Elivaldogene autotemcel, sold under the brand name Skysona, is a

gene therapy Gene therapy is a medical field which focuses on the genetic modification of cells to produce a therapeutic effect or the treatment of disease by repairing or reconstructing defective genetic material. The first attempt at modifying human D ...

used to treat cerebral

adrenoleukodystrophy Adrenoleukodystrophy (ALD) is a disease linked to the X chromosome. It is a result of fatty acid buildup caused by peroxisomal fatty acid beta oxidation which results in the accumulation of very long chain fatty acids in tissues throughout the b ...

(CALD). It was developed by Bluebird bio and was given breakthrough therapy designation by the U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

in May 2018. Elivaldogene autotemcel is made specifically for each recipient, using the recipient's

hematopoietic Haematopoiesis (, from Greek , 'blood' and 'to make'; also hematopoiesis in American English; sometimes also h(a)emopoiesis) is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells ...

stem cells. It was approved for medical use by the U.S. Food and Drug Administration in September 2022.

Medical uses

Elivaldogene autotemcel is indicated for the treatment of people with early, active CALD in boys aged 4 to 17 for whom a matched hematopoietic stem cell donor is not available. Early, active CALD refers to asymptomatic or mildly symptomatic boys with gadolinium enhancement on brain MRI and a Loes score of 0.5-9, a scale that rates the severity of CALD white matter lesions on a scale of 0 (normal) to 34 (abnormal) in adrenoleukodystrophy. Elivaldogene autotemcel is a form of

autologous Autotransplantation is the organ transplantation, transplantation of Organ (anatomy), organs, Biological tissue, tissues, or even particular proteins from one part of the body to another in the same person (''wikt:auto-, auto-'' meaning "self" ...

hematopoietic stem cell therapy where stem cells are mobilized and collected from the patient and genetically modified to carry a functional copy of the ABCD1 gene using a lentiviral vector. Patients undergo myeloablative

chemotherapy Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemothe ...

conditioning to kill stem cells in the bone marrow before infusion with elivaldogene autotemcel, which allows their modified stem cells to replace stem cells lacking a functional copy of the ABCD1 gene. Elivaldogene autotemcel is a one-time treatment given as an autologous

intravenous infusion Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...

. Dose depends on the patient's body weight. One infusion of elivaldogene autotemcel is expected to last for a patient's lifetime; follow-up studies have shown that 90% of patients have reached 24 months of major functional disabilities (MFD)-free survival, and 14 patients have reached their five-year follow-up visit MFD-free.

Mechanism of action

Cerebral adrenoleukodystrophy is caused by a

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...

in the

ABCD1 ABCD1 is a protein that transfers fatty acids into peroxisomes. Function The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and i ...

gene on the

X chromosome The X chromosome is one of the two sex-determining chromosomes ( allosomes) in many organisms, including mammals (the other is the Y chromosome), and is found in both males and females. It is a part of the XY sex-determination system and XO se ...

, which codes for the ALD protein that helps transport

very long chain fatty acids A very-long-chain fatty acid (VLCFA) is a fatty acid with 22 or more carbons. Their biosynthesis occurs in the endoplasmic reticulum. VLCFA's can represent up to a few percent of the total fatty acid content of a cell. Unlike most fatty acids, VL ...

(VLCFAs) to

peroxisomes A peroxisome () is a membrane-bound organelle, a type of microbody, found in the cytoplasm of virtually all eukaryotic cells. Peroxisomes are oxidative organelles. Frequently, molecular oxygen serves as a co-substrate, from which hydrogen pe ...

for degradation. Patients with a dysfunctional ABCD1 gene lack a functional ALD protein, causing VLCFAs to improperly degrade and abnormally accumulate in the blood and central nervous system. Improperly degraded VLCFAs cross the blood-brain barrier and incorporate inappropriately in the white matter, causing

myelin Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can be l ...

damage. ABCD1 deficient

macrophages Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...

and

microglia Microglia are a type of neuroglia (glial cell) located throughout the brain and spinal cord. Microglia account for about 7% of cells found within the brain. As the resident macrophage cells, they act as the first and main form of active immune ...

cannot degrade VLCFAs from damaged myelin, causing further neurotoxicity. Treatment with elivaldogene autotemcel adds functional copies of the ABCD1 gene using a lentiviral vector, which integrates the functional gene into the stem cell genome. Modified bone marrow replaces dysfunctional bone marrow with elivaldogene autotemcel infusion, which allows differentiated hematopoietic cells to breakdown VLCFAs in the blood and brain, slowing or stabilizing the progression of CALD.

Adverse effects

Elivaldogene autotemcel has a

black box warning In the United States, a boxed warning (sometimes "black box warning", colloquially) is a type of warning that appears on the package insert for certain prescription drugs, so called because the U.S. Food and Drug Administration specifies that it ...

for hematological malignancy, as patients have developed

myelodysplastic syndrome A myelodysplastic syndrome (MDS) is one of a group of cancers in which immature blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may ...

(MDS) due to lentiviral integration into

proto-oncogenes An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.

. Patients must be monitored with a

complete blood count A complete blood count (CBC), also known as a full blood count (FBC), is a set of medical laboratory tests that provide information about the cells in a person's blood. The CBC indicates the counts of white blood cells, red blood cells and ...

once every six months for fifteen years after treatment for evidence of MDS. Serious opportunistic infections have occurred, including

cytomegalovirus ''Cytomegalovirus'' (''CMV'') (from ''cyto-'' 'cell' via Greek - 'container' + 'big, megalo-' + -''virus'' via Latin 'poison') is a genus of viruses in the order '' Herpesvirales'', in the family '' Herpesviridae'', in the subfamily '' Betahe ...

reactivation,

candidiasis Candidiasis is a fungal infection due to any type of '' Candida'' (a type of yeast). When it affects the mouth, in some countries it is commonly called thrush. Signs and symptoms include white patches on the tongue or other areas of the mouth ...

, and

bacteremia Bloodstream infections (BSIs), which include bacteremias when the infections are bacterial and fungemias when the infections are fungal, are infections present in the blood. Blood is normally a sterile environment, so the detection of microb ...

. Patients have exhibited prolonged

cytopenias Cytopenia is a reduction in the number of mature blood cells. It is common in cancer patients being treated with radiation and/or chemotherapy. Types Anemia – a reduction of the red blood cells in the body. Leukopenia – a deficiency of whit ...

, including

pancytopenia Pancytopenia is a medical condition in which there is significant reduction in the number of almost all blood cells (red blood cells, white blood cells, platelets, monocytes, lymphocytes, etc.). If only two parameters from the complete blood coun ...

, over one year following infusion. Patients may exhibit hypersensitivity reactions, including

anaphylaxis Anaphylaxis is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of use of emergency medication on site. It typically causes more than one of the follo ...

, due to

dimethyl sulfoxide Dimethyl sulfoxide (DMSO) is an organosulfur compound with the formula ( CH3)2. This colorless liquid is the sulfoxide most widely used commercially. It is an important polar aprotic solvent that dissolves both polar and nonpolar compounds ...

in elivaldogene autotemcel. The most common adverse effects during mobilization and conditioning include nausea (79%), vomiting (72%),

anorexia Anorexia nervosa, often referred to simply as anorexia, is an eating disorder characterized by low weight, food restriction, body image disturbance, fear of gaining weight, and an overpowering desire to be thin. ''Anorexia'' is a term of Gre ...

(42%), catheter site pain (39%), constipation (30%), headache (24%), abdominal pain (21%), and rash (13%). The most common side effects in the first 60 days after treatment include

mucositis Mucositis is the painful inflammation and ulceration of the mucous membranes lining the digestive tract, usually as an adverse effect of chemotherapy and radiotherapy treatment for cancer. Mucositis can occur anywhere along the gastrointestinal ...

(88%), febrile neutropenia (73%), alopecia (72%), abdominal pain (33%), vomiting (31%), anorexia (31%),

pyrexia Fever, also referred to as pyrexia, is defined as having a temperature above the normal range due to an increase in the body's temperature set point. There is not a single agreed-upon upper limit for normal temperature with sources using val ...

(27%), nausea (27%), constipation (21%), diarrhea (21%),

epistaxis A nosebleed, also known as epistaxis, is bleeding from the nose. Blood can flow down into the stomach, and cause nausea and vomiting. In more severe cases, blood may come out of both nostrils. Rarely, bleeding may be so significant that low bloo ...

(19%),

pruritis Itch (also known as pruritus) is a sensation that causes the desire or reflex to scratch. Itch has resisted many attempts to be classified as any one type of sensory experience. Itch has many similarities to pain, and while both are unpleasant s ...

(18%), headache (16%), oropharyngeal pain (16%), skin hyperpigmentation (16%), and anxiety (15%). The most common side effects between 60 days and 1 year after treatment include pyrexia (9%) and vomiting (6%). The most common side effects 1 year after treatment include

seizure An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with l ...

(15%) and myelodysplastic syndrome (6%).

History

Elivaldogene autotemcel was designated an

orphan drug An orphan drug is a pharmaceutical agent developed to treat medical conditions which, because they are so rare, would not be profitable to produce without government assistance. The conditions are referred to as orphan diseases. The assignment o ...

by the European Medicines Agency (EMA) in 2012. Elivaldogene autotemcel was granted

, rare pediatric disease, and

breakthrough therapy Breakthrough therapy is a United States Food and Drug Administration designation that expedites drug development that was created by Congress under Section 902 of the 9 July 2012 Food and Drug Administration Safety and Innovation Act. The FDA's " ...

designations by the U.S.

(FDA). In September 2022, elivaldogene autotemcel was granted accelerated approval. On 20 May 2021, the

Committee for Medicinal Products for Human Use The Committee for Medicinal Products for Human Use (CHMP), formerly known as Committee for Proprietary Medicinal Products (CPMP), is the European Medicines Agency's committee A committee or commission is a body of one or more persons subordin ...

(CHMP) of the European Medicines Agency (EMA) recommended the granting of a marketing authorization for elivaldogene autotemcel. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged. The applicant was Bluebird Bio (Netherlands) B.V. In July 2021, the European Commission approved elivaldogene autotemcel under the tradename Skysona for CALD patients who have certain genetic mutations and don't have a sibling who is a match for a stem cell transplant. In July 2021, after receiving marketing authorization through the EMA, bluebird bio reported it planned to close operations and clinical trials in Europe, citing an inability to come to an agreement regarding reimbursement for therapy cost. This decision came after the withdrawal of Zynteglo, a gene therapy for severe beta thalassemia, from Germany in 2021 due to similar difficulties in reaching reimbursement agreements. The first commercial infusion with elivaldogene autotemcel was completed in March 2023.

Society and culture

Names

Elivaldogene autotemcel is the recommended international nonproprietary name (INN).

Pricing

One course of treatment with elivaldogene autotemcel costs $3.0 million. As of May 2023, it is the second most expensive drug in the US.