Nusinersen

Last updated
Nusinersen
Nusinersen sodium colored.svg
Clinical data
Trade names Spinraza
Other namesIONIS-SMNRx, ISIS-SMNRx
AHFS/Drugs.com Monograph
MedlinePlus a617010
License data
Pregnancy
category
  • AU:B1
Routes of
administration 		Intrathecal
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 100% (intrathecal)
Protein binding <25% (in CSF), >94% (in plasma) [5]
Metabolism Exonuclease (3'- and 5')-mediated hydrolysis
Elimination half-life 135–177 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 [6]
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
Chemical and physical data
Formula C234H323N61Na17O128P17S17 [4]
Molar mass 7500.86 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, [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.

Contents

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

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. [9]

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. [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

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

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

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. [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]

Related Research Articles

<span class="mw-page-title-main">Biogen</span> Pharmaceutical company

Biogen Inc. is an American multinational biotechnology company based in Cambridge, Massachusetts, United States specializing in the discovery, development, and delivery of therapies for the treatment of neurological diseases to patients worldwide. Biogen operates in Argentina, Brazil, Canada, China, France, Germany, Hungary, India, Italy, Japan, Mexico, Netherlands, Poland, Sweden, and Switzerland.

<span class="mw-page-title-main">Spinal muscular atrophies</span> Group of disorders

Spinal muscular atrophies (SMAs) are a genetically and clinically heterogeneous group of rare debilitating disorders characterised by the degeneration of lower motor neurons and subsequent atrophy (wasting) of various muscle groups in the body. While some SMAs lead to early infant death, other diseases of this group permit normal adult life with only mild weakness.

Antisense therapy is a form of treatment that uses antisense oligonucleotides (ASOs) to target messenger RNA (mRNA). ASOs are capable of altering mRNA expression through a variety of mechanisms, including ribonuclease H mediated decay of the pre-mRNA, direct steric blockage, and exon content modulation through splicing site binding on pre-mRNA. Several ASOs have been approved in the United States, the European Union, and elsewhere.

<span class="mw-page-title-main">Spinal muscular atrophy</span> Rare congenital neuromuscular disorder

Spinal muscular atrophy (SMA) is a rare neuromuscular disorder that results in the loss of motor neurons and progressive muscle wasting. It is usually diagnosed in infancy or early childhood and if left untreated it is the most common genetic cause of infant death. It may also appear later in life and then have a milder course of the disease. The common feature is progressive weakness of voluntary muscles, with arm, leg and respiratory muscles being affected first. Associated problems may include poor head control, difficulties swallowing, scoliosis, and joint contractures.

<span class="mw-page-title-main">Survival of motor neuron</span> Protein in animal cells

Survival of motor neuron or survival motor neuron (SMN) is a protein that in humans is encoded by the SMN1 and SMN2 genes.

<i>SMN1</i> Protein-coding gene in the species Homo sapiens

Survival of motor neuron 1 (SMN1), also known as component of gems 1 or GEMIN1, is a gene that encodes the SMN protein in humans.

<span class="mw-page-title-main">NAIP (gene)</span> Protein and coding gene in humans

Baculoviral IAP repeat-containing protein 1 is a protein that in humans is encoded by the NAIP gene.

<i>SMN2</i> Protein-coding gene in the species Homo sapiens

Survival of motor neuron 2 (SMN2) is a gene that encodes the SMN protein in humans.

<span class="mw-page-title-main">Ionis Pharmaceuticals</span> Biotechnology company

Ionis Pharmaceuticals, Inc. is a biotechnology company based in Carlsbad, California, that specializes in discovering and developing RNA-targeted therapeutics. The company has three commercially approved medicines: Spinraza (Nusinersen), Tegsedi (Inotersen), and Waylivra (Volanesorsen) and has four drugs in pivotal studies: tominersen for Huntington's disease, tofersen for SOD1-ALS, AKCEA-APO(a)-LRx for cardiovascular disease, and AKCEA-TTR-LRx for all forms of TTR amyloidosis.

<span class="mw-page-title-main">Branaplam</span> Chemical compound

Branaplam is a pyridazine derivative that is being studied as an experimental drug. It was originally developed by Novartis to treat spinal muscular atrophy (SMA); since 2020 it was being developed to treat Huntington's disease (HD) but the trial ended in 2023 with harmful side effects.

<span class="mw-page-title-main">Risdiplam</span> Chemical compound

Risdiplam, sold under the brand name Evrysdi, is a medication used to treat spinal muscular atrophy (SMA) and the first oral medication approved to treat this disease.

Onasemnogene abeparvovec, sold under the brand name Zolgensma, is a gene therapy used to treat spinal muscular atrophy (SMA), a disease causing muscle function loss in children. It involves a one-time infusion of the medication into a vein. It works by providing a new copy of the SMN gene that produces the SMN protein.

Novartis Gene Therapies, until 2020 known as AveXis, is a biotechnology company that develops treatments for rare neurological genetic disorders. It was founded in Dallas, Texas, United States in 2012 by John Carbona after reorganizing a company called BioLife Cell Bank founded by David Genecov and John Harkey. Work done at Nationwide Children's Hospital in the laboratory of Brian Kaspar was licensed to AveXis in October 2013. Unusual for the time, Nationwide Children's Hospital, in addition to upfront and milestone payments, also took an equity position in AveXis. Kaspar became paid consultant pari passu with the license agreement in 2013. The company was built specifically around a discovery of a novel method of treating spinal muscular atrophy using gene therapy.

<span class="mw-page-title-main">C. Frank Bennett</span> American pharmacologist

C. Frank Bennett is an American pharmacologist. Bennett is currently the Senior Vice President of Research and Neurology Franchise Leader at Ionis Pharmaceuticals. He is a 2019 Breakthrough Prize winner in Life Sciences, which he shared with his collaborator Adrian R. Krainer for the development of an effective antisense oligonucleotide therapy for children with the neurodegenerative disease spinal muscular atrophy.

<span class="mw-page-title-main">Charlotte Sumner</span> American neurologist

Charlotte Jane Sumner is an American neurologist. She is a professor in the Departments of Neurology and Neuroscience at Johns Hopkins School of Medicine. Dr. Sumner cares for patients with genetically mediated neuromuscular diseases and directs a laboratory focused on developing treatments for these diseases. She co-directs the Johns Hopkins Muscular Dystrophy Association Care Center, the Spinal Muscular Atrophy (SMA), and the Charcot-Marie-Tooth (CMT) clinics, which deliver multidisciplinary clinical care, engage in international natural history studies, and provide cutting edge therapeutics.

Viltolarsen, sold under the brand name Viltepso, is a medication used for the treatment of Duchenne muscular dystrophy (DMD). Viltolarsen is a Morpholino antisense oligonucleotide.

Toshifumi (Toshi) Yokota is a medical scientist and professor of medical genetics at the University of Alberta, where he also holds the titles of the Friends of Garrett Cumming Research & Muscular Dystrophy Canada Endowed Research Chair and the Henri M. Toupin Chair in Neurological Science. He is best known for his pioneering research in antisense therapy for muscular dystrophy that led to the development of an FDA-approved drug viltolarsen. His research interests include precision medicine for muscular dystrophy and genetic diseases. He has co-edited three books published in the Methods in Molecular Biology series from Humana Press, Springer-Nature, and has published more than 100 refereed papers and patents. He is a fellow of the Canadian Academy of Health Sciences, a member of the editorial boards for the International Journal of Molecular Sciences, Genes, Frontiers in Genome Editing, Frontiers in Physiology, and Nucleic Acid Therapeutics, a member of the Medical and Scientific Advisory Committee of Muscular Dystrophy Canada, and a co-founder of the Canadian Neuromuscular Network (CAN-NMD).

<span class="mw-page-title-main">Alberto Kornblihtt</span> Argentine molecular biologist

Alberto Kornblihtt is an Argentine molecular biologist who specializes in alternative ribonucleic acid splicing. During his postdoctoral training with Francisco Baralle in Oxford, Kornblihtt documented one of the first cases of alternative splicing, explaining how a single transcribed gene can generate multiple protein variants. Kornblihtt was elected as a foreign associate of the National Academy of Sciences of the United States in 2011, received the Diamond Award for the most relevant scientist of Argentina of the decade, alongside physicist Juan Martin Maldacena, in 2013, and was incorporated to the Académie des Sciences of France in 2022.

Tofersen, sold under the brand name Qalsody, is a medication used for the treatment of amyotrophic lateral sclerosis (ALS). Tofersen is an antisense oligonucleotide that targets the production of superoxide dismutase 1, an enzyme whose mutant form is commonly associated with ALS. It is administered as an intrathecal injection.

Stephen Donald Wilton, also known as Steve Wilton, is an Australian molecular biologist and academic, serving as the Foundation Professor of Molecular Therapy at Murdoch University and adjunct professor at the University of Western Australia (UWA). He also fulfills dual roles as a Director at the Perron Institute for Neurological and Translational Science and deputy director at Murdoch's Centre for Molecular Medicine and Innovative Therapeutics (CMMIT).

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. 1 2 3 4 5 6 7 8 9 10 11 12 "Spinraza- nusinersen injection, solution". DailyMed. 30 June 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. 53 (6). Clarivate Analytics (US): 327–337. doi:10.1358/dot.2017.53.6.2652413. ISSN   1699-3993. PMID   28799578.
  6. 1 2 "International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 74" (PDF). World Health Organization. pp. 413–414. Retrieved 13 March 2017.
  7. ↑ 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.
  8. ↑ "Nusinersen". UK Specialist Pharmacy Service. 28 January 2016. Archived from the original on 13 April 2019. Retrieved 31 December 2016.
  9. ↑ "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.
  10. 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ Wadman M (23 December 2016). "Updated: FDA approves drug that rescues babies with fatal neurodegenerative disease". Science. doi:10.1126/science.aal0476.
  14. ↑ Offord C (December 1, 2016). "Oligonucleotide Therapeutics Near Approval". The Scientist.
  15. ↑ 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.
  16. ↑ "Therapeutic Approaches". www.curesma.org. Cure SMA. Archived from the original on 1 January 2017. Retrieved 1 January 2017.
  17. ↑ 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.
  18. ↑ "Biogen Shells Out $75M to Develop Ionis' Nusinersen after Positive Phase III Results", Genetic Engineering News, August 1, 2016
  19. ↑ "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.
  20. ↑ "Regulatory Applications for SMA Therapy Nusinersen Accepted in US, EU". BioNews Services, LLC. November 2016. Retrieved 2016-11-15.
  21. 1 2 Thomas K (December 30, 2016). "Costly Drug for Fatal Muscular Disease Wins F.D.A. Approval". New York Times.
  22. ↑ Grant C (2016-12-27). "Surprise Drug Approval Is Holiday Gift for Biogen". Wall Street Journal. ISSN   0099-9660 . Retrieved 2016-12-27.
  23. ↑ "Spinraza (nusinersen)". European Medicines Agency. Archived from the original on 2017-10-28. Retrieved 2017-10-27.
  24. ↑ "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.
  25. ↑ "Biogen to launch Spinraza in Japan soon". 2017-07-10.
  26. ↑ "Remédio inédito para atrofia muscular espinhal é liberado" (in Brazilian Portuguese). 2017-08-25.
  27. ↑ "Spinraza – Zulassung nun auch in der Schweiz" (in Swiss High German). SMA Schweiz. 2017-09-30.
  28. ↑ "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.
  29. ↑ "Spinraza Prices, Coupons & Patient Assistance Programs". Drugs.com. Retrieved 2021-09-10.
  30. ↑ Medicinrådet siger nej til lægemiddel til børn med muskelsvind: 'Urimeligt' dyrt Retrieved October 13, 2017.
  31. 1 2 Dette er uforståelig og utrolig urettferdig This is incomprehensible and incredibly unfair (google translate)
  32. ↑ Omland, Ellen (2023-04-11). "Beslutningsforum seier ja til Spinraza for muskelsjuke i ekstramøte". NRK (in Norwegian Nynorsk). Retrieved 2023-04-14.
  33. ↑ "Biogen's pricey muscle drug Spinraza too costly for Britain". Reuters. 2018-08-13. Retrieved 2019-05-28.
  34. ↑ "Biogen statement on Expanded Access Programme". Muscular Dystrophy UK. 2 December 2018. Retrieved 27 February 2019.
  35. ↑ "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.
  36. ↑ Nusinersen for treating spinal muscular atrophy. NICE Technology appraisal guidance [TA588] 2019
  37. ↑ "Drugmaker urges HSE to revisit pricing of muscle-wasting disease treatment". Irish Times. 25 February 2019. Retrieved 27 February 2019.
  38. ↑ "Spinraza access by country". TreatSMA. 18 October 2018. Retrieved 2019-05-28.
  39. ↑ "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.
  40. ↑ "China's 2021 NDRL listing sees price cuts of up to 95%". www.thepharmaletter.com. Retrieved 2022-01-27.
  41. ↑ 陈子琰. "China increases accessibility to rare disease treatment". www.chinadaily.com.cn. Retrieved 2022-01-27.

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