Nusinersen

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Nusinersen
INN: Nusinersen
Clinical data
Trade namesSpinraza
Legal status
Legal status
Identifiers
  • Nusinersen
CAS Number

Nusinersen (formerly, IONIS-SMNRx, ISIS-SMNRx), marketed as Spinraza,[1] is the first drug approved by the US Food and Drug Administration for use in treating spinal muscular atrophy (SMA), a rare neuromuscular disorder.

Medical use

The drug is used to treat spinal muscular atrophy. It is administered directly to the central nervous system (CNS) using intrathecal injection. The drug is administered every 4 months, with additional dosings at initial stage of treatment.[2]

In clinical trials, the drug halted the disease progression. In around 60% of infants affected by type 1 spinal muscular atrophy, the drug also significantly improved motor function.[2][3] Data from older patients and those with more benign forms of SMA has not been published, although FDA approval across the entire disease spectrum suggests its efficacy.

Side effects

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.[2]

Like other antisense drugs, there is a risk of abnormalities in blood clotting and a reduction in platelets as well as a risk of kidney damage.[2] Some people may develop antibodies against the drug; as of December 2016 it was unclear what effect this might have on efficacy or safety.[2]

Pharmacology

Spinal muscular atrophy is caused by loss-of-function mutations in the SMN1 gene which codes for suvival motor neuron (SMN) protein. Patients survive thanks 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.[4] Upon administration into the CNS, the drug distributes to the peripheral nerves.

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.[2] The primary route of elimination is likely by urinary excretion for nusinersen and its metabolites.[2][5]

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.[2][4] 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-
(2-methoxyethyl)guanosine.[6]

History

Nusinersen was discovered in a collaboration between Adrian Krainer at Cold Spring Harbor Laboratory and Ionis Pharmaceuticals (formerly called Isis Pharmaceuticals).[7][8][9][10] Preclinical work was done at University of Massachusetts funded by Cure SMA.[11]

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 was to finance all development subsequent to taking the license.[12] The license to Biogen included licenses to intellectual property that Ionis had acquired from Cold Spring Harbor and U Mass.[13]

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.[14][15] It was approved by the FDA in December 2016 as the first drug for SMA.[16]

Society and culture

Nusinersen has orphan drug designation in the United States and the European Union.[17]

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."[15]

References

  1. ^ "Nusinersen". AdisInsight. Retrieved 1 January 2017.
  2. ^ a b c d e f g h "US Spinraza label" (PDF). FDA. December 2016.
  3. ^ Finkel, Richard S; Chiriboga, Claudia A; Vajsar, Jiri; Day, John W; Montes, Jacqueline; De Vivo, Darryl C; Yamashita, Mason; Rigo, Frank; Hung, Gene; Schneider, Eugene; Norris, Daniel A; Xia, Shuting; Bennett, C Frank; Bishop, Kathie M (2016). "Treatment of infantile-onset spinal muscular atrophy with nusinersen: A phase 2, open-label, dose-escalation study". The Lancet. 388 (10063): 3017. doi:10.1016/S0140-6736(16)31408-8.
  4. ^ a b 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.
  5. ^ Chiriboga, Claudia A.; Swoboda, Kathryn J.; Darras, Basil T.; Iannaccone, Susan T.; Montes, Jacqueline; De Vivo, Darryl C.; Norris, Daniel A.; Bennett, C. Frank; Bishop, Kathie M. (2016). "Results from a phase 1 study of nusinersen (ISIS-SMNRx) in children with spinal muscular atrophy". Neurology. 86 (10): 890. doi:10.1212/WNL.0000000000002445. PMID 26865511.
  6. ^ "Recommended INN: List 74" (PDF). WHO Drug Information. 29 (3). 2015.
  7. ^ 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.
  8. ^ Wadman, Meredith (23 December 2016). "Updated: FDA approves drug that rescues babies with fatal neurodegenerative disease". Science.
  9. ^ Offord, Catherine (December 1, 2016). "Oligonucleotide Therapeutics Near Approval". The Scientist.
  10. ^ 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.
  11. ^ "Therapeutic Approaches". www.curesma.org. Cure SMA. Retrieved 1 January 2017.
  12. ^ "Biogen Shells Out $75M to Develop Ionis' Nusinersen after Positive Phase III Results", Genetic Engineering News, August 1, 2016
  13. ^ "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.
  14. ^ "Regulatory Applications for SMA Therapy Nusinersen Accepted in US, EU". BioNews Services, LLC. Retrieved 2016-11-15.
  15. ^ a b Katie Thomas (December 30, 2016). "Costly Drug for Fatal Muscular Disease Wins F.D.A. Approval". New York Times.
  16. ^ Grant, Charley (2016-12-27). "Surprise Drug Approval Is Holiday Gift for Biogen". Wall Street Journal. ISSN 0099-9660. Retrieved 2016-12-27.
  17. ^ "Nusinersen". UK Specialist Pharmacy Service. Retrieved 31 December 2016.
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