Onasemnogene abeparvovec

Onasemnogene abeparvovec, sold under the trade name Zolgensma, is a gene therapy medication used to treat spinal muscular atrophy (SMA).[2] It is used with corticosteroids as a one-time injection into a vein.[2] It was approved in the United States in 2019 for children less than two years old.[3][2]

Onasemnogene abeparvovec
Clinical data
Trade namesZolgensma
Other namesAVXS-101, onasemnogene abeparvovec-xioi
AHFS/Drugs.comProfessional Drug Facts
License data
Pregnancy
category
  • US: N (Not classified yet) [1]
    Routes of
    administration    		Intravascular
    Legal status
    Legal status
    Pharmacokinetic data
    Duration of actionUnknown
    Identifiers
    CAS Number
    PubChem CID
    KEGG

    Common side effects include vomiting and increased liver enzymes.[2] Serious side effects may include liver problems, low platelets, and heart damage.[2] Onasemnogene abeparvovec works by providing a new copy of the gene that makes the human SMN protein.[2]

    Onasemnogene abeparvovec was developed by AveXis, which was acquired by Novartis,[4] based on the work of Martine Barkats from the Institut de Myologie in France.[5] It carries a list price of US$2.125 million per treatment, making it the most expensive medication in the world as of 2019.[6] A formulation that is injected into the spinal canal is being studied in people under six years old, however this study was put on hold in October 2019.[7]

    Medical use

    Onasemnogene abeparvovec is used to treat spinal muscular atrophy linked to a mutation in the survival motor neuron 1 (SMN1) gene,[8] a genetic disorder diagnosed predominantly in young children that causes progressive loss of muscle function and frequently death.

    In an intravenous formulation, it is approved in the United States for use in children up to the age of two with SMA, including before symptoms occur.[3]

    The medication is used with corticosteroids in an effort to protect the liver.[2] The use of corticosteroids is recommended for a least two months starting the day before onasemnogene abeparvovec is given.[2] If liver abnormalities persist, longer use of corticosteroids is recommended.[2]

    While marketed as a one-time treatment for SMA, it is unknown how long the onasemnogene abeparvovec-delivered transgene will persist in people. Since motor neurons do not divide, it is expected that the transgene may have long-term stability.[9]

    Adverse effects

    Common adverse reactions may include nausea and increased liver enzymes.[2] Serious adverse reactions may include liver problems, low platelets, and heart damage.[2] It is recommended to check liver function for three months after administration.[10]

    As the medication may reduce the platelet count, platelets may need to be checked before the medication is started, then weekly for the first month and every two weeks for the next two months until the level is back to baseline.[2]

    Mechanism of action

    SMA is a neuromuscular disorder caused by a mutation in the SMN1 gene, which leads to a decrease in SMN protein, a protein necessary for survival of motor neurons. Onasemnogene abeparvovec is a biologic drug consisting of AAV9 virus capsids that contains a SMN1 transgene along with synthetic promoters. Upon administration, the AAV9 viral vector delivers the SMN1 transgene to the affected motor neurons, where it leads to an increase in SMN protein.

    History

    The FDA granted the application for onasemnogene abeparvovec-xioi for fast track, breakthrough therapy, priority review, and orphan drug designations.[3] The FDA also awarded the manufacturer a rare pediatric disease priority review voucher, and granted the approval of Zolgensma to AveXis Inc.[3]

    In June 2015, the European Commission granted orphan designation for onasemnogene abeparvove.[11] In July 2019, onasemnogene abeparvovec was removed from the Committee for Medicinal Products for Human Use (CHMP) accelerated assessment program.[12]

    Society and culture

    Terminology

    Onasemnogene abeparvovec is the international nonproprietary name (INN) and US adopted name (USAN).[13] The medication is known under compound name AVXS-101 in countries where it is not approved for marketing.

    Cost

    It carries a list price of US$2.125 million per treatment, making it the most expensive medication in the world as of 2019.[6] In its first four months of sales US$160 million of medical was sold.[7]

    Approval

    Onasemnogene abeparvovec was approved for medical use in the United States in 2019.[2][3] As of 2019, it is in the approval process for the European Union and for Japan.[14]

    Controversies

    In the months leading up to the drug's approval by the FDA, a whistleblower informed Novartis that certain studies of the drug had been subject to data manipulation.[15] Novartis fired two AveXis executives it determined responsible but informed the FDA of the data integrity issue only in June 2019, a month after the drug's approval.[15] The delay drew strong condemnation of the FDA.[16] In October 2019, the company admitted to not having informed the FDA and the European Medicines Agency (EMA) for seven months about toxic effects of the intravenous formulation observed in laboratory animals.[17]

    Research

    AveXis is also developing an intrathecal formulation of onasemnogene abeparvovec, however trials in humans were halted by the US Food and Drug Administration (FDA) in October 2019 due to observed animal toxicity.[7]

    See also

    References
    1. Use During Pregnancy and Breastfeeding
    2. "Zolgensma- onasemnogene abeparvovec-xioi kit full prescribing information". DailyMed. 24 May 2019. Retrieved 18 November 2019.
    3. "FDA approves innovative gene therapy to treat pediatric patients with spinal muscular atrophy, a rare disease and leading genetic cause of infant mortality". U.S. Food and Drug Administration (FDA). 24 May 2019. Retrieved 18 November 2019. This article incorporates text from this source, which is in the public domain.
    4. "Novartis successfully completes acquisition of AveXis, Inc" (Press release). Novartis. Retrieved 6 October 2018.
    5. "AveXis receives FDA approval for Zolgensma, the first gene therapy for paediatric patients with SMA". SMA Europe. 25 May 2015. Retrieved 25 May 2019. This treatment was pioneered by Dr Martine Barkats, from the Institut de Myologie in France.
    6. "$2.1m Novartis gene therapy to become world's most expensive drug". The Guardian. London. Reuters. 25 May 2019. ISSN 0261-3077. Retrieved 25 May 2019.
    7. Miller, John (30 October 2019). "Novartis' Zolgensma study halted by FDA amid safety questions". Reuters. Retrieved 30 October 2019.
    8. "Zolgensma". FDA. 6 August 2019. Retrieved 1 November 2019. This article incorporates text from this source, which is in the public domain.
    9. "Novartis announces FDA filing acceptance and Priority Review of AVXS-101, a one-time treatment designed to address the genetic root cause of SMA Type 1". Novartis. Retrieved 4 December 2018.
    10. "FDA approves innovative gene therapy to treat pediatric patients with spinal muscular atrophy, a rare disease and leading genetic cause of infant mortality". FDA. 11 September 2019. Retrieved 18 November 2019. This article incorporates text from this source, which is in the public domain.
    11. "EU/3/15/1509". European Medicines Agency. 17 September 2018. Retrieved 19 November 2019.
    12. "Novartis' Zolgensma Joins Growing List of Medicines to Lose Accelerated Assessment Status in EU". RAPS. Retrieved 19 November 2019.
    13. "Onasemnogene abeparvovec - AveXis - AdisInsight". adisinsight.springer.com. Retrieved 6 October 2018.
    14. Hoy SM (July 2019). "Onasemnogene Abeparvovec: First Global Approval". Drugs. 79 (11): 1255–1262. doi:10.1007/s40265-019-01162-5. PMID 31270752.
    15. Erman, Michael (24 September 2019). "Novartis blames former AveXis executives for Zolgensma data manipulation". Reuters. Retrieved 26 September 2019.
    16. "Statement on data accuracy issues with recently approved gene therapy". U.S. Food and Drug Administration (FDA). 19 November 2019. Archived from the original on 19 November 2019. Retrieved 1 November 2019. This article incorporates text from this source, which is in the public domain.
    17. "Novartis says delayed telling FDA of Zolgensma concern due to 'mistake'". Reuters. 1 November 2019. Retrieved 11 November 2019.
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