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Nusinersen, marketed as Spinraza, is a medication used in treating
spinal muscular atrophy 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 genet ...
(SMA), a rare neuromuscular disorder. In December 2016, it became the first
approved drug An approved drug is a Medicine, medicinal preparation that has been validated for a therapeutic use by a Regulation of therapeutic goods, ruling authority of a government. This process is usually specific by country, unless specified otherwise. P ...
used in treating this disorder. Since the condition it treats is so rare, Nusinersen has so-called "
orphan drug An orphan drug is a pharmaceutical agent developed to treat medical conditions which, because they are so rare, would not be profitable to produce without government assistance. The conditions are referred to as orphan diseases. The assignment o ...
" designation in the United States and the European Union.


Medical uses

The drug is used to treat spinal muscular atrophy associated with a
mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...
in the '' SMN1'' gene. It is administered directly to the
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...
(CNS) using
intrathecal Intrathecal administration is a route of administration for drugs via an injection into the spinal canal, or into the subarachnoid space so that it reaches the cerebrospinal fluid (CSF) and is useful in spinal anesthesia, chemotherapy, or pa ...
injection. 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.


Side effects

People treated with nusinersen had an increased risk of upper and lower respiratory infections and congestion, ear infections, constipation,
pulmonary aspiration Pulmonary aspiration is the entry of material such as pharyngeal secretions, food or drink, or stomach contents from the oropharynx or gastrointestinal tract, into the larynx (voice box) and lower respiratory tract, the portions of the res ...
, teething, and
scoliosis Scoliosis is a condition in which a person's spine has a sideways curve. The curve is usually "S"- or "C"-shaped over three dimensions. In some, the degree of curve is stable, while in others, it increases over time. Mild scoliosis does not t ...
. There is a risk that growth of infants and children might be
stunted Stunted growth is a reduced growth rate in human development. It is a primary manifestation of malnutrition (or more precisely undernutrition) and recurrent infections, such as diarrhea and helminthiasis, in early childhood and even before birth, ...
. 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. 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. In 2018, several cases of
communicating hydrocephalus Normal-pressure hydrocephalus (NPH), also called malresorptive hydrocephalus, is a form of communicating hydrocephalus in which excess cerebrospinal fluid (CSF) occurs in the ventricles, and with normal or slightly elevated cerebrospinal fluid pr ...
in children and adults treated with nusinersen emerged; it remains unclear whether this was drug related.


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. The drug distributes to CNS and peripheral tissues. The
half-life Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable at ...
is estimated to be 135 to 177 days in
cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates. CSF is produced by specialised ependymal cells in the choroid plexus of the ventricles of the bra ...
(CSF) and 63 to 87 days in
blood plasma Blood plasma is a light amber-colored liquid component of blood in which blood cells are absent, but contains proteins and other constituents of whole blood in suspension. It makes up about 55% of the body's total blood volume. It is the ...
. The drug is metabolized via
exonuclease Exonucleases are enzymes that work by cleaving nucleotides one at a time from the end (exo) of a polynucleotide chain. A hydrolyzing reaction that breaks phosphodiester bonds at either the 3′ or the 5′ end occurs. Its close relative is t ...
(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.


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.


History

Nusinersen was developed in a collaboration between Adrian Krainer at
Cold Spring Harbor Laboratory Cold Spring Harbor Laboratory (CSHL) is a private, non-profit institution with research programs focusing on cancer, neuroscience, plant biology, genomics, and quantitative biology. It is one of 68 institutions supported by the Cancer Centers ...
and
Ionis Pharmaceuticals Ionis Pharmaceuticals, Inc. is a biotechnology company based in Carlsbad, California, that specializes in discovering and developing RNA-targeted therapeutics. The company has 3 commercially approved medicines: Spinraza ( Nusinersen), Tegsedi ( ...
(formerly called Isis Pharmaceuticals). Initial work of target discovery of nusinersen was done by Dr. Ravindra Singh and co-workers at the
University of Massachusetts Medical School The University of Massachusetts Chan Medical School is a public medical school in Worcester, Massachusetts. It is part of the University of Massachusetts system. It is home to three schools: the T.H. Chan School of Medicine, the Morningside Grad ...
funded by Cure SMA. Starting in 2012, Ionis partnered with
Biogen Biogen Inc. is an American multinational biotechnology company based in Cambridge, Massachusetts, specializing in the discovery, development, and delivery of therapies for the treatment of neurological diseases to patients worldwide. History ...
on development and, in 2015, Biogen acquired an exclusive license to the drug for a license fee, milestone payments up to , 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 Priority review is a program of the United States Food and Drug Administration (FDA) to expedite the review process for drugs that are expected to have a particularly great impact on the treatment of a disease. The priority review voucher program ...
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 SMA. Subsequently, nusinersen was approved to treat SMA in Canada (July 2017), Japan (July 2017), Brasil (August 2017), Switzerland (September 2017), and China (February 2019).


Society and culture


Economics

Nusinersen
list price The list price, also known as the manufacturer's suggested retail price (MSRP), or the recommended retail price (RRP), or the suggested retail price (SRP) of a product is the price at which its manufacturer notionally recommends that a retailer ...
in the USA is per injection which puts the treatment cost at in the first year and annually after that. According to ''
The New York Times ''The New York Times'' (''the Times'', ''NYT'', or the Gray Lady) is a daily newspaper based in New York City with a worldwide readership reported in 2020 to comprise a declining 840,000 paid print subscribers, and a growing 6 million paid ...
'', this places nusinersen "among the most expensive drugs in the world". 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. Norwegian authorities rejected the funding in October 2017 because the price of the medicine was "unethically high".Dette er uforståelig og utrolig urettferdig
https://translate.google.com/translate?hl=en&sl=no&u=https://www.abcnyheter.no/helse-og-livsstil/helse/2018/02/13/195371564/dette-er-uforstaelig-og-utrolig-urettferdig&prev=search ''This is incomprehensible and incredibly unfair'' (google translate)]
In February 2018, the funding was approved for people under 18 years old. In August 2018, the
National Institute for Health and Care Excellence The National Institute for Health and Care Excellence (NICE) is an executive non-departmental public body of the Department of Health and Social Care in England that publishes guidelines in four areas: * the use of health technologies withi ...
(NICE), which weighs the cost-effectiveness of therapies for the NHS in England and Wales, recommended against offering nusinersen to people with SMA. Children with SMA type 1 were treated in the UK under a Biogen-funded
expanded access programme Expanded access or compassionate use is the use of an unapproved drug or medical device under special forms of investigational new drug applications (IND) or IDE application for devices, outside of a clinical trial, by people with serious or lif ...
; after enrolling 80 children, the scheme closed to new people in November 2018. 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.''Nusinersen for treating spinal muscular atrophy. NICE Technology appraisal guidance [TA588]'' 2019
/ref> The Irish
Health Service Executive The Health Service Executive (HSE) ( ga, Feidhmeannacht na Seirbhíse Sláinte) is the publicly funded healthcare system in Ireland, responsible for the provision of health and personal social services. It came into operation on 1 January 2005 ...
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 The Beneluxa Initiative on Pharmaceutical Policy is an initiative involving health services in Belgium, the Netherlands, Luxembourg, Austria and Ireland to deliver sustainable access to innovative medications to people in these smaller countr ...
initiative which Ireland has been a member of since June 2018. As of May 2019, nusinersen was available in public healthcare in more than 40 countries. 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.


References


Further reading

*


External links

* * {{Other drugs for disorders of the musculo-skeletal system Antisense RNA Drugs acting on the nervous system Orphan drugs Spinal muscular atrophy Therapeutic gene modulation