Biology:Onasemnogene abeparvovec

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Short description: Gene therapy medication used to treat spinal muscular atrophy
Onasemnogene abeparvovec
Gene therapy
Target geneSMN1
VectorAdeno-associated virus serotype 9
Clinical data
Trade namesZolgensma
Other namesAVXS-101, onasemnogene abeparvovec-xioi
AHFS/Drugs.comProfessional Drug Facts
License data
Pregnancy
category
Routes of
administration		Intravascular
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
DrugBank
UNII
KEGG

Onasemnogene abeparvovec, sold under the brand name Zolgensma, is a gene therapy medication used to treat spinal muscular atrophy (SMA).[5][6] It is used as a one-time infusion into a vein.[5]

Onasemnogene abeparvovec works by providing a new copy of the gene that makes the human SMN protein.[5]

The treatment must be accompanied by a course of corticosteroids of at least two months. Common side effects include vomiting and increased liver enzymes.[5][7]

Onasemnogene abeparvovec was first approved for medical use in the United States in 2019 as a treatment for children less than two years old.[9][5] It was later approved in other jurisdictions with similar scope.[10][11][12] The approval scope in certain jurisdictions, including the European Union and Canada, is somewhat different.[7][13][14]

With an introductory price of $2.125 million per treatment, onasemnogene abeparvovec is one of the most expensive drugs in the world.

Medical uses

Onasemnogene abeparvovec has been developed to treat spinal muscular atrophy, a disease linked to a mutation in the SMN1 gene on chromosome 5q[6] and diagnosed predominantly in young children that causes progressive loss of muscle function and frequently death. The medication is administered as an intravenous infusion.[15]

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.[9] In the European Union and Canada, it is indicated for the treatment of patients 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.[7][16]

The medication is used with corticosteroids in an effort to protect the liver.[5]

Adverse effects

Common adverse reactions may include nausea and elevated liver enzymes.[5] Serious adverse reactions may include liver problems and low platelets.[5] Transient elevated levels of cardiac troponin‑I were observed in clinical trials; the clinical importance of these findings is not known.[5] However, cardiac toxicity was seen in studies of other animals.[5]

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.[5] Liver function should be monitored for three months after administration.[17]

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.[4] 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]

History

Onasemnogene abeparvovec was developed by the US biotechnology startup AveXis, which was acquired by Novartis in 2018,[18] based on the work at the Institut de Myologie in France.[19]

The U.S. Food and Drug Administration (FDA) granted the application for onasemnogene abeparvovec-xioi fast track, breakthrough therapy, priority review, and orphan drug designations.[9] The FDA also awarded the manufacturer a rare pediatric disease priority review voucher, and granted the approval of Zolgensma to AveXis Inc.[9]

In June 2015, the European Commission granted orphan designation for the drug.[20] In July 2019, the drug was removed from the Committee for Medicinal Products for Human Use (CHMP) accelerated assessment program.[21]

In May 2019, onasemnogene abeparvovec received US FDA approval as a treatment for children less than two years old.[9] Since 2019, the treatment has been reimbursed in Qatar[22] and Israel[23] In March 2020, onasemnogene abeparvovec was granted regulatory approval in Japan with the label identical to the US one.[10] Also in March 2020, the European Medicines Agency recommended a conditional marketing authorization for use in people with SMA type 1 or with any SMA type and having no more than three copies of the SMN2 gene.[24][7] In May 2020, Onasemnogene abeparvovec was conditionally approved in Europe.[7][25]

In August 2020, onasemnogene abeparvovec was granted regulatory approval in Brazil by the Brazilian Health Regulatory Agency (ANVISA).[26]

In December 2020, onasemnogene abeparvovec was approved for medical use in Canada.[27][28]

Onasemnogene abeparvovec was approved for medical use in Australia in February 2021.[1][2][29]

An official approval in Russia was granted in December 2021.[30]

According to Singapore's Health Sciences Authority register, Zolgensma was approved on April 21.[31]

Society and culture

Economics

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).[32] In its first full quarter of sales US$160 million of medication was sold.[33]

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.[34] The Central Social Insurance Medical Council, responsible for approving the universal drug fee schedule in Japan, has negotiated the price down to ¥167,077,222 (approx. USD 1,510,000) per patient.[35][36]

Controversy

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.[37] Novartis fired two AveXis executives it determined responsible for the alleged data manipulation but informed the FDA of the data integrity issue only in June 2019, a month after the drug's approval.[37] The delay drew strong condemnation from the FDA.[38] 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.[39] Due to data manipulation issue, the EMA withdrew their decision to allow an accelerated assessment of the medication.[40]

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,[41] was received with much criticism by the European Commission,[42] some European healthcare regulators[43] and patient groups who see it as emotionally burdening, suboptimal, and ethically questionable.[44] Novartis did not consult with families or doctors before announcing the scheme.[45][46]

Names

Onasemnogene abeparvovec is the international nonproprietary name (INN)[47] and the United States Adopted Name (USAN).[48]

References

  1. ↑ 1.0 1.1 1.2 "Zolgensma". 10 March 2021. https://www.tga.gov.au/apm-summary/zolgensma. 
  2. ↑ 2.0 2.1 2.2 "AusPAR: Onasemnogene abeparvovec". 22 April 2021. https://www.tga.gov.au/auspar/auspar-onasemnogene-abeparvovec. 
  3. ↑ "Summary Basis of Decision (SBD) for Zolgensma". 23 October 2014. https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?linkID=SBD00521&lang=en. 
  4. ↑ 4.0 4.1 "Zolgensma 2 x 1013 vector genomes/mL solution for infusion - Summary of Product Characteristics (SmPC)". 30 June 2020. https://www.medicines.org.uk/emc/product/11572/smpc. 
  5. ↑ 5.00 5.01 5.02 5.03 5.04 5.05 5.06 5.07 5.08 5.09 5.10 5.11 "Zolgensma- onasemnogene abeparvovec-xioi kit full prescribing information". 24 May 2019. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=68cd4f06-70e1-40d8-bedb-609ec0afa471. 
  6. ↑ 6.0 6.1 6.2 "Zolgensma". 6 August 2019. https://www.fda.gov/vaccines-blood-biologics/zolgensma.  This article incorporates text from this source, which is in the public domain.
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 "Zolgensma EPAR". 24 March 2020. https://www.ema.europa.eu/en/medicines/human/EPAR/zolgensma.  Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  8. ↑ "Zolgensma Product information". https://ec.europa.eu/health/documents/community-register/html/h1443.htm. 
  9. ↑ 9.0 9.1 9.2 9.3 9.4 "FDA approves innovative gene therapy to treat pediatric patients with spinal muscular atrophy, a rare disease and leading genetic cause of infant mortality". 24 May 2019. https://www.fda.gov/news-events/press-announcements/fda-approves-innovative-gene-therapy-treat-pediatric-patients-spinal-muscular-atrophy-rare-disease.  This article incorporates text from this source, which is in the public domain.
  10. ↑ 10.0 10.1 "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 (Press release). Retrieved 29 March 2020.
  11. ↑ Mueller, Casimir Jones SC-Lisa L. (September 2020). "First Gene Therapy Products Approved in Brazil". https://www.lexology.com/library/detail.aspx?g=5347d335-423c-4bb8-8746-187e126c8de8. 
  12. ↑ "New Zolgensma data demonstrate age-appropriate development when used early, real-world benefit in older children and durability 5+ years post-treatment". 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. 
  13. ↑ "Health Canada approves Zolgensma, the one-time gene therapy for pediatric patients". https://www.bioquebec.com/press-releases/2021/health-canada-approves-zolgensma. 
  14. ↑ "onasemnogene abeparvovec". 26 May 2020. https://cadth.ca/onasemnogene-abeparvovec. 
  15. ↑ "Onasemnogene Abeparvovec". LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. NCBI Bookshelf. 20 August 2020. Bookshelf ID: NBK564658. https://www.ncbi.nlm.nih.gov/books/NBK564658/. Retrieved 13 August 2022. 
  16. ↑ "Health Canada approves Zolgensma, the one-time gene therapy for pediatric patients with spinal muscular atrophy (SMA)". Newswire Canada (Cision). 16 December 2020. 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. 
  17. ↑ "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) (Press release). 11 September 2019. Archived from the original on 1 September 2019. Retrieved 18 November 2019. This article incorporates text from this source, which is in the public domain.
  18. ↑ "Novartis successfully completes acquisition of AveXis, Inc" (Press release). Novartis. Archived from the original on 9 September 2019. Retrieved 6 October 2018.
  19. ↑ "AveXis receives FDA approval for Zolgensma, the first and only gene therapy for pediatric patients with spinal muscular atrophy (SMA)". Novartis (Press release). 24 May 2019. Retrieved 13 August 2022.
  20. ↑ "EU/3/15/1509". 17 September 2018. https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu3151509. 
  21. ↑ "Novartis' Zolgensma Joins Growing List of Medicines to Lose Accelerated Assessment Status in EU". https://www.raps.org/news-and-articles/news-articles/2019/7/novartis-zolgensma-joins-growing-list-of-medicine. 
  22. ↑ "HMC implements innovative gene therapy to treat congenital spinal muscular atrophy". 20 November 2019. https://thepeninsulaqatar.com/article/20/11/2019/HMC-implements-innovative-gene-therapy-to-treat-congenital-spinal-muscular-atrophy. 
  23. ↑ "In First, World's Most Expensive Medicine Used to Treat Israeli Toddler". https://www.jewishpress.com/news/health-and-medicine/in-first-worlds-most-expensive-medicine-used-to-treat-israeli-toddler/2019/11/21/. 
  24. ↑ "New gene therapy to treat spinal muscular atrophy". European Medicines Agency (Press release). 27 March 2020. Archived from the original on 29 March 2020. Retrieved 29 March 2020.
  25. ↑ "Global Novartis News Archive". Novartis (Press release). Archived from the original on 29 May 2020. Retrieved 20 May 2020.
  26. ↑ "Medicamento conhecido como mais caro do mundo recebe registro da Anvisa" (in pt-br). https://g1.globo.com/ciencia-e-saude/noticia/2020/08/17/medicamento-conhecido-como-mais-caro-do-mundo-recebe-registro-da-anvisa.ghtml. 
  27. ↑ "Health Canada approves Zolgensma, the one-time gene therapy for pediatric patients with spinal muscular atrophy (SMA)" (Press release). Novartis Pharmaceuticals Canada. 16 December 2020. Archived from the original on 3 June 2021. Retrieved 27 May 2021 – via Cision.
  28. ↑ "PRODUCT MONOGRAPH INCLUDING PATIENT MEDICATION INFORMATION : ZOLGENSMA". https://pdf.hres.ca/dpd_pm/00059243.PDF. 
  29. ↑ "TGA eBS - Product and Consumer Medicine Information Licence". https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2021-PI-01276-1. 
  30. ↑ "Минздрав зарегистрировал препарат для лечения СМА «Золгенсма»" (in ru). https://www.vedomosti.ru/society/news/2021/12/09/899915-minzdrav-zaregistriroval-preparat. 
  31. ↑ Iau, Jean (2023-05-19). "Toddler with rare genetic condition can be treated after $2m raised, drug registered" (in en). The Straits Times. ISSN 0585-3923. https://www.straitstimes.com/singapore/toddler-with-rare-genetic-condition-to-receive-treatment-after-2-mil-crowdfunding-and-drug-getting-registered. 
  32. ↑ "$2.1m Novartis gene therapy to become world's most expensive drug". The Guardian. Reuters (London). 25 May 2019. https://www.theguardian.com/science/2019/may/25/21m-novartis-gene-therapy-to-become-worlds-most-expensive-drug. 
  33. ↑ Miller, John (30 October 2019). "Novartis' Zolgensma study halted by FDA amid safety questions". Reuters. https://www.reuters.com/article/us-novartis-gene-therapy/novartis-zolgensma-study-halted-by-fda-amid-safety-questions-idUSKBN1X90XS. 
  34. ↑ 初の「億超え新薬」ゾルゲンスマの薬価はどう決まったか (Japanese). AnswersNews.
  35. ↑ 厚生労働省告示第二百十四号 (Japanese). Ministry of Health, Labour and Welfare, Japan.
  36. ↑ 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 (Japanese). Novartis Pharma.
  37. ↑ 37.0 37.1 "Novartis blames former AveXis executives for Zolgensma data manipulation". Reuters. 24 September 2019. https://news.yahoo.com/novartis-blames-former-avexis-execs-151942378.html. 
  38. ↑ "Statement on data accuracy issues with recently approved gene therapy". U.S. Food and Drug Administration (FDA) (Press release). 19 November 2019. Archived from the original on 19 November 2019. Retrieved 1 December 2019. This article incorporates text from this source, which is in the public domain.
  39. ↑ "Novartis says delayed telling FDA of Zolgensma concern due to 'mistake'". Reuters. 1 November 2019. https://www.reuters.com/article/us-novartis-zolgensma-idUSKBN1XB4SC. 
  40. ↑ "Zolgensma°: the drug of extremes". April 2020. p. 107. https://english.prescrire.org/en/6D1C355D9A772C0070646CD88C375155/Download.aspx. 
  41. ↑ "Novartis in talks with patients upset about lottery-like gene therapy giveaway". Reuters. 20 December 2019. https://www.reuters.com/article/us-novartis-gene-therapy/novartis-in-talks-with-patients-upset-about-lottery-like-gene-therapy-giveaway-idUKKBN1YO2BR. 
  42. ↑ "Answer given by Ms Kyriakides on behalf of the European Commission". 19 February 2020. https://www.europarl.europa.eu/doceo/document/P-9-2020-000202-ASW_EN.html. 
  43. ↑ "No "lottery for life" - Statement by Beneluxa Health Ministers addressing the global managed access program designed by Novartis and Avexis". 30 January 2020. https://beneluxa.org/news1. 
  44. ↑ "AVXS-101 (Zolgensma) to be made available globally through a controversial programme". 26 December 2019. https://www.sma-europe.eu/news/avxs-101-zolgensma-to-be-made-available-globally-through-a-controversial-programme/. 
  45. ↑ "Dismay at lottery for $2.1m drug to treat children with muscle-wasting disease". The Guardian. 20 December 2019. https://www.theguardian.com/society/2019/dec/20/lottery-prize-zolgensma-drug-zolgensma-children-muscle-wasting-disease. 
  46. ↑ "Novartis to Offer World's Most Expensive Drug for Free Via Lottery". The Wall Street Journal. 19 December 2019. https://www.wsj.com/articles/novartis-to-offer-worlds-most-expensive-drug-for-free-via-lottery-11576767894. 
  47. ↑ "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 79". WHO Drug Information 32 (1): 95–6. 2018. 
  48. ↑ "Onasemnogene abeparvovec (USAN/INN)". https://pubchem.ncbi.nlm.nih.gov/substance/384585535. 

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