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Elivaldogene autotemcel
Clinical data
Trade names	Skysona
Other names	Lenti-D, eli-cel
License data	US DailyMed: Elivaldogene autotemcel;
Routes of; administration	Intravenous
ATC code	A16AX21 (WHO) ;
Legal status
Legal status	US: WARNINGRx-only; EU: Rx-only;
Identifiers
DrugBank	DB16746;
UNII	KUM75TD6SG;
KEGG	D12150;

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]

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]

References

^ "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.
^ "Skysona- elivaldogene autotemcel suspension". DailyMed. 26 September 2022. Retrieved 19 November 2022.
^ "Skysona". U.S. Food and Drug Administration. 24 October 2022. Retrieved 19 November 2022.
^ "Skysona EPAR". European Medicines Agency. 19 May 2021. Retrieved 22 November 2021.
^ "Lenti-D (Elivaldogene Autotemcel or Eli-Cel) for CALD". Adrenoleukodystrophy News. Retrieved 24 July 2023.
^ ^a ^b ^c "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.
^ 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.
^ "bluebird bio gets green light for Skysona gene therapy in the US". biopharma-reporter.com. 19 September 2022. Retrieved 24 July 2023.
^ "Skysona". U.S. Food and Drug Administration (FDA). 24 October 2022.
^ "First gene therapy for adrenoleukodystrophy". Nature Biotechnology. 39 (11): 1319. November 2021. doi:10.1038/s41587-021-01127-8. PMID 34754125. S2CID 243939454.
^ 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.
^ 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.
^ 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.
^ "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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ "FDA halts trial of gene therapy for rare neurological disease due to cancer risk". www.healio.com. Retrieved 25 July 2023.
^ "MEDICATION GUIDE SKYSONA® (pronounced sky-SO-nuh) (elivaldogene autotemcel)" (PDF). September 2022.
^ "Package Insert - SKYSONA". U.S. Food and Drug Administration (FDA). September 2022. Retrieved 25 July 2023.
^ "EU/3/12/1003". European Medicines Agency (EMA). 17 September 2018. Retrieved 1 June 2021.
^ "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.
^ "Skysona". U.S. Food and Drug Administration (FDA). 19 September 2022.
^ "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.
^ 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.
^ "Bluebird, winding down in Europe, withdraws another rare disease gene therapy". BioPharma Dive. Retrieved 25 July 2023.
^ Bruce F (22 April 2021). "Bluebird Bio Withdraws Zynteglo From Germany Over Pricing". Pink Sheet Citeline Regulatory. Retrieved 25 July 2023.
^ "bluebird bio Reports First Quarter 2023 Financial Results and Highlights Operational Progress". www.businesswire.com. 9 May 2023. Retrieved 25 July 2023.
^ World Health Organization (2020). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 83" (PDF). WHO Drug Information. 34 (1).
^ 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.
^ 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.

[FDA-AllBoxedWarnings-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.

[Skysona_FDA_label-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.

[Skysona_EPAR-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.

[Skysona:_Pending_EC_decision-6] "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.

[EMA_PR-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.

[DeepDive-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.

[INN-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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PROFILPELAJAR.COM

Elivaldogene autotemcel

Medical uses

Mechanism of action

Adverse effects

History

Society and culture

Names

Pricing

References

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