Nusinersen

Nusinersen
Clinical data
Trade namesSpinraza
Other namesIONIS-SMNRx, ISIS-SMNRx
AHFS/Drugs.comMonograph
MedlinePlusa617010
License data
Pregnancy
category
  • AU: B1
Routes of
administration		Intrathecal
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability100% (intrathecal)
Protein binding<25% (in CSF), >94% (in plasma)[6]
MetabolismExonuclease (3'- and 5')-mediated hydrolysis
Elimination half-life135–177 days (in CSF), 63–87 days (in plasma)
Identifiers
  • all-P-ambo-2'-O-(2-Methoxyethyl)-5-methyl-P-thiouridylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiocytidylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioadenylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiocytidylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiocytidylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioadenylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioadenylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioadenylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioguanylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiocytidylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioguanylyl-(3'→5')-2'-O-(2-methoxyethyl)guanosine[7]
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
Chemical and physical data
FormulaC234H323N61Na17O128P17S17[4]
Molar mass7500.86 g·mol−1
  • Cc1cn(c(=O)[nH]c1=O)[C@H]2[C@@H]([C@@H]([C@H](O2)CO)OP(=S)(O)OC[C@@H]3[C@H]([C@H]([C@@H](O3)n4cc(c(nc4=O)N)C)OCCOC)OP(=S)(O)OC[C@@H]5[C@H]([C@H]([C@@H](O5)n6cnc7c6ncnc7N)OCCOC)OP(=S)(O)OC[C@@H]8[C@H]([C@H]([C@@H](O8)n9cc(c(nc9=O)N)C)OCCOC)OP(=S)(O)OC[C@@H]1[C@H]([C@H]([C@@H](O1)n1cc(c(=O)[nH]c1=O)C)OCCOC)OP(=S)(O)OC[C@@H]1[C@H]([C@H]([C@@H](O1)n1cc(c(=O)[nH]c1=O)C)OCCOC)OP(=S)(O)OC[C@@H]1[C@H]([C@H]([C@@H](O1)n1cc(c(=O)[nH]c1=O)C)OCCOC)OP(=S)(O)OC[C@@H]1[C@H]([C@H]([C@@H](O1)n1cc(c(nc1=O)N)C)OCCOC)OP(=S)(O)OC[C@@H]1[C@H]([C@H]([C@@H](O1)n1cnc2c1ncnc2N)OCCOC)OP(=S)(O)OC[C@@H]1[C@H]([C@H]([C@@H](O1)n1cc(c(=O)[nH]c1=O)C)OCCOC)OP(=S)(O)OC[C@@H]1[C@H]([C@H]([C@@H](O1)n1cnc2c1ncnc2N)OCCOC)OP(=S)(O)OC[C@@H]1[C@H]([C@H]([C@@H](O1)n1cnc2c1ncnc2N)OCCOC)OP(=S)(O)OC[C@@H]1[C@H]([C@H]([C@@H](O1)n1cc(c(=O)[nH]c1=O)C)OCCOC)OP(=S)(O)OC[C@@H]1[C@H]([C@H]([C@@H](O1)n1cnc2c1nc([nH]c2=O)N)OCCOC)OP(=S)(O)OC[C@@H]1[C@H]([C@H]([C@@H](O1)n1cc(c(nc1=O)N)C)OCCOC)OP(=S)(O)OC[C@@H]1[C@H]([C@H]([C@@H](O1)n1cc(c(=O)[nH]c1=O)C)OCCOC)OP(=S)(O)OC[C@@H]1[C@H]([C@H]([C@@H](O1)n1cnc2c1nc([nH]c2=O)N)OCCOC)OP(=S)(O)OC[C@@H]1[C@H]([C@H]([C@@H](O1)n1cnc2c1nc([nH]c2=O)N)OCCOC)O)OCCOC

Nusinersen,[7] marketed as Spinraza,[4] is a medication used in treating spinal muscular atrophy (SMA), a rare neuromuscular disorder.[8][4] In December 2016, it became the first approved drug used in treating this disorder.

Since the condition it treats is so rare, Nusinersen has so-called "orphan drug" designation in the United States and the European Union.[9]

Medical uses

The drug is used to treat spinal muscular atrophy associated with a mutation in the SMN1 gene. It is administered directly to the central nervous system (CNS) using intrathecal injection.[4]

In clinical trials, the drug halted the disease progression. In around 60% of infants affected by type 1 spinal muscular atrophy, it improves motor function.[4]

Side effects

People treated with nusinersen had an increased risk of upper and lower respiratory infections and congestion, ear infections, constipation, pulmonary aspiration, teething, and scoliosis. There is a risk that growth of infants and children might be stunted. In older clinical trial subjects, the most common adverse events were headache, back pain, and other adverse effects from the spinal injection, such as post-dural-puncture headache.[4]

Although not observed in the trial patients, a reduction in platelets as well as a risk of kidney damage are theoretical risks for antisense drugs and therefore platelets and kidney function should be monitored during treatment.[4]

In 2018, several cases of communicating hydrocephalus in children and adults treated with nusinersen emerged; it remains unclear whether this was drug related.[10]

Pharmacology

Spinal muscular atrophy is caused by loss-of-function mutations in the SMN1 gene which codes for survival motor neuron (SMN) protein. People survive owing to low amounts of the SMN protein produced from the SMN2 gene. Nusinersen modulates alternative splicing of the SMN2 gene, functionally converting it into SMN1 gene, thus increasing the level of SMN protein in the CNS.[11]

The drug distributes to CNS and peripheral tissues.[4]

The half-life is estimated to be 135 to 177 days in cerebrospinal fluid (CSF) and 63 to 87 days in blood plasma. The drug is metabolized via exonuclease (3′- and 5′)-mediated hydrolysis and does not interact with CYP450 enzymes.[4] The primary route of elimination is likely by urinary excretion for nusinersen and its metabolites.[4]

Chemistry

Nusinersen is an antisense oligonucleotide in which the 2'-hydroxy groups of the ribofuranosyl rings are replaced with 2'-O-2-methoxyethyl groups and the phosphate linkages are replaced with phosphorothioate linkages.[4][11][12]

History

Nusinersen was developed in a collaboration between Adrian Krainer at Cold Spring Harbor Laboratory and Ionis Pharmaceuticals (formerly called Isis Pharmaceuticals).[13][14][15][16] Initial work of target discovery of nusinersen was done by Ravindra N. Singh and co-workers at the University of Massachusetts Medical School funded by Cure SMA.[17][18]

Starting in 2012, Ionis partnered with Biogen on development and, in 2015, Biogen acquired an exclusive license to the drug for a US$75 million license fee, milestone payments up to US$150 million, and tiered royalties thereafter; Biogen also paid the costs of development subsequent to taking the license.[19] The license to Biogen included licenses to intellectual property that Ionis had acquired from Cold Spring Harbor Laboratory and University of Massachusetts.[20]

In November 2016, the new drug application was accepted under the FDA's priority review process on the strength of the Phase III trial and the unmet need, and was also accepted for review at the European Medicines Agency (EMA) at that time.[21][22] It was approved by the FDA in December 2016 and by EMA in May 2017 as the first drug to treat SMA.[23][24] Subsequently, nusinersen was approved to treat SMA in Canada (July 2017),[25] Japan (July 2017),[26] Brazil (August 2017),[27] Switzerland (September 2017),[28] and China (February 2019).[29]

In 2023, additional clinical trials continued to validate the efficacy of nusinersen, particularly emphasizing the benefits of early intervention. The trials demonstrated significant improvements in motor function and survival rates among infants with SMA Type 1, underscoring the importance of prompt treatment to achieve optimal clinical outcomes. [30]

Society and culture

Economics

Nusinersen list price in the USA is US$125,000 per injection which puts the treatment cost at US$750,000 in the first year and US$375,000 annually after that.[31] According to The New York Times, this places nusinersen "among the most expensive drugs in the world".[22]

In October 2017, the authorities in Denmark recommended nusinersen for use only in a small subset of people with SMA type 1 (young babies) and refused to offer it as a standard treatment for all other people with SMA quoting an "unreasonably high price" compared to the benefit.[32]

Norwegian authorities rejected the funding in October 2017 because the price of the medicine was "unethically high".[33] In February 2018, the funding was approved for people under 18 years old.[33] In April 2023 funding was expanded to include adults.[34]

In August 2018, the National Institute for Health and Care Excellence (NICE), which weighs the cost-effectiveness of therapies for the NHS in England and Wales, recommended against offering nusinersen to people with SMA.[35] Children with SMA type 1 were treated in the UK under a Biogen-funded expanded access programme; after enrolling 80 children, the scheme closed to new people in November 2018.[36] In May 2019, however, NICE reversed its stance and announced its decision to recommend nusinersen for use across a wide spectrum of SMA for a 5-year period.[37][38]

The Irish Health Service Executive decided in February 2019 that nusinersen was too expensive to fund, saying the cost would be about €600,000 per patient in the first year and around €380,000 a year thereafter "with an estimated budget impact in excess of €20 million over a five-year period" for the 25 children with SMA living in Ireland. Both the manufacturer and patient groups disputed the numbers and pointed out that actual pricing arrangements for Ireland are in line with the negotiated price for the BeneluxA initiative which Ireland has been a member of since June 2018.[39]

As of May 2019, nusinersen was available in public healthcare in more than 40 countries.[40]

In December 2021, nusinersen was included in the extended insurance coverage of China, and the price was reduced from ¥697,000 per vial to around ¥33,000 (~US$5,100) per vial.[41][42][43]

References

  1. ^ "Prescription medicines: registration of new chemical entities in Australia, 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 9 April 2023.
  2. ^ "Prescription medicines and biologicals: TGA annual summary 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 31 March 2024.
  3. ^ "Genetic disorders". Health Canada. 9 May 2018. Retrieved 13 April 2024.
  4. ^ a b c d e f g h i j k l "Spinraza- nusinersen injection, solution". DailyMed. 30 June 2020. Retrieved 3 November 2020.
  5. ^ "Spinraza EPAR". European Medicines Agency. 2 April 2012. Retrieved 29 June 2024.
  6. ^ Paton D (2017). "Nusinersen: antisense oligonucleotide to increase SMN protein production in spinal muscular atrophy". Drugs of Today. 53 (6). Clarivate Analytics (US): 327–337. doi:10.1358/dot.2017.53.6.2652413. ISSN 1699-3993. PMID 28799578.
  7. ^ a b "International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 74" (PDF). World Health Organization. pp. 413–414. Retrieved 13 March 2017.
  8. ^ Ottesen EW (January 2017). "ISS-N1 makes the First FDA-approved Drug for Spinal Muscular Atrophy". Translational Neuroscience. 8 (1): 1–6. doi:10.1515/tnsci-2017-0001. PMC 5382937. PMID 28400976.
  9. ^ "Nusinersen". UK Specialist Pharmacy Service. 28 January 2016. Archived from the original on 13 April 2019. Retrieved 31 December 2016.
  10. ^ "New warning of nusinersen-related communicating hydrocephalus". Reactions Weekly. 1714 (1): 3. 1 August 2018. doi:10.1007/s40278-018-50183-2. ISSN 1179-2051. S2CID 195086499.
  11. ^ a b Zanetta C, Nizzardo M, Simone C, Monguzzi E, Bresolin N, Comi GP, et al. (January 2014). "Molecular therapeutic strategies for spinal muscular atrophies: current and future clinical trials". Clinical Therapeutics. 36 (1): 128–40. doi:10.1016/j.clinthera.2013.11.006. PMID 24360800.
  12. ^ Pao PW, Wee KB, Yee WC, Pramono ZA, Dwipramono ZA (April 2014). "Dual masking of specific negative splicing regulatory elements resulted in maximal exon 7 inclusion of SMN2 gene". Molecular Therapy. 22 (4): 854–61. doi:10.1038/mt.2013.276. PMC 3982506. PMID 24317636. The sequence of nusinersen (UCACUUUCAUAAUGCUGG) is listed as N1-Hua in Table I.
  13. ^ Garber K (October 2016). "Big win possible for Ionis/Biogen antisense drug in muscular atrophy". Nature Biotechnology. 34 (10): 1002–1003. doi:10.1038/nbt1016-1002. PMID 27727217. S2CID 37479367.
  14. ^ Wadman M (23 December 2016). "Updated: FDA approves drug that rescues babies with fatal neurodegenerative disease". Science. doi:10.1126/science.aal0476.{{cite journal}}: CS1 maint: overridden setting (link)
  15. ^ Offord C (1 December 2016). "Oligonucleotide Therapeutics Near Approval". The Scientist.{{cite news}}: CS1 maint: overridden setting (link)
  16. ^ Tarr P (24 December 2016). "CSHL FDA approval of life-saving SMA drug is hailed by its researcher-inventor at CSHL". Cold Spring Harbor Laboratory. Archived from the original on 1 January 2017. Retrieved 1 January 2017.{{cite news}}: CS1 maint: overridden setting (link)
  17. ^ "Therapeutic Approaches". www.curesma.org. Cure SMA. Archived from the original on 1 January 2017. Retrieved 1 January 2017.
  18. ^ Singh NN, Howell MD, Androphy EJ, Singh RN (2019). "How the discovery of ISS-N1 led to the first medical therapy for spinal muscular atrophy". Gene Therapy. 24 (9): 520–526. doi:10.1038/gt.2017.34. PMC 5623086. PMID 28485722.
  19. ^ "Biogen Shells Out $75M to Develop Ionis' Nusinersen after Positive Phase III Results", Genetic Engineering News, 1 August 2016
  20. ^ "Press release: Biogen and Ionis Pharmaceuticals Report Nusinersen Meets Primary Endpoint at Interim Analysis of Phase 3 ENDEAR Study in Infantile-Onset Spinal Muscular Atrophy | Biogen Media". Biogen. 1 August 2016. Archived from the original on 10 August 2017. Retrieved 1 January 2017.
  21. ^ "Regulatory Applications for SMA Therapy Nusinersen Accepted in US, EU". BioNews Services, LLC. November 2016. Retrieved 15 November 2016.
  22. ^ a b Thomas K (30 December 2016). "Costly Drug for Fatal Muscular Disease Wins F.D.A. Approval". New York Times.{{cite news}}: CS1 maint: overridden setting (link)
  23. ^ Grant C (27 December 2016). "Surprise Drug Approval Is Holiday Gift for Biogen". Wall Street Journal. ISSN 0099-9660. Retrieved 27 December 2016.{{cite web}}: CS1 maint: overridden setting (link)
  24. ^ "Spinraza (nusinersen)". European Medicines Agency. Archived from the original on 28 October 2017. Retrieved 27 October 2017.
  25. ^ "Biogen's SPINRAZA™ (nusinersen) Receives Notice of Compliance from Health Canada for the Treatment of 5q Spinal Muscular Atrophy (SMA)". Cision. 4 July 2017. Archived from the original on 4 December 2017. Retrieved 13 October 2017.
  26. ^ "Biogen to launch Spinraza in Japan soon". 10 July 2017.
  27. ^ "Remédio inédito para atrofia muscular espinhal é liberado" (in Brazilian Portuguese). 25 August 2017.
  28. ^ "Spinraza – Zulassung nun auch in der Schweiz" (in Swiss High German). SMA Schweiz. 30 September 2017.
  29. ^ "Biogen Further Expands Presence in China with Approval of SPINRAZA® (nusinersen), the First and Only Treatment for Spinal Muscular Atrophy | Biogen". investors.biogen.com. Retrieved 10 January 2022.
  30. ^ "Nusinersen (Spinraza®) – Spinal Muscular Atrophy (SMA) | National Institute of Neurological Disorders and Stroke". www.ninds.nih.gov. Retrieved 3 June 2024.
  31. ^ "Spinraza Prices, Coupons & Patient Assistance Programs". Drugs.com. Retrieved 10 September 2021.
  32. ^ Medicinrådet siger nej til lægemiddel til børn med muskelsvind: 'Urimeligt' dyrt Retrieved 13 October 2017.
  33. ^ a b Dette er uforståelig og utrolig urettferdigThis is incomprehensible and incredibly unfair (google translate)
  34. ^ Omland E (11 April 2023). "Beslutningsforum seier ja til Spinraza for muskelsjuke i ekstramøte". NRK (in Norwegian Nynorsk). Retrieved 14 April 2023.
  35. ^ "Biogen's pricey muscle drug Spinraza too costly for Britain". Reuters. 13 August 2018. Retrieved 28 May 2019.
  36. ^ "Biogen statement on Expanded Access Programme". Muscular Dystrophy UK. 2 December 2018. Archived from the original on 28 February 2019. Retrieved 27 February 2019.
  37. ^ "NICE recommends first ever treatment for children with rare muscle-wasting condition". National Institute of Health and Care Excellence. 15 May 2019. Archived from the original on 28 May 2019. Retrieved 28 May 2019.
  38. ^ Nusinersen for treating spinal muscular atrophy. NICE Technology appraisal guidance [TA588] 2019
  39. ^ "Drugmaker urges HSE to revisit pricing of muscle-wasting disease treatment". Irish Times. 25 February 2019. Retrieved 27 February 2019.
  40. ^ "Spinraza access by country". TreatSMA. 18 October 2018. Retrieved 28 May 2019.
  41. ^ "Biogen's Spinraza, Fosun Kite's Yescarta and a controversial Alzheimer's drug: All you need to know about China's new state coverage". FiercePharma. 3 December 2021. Retrieved 27 January 2022.
  42. ^ "China's 2021 NDRL listing sees price cuts of up to 95%". www.thepharmaletter.com. Retrieved 27 January 2022.
  43. ^ 陈子琰. "China increases accessibility to rare disease treatment". www.chinadaily.com.cn. Retrieved 27 January 2022.

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Soriano nel Cimino

This article includes a list of references, related reading, or external links, but its sources remain unclear because it lacks inline citations. Please help improve this article by introducing more precise citations. (November 2018) (Learn how and when to remove this message) Comune in Lazio, ItalySoriano nel CiminoComuneComune di Soriano nel Cimino Coat of armsLocation of Soriano nel Cimino Soriano nel CiminoLocation of Soriano nel Cimino in ItalyShow map of ItalySoriano nel CiminoSoriano n...