Nusinersen (INN), marketed as Spinraza, is a drug used in treating spinal muscular atrophy (SMA), 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.
|AHFS/Drugs.com||Multum Consumer Information|
|Injection into cerebrospinal fluid|
|Metabolism||Exonuclease (3’- and 5’)-mediated hydrolysis|
|Biological half-life||135–177 days (in CSF), 63–87 days (in plasma)|
|Chemical and physical data|
|Molar mass||7501 Da|
|3D model (JSmol)|
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.
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.
Some people may develop antibodies against the drug; as of December 2016 it was unclear what effect this might have on efficacy or safety.
Spinal muscular atrophy is caused by loss-of-function mutations in the SMN1 gene which codes for survival motor neuron (SMN) protein. Patients 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.
The drug distributes to CNS and to peripheral tissues.
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. The primary route of elimination is likely by urinary excretion for nusinersen and its metabolites.
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.
Nusinersen was discovered in a collaboration between Adrian Krainer at Cold Spring Harbor Laboratory and Ionis Pharmaceuticals (formerly called Isis Pharmaceuticals). Partial work was done at the University of Massachusetts Medical School funded by Cure SMA.
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. The license to Biogen included licenses to intellectual property that Ionis had acquired from Cold Spring Harbor Laboratory and University of Massachusetts.
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. It was approved by the FDA in December 2016 and by EMA in May 2017 as the first drug to treat spinal muscular atrophy. Subsequently, nusinersen was approved to treat SMA in Canada (July 2017), Japan (July 2017), Brasil (August 2017) and Switzerland (September 2017).
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".
As of October 2017, Spinraza is reimbursed by health insurance providers in the United States and by the public healthcare systems in France (SMA type 1 and 2 patients only), Germany (all patients), Iceland (all patients), Italy (all patients) and Japan (SMA type 1 only).
In October 2017, the authorities in Denmark recommended Spinraza for use only in a small subset of patients with SMA type 1 (young babies) and refused to offer it as a standard treatment in all other SMA patients quoting an "unreasonably high price" compared to the clinical effect.
In January 2018 public funding of Spinraza was approved in Israel.
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