life-threatening diseases.
Bluebird’s decision was mainly due to the commercial failure of the gene therapy Zynteglo (betibeglogene autotemcel) for the treatment of transfusion-dependent beta-thalassemia. The European price of Zynteglo, administered once, was set at €1.575 million ($1.77 million), which proved to be an unaffordable sum for state budgets.
One dose of betibeglogene autotemcel will permanently eliminate the dependence on regular blood transfusions.
The United States market, being the most desirable for any pharmaceutical manufacturer, is structured differently, and drug prices, even though they are astronomical and generally unregulated in any way, have essentially no effect on demand. If health insurance providers are convinced that gene therapy, which actually cures cerebral adrenoleukodystrophy, is justified, American patients will receive Skysona without any delay.
Approximately 50 new cases of cerebral adrenoleukodystrophy are diagnosed in the United States each year, and Bluebird is prepared to cure one in five, so the commercial prospects for Skysona are very slim. On the contrary, there are many more patients with beta-thalassemia that can be cured with the gene therapy Zynteglo.
The main complaint about Skysona is the risk of developing myelodysplastic syndrome, which, however, can be treated with hematopoietic stem cell transplantation. Again, the risk, which is relatively low, is outweighed by the clear therapeutic benefits of treatment.
Meanwhile, in mid-September 2022, Spain’s Mynorix Therapeutics submitted an application to the EMA for authorization of leriglitazone for the treatment of X-linked adrenoleukodystrophy.
In a 96-week ADVANCE (NCT03231878) phase 2/3 clinical trial among adult male patients (n=116) with X-linked adrenoleukodystrophy with adrenomyeloneuropathy phenotype, administration of leriglitazone provided control of progression of brain lesions, including development of cerebral adrenoleukodystrophy, and myelopathy symptoms such as balance deterioration.
The NEXUS (2019-000654-59) phase 2/3 clinical trial, which tests the hypothesis of whether leriglitazone can stop the progression of cerebral adrenoleukodystrophy in boys 2–12 years old before a hematopoietic stem cell transplantation, is ongoing.
Leriglitazone (MIN-102) is a selective peroxisome proliferator-activated receptor gamma (PPARγ) agonist. Oral leriglitazone, as a metabolite of pioglitazone, activates PPARγ, thus modulating the expression of genes involved in mitochondrial biogenesis (PGC-1a), and therefore restores lost energy balance, reduces oxidative stress and restores mitochondrial function impaired by very long chain fatty acids (VLCFAs) accumulation. Leriglitazone enhances the expression of genes involved in oligodendrocyte differentiation (olig2, neuroD1), promoting remyelination by improving oligodendrocyte survival and differentiation, and modulates neurotrophin levels, leading to improved neuronal survival. Leriglitazone interacts with the inflammatory pathway active in adrenoleukodystrophy by reducing levels of NF-kB, inhibiting macrophage and microglia activation and the accompanying neuroinflammation. Leriglitazone reduces monocyte adhesion to endothelial cells of the blood–brain barrier (BBB), a mechanism that leads to disruption of BBB integrity and that plays an important role in the adrenoleukodystrophy phenotype. 
France’s Poxel is ready to conduct clinical trials NCT05200104 and NCT05146284 phase 2a of treatment for X-linked adrenoleukodystrophy with the adrenomyeloneuropathy phenotype with two experimental drugs, if funding is available, PXL065 and PXL770, an R-stereoisomer of pioglitazone stabilized by deuterium chemistry and a direct activator of adenosine monophosphate-activated protein kinase (AMPK), respectively.  
Viking Therapeutics is conducting the NCT04973657 phase Ib clinical trial of experimental VK0214, an oral selective thyroid hormone receptor beta (TRβ) agonist being studied in the treatment of adult patients with X-linked adrenoleukodystrophy with adrenomyeloneuropathy phenotype.
Skysona (elivaldogene autotemcel). Prescribing information. U.S. [PDF]
Skysona (elivaldogene autotemcel). Prescribing information. Europe [PDF]