Nusinersen: Difference between revisions

Nusinersen
Clinical data
Trade names	Spinraza
Other names	IONIS-SMNRx, ISIS-SMNRx
AHFS/Drugs.com	Monograph
MedlinePlus	a617010
License data	US DailyMed: Nusinersen;
Pregnancy; category	AU: B1; ;
Routes of; administration	Intrathecal
ATC code	M09AX07 (WHO) ;
Legal status
Legal status	AU: S4 (Prescription only); CA: ℞-only; UK: POM (Prescription only); US: ℞-only; EU: Rx-only;
Pharmacokinetic data
Bioavailability	100% (intrathecal)
Protein binding	<25% (in CSF), >94% (in plasma)
Metabolism	Exonuclease (3'- and 5')-mediated hydrolysis
Elimination half-life	135–177 days (in CSF), 63–87 days (in plasma)
Identifiers
	IUPAC name 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;
CAS Number	1258984-36-9;
PubChem CID	124037382;
DrugBank	DB13161;
ChemSpider	34983394;
UNII	5Z9SP3X666;
KEGG	D10881; as salt: D10791;
Chemical and physical data
Formula	C234H323N61Na17O128P17S17
Molar mass	7500.86 g·mol−1
	SMILES 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;

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Nusinersen,^[6] marketed as Spinraza,^[4] is a medication used in treating spinal muscular atrophy (SMA), a rare neuromuscular disorder.^[7]^[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.^[8]

Medical uses[edit]

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[edit]

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.^[9]

Pharmacology[edit]

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.^[10]

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[edit]

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]^[10]^[11]

History[edit]

Nusinersen was developed in a collaboration between Adrian Krainer at Cold Spring Harbor Laboratory and Ionis Pharmaceuticals (formerly called Isis Pharmaceuticals).^[12]^[13]^[14]^[15] Initial work of target discovery of nusinersen was done by Dr. Ravindra Singh and co-workers at the University of Massachusetts Medical School funded by Cure SMA.^[16]^[17]

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.^[18] The license to Biogen included licenses to intellectual property that Ionis had acquired from Cold Spring Harbor Laboratory and University of Massachusetts.^[19]

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.^[20]^[21] It was approved by the FDA in December 2016 and by EMA in May 2017 as the first drug to treat SMA.^[22]^[23] Subsequently, nusinersen was approved to treat SMA in Canada (July 2017),^[24] Japan (July 2017),^[25] Brasil (August 2017),^[26] Switzerland (September 2017),^[27] and China (February 2019).^[28]

Society and culture[edit]

Economics[edit]

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.^[29] According to The New York Times, this places nusinersen "among the most expensive drugs in the world".^[21]

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.^[30]

Norwegian authorities rejected the funding in October 2017 because the price of the medicine was "unethically high".^[31] In February 2018, the funding was approved for people under 18 years old.^[31] In April 2023 funding was expanded to include adults.^[32]

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.^[33] 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.^[34] 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.^[35]^[36]

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.^[37]

As of May 2019, nusinersen was available in public healthcare in more than 40 countries.^[38]

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.^[39]^[40]^[41]

References[edit]

^ "Prescription medicines: registration of new chemical entities in Australia, 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 9 April 2023.
^ "Prescription medicines and biologicals: TGA annual summary 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 31 March 2024.
^ "Genetic disorders". Health Canada. 9 May 2018. Retrieved 13 April 2024.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l "Spinraza- nusinersen injection, solution". DailyMed. 30 June 2020. Retrieved 3 November 2020.
^ Paton, D.M. (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.
^ ^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.
^ 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.
^ "Nusinersen". UK Specialist Pharmacy Service. 28 January 2016. Archived from the original on 13 April 2019. Retrieved 31 December 2016.
^ "New warning of nusinersen-related communicating hydrocephalus". Reactions Weekly. 1714 (1): 3. 2018-08-01. doi:10.1007/s40278-018-50183-2. ISSN 1179-2051. S2CID 195086499.
^ ^a ^b Zanetta C, Nizzardo M, Simone C, Monguzzi E, Bresolin N, Comi GP, Corti S (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.
^ 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.
^ 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.
^ Wadman M (23 December 2016). "Updated: FDA approves drug that rescues babies with fatal neurodegenerative disease". Science. doi:10.1126/science.aal0476.
^ Offord C (December 1, 2016). "Oligonucleotide Therapeutics Near Approval". The Scientist.
^ 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.
^ "Therapeutic Approaches". www.curesma.org. Cure SMA. Archived from the original on 1 January 2017. Retrieved 1 January 2017.
^ 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.
^ "Biogen Shells Out $75M to Develop Ionis' Nusinersen after Positive Phase III Results", Genetic Engineering News, August 1, 2016
^ "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. August 1, 2016. Archived from the original on August 10, 2017. Retrieved January 1, 2017.
^ "Regulatory Applications for SMA Therapy Nusinersen Accepted in US, EU". BioNews Services, LLC. November 2016. Retrieved 2016-11-15.
^ ^a ^b Thomas K (December 30, 2016). "Costly Drug for Fatal Muscular Disease Wins F.D.A. Approval". New York Times.
^ Grant C (2016-12-27). "Surprise Drug Approval Is Holiday Gift for Biogen". Wall Street Journal. ISSN 0099-9660. Retrieved 2016-12-27.
^ "Spinraza (nusinersen)". European Medicines Agency. Archived from the original on 2017-10-28. Retrieved 2017-10-27.
^ "Biogen's SPINRAZA™ (nusinersen) Receives Notice of Compliance from Health Canada for the Treatment of 5q Spinal Muscular Atrophy (SMA)". Cision. 2017-07-04. Archived from the original on 2017-12-04. Retrieved 2017-10-13.
^ "Biogen to launch Spinraza in Japan soon". 2017-07-10.
^ "Remédio inédito para atrofia muscular espinhal é liberado" (in Brazilian Portuguese). 2017-08-25.
^ "Spinraza – Zulassung nun auch in der Schweiz" (in Swiss High German). SMA Schweiz. 2017-09-30.
^ "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 2022-01-10.
^ "Spinraza Prices, Coupons & Patient Assistance Programs". Drugs.com. Retrieved 2021-09-10.
^ Medicinrådet siger nej til lægemiddel til børn med muskelsvind: 'Urimeligt' dyrt Retrieved October 13, 2017.
^ ^a ^b Dette er uforståelig og utrolig urettferdig This is incomprehensible and incredibly unfair (google translate)
^ Omland, Ellen (2023-04-11). "Beslutningsforum seier ja til Spinraza for muskelsjuke i ekstramøte". NRK (in Norwegian Nynorsk). Retrieved 2023-04-14.
^ "Biogen's pricey muscle drug Spinraza too costly for Britain". Reuters. 2018-08-13. Retrieved 2019-05-28.
^ "Biogen statement on Expanded Access Programme". Muscular Dystrophy UK. 2 December 2018. Retrieved 27 February 2019.
^ "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 2019-05-28. Retrieved 2019-05-28.
^ Nusinersen for treating spinal muscular atrophy. NICE Technology appraisal guidance [TA588] 2019
^ "Drugmaker urges HSE to revisit pricing of muscle-wasting disease treatment". Irish Times. 25 February 2019. Retrieved 27 February 2019.
^ "Spinraza access by country". TreatSMA. 18 October 2018. Retrieved 2019-05-28.
^ "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 2022-01-27.
^ "China's 2021 NDRL listing sees price cuts of up to 95%". www.thepharmaletter.com. Retrieved 2022-01-27.
^ 陈子琰. "China increases accessibility to rare disease treatment". www.chinadaily.com.cn. Retrieved 2022-01-27.

@@ Line 1: / Line 1: @@
-{{short description|Medication used for spinal muscular atrophy}}
+{{Short description|Medication used for spinal muscular atrophy}}
 {{Infobox drug
+| image              = Nusinersen sodium colored.svg
-| IUPAC_name = ''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<ref name="INN" />
+| width              = 300
-| image = Nusinersen sodium colored.svg
+| alt                =
-| width = 300
-| alt =
+| caption            =
-| caption =
 <!-- Clinical data -->
-| pronounce =
+| pronounce          =
-| tradename = Spinraza
+| tradename          = Spinraza
-| Drugs.com = {{drugs.com|MTM|spinraza-injection}}
+| Drugs.com          = {{drugs.com|monograph|nusinersen-sodium}}
-| MedlinePlus =
+| MedlinePlus        = a617010
+| DailyMedID         = Nusinersen
-| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
+| pregnancy_AU       = B1
-| pregnancy_AU_comment =
+| pregnancy_AU_comment =
-| pregnancy_US = <!-- A / B / C / D / X / N -->
+| routes_of_administration = [[Intrathecal administration|Intrathecal]]
-| pregnancy_category =
+| class              =
-| routes_of_administration = Injection into [[cerebrospinal fluid]]
+| ATC_prefix         = M09
-| licence_EU = yes
+| ATC_suffix         = AX07
-| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled-->
-| legal_AU_comment =
+| legal_AU           = S4
-| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->
+| legal_AU_comment = <ref>{{cite web | title=Prescription medicines: registration of new chemical entities in Australia, 2017 | website=Therapeutic Goods Administration (TGA) | date=21 June 2022 | url=https://www.tga.gov.au/resources/publication/publications/prescription-medicines-registration-new-chemical-entities-australia-2017 | access-date=9 April 2023}}</ref><ref>{{cite web | title=Prescription medicines and biologicals: TGA annual summary 2017 | website=Therapeutic Goods Administration (TGA) | date=21 June 2022 | url=https://www.tga.gov.au/resources/publication/publications/prescription-medicines-and-biologicals-tga-annual-summary-2017 | access-date=31 March 2024}}</ref>
-| legal_DE = <!-- Anlage I, II, III -->
+| legal_CA = Rx-only
-| legal_NZ = <!-- Class A, B, C -->
+| legal_CA_comment = <ref>{{cite web | title=Genetic disorders | website=[[Health Canada]] | date=9 May 2018 | url=https://www.canada.ca/en/services/health/drug-health-products/drug-medical-device-highlights-2017/approved-drugs/genetic-disorders.html | access-date=13 April 2024}}</ref>
-| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->
+| legal_DE           = <!-- Anlage I, II, III -->
-| legal_US = Rx-only
-| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV-->
+| legal_NZ           = <!-- Class A, B, C -->
+| legal_UK           = POM
-| legal_status = <!-- Free text -->
+| legal_US           = Rx-only
+| legal_US_comment   = <ref name="Spinraza FDA label" />
+| legal_EU           = Rx-only
+| legal_UN           = <!-- N I, II, III, IV / P I, II, III, IV-->
+| legal_status       = <!-- Free text -->
 <!-- Pharmacokinetic data -->
-| bioavailability =
+| bioavailability    = 100% (intrathecal)
+| protein_bound      = <25% (in CSF), >94% (in plasma)<ref name="Paton 2017 p=327">{{cite journal | last=Paton | first=D.M. | title=Nusinersen: antisense oligonucleotide to increase SMN protein production in spinal muscular atrophy | journal=Drugs of Today | publisher=Clarivate Analytics (US) | volume=53 | issue=6 | year=2017 | pages=327–337 | issn=1699-3993 | doi=10.1358/dot.2017.53.6.2652413 | pmid=28799578 }}</ref>
-| protein_bound =
-| metabolism = Exonuclease (3’- and 5’)-mediated hydrolysis
+| metabolism         = Exonuclease (3'- and 5')-mediated hydrolysis
-| metabolites =
+| metabolites        =
-| onset =
+| onset              =
 | elimination_half-life = 135–177 days (in [[Cerebrospinal fluid|CSF]]), 63–87 days (in [[Blood plasma|plasma]])
 | duration_of_action =
-| excretion =
+| excretion          =
 <!-- Identifiers -->
+| index2_label = as salt
-| CAS_number = 1258984-36-9
+| CAS_number         = 1258984-36-9
-| class =
+| PubChem            = 124037382
-| ATCvet =
+| DrugBank           = DB13161
-| ATC_prefix = M09
+| ChemSpiderID       = 34983394
-| ATC_suffix = AX07
+| UNII_Ref           = {{fdacite|correct|FDA}}
-| PubChem = 124037382
+| UNII               = 5Z9SP3X666
-| UNII_Ref = {{fdacite|correct|FDA}}
+| KEGG               = D10881
-| UNII = 5Z9SP3X666
+| KEGG2              = D10791
-| DrugBank = DB13161
+| synonyms           = IONIS-SMN<sub>Rx</sub>, ISIS-SMN<sub>Rx</sub>
-| ChemSpiderID = 34983394
-| KEGG = D10881
-| synonyms = IONIS-SMN<sub>Rx</sub>, ISIS-SMN<sub>Rx</sub>
 <!-- Chemical and physical data -->
+| IUPAC_name         = ''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<ref name="INN" />
-| chemical_formula  =
-| C = 234 | H = 323 | N = 61 | Na = 17 | O = 128 | P = 17 | S = 17
+| C                  = 234
+| H                  = 323
-| chemical_formula_ref = <ref name="USlabel2016" />
+| N                  = 61
-| molecular_weight = 7501 [[Unified atomic mass unit|Da]]<ref name="USlabel2016" />
+| Na                 = 17
-| smiles = 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
+| O                  = 128
-|Jmol=none
+| P                  = 17
+| S                  = 17
+| chemical_formula_ref = <ref name="Spinraza FDA label" />
+| smiles             = 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
+| Jmol               = none
 }}
-'''Nusinersen''',<ref name = "INN">{{cite web | title = International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 74 | url = http://www.who.int/medicines/publications/druginformation/innlists/RL74.pdf | publisher = World Health Organization | accessdate = 13 March 2017 | pages = 413–414}}</ref> marketed as '''Spinraza''',<ref name="Adis">{{cite web | title=Nusinersen | url = http://adisinsight.springer.com/drugs/800031116 | publisher = AdisInsight | accessdate = 1 January 2017}}</ref> is a medication used in treating [[spinal muscular atrophy]] (SMA), a rare neuromuscular disorder.<ref>{{Cite journal|last=Ottesen|first=Eric W.|date=2017-01-01|title=ISS-N1 makes the first FDA-approved drug for spinal muscular atrophy|journal=Translational Neuroscience|language=en|volume=8|issue=1|pages=1–6|doi=10.1515/tnsci-2017-0001|issn=2081-6936|pmc=5382937|pmid=28400976}}</ref> In December 2016, it became the first [[marketing authorisation|approved drug]] used in treating this disorder.
+'''Nusinersen''',<ref name = "INN">{{cite web | title = International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 74 | url =https://www.who.int/medicines/publications/druginformation/innlists/RL74.pdf | publisher = World Health Organization | access-date = 13 March 2017 | pages = 413–414}}</ref> marketed as '''Spinraza''',<ref name="Spinraza FDA label" /> is a medication used in treating [[spinal muscular atrophy]] (SMA), a rare [[neuromuscular disorder]].<ref>{{cite journal | vauthors = Ottesen EW | title = ISS-N1 makes the First FDA-approved Drug for Spinal Muscular Atrophy | journal = Translational Neuroscience | volume = 8 | issue = 1 | pages = 1–6 | date = January 2017 | pmid = 28400976 | pmc = 5382937 | doi = 10.1515/tnsci-2017-0001 }}</ref><ref name="Spinraza FDA label" /> In December 2016, it became the first [[approved drug]] used in treating this disorder.
-Nusinersen cost {{USD|750,000}} in the first year and {{USD|375,000}} annually after that in the United States as of 2019.<ref name="NYT_Spinraza_Thomas" /> Nusinersen has [[orphan drug]] designation in the [[United States]] and the [[European Union]].<ref>{{cite web|url=https://www.sps.nhs.uk/medicines/nusinersen/|title=Nusinersen|publisher=UK Specialist Pharmacy Service|accessdate=31 December 2016}}</ref>
+Since the condition it treats is so rare, Nusinersen has so-called "[[orphan drug]]" designation in the United States and the European Union.<ref>{{cite web|url=https://www.sps.nhs.uk/medicines/nusinersen/|title=Nusinersen|date=28 January 2016|publisher=UK Specialist Pharmacy Service|access-date=31 December 2016|archive-date=13 April 2019|archive-url=https://web.archive.org/web/20190413012237/https://www.sps.nhs.uk/medicines/nusinersen/|url-status=dead}}</ref>
-== Medical use==
-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.<ref name="USlabel2016">{{cite web|title=Nusinersen US Label|url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/209531lbl.pdf|publisher=FDA|date=December 2016}} For updates see [http://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=209531 FDA index page for NDA 209531]</ref>
+== Medical uses==
-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.<ref name="USlabel2016" />
+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.<ref name="Spinraza FDA label">{{cite web | title=Spinraza- nusinersen injection, solution | website=DailyMed | date=30 June 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=dd70cd5f-b0fc-4ba4-a5ea-89a34778bd94 | access-date=3 November 2020}}</ref>
+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.<ref name="Spinraza FDA label" />
 ==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 [[Lumbar puncture#Adverse effects|other adverse effects from the spinal injection]].<ref name = USlabel2016/>
+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 growth|stunted]]. In older clinical trial subjects, the most common adverse events were headache, back pain, and [[Lumbar puncture#Adverse effects|other adverse effects from the spinal injection]], such as [[post-dural-puncture headache]].<ref name ="Spinraza FDA label" />
-Although not observed in the trial patients, [[thrombocytopenia|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.<ref name="USlabel2016" />
+Although not observed in the trial patients, [[thrombocytopenia|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.<ref name="Spinraza FDA label" />
-In summer 2018, several cases of [[Normal pressure hydrocephalus|communicating hydrocephalus]] in children and adults treated with nusinersen emerged; it remains unclear whether this was drug related.<ref>{{Cite journal|date=2018-08-01|title=New warning of nusinersen-related communicating hydrocephalus|journal=Reactions Weekly|language=en|volume=1714|issue=1|pages=3|doi=10.1007/s40278-018-50183-2|issn=1179-2051}}</ref>
+In 2018, several cases of [[Normal pressure hydrocephalus|communicating hydrocephalus]] in children and adults treated with nusinersen emerged; it remains unclear whether this was drug related.<ref>{{Cite journal|date=2018-08-01|title=New warning of nusinersen-related communicating hydrocephalus|journal=Reactions Weekly|volume=1714|issue=1|pages=3|doi=10.1007/s40278-018-50183-2|issn=1179-2051|s2cid=195086499}}</ref>
 ==Pharmacology==
-Spinal muscular atrophy is caused by [[Mutation#By effect on function|loss-of-function mutations]] in the ''[[SMN1]]'' gene which codes for [[survival motor neuron|survival motor neuron (SMN) protein]]. People survive owing to low amounts of the SMN protein produced from the ''[[SMN2]]'' gene. Nusinersen modulates [[alternate splicing]] of the ''SMN2'' gene, functionally converting it into ''SMN1'' gene, thus increasing the level of SMN protein in the CNS.<ref name = "Zanetta">{{cite journal | last1 = Zanetta | first1 = C | last2 = Nizzardo | first2 = M | last3 = Simone | first3 = C | last4 = Monguzzi | first4 = E | last5 = Bresolin | first5 = N | last6 = Comi | first6 = GP | last7 = Corti | first7 = S | title = Molecular Therapeutic Strategies for Spinal Muscular Atrophies: Current and Future Clinical Trials | journal = Clinical Therapeutics | date = 1 January 2014 | volume = 36 | issue = 1 | pages = 128–140 | doi = 10.1016/j.clinthera.2013.11.006 | pmid = 24360800}}</ref>
+Spinal muscular atrophy is caused by [[Mutation#By effect on function|loss-of-function mutations]] in the ''[[SMN1]]'' gene which codes for [[survival motor neuron|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.<ref name = "Zanetta">{{cite journal | vauthors = Zanetta C, Nizzardo M, Simone C, Monguzzi E, Bresolin N, Comi GP, Corti S | title = Molecular therapeutic strategies for spinal muscular atrophies: current and future clinical trials | journal = Clinical Therapeutics | volume = 36 | issue = 1 | pages = 128–40 | date = January 2014 | pmid = 24360800 | doi = 10.1016/j.clinthera.2013.11.006 | doi-access = free }}</ref>
-The drug distributes to CNS and to peripheral tissues.<ref name="USlabel2016" />
+The drug distributes to CNS and peripheral tissues.<ref name="Spinraza FDA label" />
-The half-life is estimated to be 135 to 177 days in 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.<ref name="USlabel2016" /> The primary route of elimination is likely by urinary excretion for nusinersen and its metabolites.<ref name="USlabel2016" />
+The [[Drug half-life|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.<ref name="Spinraza FDA label" /> The primary route of elimination is likely by urinary excretion for nusinersen and its metabolites.<ref name="Spinraza FDA label" />
 ==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.<ref name="USlabel2016" /><ref name = "Zanetta" /><ref>{{cite journal|title=Dual Masking of Specific Negative Splicing Regulatory Elements Resulted in Maximal Exon 7 Inclusion of SMN2 Gene|author=Peng Wen Pao, Keng Boon Wee, Woon Chee Yee and Zacharias Aloysius DwiPramono|journal=Molecular Therapy|volume=22|number=4|pages=854–861|date=April 2014|doi=10.1038/mt.2013.276|pmid=24317636|pmc=3982506}}  The sequence of nusinersen (UCACUUUCAUAAUGCUGG) is listed as N1-Hua in Table I.</ref>
+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.<ref name="Spinraza FDA label" /><ref name = "Zanetta" /><ref>{{cite journal | vauthors = Pao PW, Wee KB, Yee WC, Pramono ZA, Dwipramono ZA | title = Dual masking of specific negative splicing regulatory elements resulted in maximal exon 7 inclusion of SMN2 gene | journal = Molecular Therapy | volume = 22 | issue = 4 | pages = 854–61 | date = April 2014 | pmid = 24317636 | pmc = 3982506 | doi = 10.1038/mt.2013.276 }}  The sequence of nusinersen (UCACUUUCAUAAUGCUGG) is listed as N1-Hua in Table I.</ref>
 ==History==
-Nusinersen was developed in a collaboration between Adrian Krainer at [[Cold Spring Harbor Laboratory]] and [[Ionis Pharmaceuticals]] (formerly called Isis Pharmaceuticals).<ref>{{cite journal|last1=Garber|first1=K|title=Big win possible for Ionis/Biogen antisense drug in muscular atrophy.|journal=Nature Biotechnology|date=11 October 2016|volume=34|issue=10|pages=1002–1003|doi=10.1038/nbt1016-1002|pmid=27727217}}</ref><ref>{{cite journal|last1=Wadman|first1=Meredith|title=Updated: FDA approves drug that rescues babies with fatal neurodegenerative disease|journal=Science|date=23 December 2016|doi=10.1126/science.aal0476|url=http://www.sciencemag.org/news/2016/12/novel-drug-rescues-babies-fatal-neurodegenerative-disease}}</ref><ref>{{cite news|last1=Offord|first1=Catherine|title=Oligonucleotide Therapeutics Near Approval|url=http://www.the-scientist.com/?articles.view/articleNo/47499/title/Oligonucleotide-Therapeutics-Near-Approval/|work=The Scientist|date=December 1, 2016}}</ref><ref>{{cite news|last1=Tarr|first1=Peter|title=CSHL FDA approval of life-saving SMA drug is hailed by its researcher-inventor at CSHL |url=http://www.cshl.edu/news-and-features/fda-approval-of-life-saving-sma-drug-is-hailed-by-its-researcher-inventor-at-cshl.html|work=Cold Spring Harbor Laboratory|date=24 December 2016}}</ref> Initial work of target discovery of Nusinersen was done by Dr. Ravindra Singh and co-workers at the [[University of Massachusetts Medical School]] funded by Cure SMA.<ref>{{cite web|title=Therapeutic Approaches|url=http://www.curesma.org/research/our-strategy/drug-discovery/therapeutic-approaches/#SMN2|website=www.curesma.org|publisher=Cure SMA|accessdate=1 January 2017}}</ref>
+Nusinersen was developed in a collaboration between [[Adrian Krainer (scientist)|Adrian Krainer]] at [[Cold Spring Harbor Laboratory]] and [[Ionis Pharmaceuticals]] (formerly called Isis Pharmaceuticals).<ref>{{cite journal | vauthors = Garber K | s2cid = 37479367 | title = Big win possible for Ionis/Biogen antisense drug in muscular atrophy | journal = Nature Biotechnology | volume = 34 | issue = 10 | pages = 1002–1003 | date = October 2016 | pmid = 27727217 | doi = 10.1038/nbt1016-1002 }}</ref><ref>{{cite journal |last1=Wadman |first1=Meredith | name-list-style = vanc |title=Updated: FDA approves drug that rescues babies with fatal neurodegenerative disease|journal=Science|date=23 December 2016|doi=10.1126/science.aal0476|url=http://www.sciencemag.org/news/2016/12/novel-drug-rescues-babies-fatal-neurodegenerative-disease}}</ref><ref>{{cite news |last1=Offord |first1=Catherine | name-list-style = vanc |title=Oligonucleotide Therapeutics Near Approval|url=http://www.the-scientist.com/?articles.view/articleNo/47499/title/Oligonucleotide-Therapeutics-Near-Approval/|work=The Scientist|date=December 1, 2016}}</ref><ref>{{cite news |last1=Tarr |first1=Peter | name-list-style = vanc |title=CSHL FDA approval of life-saving SMA drug is hailed by its researcher-inventor at CSHL|url=http://www.cshl.edu/news-and-features/fda-approval-of-life-saving-sma-drug-is-hailed-by-its-researcher-inventor-at-cshl.html|work=Cold Spring Harbor Laboratory|date=24 December 2016|access-date=1 January 2017|archive-url=https://web.archive.org/web/20170101162319/http://www.cshl.edu/news-and-features/fda-approval-of-life-saving-sma-drug-is-hailed-by-its-researcher-inventor-at-cshl.html|archive-date=1 January 2017|url-status=dead}}</ref> Initial work of target discovery of nusinersen was done by Dr. Ravindra Singh and co-workers at the [[University of Massachusetts Medical School]] funded by Cure SMA.<ref>{{cite web|title=Therapeutic Approaches|url=http://www.curesma.org/research/our-strategy/drug-discovery/therapeutic-approaches/#SMN2|website=www.curesma.org|publisher=Cure SMA|access-date=1 January 2017|archive-url=https://web.archive.org/web/20170101162207/http://www.curesma.org/research/our-strategy/drug-discovery/therapeutic-approaches/#SMN2|archive-date=1 January 2017|url-status=dead}}</ref><ref>{{cite journal | vauthors = Singh NN, Howell MD, Androphy EJ, Singh RN | title = How the discovery of ISS-N1 led to the first medical therapy for spinal muscular atrophy | journal = Gene Therapy | volume = 24 | issue = 9 | pages = 520–526 | date = 2019 | pmid = 28485722 | doi = 10.1038/gt.2017.34 | pmc = 5623086 }}</ref>
+Starting in 2012, Ionis partnered with [[Biogen]] on development and, in 2015, Biogen acquired an exclusive license to the drug for a {{USD|75 million}} license fee, milestone payments up to {{USD|150 million}}, and tiered royalties thereafter; Biogen also paid the costs of development subsequent to taking the license.<ref name="genengnews_2016">{{citation |url=http://www.genengnews.com/gen-news-highlights/biogen-shells-out-75m-to-develop-ionis-nusinersen-after-positive-phase-iii-results/81253027 |date=August 1, 2016 |title=Biogen Shells Out $75M to Develop Ionis' Nusinersen after Positive Phase III Results |work=Genetic Engineering News }}</ref> The license to Biogen included licenses to intellectual property that Ionis had acquired from Cold Spring Harbor Laboratory and University of Massachusetts.<ref>{{cite news|title=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|url=http://media.biogen.com/press-release/investor-relations/biogen-and-ionis-pharmaceuticals-report-nusinersen-meets-primary-en|work=Biogen|date=August 1, 2016|access-date=January 1, 2017|archive-url=https://web.archive.org/web/20170810211512/http://media.biogen.com/press-release/investor-relations/biogen-and-ionis-pharmaceuticals-report-nusinersen-meets-primary-en|archive-date=August 10, 2017|url-status=dead}}</ref>
+In November 2016, the [[new drug application]] was accepted under the [[FDA]]'s [[Priority review (FDA)|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.<ref>{{cite web|url=http://smanewstoday.com/2016/11/01/regulatory-applications-sma-therapy-nusinersen-accepted-us-fda-eu-ema |title=Regulatory Applications for SMA Therapy Nusinersen Accepted in US, EU |publisher=BioNews Services, LLC|date= November 2016|access-date=2016-11-15}}</ref><ref name="NYT_Spinraza_Thomas">{{cite news|url=https://www.nytimes.com/2016/12/30/business/spinraza-price.html |title=Costly Drug for Fatal Muscular Disease Wins F.D.A. Approval | first = Katie | last = Thomas | name-list-style = vanc |date=December 30, 2016 |newspaper=New York Times}}</ref> It was approved by the FDA in December 2016 and by EMA in May 2017 as the first drug to treat SMA.<ref>{{Cite web|url=https://www.wsj.com/articles/surprise-drug-approval-is-holiday-gift-for-biogen-1482856447|title=Surprise Drug Approval Is Holiday Gift for Biogen|last=Grant|first=Charley | name-list-style = vanc |date=2016-12-27|newspaper=Wall Street Journal|issn=0099-9660|access-date=2016-12-27}}</ref><ref>{{cite web|url=http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/004312/human_med_002119.jsp|title=Spinraza (nusinersen)|publisher=[[European Medicines Agency]]|access-date=2017-10-27|archive-date=2017-10-28|archive-url=https://web.archive.org/web/20171028043654/http://www.ema.europa.eu/ema/index.jsp?curl=pages%2Fmedicines%2Fhuman%2Fmedicines%2F004312%2Fhuman_med_002119.jsp|url-status=dead}}</ref> Subsequently, nusinersen was approved to treat SMA in Canada (July 2017),<ref>{{cite news | url=http://www.newswire.ca/news-releases/biogens-spinraza-nusinersen-receives-notice-of-compliance-from-health-canada-for-the-treatment-of-5q-spinal-muscular-atrophy-sma-632452943.html | title=Biogen's SPINRAZA™ (nusinersen) Receives Notice of Compliance from Health Canada for the Treatment of 5q Spinal Muscular Atrophy (SMA) | publisher=[[Cision]] | date=2017-07-04 | access-date=2017-10-13 | archive-date=2017-12-04 | archive-url=https://web.archive.org/web/20171204064319/http://www.newswire.ca/news-releases/biogens-spinraza-nusinersen-receives-notice-of-compliance-from-health-canada-for-the-treatment-of-5q-spinal-muscular-atrophy-sma-632452943.html | url-status=dead }}</ref> Japan (July 2017),<ref>{{cite web |url= https://www.thepharmaletter.com/article/biogen-to-launch-spinraza-in-japan-soon |title= Biogen to launch Spinraza in Japan soon |date= 2017-07-10 }}</ref> Brasil (August 2017),<ref>{{cite web |url= http://www.brasil.gov.br/saude/2017/08/remedio-inedito-para-atrofia-muscular-espinhal-e-liberado | title= Remédio inédito para atrofia muscular espinhal é liberado |date= 2017-08-25 |language=pt-br }}</ref> Switzerland (September 2017),<ref>{{cite web |url= http://www.sma-schweiz.ch/spinraza-zulassung-nun-auch-in-der-schweiz/ |title= Spinraza – Zulassung nun auch in der Schweiz |publisher= SMA Schweiz |date= 2017-09-30 |language=de-ch }}</ref> and China (February 2019).<ref>{{Cite web|title=Biogen Further Expands Presence in China with Approval of SPINRAZA® (nusinersen), the First and Only Treatment for Spinal Muscular Atrophy {{!}} Biogen|url=https://investors.biogen.com/news-releases/news-release-details/biogen-further-expands-presence-china-approval-spinrazar|access-date=2022-01-10|website=investors.biogen.com|language=en}}</ref>
+== Society and culture ==
+=== Economics ===
-Starting in 2012, Ionis partnered with [[Biogen]] on development and in 2015 Biogen acquired an exclusive license to the drug for a {{USD|75 million}} license fee, milestone payments up to {{USD|150 million}}, and tiered royalties thereafter; Biogen also paid the costs of development subsequent to taking the license.<ref name="genengnews_2016">{{citation |url=http://www.genengnews.com/gen-news-highlights/biogen-shells-out-75m-to-develop-ionis-nusinersen-after-positive-phase-iii-results/81253027 |date=August 1, 2016 |title=Biogen Shells Out $75M to Develop Ionis' Nusinersen after Positive Phase III Results |work=Genetic Engineering News|author=}}</ref> The license to Biogen included licenses to intellectual property that Ionis had acquired from Cold Spring Harbor Laboratory and University of Massachusetts.<ref>{{cite news|title=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|url=http://media.biogen.com/press-release/investor-relations/biogen-and-ionis-pharmaceuticals-report-nusinersen-meets-primary-en|work=Biogen|date=August 1, 2016}}</ref>
+Nusinersen [[list price]] in the USA is {{USD|125,000}} per injection which puts the treatment cost at {{USD|750,000}} in the first year and {{USD|375,000}} annually after that.<ref>{{Cite web|title=Spinraza Prices, Coupons & Patient Assistance Programs|url=https://www.drugs.com/price-guide/spinraza|access-date=2021-09-10|website=Drugs.com|language=en}}</ref> According to ''[[The New York Times]]'', this places nusinersen "among the most expensive drugs in the world".<ref name="NYT_Spinraza_Thomas" />
-In November 2016, the [[new drug application]] was accepted under the FDA's [[Priority review (FDA)|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.<ref>{{cite web|url=http://smanewstoday.com/2016/11/01/regulatory-applications-sma-therapy-nusinersen-accepted-us-fda-eu-ema |title=Regulatory Applications for SMA Therapy Nusinersen Accepted in US, EU |publisher=BioNews Services, LLC|date= |accessdate=2016-11-15}}</ref><ref name="NYT_Spinraza_Thomas">{{cite news|url=https://www.nytimes.com/2016/12/30/business/spinraza-price.html |title=Costly Drug for Fatal Muscular Disease Wins F.D.A. Approval |author=Katie Thomas |date=December 30, 2016 |newspaper=New York Times}}</ref> It was approved by the FDA in December 2016 and by EMA in May 2017 as the first drug to treat spinal muscular atrophy.<ref>{{Cite web|url=https://www.wsj.com/articles/surprise-drug-approval-is-holiday-gift-for-biogen-1482856447|title=Surprise Drug Approval Is Holiday Gift for Biogen|last=Grant|first=Charley|date=2016-12-27|newspaper=Wall Street Journal|issn=0099-9660|access-date=2016-12-27|via=}}</ref><ref>{{cite web |url=http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/004312/human_med_002119.jsp| title=Spinraza (nusinersen) |publisher=[[European Medicines Agency]]| accessdate=2017-10-27}}</ref> Subsequently, nusinersen was approved to treat SMA in Canada (July 2017),<ref>{{cite news | url=http://www.newswire.ca/news-releases/biogens-spinraza-nusinersen-receives-notice-of-compliance-from-health-canada-for-the-treatment-of-5q-spinal-muscular-atrophy-sma-632452943.html | title=Biogen's SPINRAZA™ (nusinersen) Receives Notice of Compliance from Health Canada for the Treatment of 5q Spinal Muscular Atrophy (SMA) |publisher= [[Cision]] |date= 2017-07-04 }}</ref> Japan (July 2017),<ref>{{cite web |url= https://www.thepharmaletter.com/article/biogen-to-launch-spinraza-in-japan-soon |title= Biogen to launch Spinraza in Japan soon |date= 2017-07-10 }}</ref> Brasil (August 2017)<ref>{{cite web |url= http://www.brasil.gov.br/saude/2017/08/remedio-inedito-para-atrofia-muscular-espinhal-e-liberado | title= Remédio inédito para atrofia muscular espinhal é liberado |date= 2017-08-25 |language=pt-br }}</ref> and Switzerland (September 2017).<ref>{{cite web |url= http://www.sma-schweiz.ch/spinraza-zulassung-nun-auch-in-der-schweiz/ |title= Spinraza – Zulassung nun auch in der Schweiz |publisher= SMA Schweiz |date= 2017-09-30 |language=de-ch }}</ref>
+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.<ref>[http://www.dr.dk/nyheder/indland/medicinraadet-siger-nej-til-laegemiddel-til-boern-med-muskelsvind-urimeligt-dyrt Medicinrådet siger nej til lægemiddel til børn med muskelsvind: 'Urimeligt' dyrt] Retrieved October 13, 2017.</ref>
-==Cost==
-Nusinersen [[list price]] in the USA is {{USD|125,000}} per injection which puts the treatment cost at {{USD|750,000}} in the first year and {{USD|375,000}} annually after that. According to ''[[The New York Times]]'', this places nusinersen "among the most expensive drugs in the world".<ref name="NYT_Spinraza_Thomas" />
+Norwegian authorities rejected the funding in October 2017 because the price of the medicine was "unethically high".<ref name="abcnyheter">[https://www.abcnyheter.no/helse-og-livsstil/helse/2018/02/13/195371564/dette-er-uforstaelig-og-utrolig-urettferdig Dette er uforståelig og utrolig urettferdig][https://translate.google.com/translate?hl=en&sl=no&u=https://www.abcnyheter.no/helse-og-livsstil/helse/2018/02/13/195371564/dette-er-uforstaelig-og-utrolig-urettferdig&prev=search ''This is incomprehensible and incredibly unfair'' (google translate)]</ref> In February 2018, the funding was approved for people under 18 years old.<ref name="abcnyheter" /> In April 2023 funding was expanded to include adults.<ref>{{Cite web |last=Omland |first=Ellen |date=2023-04-11 |title=Beslutningsforum seier ja til Spinraza for muskelsjuke i ekstramøte |url=https://www.nrk.no/norge/beslutningsforum-seier-ja-til-spinraza-for-muskelsjuke-i-ekstramote-1.16369312 |access-date=2023-04-14 |website=NRK |language=nn-NO}}</ref>
-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.<ref>[http://www.dr.dk/nyheder/indland/medicinraadet-siger-nej-til-laegemiddel-til-boern-med-muskelsvind-urimeligt-dyrt Medicinrådet siger nej til lægemiddel til børn med muskelsvind: 'Urimeligt' dyrt] Retrieved October 13, 2017.</ref>
+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.<ref name="NHS">{{Cite news|url=https://www.reuters.com/article/us-biogen-britain-spinraza-idUSKBN1KY2DH|title=Biogen's pricey muscle drug Spinraza too costly for Britain|date=2018-08-13|work=Reuters|access-date=2019-05-28}}</ref> 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.<ref>{{cite news|url=https://www.musculardystrophyuk.org/news/news/biogen-statement-on-expanded-access-programme/|title=Biogen statement on Expanded Access Programme|date=2 December 2018|access-date=27 February 2019|publisher=Muscular Dystrophy UK}}</ref> 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.<ref>{{Cite web|url=https://www.nice.org.uk/news/article/nice-recommends-first-ever-treatment-for-children-with-rare-muscle-wasting-condition|title=NICE recommends first ever treatment for children with rare muscle-wasting condition|date=15 May 2019|publisher=National Institute of Health and Care Excellence|access-date=2019-05-28|archive-date=2019-05-28|archive-url=https://web.archive.org/web/20190528125522/https://www.nice.org.uk/news/article/nice-recommends-first-ever-treatment-for-children-with-rare-muscle-wasting-condition|url-status=dead}}</ref><ref name=NICE-TA588-2019>[https://www.nice.org.uk/guidance/TA588/history ''Nusinersen for treating spinal muscular atrophy. NICE Technology appraisal guidance &#91;TA588&#93;'' 2019]</ref>
-Norwegian authorities rejected the funding in October 2017 because the price of the medicine was "unethically high".<ref name="abcnyheter">[https://www.abcnyheter.no/helse-og-livsstil/helse/2018/02/13/195371564/dette-er-uforstaelig-og-utrolig-urettferdig Dette er uforståelig og utrolig urettferdig][https://translate.google.com/translate?hl=en&sl=no&u=https://www.abcnyheter.no/helse-og-livsstil/helse/2018/02/13/195371564/dette-er-uforstaelig-og-utrolig-urettferdig&prev=search ''This is incomprehensible and incredibly unfair'' (google translate)]</ref> In February 2018 the funding was approved for people under 18 years old.<ref name="abcnyheter" />
+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.<ref>{{cite news|url=https://www.irishtimes.com/business/health-pharma/drugmaker-urges-hse-to-revisit-pricing-of-muscle-wasting-disease-treatment-1.3804091|title=Drugmaker urges HSE to revisit pricing of muscle-wasting disease treatment|date=25 February 2019|access-date=27 February 2019|publisher=Irish Times}}</ref>
-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.<ref name="NHS">{{Cite news|url=https://www.reuters.com/article/us-biogen-britain-spinraza-idUSKBN1KY2DH|title=Biogen's pricey muscle drug Spinraza too costly for Britain|date=2018-08-13|work=Reuters|access-date=2019-05-28|language=en}}</ref> Children with SMA type 1 were treated in the UK under Biogen-funded Expanded Access Programme; after enrolling 80 children, the scheme closed to new people in November 2018.<ref>{{cite news|url=https://www.musculardystrophyuk.org/news/news/biogen-statement-on-expanded-access-programme/|title=Biogen statement on Expanded Access Programme|date=2 December 2018|accessdate=27 February 2019|publisher=Muscular Dystrophy UK}}</ref> 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.<ref>{{Cite web|url=https://www.nice.org.uk/news/article/nice-recommends-first-ever-treatment-for-children-with-rare-muscle-wasting-condition|title=NICE recommends first ever treatment for children with rare muscle-wasting condition|date=15 May 2019|publisher=National Institute of Health and Care Excellence|access-date=2019-05-28}}</ref><ref name=NICE-TA588-2019>[https://www.nice.org.uk/guidance/TA588/history ''Nusinersen for treating spinal muscular atrophy. NICE Technology appraisal guidance [TA588]'' 2019]</ref>
+As of May 2019, nusinersen was available in public healthcare in more than 40 countries.<ref>{{Cite web|url=https://www.treatsma.uk/treatments/spinraza/spinraza-access-by-country/|title=Spinraza access by country|website=TreatSMA|date=18 October 2018 |access-date=2019-05-28}}</ref>
-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.<ref>{{cite news|url=https://www.irishtimes.com/business/health-pharma/drugmaker-urges-hse-to-revisit-pricing-of-muscle-wasting-disease-treatment-1.3804091|title=Drugmaker urges HSE to revisit pricing of muscle-wasting disease treatment|date=25 February 2019|accessdate=27 February 2019|publisher=Irish Times}}</ref>
+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.<ref>{{Cite web|title=Biogen's Spinraza, Fosun Kite's Yescarta and a controversial Alzheimer's drug: All you need to know about China's new state coverage|url=https://www.fiercepharma.com/pharma-asia/biogen-spinraza-fosun-kite-yescarta-controversial-alzheimer-s-drug-china-national-drug|access-date=2022-01-27|website=FiercePharma|date=3 December 2021 |language=en}}</ref><ref>{{Cite web|title=China's 2021 NDRL listing sees price cuts of up to 95%|url=https://www.thepharmaletter.com/article/china-s-2021-ndrl-listing-sees-price-cuts-of-up-to-95|access-date=2022-01-27|website=www.thepharmaletter.com}}</ref><ref>{{Cite web|last=陈子琰|title=China increases accessibility to rare disease treatment|url=https://www.chinadaily.com.cn/a/202112/21/WS61c1831da310cdd39bc7cad0.html|access-date=2022-01-27|website=www.chinadaily.com.cn}}</ref>
-As of May 2019, nusinersen was available on public healthcare in more than 40 countries.<ref>{{Cite web|url=https://www.treatsma.uk/treatments/spinraza/spinraza-access-by-country/|title=Spinraza access by country|website=TreatSMA|language=en-GB|access-date=2019-05-28}}</ref>
 == References ==
@@ Line 110: / Line 123: @@
 == Further reading ==
+{{refbegin}}
-* {{cite journal |doi=10.1016/S0140-6736(16)31408-8 |pmid=27939059 |title=Treatment of infantile-onset spinal muscular atrophy with nusinersen: A phase 2, open-label, dose-escalation study |journal=The Lancet |volume=388 |issue=10063 |pages=3017–3026 |year=2016 |last1=Finkel |first1=Richard S |last2=Chiriboga |first2=Claudia A |last3=Vajsar |first3=Jiri |last4=Day |first4=John W |last5=Montes |first5=Jacqueline |last6=De Vivo |first6=Darryl C |last7=Yamashita |first7=Mason |last8=Rigo |first8=Frank |last9=Hung |first9=Gene |last10=Schneider |first10=Eugene |last11=Norris |first11=Daniel A |last12=Xia |first12=Shuting |last13=Bennett |first13=C Frank |last14=Bishop |first14=Kathie M }}
+* {{cite journal | vauthors = Finkel RS, Chiriboga CA, Vajsar J, Day JW, Montes J, De Vivo DC, Yamashita M, Rigo F, Hung G, Schneider E, Norris DA, Xia S, Bennett CF, Bishop KM | s2cid = 40696239 | display-authors = 6 | title = Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study | journal = Lancet | volume = 388 | issue = 10063 | pages = 3017–3026 | date = December 2016 | pmid = 27939059 | doi = 10.1016/S0140-6736(16)31408-8 }}
+{{refend}}
+{{Other drugs for disorders of the musculo-skeletal system}}
-== External links ==
-* {{Cite web|url=http://yourekascience.org/portfolio/cut-and-paste-treating-spinal-muscular-atrophy/|title=Cut and Paste: Treating Spinal Muscular Atrophy with Nusinersen | publisher=Youreka Science|language=en-US|access-date=2019-05-28}}
-* {{Cite web|url=https://www.treatsma.uk/treatments/spinraza/spinraza-access-by-country/|title=Spinraza access by country|publisher=TreatSMA|language=en-GB|access-date=2019-05-28}}
 [[Category:Antisense RNA]]
@@ Line 120: / Line 133: @@
 [[Category:Orphan drugs]]
 [[Category:Spinal muscular atrophy]]
+[[Category:Therapeutic gene modulation]]
+[[Category:Muscle protectors]]
+[[Category:Muscle stabilizers]]

v t e Other drugs for disorders of the musculo-skeletal system (M09)
Quinine and derivatives	Hydroquinine
Enzymes	Bromelains Chymopapain Collagenase clostridium histolyticum Trypsin
Gene therapies	Delandistrogene moxeparvovec Onasemnogene abeparvovec
Antisense oligonucleotides	Casimersen Drisapersen^† Eteplirsen Golodirsen Nusinersen Viltolarsen
Glucocorticoids	Deflazacort Vamorolone
Histone deacetylase inhibitors	Givinostat
Other	Aceneuramic acid Ataluren Branaplam Chondrocytes Hyaluronic acid Palovarotene Risdiplam
^#WHO-EM ^‡Withdrawn from market Clinical trials: ^†Phase III ^§Never to phase III