Nusinersen: Difference between revisions
Content deleted Content added
Major copyedit. Infobox added. |
|||
| Line 1: | Line 1: | ||
{{Infobox drug |
|||
{{in use|date=January 2017}} |
|||
| drug_name = Nusinersen |
|||
| ⚫ | '''Nusinersen''' (formerly, IONIS-SMN<sub>Rx</sub>, ISIS-SMN<sub>Rx</sub>), marketed as Spinraza,<ref name=Adis>{{cite web|title=Nusinersen|url=http://adisinsight.springer.com/drugs/800031116|publisher=AdisInsight|accessdate=1 January 2017}}</ref> is the first drug approved by the |
||
| INN = Nusinersen |
|||
| type =<!-- empty --> |
|||
| IUPAC_name = Nusinersen |
|||
| image = |
|||
| alt = |
|||
| caption = |
|||
<!-- Clinical data --> |
|||
| pronounce = |
|||
| tradename = Spinraza |
|||
| Drugs.com = |
|||
| MedlinePlus = |
|||
| pregnancy_AU = <!-- A/B1/B2/B3/C/D/X --> |
|||
| pregnancy_AU_comment = |
|||
| pregnancy_US = <!-- A/B/C/D/X/N --> |
|||
| pregnancy_category= |
|||
| routes_of_administration = |
|||
| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled--> |
|||
| legal_AU_comment = |
|||
| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII --> |
|||
| legal_DE = <!-- Anlage I, II, III --> |
|||
| legal_NZ = <!-- Class A, B, C --> |
|||
| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C --> |
|||
| legal_US = Rx-only |
|||
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV--> |
|||
| legal_status = <!-- Free text --> |
|||
<!-- Pharmacokinetic data --> |
|||
| bioavailability = |
|||
| protein_bound = |
|||
| metabolism = |
|||
| metabolites = |
|||
| > |
|||
| elimination_half-life = |
|||
| duration_of_action = |
|||
| excretion = |
|||
<!-- Identifiers --> |
|||
| CAS_number = 1258984-36-9 |
|||
| class = |
|||
| ATCvet = |
|||
| ATC_prefix = <!-- 'none' if uncategorised --> |
|||
| ATC_suffix = |
|||
| PubChem = |
|||
| DrugBank = |
|||
<!-- Chemical and physical data --> |
|||
| chemical_formula = |
|||
| molecular_weight = |
|||
}} |
|||
| ⚫ | '''Nusinersen''' (formerly, IONIS-SMN<sub>Rx</sub>, ISIS-SMN<sub>Rx</sub>), marketed as Spinraza,<ref name=Adis>{{cite web|title=Nusinersen|url=http://adisinsight.springer.com/drugs/800031116|publisher=AdisInsight|accessdate=1 January 2017}}</ref> 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== |
== Medical use== |
||
The drug is used to treat |
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.<ref name=USlabel>{{cite web|title=US Spinraza label|url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/209531lbl.pdf|publisher=FDA|date=December 2016}}</ref> |
||
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.<ref name=USlabel/><ref name="Finkel2016">{{cite journal |doi=10.1016/S0140-6736(16)31408-8 }}</ref> Data from older patients and those with more benign forms of SMA has not been published. |
|||
==Side effects== |
==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 [[Lumbar puncture#Adverse effects|adverse effects from the spinal injection]].<ref name=USlabel/> |
||
| ⚫ | |||
| ⚫ | Like other antisense drugs, there is a risk of abnormalities in blood clotting and [[thrombocytopenia|a reduction in platelets]] as well as a risk of kidney damage.<ref name=USlabel/> Some people may develop antibodies against the drug; as of December 2016 it was unclear what effect this might have on efficacy or safety.<ref name=USlabel/> |
||
| ⚫ | 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]]. |
||
Some people may develop antibodies against the drug; as of December 2016 it was unclear what effect this might have on efficacy or safety.<ref name=USlabel/> |
|||
==Pharmacology== |
==Pharmacology== |
||
Spinal muscular atrophy is caused by [[Mutation#By effect on function|loss-of-function mutations]] in the ''[[SMN1]]'' gene. |
Spinal muscular atrophy is caused by [[Mutation#By effect on function|loss-of-function mutations]] in the ''[[SMN1]]'' gene which codes for [[suvival motor neuron|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.<ref name=Zanetta2014rev>{{cite journal|last1=Zanetta|first1=C|last2=Nizzardo|first2=M|last3=Simone|first3=C|last4=Monguzzi|first4=E|last5=Bresolin|first5=N|last6=Comi|first6=GP|last7=Corti|first7=S|title=Molecular therapeutic strategies for spinal muscular atrophies: current and future clinical trials.|journal=Clinical therapeutics|date=1 January 2014|volume=36|issue=1|pages=128–40|doi=10.1016/j.clinthera.2013.11.006|pmid=24360800}}</ref> Upon administration into the CNS, the drug distributes to the [[peripheral nerve]]s. |
||
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.<ref name=USlabel/> The primary route of elimination is likely by urinary excretion for nusinersen and its metabolites.<ref name=USlabel/><ref name="Chiriboga2016">{{cite journal |doi=10.1212/WNL.0000000000002445 }}</ref> |
|||
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.<ref name=USlabel/> |
|||
==Chemistry== |
==Chemistry== |
||
Nusinersen is an antisense |
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.<ref name=USlabel/><ref name=Zanetta2014rev/> |
phosphate linkages are replaced with [[phosphorothioate]] linkages.<ref name=USlabel/><ref name=Zanetta2014rev/> Its chemical name is: |
||
Its chemical name is: |
|||
all-P-ambo-2'-O-<br>(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3'→5')-2'-O-<br>(2-methoxyethyl)-5-methyl-P-thiocytidylyl-(3'→5')-2'-O-<br>(2-methoxyethyl)-P-thioadenylyl-(3'→5')-2'-O-<br> |
all-P-ambo-2'-O-<br>(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3'→5')-2'-O-<br>(2-methoxyethyl)-5-methyl-P-thiocytidylyl-(3'→5')-2'-O-<br>(2-methoxyethyl)-P-thioadenylyl-(3'→5')-2'-O-<br> |
||
| Line 29: | Line 73: | ||
==History== |
==History== |
||
Nusinersen was [[drug discovery|discovered]] in a collaboration between Adrian Krainer at [[Cold Spring Harbor Laboratory]] and [[Ionis Pharmaceuticals]] (formerly called Isis Pharmaceuticals)<ref>{{cite journal|last1=Garber|first1=K|title=Big win possible for Ionis/Biogen antisense drug in muscular atrophy.|journal=Nature biotechnology|date=11 October 2016|volume=34|issue=10|pages=1002–1003|doi=10.1038/nbt1016-1002|pmid=27727217}}</ref><ref>{{cite journal|last1=Wadman|first1=Meredith|title=Updated: FDA approves drug that rescues babies with fatal neurodegenerative disease|journal=Science|date=23 December 2016|url=http://www.sciencemag.org/news/2016/12/novel-drug-rescues-babies-fatal-neurodegenerative-disease}}</ref><ref>{{cite news|last1=Offord|first1=Catherine|title=Oligonucleotide Therapeutics Near Approval|url=http://www.the-scientist.com/?articles.view/articleNo/47499/title/Oligonucleotide-Therapeutics-Near-Approval/|work=The Scientist|date=December 1, 2016}}</ref><ref>{{cite news|last1=Tarr|first1=Peter|title=CSHL FDA approval of life-saving SMA drug is hailed by its researcher-inventor at CSHL |url=http://www.cshl.edu/news-and-features/fda-approval-of-life-saving-sma-drug-is-hailed-by-its-researcher-inventor-at-cshl.html|work=Cold Spring Harbor Laboratory|date=24 December 2016}}</ref> |
Nusinersen was [[drug discovery|discovered]] in a collaboration between Adrian Krainer at [[Cold Spring Harbor Laboratory]] and [[Ionis Pharmaceuticals]] (formerly called Isis Pharmaceuticals).<ref>{{cite journal|last1=Garber|first1=K|title=Big win possible for Ionis/Biogen antisense drug in muscular atrophy.|journal=Nature biotechnology|date=11 October 2016|volume=34|issue=10|pages=1002–1003|doi=10.1038/nbt1016-1002|pmid=27727217}}</ref><ref>{{cite journal|last1=Wadman|first1=Meredith|title=Updated: FDA approves drug that rescues babies with fatal neurodegenerative disease|journal=Science|date=23 December 2016|url=http://www.sciencemag.org/news/2016/12/novel-drug-rescues-babies-fatal-neurodegenerative-disease}}</ref><ref>{{cite news|last1=Offord|first1=Catherine|title=Oligonucleotide Therapeutics Near Approval|url=http://www.the-scientist.com/?articles.view/articleNo/47499/title/Oligonucleotide-Therapeutics-Near-Approval/|work=The Scientist|date=December 1, 2016}}</ref><ref>{{cite news|last1=Tarr|first1=Peter|title=CSHL FDA approval of life-saving SMA drug is hailed by its researcher-inventor at CSHL |url=http://www.cshl.edu/news-and-features/fda-approval-of-life-saving-sma-drug-is-hailed-by-its-researcher-inventor-at-cshl.html|work=Cold Spring Harbor Laboratory|date=24 December 2016}}</ref> Preclinical work was done at [[University of Massachusetts]] funded by Cure SMA.<ref>{{cite web|title=Therapeutic Approaches|url=http://www.curesma.org/research/our-strategy/drug-discovery/therapeutic-approaches/#SMN2|website=www.curesma.org|publisher=Cure SMA|accessdate=1 January 2017}}</ref> |
||
Starting in 2012, Ionis partnered with [[Biogen]] on development and in 2015 Biogen acquired an exclusive license to the drug for a {{USD|75 million}} license fee, milestone payments up to {{USD|150 million}}, and tiered royalties thereafter; Biogen also was to finance all development subsequent to taking the license.<ref name="genengnews_2016">{{citation |url=http://www.genengnews.com/gen-news-highlights/biogen-shells-out-75m-to-develop-ionis-nusinersen-after-positive-phase-iii-results/81253027 |date=August 1, 2016 |title=Biogen Shells Out $75M to Develop Ionis' Nusinersen after Positive Phase III Results |work=Genetic Engineering News|author=}}</ref> The license to Biogen included licenses to intellectual property that Ionis had acquired from Cold Spring Harbor and U Mass.<ref>{{cite news|title=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|url=http://media.biogen.com/press-release/investor-relations/biogen-and-ionis-pharmaceuticals-report-nusinersen-meets-primary-en|work=Biogen|date=August 1, 2016}}</ref> |
|||
In November 2016 the [[new drug application]] was accepted under the FDA's [[Priority review (FDA)|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.<ref>{{cite web|url=http://smanewstoday.com/2016/11/01/regulatory-applications-sma-therapy-nusinersen-accepted-us-fda-eu-ema |title=Regulatory Applications for SMA Therapy Nusinersen Accepted in US, EU |publisher=BioNews Services, LLC|date= |accessdate=2016-11-15}}</ref><ref name="NYT_Spinraza_Thomas">{{cite news|url=http://www.nytimes.com/2016/12/30/business/spinraza-price.html |title=Costly Drug for Fatal Muscular Disease Wins F.D.A. Approval |author=Katie Thomas |date=December 30, 2016 |newspaper=New York Times}}</ref> |
In November 2016, the [[new drug application]] was accepted under the FDA's [[Priority review (FDA)|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.<ref>{{cite web|url=http://smanewstoday.com/2016/11/01/regulatory-applications-sma-therapy-nusinersen-accepted-us-fda-eu-ema |title=Regulatory Applications for SMA Therapy Nusinersen Accepted in US, EU |publisher=BioNews Services, LLC|date= |accessdate=2016-11-15}}</ref><ref name="NYT_Spinraza_Thomas">{{cite news|url=http://www.nytimes.com/2016/12/30/business/spinraza-price.html |title=Costly Drug for Fatal Muscular Disease Wins F.D.A. Approval |author=Katie Thomas |date=December 30, 2016 |newspaper=New York Times}}</ref> It was approved by the FDA in December 2016 as the first drug for SMA.<ref>{{Cite news|url=http://www.wsj.com/articles/surprise-drug-approval-is-holiday-gift-for-biogen-1482856447|title=Surprise Drug Approval Is Holiday Gift for Biogen|last=Grant|first=Charley|date=2016-12-27|work=|newspaper=Wall Street Journal|issn=0099-9660|access-date=2016-12-27|via=}}</ref> |
||
==Society and culture== |
==Society and culture== |
||
Nusinersen has [[orphan drug]] designation in the [[United States]] and the [[European Union]].<ref>{{cite web|title=Nusinersen|url=https://www.sps.nhs.uk/medicines/nusinersen/|publisher=UK Specialist Pharmacy Service|accessdate=31 December 2016}}</ref> |
Nusinersen has [[orphan drug]] designation in the [[United States]] and the [[European Union]].<ref>{{cite web|title=Nusinersen|url=https://www.sps.nhs.uk/medicines/nusinersen/|publisher=UK Specialist Pharmacy Service|accessdate=31 December 2016}}</ref> |
||
According to the ''[[New York Times]]'', Spinraza |
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."<ref name="NYT_Spinraza_Thomas" /> |
||
== References == |
== References == |
||
Revision as of 16:00, 1 January 2017
| Clinical data | |
|---|---|
| Trade names | Spinraza |
| Legal status | |
| Legal status |
|
| Identifiers | |
| |
| 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.
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
- ^ "Nusinersen". AdisInsight. Retrieved 1 January 2017.
- ^ a b c d e f g h "US Spinraza label" (PDF). FDA. December 2016.
- ^ . doi:10.1016/S0140-6736(16)31408-8.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help) - ^ 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.
- ^ . doi:10.1212/WNL.0000000000002445.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help) - ^ "Recommended INN: List 74" (PDF). WHO Drug Information. 29 (3). 2015.
- ^ 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.
- ^ Wadman, Meredith (23 December 2016). "Updated: FDA approves drug that rescues babies with fatal neurodegenerative disease". Science.
- ^ Offord, Catherine (December 1, 2016). "Oligonucleotide Therapeutics Near Approval". The Scientist.
- ^ 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.
- ^ "Therapeutic Approaches". www.curesma.org. Cure SMA. Retrieved 1 January 2017.
- ^ "Biogen Shells Out $75M to Develop Ionis' Nusinersen after Positive Phase III Results", Genetic Engineering News, August 1, 2016
- ^ "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.
- ^ "Regulatory Applications for SMA Therapy Nusinersen Accepted in US, EU". BioNews Services, LLC. Retrieved 2016-11-15.
- ^ a b Katie Thomas (December 30, 2016). "Costly Drug for Fatal Muscular Disease Wins F.D.A. Approval". New York Times.
- ^ Grant, Charley (2016-12-27). "Surprise Drug Approval Is Holiday Gift for Biogen". Wall Street Journal. ISSN 0099-9660. Retrieved 2016-12-27.
- ^ "Nusinersen". UK Specialist Pharmacy Service. Retrieved 31 December 2016.
 | This pharmacology-related article is a stub. You can help Wikipedia by expanding it. |