Nusinersen

Nusinersen

Clinical data
Trade names	Spinraza
Synonyms	IONIS-SMNRx, ISIS-SMNRx
AHFS/Drugs.com	Multum Consumer Information
License data	EU EMA: by INN
Routes of administration	Injection into cerebrospinal fluid
ATC code	M09AX07 (WHO)
Legal status
Legal status	US: ℞-only
Pharmacokinetic data
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[1]
CAS Number	1258984-36-9
PubChem CID	124037382
DrugBank	DB13161
ChemSpider	34983394
UNII	5Z9SP3X666
KEGG	D10881
Chemical and physical data
Formula	C234H323N61Na17O128P17S17[2]
Molar mass	7501 Da[2]
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,^[1] marketed as Spinraza,^[3] is a medication used in treating spinal muscular atrophy (SMA),^[4] a rare neuromuscular disorder. In December 2016, it became the first approved drug used in treating this disorder. Nusinersen has orphan drug designation in the United States and the European Union.^[5]

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.^[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]

Side effects

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]

In clinical trials, people treated with nusinersen had an increased risk of upper and lower respiratory infections and congestion, ear infections, constipation, pulmonary 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]

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 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.^[6]

The drug distributes to CNS and to peripheral tissues.^[2]

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]

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][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]} Partial work was done at the University of Massachusetts Medical School 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 paid the costs of development subsequent to taking the license.^[12] The license to Biogen included licenses to intellectual property that Ionis had acquired from Cold Spring Harbor Laboratory and University of Massachusetts.^[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 (EMA) at that time.^[14][15] It was approved by the FDA in December 2016 and by EMA in May 2017 as the first drug to treat spinal muscular atrophy.^[16][17] Subsequently, nusinersen was approved to treat SMA in Canada (July 2017),^[18] Japan (July 2017),^[19] Brasil (August 2017)^[20] and Switzerland (September 2017).^[21]

Controversy and access

Spinraza list price 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. According to the New York Times, this places Spinraza "among the most expensive drugs in the world".^[15]

In October 2017, the authorities in Denmark recommended Spinraza 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 clinical effect.^[22] Norwegian authorities rejected the funding in October 2017 because the price of the medicine was "unethically high".^[23] In February 2018 the funding was approved for people under 18 years old.^[23]

In January 2018 public funding of Spinraza was approved in Israel. In May 2018 the Australian Government announced it would provide subsidised access to Spinraza from June 2018.^[24]

References

Further reading

• 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.