Nusinersen

Nusinersen
Names
Trade namesSpinraza
Other namesIONIS-SMNRx, ISIS-SMNRx
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[1]
Clinical data
Drug classAntisense oligonucleotide[2]
Main usesSpinal muscular atrophy (SMA)[3]
Side effectsRespiratory infection, constipation, ear infection[3]
Pregnancy
category
  • AU: B1
  • US: N (Not classified yet)
    Routes of
    use    		Intrathecal
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa617010
    Legal
    License data
    Legal status
    • AU: S4 (Prescription only)
    • UK: POM (Prescription only)
    • US: ℞-only [4]
    • EU: Rx-only
    Pharmacokinetics
    Bioavailability100% (intrathecal)
    Protein binding<25% (in CSF), >94% (in plasma)[5]
    MetabolismExonuclease (3’- and 5’)-mediated hydrolysis
    Elimination half-life135–177 days (in CSF), 63–87 days (in plasma)
    Chemical and physical data
    FormulaC234H323N61Na17O128P17S17[4]
    Molar mass7500.86 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

    Nusinersen, sold under the brand name Spinraza, is a medication used to treat spinal muscular atrophy (SMA).[3] It improves motor function.[3] It is given by injection into the spinal canal.[3]

    Common side effects include respiratory infection, constipation, and ear infection.[3] Other side effects include low platelets, bleeding, and kidney problems.[3] Safety in pregnancy is unclear.[3] It is an antisense oligonucleotide which increases survival motor neuron.[2]

    Nusinersen was approved for medical use in the United States in 2016 and Europe in 2017.[3][6] In the United Kingdom it costs about £75,000 a dose as of 2021.[2] In the United States this amount costs about 133,000 USD.[7]

    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]

    Dosage

    It is given at a dose of 12 mg on day 0, 14, 28, and 63 followed by every 4 months.[2]

    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.[8]

    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.[9]

    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][9][10]

    History

    Nusinersen was developed in a collaboration between Adrian Krainer at Cold Spring Harbor Laboratory and Ionis Pharmaceuticals (formerly called Isis Pharmaceuticals).[11][12][13][14] 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.[15][16]

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

    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.[19][20] It was approved by the FDA in December 2016 and by EMA in May 2017 as the first drug to treat SMA.[21][22] Subsequently, nusinersen was approved to treat SMA in Canada (July 2017),[23] Japan (July 2017),[24] Brasil (August 2017),[25] and Switzerland (September 2017).[26]

    It has an orphan drug designation in the United States and Europe.[27]

    Society and culture

    Cost

    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.[28] According to The New York Times, this places nusinersen "among the most expensive drugs in the world".[20]

    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.[29]

    Norwegian authorities rejected the funding in October 2017 because the price of the medicine was "unethically high".[30] In February 2018, the funding was approved for people under 18 years old.[30]

    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.[31] 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.[32] 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.[33][34]

    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.[35]

    As of May 2019, nusinersen was available in public healthcare in more than 40 countries.[36]

    References

    1. ↑ "International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 74" (PDF). World Health Organization. pp. 413–414. Archived (PDF) from the original on 18 May 2016. Retrieved 13 March 2017.
    2. 1 2 3 4 BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 1170. ISBN 978-0857114105.
    3. 1 2 3 4 5 6 7 8 9 "Nusinersen Monograph for Professionals". Drugs.com. Archived from the original on 21 January 2021. Retrieved 13 November 2021.
    4. 1 2 3 4 5 6 7 8 9 10 "Spinraza- nusinersen injection, solution". DailyMed. 30 June 2020. Archived from the original on 17 October 2020. Retrieved 3 November 2020.
    5. ↑ Paton, D.M. (2017). "Nusinersen: antisense oligonucleotide to increase SMN protein production in spinal muscular atrophy". Drugs of Today. Clarivate Analytics (US). 53 (6): 327–337. doi:10.1358/dot.2017.53.6.2652413. ISSN 1699-3993. PMID 28799578.
    6. ↑ "Spinraza". Archived from the original on 4 January 2021. Retrieved 13 November 2021.
    7. ↑ "Spinraza Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 10 September 2021. Retrieved 13 November 2021.
    8. ↑ "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.
    9. 1 2 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.
    10. ↑ 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.
    11. ↑ 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.
    12. ↑ Wadman M (23 December 2016). "Updated: FDA approves drug that rescues babies with fatal neurodegenerative disease". Science. doi:10.1126/science.aal0476. Archived from the original on 25 May 2017. Retrieved 17 September 2021.
    13. ↑ Offord C (December 1, 2016). "Oligonucleotide Therapeutics Near Approval". The Scientist. Archived from the original on April 11, 2018. Retrieved February 10, 2022.
    14. ↑ 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.
    15. ↑ "Therapeutic Approaches". www.curesma.org. Cure SMA. Archived from the original on 1 January 2017. Retrieved 1 January 2017.
    16. ↑ 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.
    17. ↑ "Biogen Shells Out $75M to Develop Ionis' Nusinersen after Positive Phase III Results", Genetic Engineering News, August 1, 2016, archived from the original on June 14, 2018, retrieved September 17, 2021
    18. ↑ "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.
    19. ↑ "Regulatory Applications for SMA Therapy Nusinersen Accepted in US, EU". BioNews Services, LLC. Archived from the original on 2020-08-15. Retrieved 2016-11-15.
    20. 1 2 Thomas K (December 30, 2016). "Costly Drug for Fatal Muscular Disease Wins F.D.A. Approval". New York Times. Archived from the original on November 8, 2020. Retrieved September 17, 2021.
    21. ↑ Grant C (2016-12-27). "Surprise Drug Approval Is Holiday Gift for Biogen". Wall Street Journal. ISSN 0099-9660. Archived from the original on 2020-11-08. Retrieved 2016-12-27.
    22. ↑ "Spinraza (nusinersen)". European Medicines Agency. Archived from the original on 2017-10-28. Retrieved 2017-10-27.
    23. ↑ "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 2021-09-17.
    24. ↑ "Biogen to launch Spinraza in Japan soon". 2017-07-10. Archived from the original on 2020-01-12. Retrieved 2021-09-17.
    25. ↑ "Remédio inédito para atrofia muscular espinhal é liberado" (in português do Brasil). 2017-08-25. Archived from the original on 2018-12-13. Retrieved 2021-09-17.
    26. ↑ "Spinraza – Zulassung nun auch in der Schweiz" (in Schweizer Hochdeutsch). SMA Schweiz. 2017-09-30. Archived from the original on 2020-10-27. Retrieved 2021-09-17.
    27. ↑ "Nusinersen". UK Specialist Pharmacy Service. Archived from the original on 13 April 2019. Retrieved 31 December 2016.
    28. ↑ "Spinraza Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 2021-09-10. Retrieved 2021-09-10.
    29. ↑ Medicinrådet siger nej til lægemiddel til børn med muskelsvind: 'Urimeligt' dyrt Archived 2020-11-12 at the Wayback Machine Retrieved October 13, 2017.
    30. 1 2 Dette er uforståelig og utrolig urettferdig Archived 2020-12-02 at the Wayback MachineThis is incomprehensible and incredibly unfair (google translate) Archived 2021-10-28 at the Wayback Machine
    31. ↑ "Biogen's pricey muscle drug Spinraza too costly for Britain". Reuters. 2018-08-13. Archived from the original on 2019-05-28. Retrieved 2019-05-28.
    32. ↑ "Biogen statement on Expanded Access Programme". Muscular Dystrophy UK. 2 December 2018. Archived from the original on 28 February 2019. Retrieved 27 February 2019.
    33. ↑ "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.
    34. ↑ "Nusinersen for treating spinal muscular atrophy. NICE Technology appraisal guidance [TA588] 2019". Archived from the original on 2020-11-11. Retrieved 2021-09-17.
    35. ↑ "Drugmaker urges HSE to revisit pricing of muscle-wasting disease treatment". Irish Times. 25 February 2019. Archived from the original on 27 February 2019. Retrieved 27 February 2019.
    36. ↑ "Spinraza access by country". TreatSMA. Archived from the original on 2019-05-28. Retrieved 2019-05-28.
    • Finkel RS, Chiriboga CA, Vajsar J, Day JW, Montes J, De Vivo DC, et al. (December 2016). "Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study". Lancet. 388 (10063): 3017–3026. doi:10.1016/S0140-6736(16)31408-8. PMID 27939059. S2CID 40696239.
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