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

gene therapy Gene therapy is Health technology, medical technology that aims to produce a therapeutic effect through the manipulation of gene expression or through altering the biological properties of living cells. The first attempt at modifying human DNA ...

used to treat cerebral

adrenoleukodystrophy Adrenoleukodystrophy (ALD) is a genetic disorder, disease linked to the X chromosome. It is a result of fatty acid buildup caused by failure of peroxisome#Metabolic functions, peroxisomal fatty acid beta oxidation which results in the accumulation ...

(CALD). It was developed by Bluebird Bio and was given breakthrough therapy designation by the US

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

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

hematopoietic Haematopoiesis (; ; also hematopoiesis in American English, sometimes h(a)emopoiesis) is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells. In a healthy adult human, roughly ten ...

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 Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to generate pictures of the anatomy and the physiological processes inside the body. MRI scanners use strong magnetic fields, magnetic field gradients, and rad ...

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 transplantation of organs, tissues, or even particular proteins from one part of the body to another in the same person ('' auto-'' meaning "self" in Greek). The autologous tissue (also called autogenous, autogenei ...

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 chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs (list of chemotherapeutic agents, chemotherapeutic agents or alkylating agents) in a standard chemotherapy re ...

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 nutr ...

. 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, ...

in the ABCD1 gene on the

X chromosome The X chromosome is one of the two sex chromosomes in many organisms, including mammals, and is found in both males and females. It is a part of the XY sex-determination system and XO sex-determination system. The X chromosome was named for its u ...

, which codes for the ALD protein that helps transport

very long chain fatty acid 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, V ...

s (VLCFAs) to

peroxisome 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 perox ...

s 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 Sheath ( ) is a lipid-rich material that in most vertebrates surrounds the axons of neurons to insulate them and increase the rate at which electrical impulses (called action potentials) pass along the axon. The myelinated axon can be lik ...

damage. ABCD1 deficient

macrophage Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...

s and

microglia Microglia are a type of glia, glial cell located throughout the brain and spinal cord of the central nervous system (CNS). Microglia account for about around 5–10% of cells found within the brain. As the resident macrophage cells, they act as t ...

cannot degrade VLCFAs from damaged myelin, causing further

neurotoxicity Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. It occurs when exposure to a substance – specifical ...

. 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 near the beginning of the package insert for certain prescription drugs, so called because the U.S. Food and Drug Administratio ...

for hematological cancers, as patients have developed

myelodysplastic syndrome A myelodysplastic syndrome (MDS) is one of a group of cancers in which 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 includ ...

(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) or full haemogram (FHG), is a set of medical laboratory tests that provide cytometry, information about the cells in a person's blood. The CBC indicates the counts of white blo ...

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 '' Betaherp ...

reactivation,

candidiasis Candidiasis is a fungal infection due to any species of the genus '' Candida'' (a 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 ...

, and

bacteremia Bloodstream infections (BSIs) are infections of blood caused by blood-borne pathogens. The detection of microbes in the blood (most commonly accomplished by blood cultures) is always abnormal. A bloodstream infection is different from sepsis, wh ...

. Patients have exhibited prolonged

cytopenia Cytopenia is a reduction in the number of mature blood cells. It can have many causes, and commonly occurs in people with cancer being treated with radiation therapy or chemotherapy. Types * Anemia – a reduction of the red blood cells in the bo ...

s, 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 cou ...

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

anaphylaxis Anaphylaxis (Greek: 'up' + 'guarding') is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of the use of emergency medication on site. It typicall ...

, due to

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

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

anorexia Anorexia nervosa (AN), often referred to simply as anorexia, is an eating disorder characterized by Calorie restriction, food restriction, body image disturbance, fear of gaining weight, and an overpowering desire to be thin. Individuals wit ...

(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 (G ...

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

pyrexia Fever or pyrexia in humans is a symptom of an anti-infection defense mechanism that appears with body temperature exceeding the normal range caused by an increase in the body's temperature set point in the hypothalamus. There is no single agre ...

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

epistaxis A nosebleed, also known as epistaxis, is an instance of 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 significan ...

(19%),

pruritis An itch (also known as pruritus) is a sensation that causes a strong desire or reflex to scratch. Itches have resisted many attempts to be classified as any one type of sensory experience. Itches have many similarities to pain, and while both ...

(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 A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...

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

History

Elivaldogene autotemcel was designated an

orphan drug An orphan drug is a medication, pharmaceutical agent that is developed to treat certain rare medical conditions. An orphan drug would not be profitable to produce without government assistance, due to the small population of patients affected by th ...

by the

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of pharmaceutical products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products ...

(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 "b ...

designations by the US

(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 the Committee for Proprietary Medicinal Products (CPMP), is the European Medicines Agency's committee responsible for elaborating the agency's opinions on all issues regar ...

(CHMP) of the

(EMA) recommended the granting of a marketing authorization for elivaldogene autotemcel. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged. Text was copied from this source which is copyright 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.

References

{{DEFAULTSORT:Elivaldogene Autotemcel Approved gene therapies Orphan drugs