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Onasemnogene abeparvovec

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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 used to treat spinal muscular atrophy (SMA),[6][7] a disease causing muscle function loss in children. It involves a one-time infusion of the medication into a vein.[6] It works by providing a new copy of the SMN gene that produces the SMN protein.[6]

SMA stems from an SMN1 gene mutation, causing SMN protein deficiency vital for motor neuron survival. Onasemnogene abeparvovec, a biologic drug utilizing AAV9 virus capsids containing an SMN1 transgene, is administered to motor neurons, boosting SMN protein levels. Common side effects include vomiting and elevated liver enzymes, while more severe reactions involve liver issues and low platelet count.[6][8]

Developed by AveXis and acquired by Novartis, onasemnogene abeparvovec gained various FDA designations and approvals globally. Controversies included data manipulation concerns and delayed reporting to regulatory agencies. Onasemnogene abeparvovec's price is high, earning it the title of the world's most expensive medication at the time of commercial approval.[10] This has later been exceeded by other gene therapies like Hemgenix. Japan negotiated a lower price for Zolgensma for its public healthcare system.[11][12]

Medical uses

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Onasemnogene abeparvovec has been developed to treat spinal muscular atrophy, a disease linked to a mutation in the SMN1 gene on chromosome 5q[7] and diagnosed predominantly in young children that causes progressive loss of muscle function and frequently death. The medication is administered as an intravenous infusion.[13]

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.[6]

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.[14] 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.[8][15][16]

Adverse effects

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Common adverse reactions may include nausea and elevated liver enzymes.[6] Serious adverse reactions may include liver problems and low platelets.[6] Transient elevated levels of cardiac troponin‑I were observed in clinical trials; the clinical importance of these findings is not known.[6] However, cardiac toxicity was seen in studies of other animals.[6]

Mechanism of action

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Mechanism of action of onasemnogene abeparvovec

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.[5] 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

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Onasemnogene abeparvovec, developed by the US biotechnology startup AveXis, which was acquired by Novartis in 2018,[17] is based on research conducted at the Institut de Myologie in France.[18]

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.[14] Additionally, the FDA awarded the manufacturer a rare pediatric disease priority review voucher and approved onasemnogene abeparvovec for AveXis Inc.[14]

In June 2015, the European Commission granted orphan designation to the drug.[19] However, in July 2019, the drug was removed from the Committee for Medicinal Products for Human Use (CHMP) accelerated assessment program.[20]

In May 2019, onasemnogene abeparvovec received US FDA approval as a treatment for children under two years old.[14] Since 2019, the treatment has been reimbursed in Qatar[21] and Israel.[22] In March 2020, it gained regulatory approval in Japan with the same labeling as in the US.[23] 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.[8][24]

In August 2020, onasemnogene abeparvovec received regulatory approval in Brazil from the Brazilian Health Regulatory Agency (ANVISA).[25] Subsequently, it was approved for medical use in Canada in December 2020,[26][27] in Australia in February 2021,[1][2][28] and in Russia in December 2021.[29]

According to the Health Sciences Authority register of Singapore, onasemnogene abeparvovec was approved in April 2023.[30]

Society and culture

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Initially approved in the United States in 2019 for children under two,[14][6] onasemnogene abeparvovec's approval varies in different regions.[23][31][32]

Economics

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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.[33] In its first full quarter of sales US$160 million of medication was sold.[34]

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.[10] 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 1,530,000) per patient.[11][12]

Controversy

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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.[35] 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.[36][35] 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.[35] The delay drew strong condemnation from the FDA.[37] 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.[38] Due to data manipulation issue, the EMA withdrew their decision to allow an accelerated assessment of the medication.[39]

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

Novartis faced criticism for donating onasemnogene abeparvovec doses through a lottery system.[41][42][43]

Names

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Onasemnogene abeparvovec is the international nonproprietary name (INN)[46] and the United States Adopted Name (USAN).[47]

References

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  1. ^ a b c "Zolgensma". Therapeutic Goods Administration (TGA). 10 March 2021. Archived from the original on 9 September 2021. Retrieved 8 September 2021.
  2. ^ a b c "AusPAR: Onasemnogene abeparvovec". Therapeutic Goods Administration (TGA). 22 April 2021. Archived from the original on 9 September 2021. Retrieved 8 September 2021.
  3. ^ "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.
  4. ^ "Summary Basis of Decision (SBD) for Zolgensma". Health Canada. 23 October 2014. Archived from the original on 30 May 2022. Retrieved 29 May 2022.
  5. ^ a b "Zolgensma 2 x 1013 vector genomes/mL solution for infusion - Summary of Product Characteristics (SmPC)". (emc). 30 June 2020. Archived from the original on 28 October 2020. Retrieved 30 July 2020.
  6. ^ a b c d e f g h i j k "Zolgensma- onasemnogene abeparvovec-xioi kit full prescribing information". DailyMed. 24 May 2019. Archived from the original on 19 November 2019. Retrieved 18 November 2019.
  7. ^ a b c "Zolgensma". U.S. Food and Drug Administration (FDA). 6 August 2019. STN: 125694. Archived from the original on 19 November 2019. Retrieved 1 November 2019. Public Domain This article incorporates text from this source, which is in the public domain.
  8. ^ a b c d "Zolgensma EPAR". European Medicines Agency (EMA). 24 March 2020. Archived from the original on 17 July 2020. Retrieved 30 July 2020. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  9. ^ "Zolgensma Product information". Union Register of medicinal products. Retrieved 3 March 2023.
  10. ^ a b 初の「億超え新薬」ゾルゲンスマの薬価はどう決まったか Archived 15 August 2020 at the Wayback Machine (Japanese). AnswersNews.
  11. ^ a b 厚生労働省告示第二百十四号 Archived 31 October 2020 at the Wayback Machine (Japanese). Ministry of Health, Labour and Welfare, Japan.
  12. ^ a b 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 Archived 28 October 2020 at the Wayback Machine (Japanese). Novartis Pharma.
  13. ^ "Onasemnogene Abeparvovec". LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. NCBI Bookshelf. 20 August 2020. PMID 33242238. Bookshelf ID: NBK564658. Archived from the original on 14 August 2022. Retrieved 13 August 2022.
  14. ^ a b c d e "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. Archived from the original on 1 September 2019. Retrieved 18 November 2019. Public Domain This article incorporates text from this source, which is in the public domain.
  15. ^ "Health Canada approves Zolgensma, the one-time gene therapy for pediatric patients with spinal muscular atrophy (SMA)" (Press release). Novartis. 16 December 2020. Archived from the original on 3 June 2021. Retrieved 2 July 2021 – via Cision.
  16. ^ "onasemnogene abeparvovec". Canadian Agency for Drugs and Technologies in Health (CADTH). 26 May 2020. Archived from the original on 2 June 2021. Retrieved 1 June 2021.
  17. ^ "Novartis successfully completes acquisition of AveXis, Inc" (Press release). Novartis. Archived from the original on 9 September 2019. Retrieved 6 October 2018.
  18. ^ "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.
  19. ^ "EU/3/15/1509". European Medicines Agency. 17 September 2018. Archived from the original on 19 November 2019. Retrieved 19 November 2019.
  20. ^ "Novartis' Zolgensma Joins Growing List of Medicines to Lose Accelerated Assessment Status in EU". RAPS. Archived from the original on 19 November 2019. Retrieved 19 November 2019.
  21. ^ "HMC implements innovative gene therapy to treat congenital spinal muscular atrophy". The Peninsula. 20 November 2019. Archived from the original on 29 March 2020. Retrieved 29 March 2020.
  22. ^ Julian HL (21 November 2019). "In First, World's Most Expensive Medicine Used to Treat Israeli Toddler". Archived from the original on 29 March 2020. Retrieved 29 March 2020.
  23. ^ a b "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.
  24. ^ "Global Novartis News Archive". Novartis (Press release). Archived from the original on 29 May 2020. Retrieved 20 May 2020.
  25. ^ "Medicamento conhecido como mais caro do mundo recebe registro da Anvisa". G1 (in Brazilian Portuguese). 17 August 2020. Archived from the original on 31 August 2020. Retrieved 18 August 2020.
  26. ^ "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.
  27. ^ "PRODUCT MONOGRAPH INCLUDING PATIENT MEDICATION INFORMATION : ZOLGENSMA" (PDF). Pdf.hres.ca. Archived (PDF) from the original on 14 June 2021. Retrieved 24 March 2022.
  28. ^ "TGA eBS - Product and Consumer Medicine Information Licence". Ebs.tga.gov.au. Archived from the original on 9 September 2021. Retrieved 24 March 2022.
  29. ^ "Минздрав зарегистрировал препарат для лечения СМА «Золгенсма»". Ведомости (in Russian). 9 December 2021. Archived from the original on 10 December 2021. Retrieved 8 July 2022.
  30. ^ Iau, Jean (19 May 2023). "Toddler with rare genetic condition can be treated after $2m raised, drug registered". The Straits Times. ISSN 0585-3923. Retrieved 20 May 2023.
  31. ^ Mueller, Casimir Jones SC-Lisa L. (September 2020). "First Gene Therapy Products Approved in Brazil". Lexology. Archived from the original on 2 June 2021. Retrieved 1 June 2021.
  32. ^ "New Zolgensma data demonstrate age-appropriate development when used early, real-world benefit in older children and durability 5+ years post-treatment". Novartis. Archived from the original on 2 June 2021. Retrieved 1 June 2021.
  33. ^ "$2.1m Novartis gene therapy to become world's most expensive drug". The Guardian. London. Reuters. 25 May 2019. Archived from the original on 7 November 2020. Retrieved 25 May 2019.
  34. ^ Miller, John (30 October 2019). "Novartis' Zolgensma study halted by FDA amid safety questions". Reuters. Archived from the original on 30 October 2019. Retrieved 30 October 2019.
  35. ^ a b c Erman M (24 September 2019). "Novartis blames former AveXis executives for Zolgensma data manipulation". Reuters. Archived from the original on 26 September 2019. Retrieved 26 September 2019.
  36. ^ Palmer, Eric (24 September 2019). "Novartis to put AveXis into protective custody after data manipulation scandal". Fierce Biotech. Retrieved 12 May 2024.
  37. ^ "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. Public Domain This article incorporates text from this source, which is in the public domain.
  38. ^ "Novartis says delayed telling FDA of Zolgensma concern due to 'mistake'". Reuters. 1 November 2019. Archived from the original on 11 November 2019. Retrieved 11 November 2019.
  39. ^ "Zolgensma°: the drug of extremes". April 2020. p. 107. Archived from the original on 29 October 2020. Retrieved 22 May 2020.
  40. ^ "Novartis in talks with patients upset about lottery-like gene therapy giveaway". Reuters. 20 December 2019. Archived from the original on 1 June 2021. Retrieved 29 May 2021.
  41. ^ a b Kyriakides S (19 February 2020). "Answer given by Ms Kyriakides on behalf of the European Commission". European Parliament. Archived from the original on 28 October 2020. Retrieved 21 April 2020.
  42. ^ a b "No "lottery for life" - Statement by Beneluxa Health Ministers addressing the global managed access program designed by Novartis and Avexis". Beneluxa. 30 January 2020. Archived from the original on 22 May 2020. Retrieved 21 April 2020.
  43. ^ a b "AVXS-101 (Zolgensma) to be made available globally through a controversial programme". SMA Europe. 26 December 2019. Archived from the original on 13 March 2020. Retrieved 21 April 2020.
  44. ^ "Dismay at lottery for $2.1m drug to treat children with muscle-wasting disease". The Guardian. 20 December 2019. Archived from the original on 21 December 2019. Retrieved 21 December 2019.
  45. ^ "Novartis to Offer World's Most Expensive Drug for Free Via Lottery". The Wall Street Journal. 19 December 2019. Archived from the original on 21 December 2019. Retrieved 21 December 2019.
  46. ^ World Health Organization (2018). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 79". WHO Drug Information. 32 (1): 95–6. hdl:10665/330941.
  47. ^ "Onasemnogene abeparvovec (USAN/INN)". PubChem. Archived from the original on 9 September 2021. Retrieved 9 September 2021.
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