Elivaldogene autotemcel

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Elivaldogene autotemcel
Clinical data
Trade names Skysona
Other namesLenti-D, eli-cel
License data
Routes of
administration 		Intravenous
ATC code
Legal status
Legal status
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DrugBank
UNII
KEGG

Elivaldogene autotemcel, sold under the brand name Skysona, is a gene therapy used to treat cerebral adrenoleukodystrophy (CALD). It was developed by Bluebird Bio and was given breakthrough therapy designation by the US Food and Drug Administration in May 2018. [5]

Contents

Elivaldogene autotemcel is made specifically for each recipient, using the recipient's hematopoietic stem cells. [6]

It was approved for medical use by the U.S. Food and Drug Administration in September 2022. [7] [8]

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. [9] [10] 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. [11]

Elivaldogene autotemcel is a form of autologous 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. [12] Patients undergo myeloablative chemotherapy 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. [13]

Elivaldogene autotemcel is a one-time treatment given as an autologous intravenous infusion. 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. [14]

Mechanism of action

Cerebral adrenoleukodystrophy is caused by a mutation in the ABCD1 gene on the X chromosome, which codes for the ALD protein that helps transport very long chain fatty acids (VLCFAs) to peroxisomes for degradation. [15] 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 damage. [16] ABCD1 deficient macrophages and microglia cannot degrade VLCFAs from damaged myelin, causing further neurotoxicity. [17] 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. [18]

Adverse effects

Elivaldogene autotemcel has a black box warning for hematological cancers, as patients have developed myelodysplastic syndrome (MDS) due to lentiviral integration into proto-oncogenes. [19] [20] Patients must be monitored with a complete blood count once every six months for fifteen years after treatment for evidence of MDS. Serious opportunistic infections have occurred, including cytomegalovirus reactivation, candidiasis, and bacteremia. Patients have exhibited prolonged cytopenias, including pancytopenia, over one year following infusion. Patients may exhibit hypersensitivity reactions, including anaphylaxis, due to dimethyl sulfoxide in elivaldogene autotemcel. [21]

The most common adverse effects during mobilization and conditioning include nausea (79%), vomiting (72%), anorexia (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 (88%), febrile neutropenia (73%), alopecia (72%), abdominal pain (33%), vomiting (31%), anorexia (31%), pyrexia (27%), nausea (27%), constipation (21%), diarrhea (21%), epistaxis (19%), pruritis (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 (15%) and myelodysplastic syndrome (6%). [22]

History

Elivaldogene autotemcel was designated an orphan drug by the European Medicines Agency (EMA) in 2012. [23]

Elivaldogene autotemcel was granted orphan drug, rare pediatric disease, and breakthrough therapy designations by the US Food and Drug Administration (FDA). [24] In September 2022, elivaldogene autotemcel was granted accelerated approval. [25]

On 20 May 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended the granting of a marketing authorization for elivaldogene autotemcel. [26] [6] The applicant was Bluebird Bio (Netherlands) B.V. [6] 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. [27]

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. [28] 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. [29]

The first commercial infusion with elivaldogene autotemcel was completed in March 2023. [30]

Society and culture

Names

Elivaldogene autotemcel is the recommended international nonproprietary name (INN). [31]

Pricing

One course of treatment with elivaldogene autotemcel costs $3.0 million. [32] As of May 2023, it is the second most expensive drug in the US. [33]

Related Research Articles

<span class="mw-page-title-main">Gene therapy</span> Medical technology

Gene therapy is a medical technology that aims to produce a therapeutic effect through the manipulation of gene expression or through altering the biological properties of living cells.

<span class="mw-page-title-main">Adrenoleukodystrophy</span> Medical condition

Adrenoleukodystrophy (ALD) is a disease linked to the X chromosome. It is a result of fatty acid buildup caused by failure of peroxisomal fatty acid beta oxidation which results in the accumulation of very long chain fatty acids in tissues throughout the body. The most severely affected tissues are the myelin in the central nervous system, the adrenal cortex, and the Leydig cells in the testes. The long chain fatty acid buildup causes damage to the myelin sheath of the neurons of the brain, resulting in seizures and hyperactivity. Other symptoms include problems in speaking, listening, and understanding verbal instructions.

<span class="mw-page-title-main">Thalassemia</span> Family of inherited blood disorders

Thalassemias are inherited blood disorders that result in abnormal hemoglobin. Symptoms depend on the type of thalassemia and can vary from none to severe. Often there is mild to severe anemia as thalassemia can affect the production of red blood cells and also affect how long the red blood cells live. Symptoms of anemia include feeling tired and having pale skin. Other symptoms of thalassemia include bone problems, an enlarged spleen, yellowish skin, pulmonary hypertension, and dark urine. Slow growth may occur in children. Symptoms and presentations of thalassemia can change over time. Older terms included Cooley's anemia and Mediterranean anemia for beta-thalassemia. These have been superseded by the terms Transfusion-Dependent Thalassemia (TDT) and non-Transfusion-Dependent Thalassemia (NTDT). Patients with TDT require regular transfusions, typically every two to five weeks. TDTs include Beta-thalassemia major, nondeletional HbH disease, survived Hb Bart's disease, and severe HbE/beta-thalassemia.

<span class="mw-page-title-main">Hematopoietic stem cell transplantation</span> Medical procedure to replace blood or immune stem cells

Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood, in order to replicate inside a patient and produce additional normal blood cells. HSCT may be autologous, syngeneic, or allogeneic.

Metachromatic leukodystrophy (MLD) is a lysosomal storage disease which is commonly listed in the family of leukodystrophies as well as among the sphingolipidoses as it affects the metabolism of sphingolipids. Leukodystrophies affect the growth and/or development of myelin, the fatty covering which acts as an insulator around nerve fibers throughout the central and peripheral nervous systems. MLD involves cerebroside sulfate accumulation. Metachromatic leukodystrophy, like most enzyme deficiencies, has an autosomal recessive inheritance pattern.

Stem-cell therapy uses stem cells to treat or prevent a disease or condition. As of 2024, the only FDA-approved therapy using stem cells is hematopoietic stem cell transplantation. This usually takes the form of a bone marrow or peripheral blood stem cell transplantation, but the cells can also be derived from umbilical cord blood. Research is underway to develop various sources for stem cells as well as to apply stem-cell treatments for neurodegenerative diseases and conditions such as diabetes and heart disease.

<span class="mw-page-title-main">Thiotepa</span> Chemical compound

Thiotepa (INN), sold under the brand name Tepadina among others, is an anti-cancer medication.

Defibrotide, sold under the brand name Defitelio, is a mixture of single-stranded oligonucleotides that is purified from the intestinal mucosa of pigs. It is used to treat veno-occlusive disease of the liver of people having had a bone marrow transplant, with different limitations in the US and the European Union. It works by protecting the cells lining blood vessels in the liver and preventing blood clotting; the way it does this is not well understood.

<span class="mw-page-title-main">Maribavir</span> Antiviral drug

Maribavir, sold under the brand name Livtencity, is an antiviral medication that is used to treat post-transplant cytomegalovirus (CMV). Maribavir is a cytomegalovirus pUL97 kinase inhibitor that works by preventing the activity of human cytomegalovirus enzyme pUL97, thus blocking virus replication.

Betibeglogene autotemcel, sold under the brand name Zynteglo, is a gene therapy for the treatment for beta thalassemia. It was developed by Bluebird Bio and was given breakthrough therapy designation by the US Food and Drug Administration in February 2015.

Autologous CD34+ enriched cell fraction that contains CD34+ cells transduced with retroviral vector that encodes for the human ADA cDNA sequence, sold under the brand name Strimvelis, is a medication used to treat severe combined immunodeficiency due to adenosine deaminase deficiency (ADA-SCID).

Axicabtagene ciloleucel, sold under the brand name Yescarta, is a medication used for the treatment for large B-cell lymphoma that has failed conventional treatment. T cells are removed from a person with lymphoma and genetically engineered to produce a specific T-cell receptor. The resulting chimeric antigen receptor T cells (CAR-Ts) that react to the cancer are then given back to the person to populate the bone marrow. Axicabtagene treatment carries a risk for cytokine release syndrome (CRS) and neurological toxicities.

bluebird bio, Inc., based in Somerville, Massachusetts, is a biotechnology company that develops gene therapies for severe genetic disorders.

Idecabtagene vicleucel, sold under the brand name Abecma, is a cell-based gene therapy to treat multiple myeloma.

OTL-103 (GSK-2696275) is a gene therapy for Wiskott–Aldrich syndrome, a rare primary immunodeficiency caused by mutations in the gene that codes for Wiskott–Aldrich syndrome protein (WASp). It was developed by Orchard Therapeutics in conjunction with GlaxoSmithKline. It is currently undergoing Phase I/II of clinical trials that are expected to conclude in October 2025.

Valoctocogene roxaparvovec, sold under the brand name Roctavian, is a gene therapy used for the treatment of hemophilia A. It was developed by BioMarin Pharmaceutical. Valoctocogene roxaparvovec is made of a virus (AAV5) that has been modified to contain the gene for factor VIII, which is lacking in people with hemophilia A. It is an adeno-associated virus vector-based gene therapy. It is given by intravenous infusion.

Atidarsagene autotemcel, sold under the brand name Libmeldy among others, is a gene therapy treatment for metachromatic leukodystrophy developed by Orchard Therapeutics. It contains an autologous CD34⁺ cell enriched population that contains haematopoietic stem and progenitor cells transduced using a lentiviral vector encoding the human arylsulfatase A (ARSA) gene.

Exagamglogene autotemcel, sold under the brand name Casgevy, is a gene therapy used for the treatment of sickle cell disease and transfusion-dependent beta thalassemia. It was developed by Vertex Pharmaceuticals and CRISPR Therapeutics.

Lovotibeglogene autotemcel, sold under the brand name Lyfgenia, is a lentiviral gene therapy used for the treatment of sickle cell disease.

References

  1. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 October 2023.
  2. ↑ "Skysona- elivaldogene autotemcel suspension". DailyMed. 26 September 2022. Retrieved 19 November 2022.
  3. ↑ "Skysona". U.S. Food and Drug Administration. 24 October 2022. Retrieved 19 November 2022.
  4. ↑ "Skysona EPAR". European Medicines Agency. 19 May 2021. Retrieved 22 November 2021.
  5. ↑ "Lenti-D (Elivaldogene Autotemcel or Eli-Cel) for CALD". Adrenoleukodystrophy News. Retrieved 24 July 2023.
  6. 1 2 3 "Skysona: Pending EC decision". European Medicines Agency (EMA). 21 May 2021. Archived from the original on 2 June 2021. Retrieved 1 June 2021. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  7. ↑ Larkin HD (November 2022). "Autologous Gene Therapy Approved for Childhood CALD". JAMA. 328 (17): 1679–1680. doi:10.1001/jama.2022.19800. PMID   36318148. S2CID   253246701.
  8. ↑ "bluebird bio gets green light for Skysona gene therapy in the US". biopharma-reporter.com. 19 September 2022. Retrieved 24 July 2023.
  9. ↑ "Skysona". U.S. Food and Drug Administration (FDA). 24 October 2022.
  10. ↑ "First gene therapy for adrenoleukodystrophy". Nature Biotechnology. 39 (11): 1319. November 2021. doi:10.1038/s41587-021-01127-8. PMID   34754125. S2CID   243939454.
  11. ↑ Loes DJ, Hite S, Moser H, Stillman AE, Shapiro E, Lockman L, et al. (October 1994). "Adrenoleukodystrophy: a scoring method for brain MR observations". AJNR. American Journal of Neuroradiology. 15 (9): 1761–1766. PMC   8333737 . PMID   7847225.
  12. ↑ Eichler F, Duncan C, Musolino PL, Orchard PJ, De Oliveira S, Thrasher AJ, et al. (October 2017). "Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy". The New England Journal of Medicine. 377 (17): 1630–1638. doi:10.1056/NEJMoa1700554. PMC   5708849 . PMID   28976817.
  13. ↑ Arbeláez-Cortés Á, Bejarano-Pineda L, Toro-Gutiérrez CE (18 July 2013). "Autologous peripheral hematopoietic stem cell transplantation". In Anaya JM, Shoenfeld Y, Rojas-Villarraga A, et al. (eds.). Autoimmunity: From Bench to Bedside [Internet]. El Rosario University Press. Retrieved 25 July 2023.
  14. ↑ "A Clinical Study to Assess the Efficacy and Safety of Gene Therapy for the Treatment of Cerebral Adrenoleukodystrophy (CALD)". www.clinicaltrials.gov. Retrieved 25 July 2023.
  15. ↑ Berger J, Forss-Petter S, Eichler FS (March 2014). "Pathophysiology of X-linked adrenoleukodystrophy". Biochimie. 98 (100): 135–142. doi:10.1016/j.biochi.2013.11.023. PMC   3988840 . PMID   24316281.
  16. ↑ Theda C, Moser AB, Powers JM, Moser HW (July 1992). "Phospholipids in X-linked adrenoleukodystrophy white matter: fatty acid abnormalities before the onset of demyelination". Journal of the Neurological Sciences. 110 (1–2): 195–204. doi: 10.1016/0022-510X(92)90028-J . PMID   1506859. S2CID   8964313.
  17. ↑ Schaumburg HH, Powers JM, Suzuki K, Raine CS (September 1974). "Adreno-leukodystrophy (sex-linked Schilder disease). Ultrastructural demonstration of specific cytoplasmic inclusions in the central nervous system". Archives of Neurology. 31 (3): 210–213. doi:10.1001/archneur.1974.00490390092013. PMID   4368379.
  18. ↑ Federico A, de Visser M (July 2021). "New disease modifying therapies for two genetic childhood-onset neurometabolic disorders (metachromatic leucodystrophy and adrenoleucodystrophy)". Neurological Sciences. 42 (7): 2603–2606. doi: 10.1007/s10072-021-05412-x . PMID   34212263. S2CID   235701552.
  19. ↑ Duncan CN, Bledsoe JR, Grzywacz B, Beckman A, Bonner M, Eichler FS, et al. (October 2024). "Hematologic Cancer after Gene Therapy for Cerebral Adrenoleukodystrophy". The New England Journal of Medicine. 391 (14): 1287–1301. doi:10.1056/NEJMoa2405541. PMID   39383458.
  20. ↑ "FDA halts trial of gene therapy for rare neurological disease due to cancer risk". www.healio.com. Retrieved 25 July 2023.
  21. ↑ "MEDICATION GUIDE SKYSONA® (pronounced sky-SO-nuh) (elivaldogene autotemcel)" (PDF). September 2022.
  22. ↑ "Package Insert - SKYSONA". U.S. Food and Drug Administration (FDA). September 2022. Retrieved 25 July 2023.
  23. ↑ "EU/3/12/1003". European Medicines Agency (EMA). 17 September 2018. Retrieved 1 June 2021.
  24. ↑ "Bluebird Bio Presents Long-Term Data for elivaldogene autotemcel (eli-cel, Lenti-D) Gene Therapy for Cerebral Adrenoleukodystrophy (CALD)" (Press release). Bluebird Bio. 15 March 2021. Retrieved 1 June 2021– via Business Wire.
  25. ↑ "Skysona". U.S. Food and Drug Administration (FDA). 19 September 2022.
  26. ↑ "First gene therapy to treat children with rare inherited neurological disease". European Medicines Agency (EMA) (Press release). 21 May 2021. Retrieved 1 June 2021. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  27. ↑ Fidler B (21 July 2021). "Bluebird, with little fanfare, is first to bring a second gene therapy to market". Industry Dive . Retrieved 22 November 2021.
  28. ↑ "Bluebird, winding down in Europe, withdraws another rare disease gene therapy". BioPharma Dive. Retrieved 25 July 2023.
  29. ↑ Bruce F (22 April 2021). "Bluebird Bio Withdraws Zynteglo From Germany Over Pricing". Pink Sheet Citeline Regulatory. Retrieved 25 July 2023.
  30. ↑ "bluebird bio Reports First Quarter 2023 Financial Results and Highlights Operational Progress". www.businesswire.com. 9 May 2023. Retrieved 25 July 2023.
  31. ↑ World Health Organization (2020). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 83" (PDF). WHO Drug Information. 34 (1).
  32. ↑ Liu A (19 September 2022). "A $3M gene therapy: Bluebird bio breaks its own pricing record with FDA approval of Skysona". Fierce Pharma. Retrieved 25 July 2023.
  33. ↑ Kansteiner F, Becker Z, Liu A, Sagonowsky E, Dunleavy K (22 May 2023). "Most expensive drugs in the US in 2023" . Retrieved 25 July 2023.
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