Onasemnogene abeparvovec

Onasemnogene abeparvovec, sold under the trade name Zolgensma, is a gene therapy medication used to treat spinal muscular atrophy (SMA).[2] It was approved for children less than two years old in 2019.[3][2] It is used as a one-time injection into a vein with at least 2 months of corticosteroids.[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
    ATC code
    • None
    Legal status
    Legal status
    Pharmacokinetic data
    Duration of actionUnknown
    Identifiers
    CAS Number
    PubChem CID
    DrugBank
    UNII
    KEGG

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

    Onasemnogene abeparvovec was approved for medical use in the United States in 2019 and in Japan in 2020.[2][3][4] In May 2020, the European Medicines Agency gave conditional approval for people with SMA type 1 or any SMA type having no more than three copies of the SMN2 gene.[5][6] The drug carries a US list price of US$2.125 million per treatment, making it the most expensive medication in the world as of 2019.[7] 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.[8]

    Medical use

    Onasemnogene abeparvovec is used to treat spinal muscular atrophy linked to a mutation in the survival motor neuron 1 (SMN1) gene,[9] 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.[10]

    Adverse effects

    Common adverse reactions may include nausea and increased liver enzymes.[2] Serious adverse reactions may include liver problems and low platelets.[2] Transient elevated levels of cardiac troponin‑I were observed in clinical trials; the clinical importance of these findings is not known.[2] However, cardiac toxicity was seen in studies of other animals.[2]

    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] Liver function should be monitored for three months after administration.[11]

    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

    Onasemnogene abeparvovec was developed by a US biotechnology startup AveXis, which was acquired by Novartis in 2018,[12] based on the work of Martine Barkats from the Institut de Myologie in France.[13]

    The U.S. Food and Drug Administration (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 the drug.[14] In July 2019, the drug was removed from the Committee for Medicinal Products for Human Use (CHMP) accelerated assessment program.[15]

    In May 2019, onasemnogene abeparvovec received US FDA approval as a treatment for children less than two years old.[3] Since late 2019, the treatment has been reimbursed in Israel[16] and Qatar.[17] In March 2020, the onasemnogene abeparvovec was granted regulatory approval in Japan with the label identical to the US one.[4] Also in March 2020, the European Medicines Agency recommended a conditional marketing authorisation for use in patients with SMA type 1 or with any SMA type and having no more than three copies of the SMN2 gene.[5] In May 2020, Onasemnogene abeparvovec was conditionally approved in Europe.[6]

    Society and culture

    Terminology

    Onasemnogene abeparvovec is the international nonproprietary name (INN) and US adopted name (USAN).[18] The medication is known under compound name AVXS-101 in countries where it is not approved for marketing.

    Cost

    The drug carries a list price of US$2.125 million per treatment, making it the most expensive medication in the world as of 2019.[7] In its first full quarter of sales US$160 million of medication was sold.[8]

    Controversies

    In the months leading up to the medication's approval by the FDA, a whistleblower informed Novartis that certain studies of the medication had been subject to data manipulation.[19] 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.[19] The delay drew strong condemnation of the FDA.[20] 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.[21] Due to data manipulation issue, EMA withdrew their decision to allow an accelerated assessment of the medication.[22]

    In December 2019, Novartis announced that it would donate 100 doses of onasemnogene abeparvovec per year to children outside the US through a global lottery. The decision, which has been claimed by Novartis to be based on a recommendation by unnamed bioethicists,[23] was received with much criticism by the European Commission,[24] some European healthcare regulators[25] and patient groups (e.g. the UK's TreatSMA, SMA Europe) who see it as emotionally burdening, suboptimal, and ethically questionable.[26] Novartis did not consult with families or doctors before announcing the scheme.[27][28] Alan Regenberg, a bioethicist at Johns Hopkins Berman Institute of Bioethics, said that the scheme was perhaps the best available since it may be impossible to reliably establish prognosis for children under two years of age. Also not all the SMA community opposes it.[23]

    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.[8]

    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 receives approval from Japanese Ministry of Health, Labour and Welfare for Zolgensma® the only gene therapy for patients with spinal muscular atrophy (SMA)". Novartis. Retrieved 29 March 2020.
    5. "New gene therapy to treat spinal muscular atrophy". European Medicines Agency. 27 March 2020. Retrieved 29 March 2020.
    6. "Global Novartis News Archive". Novartis. Retrieved 20 May 2020.
    7. "$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.
    8. Miller, John (30 October 2019). "Novartis' Zolgensma study halted by FDA amid safety questions". Reuters. Retrieved 30 October 2019.
    9. "Zolgensma". FDA. 6 August 2019. Retrieved 1 November 2019. This article incorporates text from this source, which is in the public domain.
    10. "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.
    11. "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.
    12. "Novartis successfully completes acquisition of AveXis, Inc" (Press release). Novartis. Retrieved 6 October 2018.
    13. "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.
    14. "EU/3/15/1509". European Medicines Agency. 17 September 2018. Retrieved 19 November 2019.
    15. "Novartis' Zolgensma Joins Growing List of Medicines to Lose Accelerated Assessment Status in EU". RAPS. Retrieved 19 November 2019.
    16. Julian, Hana Levi. "In First, World's Most Expensive Medicine Used to Treat Israeli Toddler". Retrieved 29 March 2020.
    17. "HMC implements innovative gene therapy to treat congenital spinal muscular atrophy". The Peninsula. 20 November 2019. Retrieved 29 March 2020.
    18. "Onasemnogene abeparvovec - AveXis - AdisInsight". adisinsight.springer.com. Retrieved 6 October 2018.
    19. Erman, Michael (24 September 2019). "Novartis blames former AveXis executives for Zolgensma data manipulation". Reuters. Retrieved 26 September 2019.
    20. "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.
    21. "Novartis says delayed telling FDA of Zolgensma concern due to 'mistake'". Reuters. 1 November 2019. Retrieved 11 November 2019.
    22. "Zolgensma°: the drug of extremes". April 2020. p. 107. Retrieved 22 May 2020.
    23. "Novartis in talks with patients upset about lottery-like gene therapy giveaway". Reuters. 20 December 2019.
    24. Kyriakides, Stella (19 February 2020). "Answer given by Ms Kyriakides on behalf of the European Commission". European Parliament. Retrieved 21 April 2020.
    25. "No "lottery for life" - Statement by Beneluxa Health Ministers addressing the global managed access program designed by Novartis and Avexis". Beneluxa. 30 January 2020. Retrieved 21 April 2020.
    26. "AVXS-101 (Zolgensma®) to be made available globally through a controversial programme". SMA Europe. Retrieved 21 April 2020.
    27. "Dismay at lottery for $2.1m drug to treat children with muscle-wasting disease". The Guardian. 20 December 2019.
    28. "Novartis to Offer World's Most Expensive Drug for Free Via Lottery". The Wall Street Journal. 19 December 2019.
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