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Nusinersen

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Nusinersen (formerly, IONIS-SMNRx, ISIS-SMNRx), marketed as Spinraza, is the first drug approved by the U.S. Food and Drug Administration for use in treating spinal muscular atrophy (SMA), a rare pediatric disease.

Medical use

The drug is used to treat spinal muscular atrophy and is administered directly to the central nervous system using intrathecal injection. The drug does not work in all people with the condition, but when it works it does not just halt disease progression but also leads to improvements; in clinical trials around 60% had improved motor function.

Side effects

Like other antisense drugs, there is a risk of abnormalities in blood clotting and a reduction in platelets and there is a risk of kidney damage.

In clinical trials, people treated with nusinersen had an increased risk of upper and lower respiratory infections and congestion, ear infections, constipation, aspiration, teething, and scoliosis. One infant in a clinical trial had severe lowering of salt levels and several had rashes. 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 adverse effects from the spinal injection.

Some people may develop antibodies against the drug; as of December 2016 it was unclear what effect this might have on efficacy or safety.

Pharmacology

Spinal muscular atrophy is caused by loss-of-function mutations in the SMN1 gene. Nusinersen is a proprietary antisense oligonucleotide that modulates alternate splicing of the SMN2 gene, functionally converting it into SMN1 gene.

It distributes from the CNS to the periphery. It is metabolized via exonuclease (3’- and 5’)-mediated hydrolysis and does not interact with CYP450 enzymes.

The half-life is estimated to be 135 to 177 days in CSF and 63 to 87 days in plasma. The primary route of elimination is likely by urinary excretion for nusinersen and its metabolites.

Chemistry

Nusinersen is an antisense drug 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.

Its chemical name is: 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-(2methoxyethyl)guanosine.

History

Nusinersen was discovered in a collaboration between Adrian Krainer at Cold Spring Harbor Laboratory and Ionis Pharmaceuticals (formerly called Isis Pharmaceuticals) and preclinical work was done at University of Massachusetts funded by Cure SMA. The drug was initially developed by Ionis (then Isis) and the early clinical trials were supported by several nonprofits, including Families of Spinal Muscular Atrophy. Ionis partnered with Biogen on development starting in 2012, and in 2015 Biogen acquired an exclusive license to the drug for a $75 million license fee, milestone payments up to $150M, and tiered royalties up to the mid-teens; Biogen also paid for all development subsequent to taking the license. The license to Biogen included licenses to intellectual property that Ionis had acquired from Cold Spring Harbor and U Mass.

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 at that time. It was approved by the FDA in December 2016 as the first drug for SMA.

Society and culture

Nusinersen has orphan drug designation in the United States and the European Union.

According to the New York Times, Spinraza, "will be among the most expensive drugs in the world", with an estimated cost $750,000 in the first year of treatment and "about $375,000 annually after that." In October 2016 peak annual sales of nusinersen were estimated to reach around $1.5 billion.

References

  1. "Nusinersen". AdisInsight. Retrieved 1 January 2017.
  2. ^ "US Spinraza label" (PDF). FDA. December 2016.
  3. ^ Zanetta, C; Nizzardo, M; Simone, C; Monguzzi, E; Bresolin, N; Comi, GP; Corti, S (1 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.
  4. "Recommended INN: List 74" (PDF). WHO Drug Information. 29 (3). 2015.
  5. Garber, K (11 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.
  6. Wadman, Meredith (23 December 2016). "Updated: FDA approves drug that rescues babies with fatal neurodegenerative disease". Science.
  7. Offord, Catherine (December 1, 2016). "Oligonucleotide Therapeutics Near Approval". The Scientist.
  8. Tarr, Peter (24 December 2016). "CSHL FDA approval of life-saving SMA drug is hailed by its researcher-inventor at CSHL". Cold Spring Harbor Laboratory.
  9. "Therapeutic Approaches". www.curesma.org. Cure SMA. Retrieved 1 January 2017.
  10. "Biogen Shells Out $75M to Develop Ionis' Nusinersen after Positive Phase III Results", Genetic Engineering News, August 1, 2016
  11. "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.
  12. "Regulatory Applications for SMA Therapy Nusinersen Accepted in US, EU". BioNews Services, LLC. Retrieved 2016-11-15.
  13. ^ Katie Thomas (December 30, 2016). "Costly Drug for Fatal Muscular Disease Wins F.D.A. Approval". New York Times. {{cite news}}: Cite has empty unknown parameter: |1= (help)
  14. Grant, Charley (2016-12-27). "Surprise Drug Approval Is Holiday Gift for Biogen". Wall Street Journal. ISSN 0099-9660. Retrieved 2016-12-27.
  15. "Nusinersen". UK Specialist Pharmacy Service. Retrieved 31 December 2016.
  16. Cory Renauer (October 5, 2016), Better Buy: Anavex Life Sciences Corp. vs. Ionis Pharmaceuticals, Inc., retrieved December 31, 2016
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