onasemnogene abeparvovec

Onasemnogene abeparvovec was developed to treat spinal muscular atrophy, a disease linked to a mutation in the SMN1 gene on chromosome 5q{{cite web|url=https://www.fda.gov/vaccines-blood-biologics/zolgensma|title=Zolgensma|date=6 August 2019|website=U.S. Food and Drug Administration (FDA)|access-date=1 November 2019|id=STN: 125694|archive-date=19 November 2019|archive-url=https://web.archive.org/web/20191119010100/https://www.fda.gov/vaccines-blood-biologics/zolgensma|url-status=live}} {{PD-notice}} and diagnosed predominantly in young children that causes progressive loss of muscle function and frequently death. The medication is administered as an intravenous infusion.{{cite book | title=LiverTox: Clinical and Research Information on Drug-Induced Liver Injury | chapter=Onasemnogene Abeparvovec | publisher=NCBI Bookshelf | date=20 August 2020 | pmid=33242238 | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK564658/ | access-date=13 August 2022 | id=Bookshelf ID: NBK564658 | archive-date=14 August 2022 | archive-url=https://web.archive.org/web/20220814025857/https://www.ncbi.nlm.nih.gov/books/NBK564658/ | url-status=live }}

In the United States, onasemnogene abeparvovec is indicated for the treatment of people less than two years of age with spinal muscular atrophy with bi-allelic mutations in the survival motor neuron 1 (SMN1) gene.

The treatment is approved in the United States and certain other countries for use in children with spinal muscular atrophy up to the age of two, including at the presymptomatic stage of the disease. In the European Union and Canada, it is indicated for the treatment of people with spinal muscular atrophy who either have a clinical diagnosis of spinal muscular atrophy type 1 or have up to three copies of the SMN2 gene.{{Cite press release|date=16 December 2020|title=Health Canada approves Zolgensma, the one-time gene therapy for pediatric patients with spinal muscular atrophy (SMA)|publisher=Novartis|via=Cision|url=https://www.newswire.ca/news-releases/health-canada-approves-zolgensma-r-the-one-time-gene-therapy-for-pediatric-patients-with-spinal-muscular-atrophy-sma-1-886604228.html|access-date=2 July 2021|archive-date=3 June 2021|archive-url=https://web.archive.org/web/20210603045310/https://www.newswire.ca/news-releases/health-canada-approves-zolgensma-r-the-one-time-gene-therapy-for-pediatric-patients-with-spinal-muscular-atrophy-sma-1-886604228.html|url-status=live}}{{Cite web |date=26 May 2020 |title=onasemnogene abeparvovec |url=https://cadth.ca/onasemnogene-abeparvovec |url-status=live |archive-url=https://web.archive.org/web/20210602220015/https://cadth.ca/onasemnogene-abeparvovec |archive-date=2 June 2021 |access-date=1 June 2021 |website=Canadian Agency for Drugs and Technologies in Health (CADTH) }}

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

File:Ijms-24-11939-g007-550 (1).webp

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.{{citation needed|date=August 2021}}

Onasemnogene abeparvovec, developed by the US biotechnology startup AveXis, which was acquired by Novartis in 2018,{{Cite press release |url=https://www.novartis.com/news/media-releases/novartis-successfully-completes-acquisition-avexis-inc |title=Novartis successfully completes acquisition of AveXis, Inc. |publisher=Novartis |access-date=6 October 2018 |archive-date=9 September 2019 |archive-url=https://web.archive.org/web/20190909202153/https://www.novartis.com/news/media-releases/novartis-successfully-completes-acquisition-avexis-inc |url-status=live}} is based on research conducted at the Institut de Myologie in France.{{cite press release |title=AveXis receives FDA approval for Zolgensma, the first and only gene therapy for pediatric patients with spinal muscular atrophy (SMA) |website=Novartis |date=24 May 2019 |url=https://www.novartis.com/news/media-releases/avexis-receives-fda-approval-zolgensma-first-and-only-gene-therapy-pediatric-patients-spinal-muscular-atrophy-sma |access-date=13 August 2022}}

The U.S. Food and Drug Administration (FDA) granted onasemnogene abeparvovec-xioi various designations including fast track, breakthrough therapy, priority review, and orphan drug designations. Additionally, the FDA awarded the manufacturer a rare pediatric disease priority review voucher and approved onasemnogene abeparvovec for AveXis Inc.

In June 2015, the European Commission granted orphan designation to the drug.{{cite web |date=17 September 2018 |title=EU/3/15/1509 |url=https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu3151509 |url-status=live |archive-url=https://web.archive.org/web/20191119012740/https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu3151509 |archive-date=19 November 2019 |access-date=19 November 2019 |website=European Medicines Agency}} However, in July 2019, the drug was removed from the Committee for Medicinal Products for Human Use (CHMP) accelerated assessment program.{{cite web |title=Novartis' Zolgensma Joins Growing List of Medicines to Lose Accelerated Assessment Status in EU |url=https://www.raps.org/news-and-articles/news-articles/2019/7/novartis-zolgensma-joins-growing-list-of-medicine |url-status=live |archive-url=https://web.archive.org/web/20191119013546/https://www.raps.org/news-and-articles/news-articles/2019/7/novartis-zolgensma-joins-growing-list-of-medicine |archive-date=19 November 2019 |access-date=19 November 2019 |website=RAPS}}

In May 2019, onasemnogene abeparvovec received US FDA approval as a treatment for children under two years old. Since 2019, the treatment has been reimbursed in Qatar{{Cite web |date=20 November 2019 |title=HMC implements innovative gene therapy to treat congenital spinal muscular atrophy |url=https://thepeninsulaqatar.com/article/20/11/2019/HMC-implements-innovative-gene-therapy-to-treat-congenital-spinal-muscular-atrophy |url-status=live |archive-url=https://web.archive.org/web/20200329174230/https://thepeninsulaqatar.com/article/20/11/2019/HMC-implements-innovative-gene-therapy-to-treat-congenital-spinal-muscular-atrophy |archive-date=29 March 2020 |access-date=29 March 2020 |website=The Peninsula}} and Israel.{{Cite web |date=21 November 2019 |title=In First, World's Most Expensive Medicine Used to Treat Israeli Toddler |url=https://www.jewishpress.com/news/health-and-medicine/in-first-worlds-most-expensive-medicine-used-to-treat-israeli-toddler/2019/11/21/ |url-status=live |archive-url=https://web.archive.org/web/20200329174233/https://www.jewishpress.com/news/health-and-medicine/in-first-worlds-most-expensive-medicine-used-to-treat-israeli-toddler/2019/11/21/ |archive-date=29 March 2020 |access-date=29 March 2020 |vauthors=Julian HL}} In March 2020, it gained regulatory approval in Japan with the same labeling as in the US. Additionally, the European Medicines Agency (EMA) recommended conditional marketing authorization in March 2020, specifically for individuals with SMA type 1 or any SMA type with no more than three copies of the SMN2 gene. This conditional approval was granted for Europe in May 2020.{{cite press release |title=Global Novartis News Archive |url=https://www.novartis.com/news/media-releases/avexis-receives-ec-approval-and-activates-%22day-one%22-access-program-zolgensma-only-gene-therapy-spinal-muscular-atrophy-sma |website=Novartis |access-date=20 May 2020 |archive-date=29 May 2020 |archive-url=https://web.archive.org/web/20200529202855/https://www.novartis.com/news/media-releases/avexis-receives-ec-approval-and-activates-%22day-one%22-access-program-zolgensma-only-gene-therapy-spinal-muscular-atrophy-sma |url-status=live}}

In August 2020, onasemnogene abeparvovec received regulatory approval in Brazil from the Brazilian Health Regulatory Agency (ANVISA).{{Cite web |date=17 August 2020 |title=Medicamento conhecido como mais caro do mundo recebe registro da Anvisa |url=https://g1.globo.com/ciencia-e-saude/noticia/2020/08/17/medicamento-conhecido-como-mais-caro-do-mundo-recebe-registro-da-anvisa.ghtml |url-status=live |archive-url=https://web.archive.org/web/20200831001220/https://g1.globo.com/ciencia-e-saude/noticia/2020/08/17/medicamento-conhecido-como-mais-caro-do-mundo-recebe-registro-da-anvisa.ghtml |archive-date=31 August 2020 |access-date=18 August 2020 |website=G1 |language=pt-br}} Subsequently, it was approved for medical use in Canada in December 2020,{{Cite press release |date=16 December 2020 |url=https://www.newswire.ca/news-releases/health-canada-approves-zolgensma-r-the-one-time-gene-therapy-for-pediatric-patients-with-spinal-muscular-atrophy-sma-1-886604228.html |title=Health Canada approves Zolgensma, the one-time gene therapy for pediatric patients with spinal muscular atrophy (SMA) |access-date=27 May 2021 |publisher=Novartis Pharmaceuticals Canada |via=Cision |archive-date=3 June 2021 |archive-url=https://web.archive.org/web/20210603045310/https://www.newswire.ca/news-releases/health-canada-approves-zolgensma-r-the-one-time-gene-therapy-for-pediatric-patients-with-spinal-muscular-atrophy-sma-1-886604228.html |url-status=live}}{{cite web |title=PRODUCT MONOGRAPH INCLUDING PATIENT MEDICATION INFORMATION : ZOLGENSMA |url=https://pdf.hres.ca/dpd_pm/00059243.PDF |url-status=live |archive-url=https://web.archive.org/web/20210614123306/https://pdf.hres.ca/dpd_pm/00059243.PDF |archive-date=14 June 2021 |access-date=24 March 2022 |website=Pdf.hres.ca}} in Australia in February 2021,{{Cite web |title=TGA eBS - Product and Consumer Medicine Information Licence |url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2021-PI-01276-1 |url-status=live |archive-url=https://web.archive.org/web/20210909062631/https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2021-PI-01276-1 |archive-date=9 September 2021 |access-date=24 March 2022 |website=Ebs.tga.gov.au}} and in Russia in December 2021.{{Cite news |date=9 December 2021 |title=Минздрав зарегистрировал препарат для лечения СМА «Золгенсма» |url=https://www.vedomosti.ru/society/news/2021/12/09/899915-minzdrav-zaregistriroval-preparat |url-status=live |archive-url=https://web.archive.org/web/20211210202718/https://www.vedomosti.ru/society/news/2021/12/09/899915-minzdrav-zaregistriroval-preparat |archive-date=10 December 2021 |access-date=8 July 2022 |website=Ведомости |language=ru}}

According to the Health Sciences Authority register of Singapore, onasemnogene abeparvovec was approved in April 2023.{{Cite news |last=Iau |first=Jean |date=19 May 2023 |title=Toddler with rare genetic condition can be treated after $2m raised, drug registered |language=en |work=The Straits Times |url=https://www.straitstimes.com/singapore/toddler-with-rare-genetic-condition-to-receive-treatment-after-2-mil-crowdfunding-and-drug-getting-registered |access-date=20 May 2023 |issn=0585-3923}}

Initially approved in the United States in 2019 for children under two,{{cite web |date=24 May 2019 |title=FDA approves innovative gene therapy to treat pediatric patients with spinal muscular atrophy, a rare disease and leading genetic cause of infant mortality |url=https://www.fda.gov/news-events/press-announcements/fda-approves-innovative-gene-therapy-treat-pediatric-patients-spinal-muscular-atrophy-rare-disease |url-status=live |archive-url=https://web.archive.org/web/20190901145211/https://www.fda.gov/news-events/press-announcements/fda-approves-innovative-gene-therapy-treat-pediatric-patients-spinal-muscular-atrophy-rare-disease |archive-date=1 September 2019 |access-date=18 November 2019 |website=U.S. Food and Drug Administration (FDA)}} {{PD-notice}} onasemnogene abeparvovec's approval varies in different regions.{{Cite press release |url=https://www.novartis.com/news/media-releases/novartis-receives-approval-from-japanese-ministry-health-labour-and-welfare-zolgensma-only-gene-therapy-patients-spinal-muscular-atrophy-sma |title=Novartis receives approval from Japanese Ministry of Health, Labour and Welfare for Zolgensma the only gene therapy for patients with spinal muscular atrophy (SMA) |website=Novartis |access-date=29 March 2020}}{{Cite web |last=Mueller |first=Casimir Jones SC-Lisa L. |date=September 2020 |title=First Gene Therapy Products Approved in Brazil |url=https://www.lexology.com/library/detail.aspx?g=5347d335-423c-4bb8-8746-187e126c8de8 |url-status=live |archive-url=https://web.archive.org/web/20210602214200/https://www.lexology.com/library/detail.aspx?g=5347d335-423c-4bb8-8746-187e126c8de8 |archive-date=2 June 2021 |access-date=1 June 2021 |website=Lexology}}{{Cite web |title=New Zolgensma data demonstrate age-appropriate development when used early, real-world benefit in older children and durability 5+ years post-treatment |url=https://www.novartis.com/news/media-releases/new-zolgensma-data-demonstrate-age-appropriate-development-when-used-early-real-world-benefit-older-children-and-durability-5-years-post-treatment |url-status=live |archive-url=https://web.archive.org/web/20210602213807/https://www.novartis.com/news/media-releases/new-zolgensma-data-demonstrate-age-appropriate-development-when-used-early-real-world-benefit-older-children-and-durability-5-years-post-treatment |archive-date=2 June 2021 |access-date=1 June 2021 |website=Novartis}}

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|lc=yes}}.{{Cite news|url=https://www.theguardian.com/science/2019/may/25/21m-novartis-gene-therapy-to-become-worlds-most-expensive-drug|title=$2.1m Novartis gene therapy to become world's most expensive drug|date=25 May 2019|newspaper=The Guardian|access-date=25 May 2019|agency=Reuters|location=London|archive-date=7 November 2020|archive-url=https://web.archive.org/web/20201107231233/https://www.theguardian.com/science/2019/may/25/21m-novartis-gene-therapy-to-become-worlds-most-expensive-drug|url-status=live}} In its first full quarter of sales {{US$|160 million}} of medication was sold.{{cite news|url=https://www.reuters.com/article/us-novartis-gene-therapy/novartis-zolgensma-study-halted-by-fda-amid-safety-questions-idUSKBN1X90XS|title=Novartis' Zolgensma study halted by FDA amid safety questions|last1=Miller|first1=John|date=30 October 2019|access-date=30 October 2019|work=Reuters|archive-date=30 October 2019|archive-url=https://web.archive.org/web/20191030092649/https://www.reuters.com/article/us-novartis-gene-therapy/novartis-zolgensma-study-halted-by-fda-amid-safety-questions-idUSKBN1X90XS|url-status=live}}

In Japan, the drug was made available through the public health care system on 20 May 2020, making it the most expensive drug covered by the Japanese public health care system.[https://answers.ten-navi.com/pharmanews/18401/ 初の「億超え新薬」ゾルゲンスマの薬価はどう決まったか] {{Webarchive|url=https://web.archive.org/web/20200815113845/https://answers.ten-navi.com/pharmanews/18401/ |date=15 August 2020 }} (Japanese). AnswersNews. The Central Social Insurance Medical Council, responsible for approving the universal drug fee schedule in Japan, has negotiated the price down to {{JPY|167,077,222}} (approx. USD {{To USD round|167077222|JPN|sf=3}}) per patient.[https://www.mhlw.go.jp/hourei/doc/hourei/H200519S0020.pdf 厚生労働省告示第二百十四号] {{Webarchive|url=https://web.archive.org/web/20201031225847/https://www.mhlw.go.jp/hourei/doc/hourei/H200519S0020.pdf |date=31 October 2020 }} (Japanese). Ministry of Health, Labour and Welfare, Japan.[https://www.novartis.co.jp/sites/www.novartis.co.jp/files/pr20200520.pdf 脊髄性筋萎縮症に対する遺伝子治療用製品「ゾルゲンスマ®点滴静注」薬価基準収載のお知らせ] {{Webarchive|url=https://web.archive.org/web/20201028210704/https://www.novartis.co.jp/sites/www.novartis.co.jp/files/pr20200520.pdf |date=28 October 2020 }} (Japanese). Novartis Pharma.

In the months leading up to the medication's approval by the US Food and Drug Administration (FDA), a whistleblower informed Novartis that certain studies of the medication had been subject to data manipulation.{{cite news |vauthors=Erman M |title=Novartis blames former AveXis executives for Zolgensma data manipulation |url=https://news.yahoo.com/novartis-blames-former-avexis-execs-151942378.html |access-date=26 September 2019 |agency=Reuters |date=24 September 2019 |archive-date=26 September 2019 |archive-url=https://web.archive.org/web/20190926205430/https://news.yahoo.com/novartis-blames-former-avexis-execs-151942378.html |url-status=live }} In a filing to the FDA, Novartis said that two executives, brothers Brian and Allan Kaspar manipulated the data, pressured others into manipulating data and then attempted to cover it up.{{Cite news |last=Palmer |first=Eric |date=24 September 2019 |title=Novartis to put AveXis into protective custody after data manipulation scandal |url=https://www.fiercepharma.com/manufacturing/novartis-to-put-avexis-into-protective-custody-after-data-manipulation-scandal |access-date=12 May 2024 |work=Fierce Biotech}} Novartis fired the executives it deemed responsible for the data manipulation but informed the FDA of the data integrity issue only in June 2019, a month after the drug's approval. The delay drew strong condemnation from the FDA.{{cite press release | title=Statement on data accuracy issues with recently approved gene therapy | website=U.S. Food and Drug Administration (FDA) | date=19 November 2019 | url=https://www.fda.gov/news-events/press-announcements/statement-data-accuracy-issues-recently-approved-gene-therapy | archive-url=https://web.archive.org/web/20191119010154/https://www.fda.gov/news-events/press-announcements/statement-data-accuracy-issues-recently-approved-gene-therapy | archive-date=19 November 2019 | url-status=live | access-date=1 December 2019}} {{PD-notice}} 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.{{Cite news|url=https://www.reuters.com/article/us-novartis-zolgensma-idUSKBN1XB4SC|title=Novartis says delayed telling FDA of Zolgensma concern due to 'mistake'|date=1 November 2019|work=Reuters|access-date=11 November 2019|archive-date=11 November 2019|archive-url=https://web.archive.org/web/20191111185235/https://www.reuters.com/article/us-novartis-zolgensma-idUSKBN1XB4SC|url-status=live}} Due to data manipulation issue, the EMA withdrew their decision to allow an accelerated assessment of the medication.{{cite web |title=Zolgensma°: the drug of extremes |url=https://english.prescrire.org/en/6D1C355D9A772C0070646CD88C375155/Download.aspx |access-date=22 May 2020 |page=107 |date=April 2020 |archive-date=29 October 2020 |archive-url=https://web.archive.org/web/20201029001030/https://english.prescrire.org/en/6D1C355D9A772C0070646CD88C375155/Download.aspx |url-status=live }}

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,{{cite news |url=https://www.reuters.com/article/us-novartis-gene-therapy/novartis-in-talks-with-patients-upset-about-lottery-like-gene-therapy-giveaway-idUKKBN1YO2BR |title=Novartis in talks with patients upset about lottery-like gene therapy giveaway |publisher=Reuters |date=20 December 2019 |access-date=29 May 2021 |archive-date=1 June 2021 |archive-url=https://web.archive.org/web/20210601200115/https://www.reuters.com/article/us-novartis-gene-therapy/novartis-in-talks-with-patients-upset-about-lottery-like-gene-therapy-giveaway-idUKKBN1YO2BR |url-status=live }} was received with much criticism by the European Commission,{{Cite web|url=https://www.europarl.europa.eu/doceo/document/P-9-2020-000202-ASW_EN.html|title=Answer given by Ms Kyriakides on behalf of the European Commission|vauthors=Kyriakides S|date=19 February 2020|website=European Parliament|access-date=21 April 2020|archive-date=28 October 2020|archive-url=https://web.archive.org/web/20201028212409/https://www.europarl.europa.eu/doceo/document/P-9-2020-000202-ASW_EN.html|url-status=live}} some European healthcare regulators{{Cite web|url=https://beneluxa.org/news1|title=No "lottery for life" - Statement by Beneluxa Health Ministers addressing the global managed access program designed by Novartis and Avexis|date=30 January 2020|website=Beneluxa|access-date=21 April 2020|archive-date=22 May 2020|archive-url=https://web.archive.org/web/20200522033518/https://beneluxa.org/news1|url-status=live}} and patient groups who see it as emotionally burdening, suboptimal, and ethically questionable.{{Cite web|url=https://www.sma-europe.eu/news/avxs-101-zolgensma-to-be-made-available-globally-through-a-controversial-programme/|title=AVXS-101 (Zolgensma) to be made available globally through a controversial programme|website=SMA Europe|date=26 December 2019|access-date=21 April 2020|archive-date=13 March 2020|archive-url=https://web.archive.org/web/20200313145046/https://www.sma-europe.eu/news/avxs-101-zolgensma-to-be-made-available-globally-through-a-controversial-programme/|url-status=live}} Novartis did not consult with families or doctors before announcing the scheme.{{cite news |url=https://www.theguardian.com/society/2019/dec/20/lottery-prize-zolgensma-drug-zolgensma-children-muscle-wasting-disease |title=Dismay at lottery for $2.1m drug to treat children with muscle-wasting disease |newspaper=The Guardian |date=20 December 2019 |access-date=21 December 2019 |archive-date=21 December 2019 |archive-url=https://web.archive.org/web/20191221220120/https://www.theguardian.com/society/2019/dec/20/lottery-prize-zolgensma-drug-zolgensma-children-muscle-wasting-disease |url-status=live }}{{cite news |url=https://www.wsj.com/articles/novartis-to-offer-worlds-most-expensive-drug-for-free-via-lottery-11576767894 |title=Novartis to Offer World's Most Expensive Drug for Free Via Lottery |newspaper=The Wall Street Journal |date=19 December 2019 |url-access=subscription |access-date=21 December 2019 |archive-date=21 December 2019 |archive-url=https://web.archive.org/web/20191221220121/https://www.wsj.com/articles/novartis-to-offer-worlds-most-expensive-drug-for-free-via-lottery-11576767894 |url-status=live }}

Onasemnogene abeparvovec is the international nonproprietary name (INN){{cite journal | vauthors=((World Health Organization)) | year=2018 | title=International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 79 | journal=WHO Drug Information | volume=32 | issue=1 | pages=95–6 | hdl=10665/330941 | hdl-access=free }} and the United States Adopted Name (USAN).{{cite web | title=Onasemnogene abeparvovec (USAN/INN) | website=PubChem | url=https://pubchem.ncbi.nlm.nih.gov/substance/384585535 | access-date=9 September 2021 | archive-date=9 September 2021 | archive-url=https://web.archive.org/web/20210909035005/https://pubchem.ncbi.nlm.nih.gov/substance/384585535 | url-status=live }}

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