ヌシネルセンナトリウム
Nusinersen Sodium
C234H323N61Na17O128P17S17 : 7500.89
[1258984-36-9 , ヌシネルセン]
Nusinersen sodium
C234H323N61O128P17S17.17Na, 7500.8854
UNII 4CHB7QQU1Q
ISIS 396443
Nusinersen sodium was approved by the US Food and Drug Administration (FDA) on Dec 23, 2016, and approved by the European Medicines Agency’s (EMA) on May 30, 2017, and approved by Pharmaceuticals and Medical Devices Agency of Japan (PMDA) on July 3, 2017.
JAPAN APPROVAL
| 2017/7/3 | Nusinersen sodium | Spinraza | Biogen Japan |
An antisense oligonucleotide that induces survival motor neuron (SMN) protein expression, it was approved by the U.S. FDA in December, 2016 as Spinraza for the treatment of children and adults with spinal muscular atrophy (SMA). It is adminstrated as direct intrathecal injection.
FREE FORM CAS: 1258984-36-9
CAS1258984-36-9
MFC234H340N61O128P17S17
ISIS-396443, ISIS-SMNRx, IONIS-SMNRx
RNA, (2′-0-(2-methoxyethyi))(p-thio)(m5u-c-a-c-m5u-m5u-m5u-c-a-m5ua- a-m5 u-g-c-m5u-g-g)
RNA, (2′-0-(2-METHOXYETHYI))(P-THIO)(M5U-C-A-C-M5U-M5U-M5U-C-A-M5UA- A-M5 U-G-C-M5U-G-G)
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
ISIS-SMNRx is a drug that is designed to modulate the splicing of the SMN2 gene to significantly increase the production of functional SMN protein. The US regulatory agency has granted Orphan Drug Designation with Fast Track Status to nusinersen for the treatment of patients with SMA. The European regulatory agency has granted Orphan Drug Designation to nusinersen for the treatment of patients with SMA.
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 drugdesignation in the United States and the European Union.[5]
FDA
FDA approves first drug for spinal muscular atrophy
New therapy addresses unmet medical need for rare disease
The U.S. Food and Drug Administration today approved Spinraza (nusinersen), the first drug approved to treat children and adults with spinal muscular atrophy (SMA), a rare and often fatal genetic disease affecting muscle strength and movement. Spinraza is an injection administered into the fluid surrounding the spinal cord.
For Immediate Release
December 23, 2016
The U.S. Food and Drug Administration today approved Spinraza (nusinersen), the first drug approved to treat children and adults with spinal muscular atrophy (SMA), a rare and often fatal genetic disease affecting muscle strength and movement. Spinraza is an injection administered into the fluid surrounding the spinal cord.
“There has been a long-standing need for a treatment for spinal muscular atrophy, the most common genetic cause of death in infants, and a disease that can affect people at any stage of life,” said Billy Dunn, M.D., director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “As shown by our suggestion to the sponsor to analyze the results of the study earlier than planned, the FDA is committed to assisting with the development and approval of safe and effective drugs for rare diseases and we worked hard to review this application quickly; we could not be more pleased to have the first approved treatment for this debilitating disease.”
SMA is a hereditary disease that causes weakness and muscle wasting because of the loss of lower motor neurons controlling movement. There is wide variability in age of onset, symptoms and rate of progression. Spinraza is approved for use across the range of spinal muscular atrophy patients.
The FDA worked closely with the sponsor during development to help design and implement the analysis upon which this approval was based. The efficacy of Spinraza was demonstrated in a clinical trial in 121 patients with infantile-onset SMA who were diagnosed before 6 months of age and who were less than 7 months old at the time of their first dose. Patients were randomized to receive an injection of Spinraza, into the fluid surrounding the spinal cord, or undergo a mock procedure without drug injection (a skin prick). Twice the number of patients received Spinraza compared to those who underwent the mock procedure. The trial assessed the percentage of patients with improvement in motor milestones, such as head control, sitting, ability to kick in supine position, rolling, crawling, standing and walking.
The FDA asked the sponsor to conduct an interim analysis as a way to evaluate the study results as early as possible; 82 of 121 patients were eligible for this analysis. Forty percent of patients treated with Spinraza achieved improvement in motor milestones as defined in the study, whereas none of the control patients did.
Additional open-label uncontrolled clinical studies were conducted in symptomatic patients who ranged in age from 30 days to 15 years at the time of the first dose, and in presymptomatic patients who ranged in age from 8 days to 42 days at the time of first dose. These studies lacked control groups and therefore were more difficult to interpret than the controlled study, but the findings appeared generally supportive of the clinical efficacy demonstrated in the controlled clinical trial in infantile-onset patients.
The most common side effects found in participants in the clinical trials on Spinraza were upper respiratory infection, lower respiratory infection and constipation. Warnings and precautions include low blood platelet count and toxicity to the kidneys (renal toxicity). Toxicity in the nervous system (neurotoxicity) was observed in animal studies.
The FDA granted this application fast track designation and priority review. The drug also received orphan drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.
The sponsor is receiving a rare pediatric disease priority review voucher under a program intended to encourage development of new drugs and biologics for the prevention and treatment of rare pediatric diseases. A voucher can be redeemed by a sponsor at a later date to receive priority review of a subsequent marketing application for a different product. This is the eighth rare pediatric disease priority review voucher issued by the FDA since the program began.
Spinraza is marketed by Biogen of Cambridge, Massachusetts and was developed by Ionis Pharmaceuticals of Carlsbad, California.
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. 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.[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
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]
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).[3]
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.[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 patients under 18 years old.[23]
In January 2018 public funding of Spinraza was approved in Israel.
Nusinersen (formerly, IONIS-SMNRx, ISIS-SMNRx), intended to be marketed as Spinraza,[1] is an investigational drug for spinal muscular atrophy developed by Ionis Pharmaceuticals and Biogen with financial support from SMA Foundation and Cure SMA. It is a proprietary antisense oligonucleotide that modulates alternate splicing of the SMN2 gene, functionally converting it into SMN1 gene.
The drug is administered directly to the central nervous system using intrathecal injection once every 3–4 months.
Nusinersen has orphan drug designation in the United States and the European Union.[2]
In August 2016, a phase III trial in type 1 SMA patients was ended early due to positive efficacy data, with Biogen deciding to file for regulatory approval for the drug.[3]Consequently, the company submitted a New Drug Application to the FDA in September 2016[4] and a marketing authorisation application to the European Medicines Agency, under the centralised procedure,[5] in the following month. The company also announced an expanded access programme of nusinersen in type 1 SMA in selected countries.
In November 2016, a phase III clinical trial in type 2 SMA patients was halted after an interim analysis indicated the drug’s efficacy also in this SMA type.[6]
P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.
References
- ^ Jump up to:a b “International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 74” (PDF). World Health Organization. pp. 413–14. Retrieved 13 March 2017.
- ^ Jump up to:a b c d e f g h i j k “Nusinersen US Label” (PDF). FDA. December 2016. For updates see FDA index page for NDA 209531
- ^ Jump up to:a b “Nusinersen”. AdisInsight. Retrieved 1 January 2017.
- Jump up^ Ottesen, Eric W. (2017-01-01). “ISS-N1 makes the first FDA-approved drug for spinal muscular atrophy”. Translational Neuroscience. 8 (1): 1–6. doi:10.1515/tnsci-2017-0001. ISSN 2081-6936. PMC 5382937
![Freely accessible]( "Freely accessible")
. PMID 28400976. - Jump up^ “Nusinersen”. UK Specialist Pharmacy Service. Retrieved 31 December 2016.
- ^ Jump up to: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.
- Jump up^ 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.
- Jump up^ Wadman, Meredith (23 December 2016). “Updated: FDA approves drug that rescues babies with fatal neurodegenerative disease”. Science.
- Jump up^ Offord, Catherine (December 1, 2016). “Oligonucleotide Therapeutics Near Approval”. The Scientist.
- Jump up^ 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.
- Jump up^ “Therapeutic Approaches”. http://www.curesma.org. Cure SMA. Retrieved 1 January 2017.
- Jump up^ “Biogen Shells Out $75M to Develop Ionis’ Nusinersen after Positive Phase III Results”, Genetic Engineering News, August 1, 2016
- Jump up^ “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.
- Jump up^ “Regulatory Applications for SMA Therapy Nusinersen Accepted in US, EU”. BioNews Services, LLC. Retrieved 2016-11-15.
- ^ Jump up to:a b Katie Thomas (December 30, 2016). “Costly Drug for Fatal Muscular Disease Wins F.D.A. Approval”. New York Times.
- Jump up^ Grant, Charley (2016-12-27). “Surprise Drug Approval Is Holiday Gift for Biogen”. Wall Street Journal. ISSN 0099-9660. Retrieved 2016-12-27.
- Jump up^ “Spinraza (nusinersen)”. European Medicines Agency. Retrieved 2017-10-27.
- Jump up^ “Biogen’s SPINRAZA
![™]()
(nusinersen) Receives Notice of Compliance from Health Canada for the Treatment of 5q Spinal Muscular Atrophy (SMA)”. Cision. 2017-07-04. - Jump up^ “Biogen to launch Spinraza in Japan soon”. 2017-07-10.
- Jump up^ “Remédio inédito para atrofia muscular espinhal é liberado” (in Portuguese). 2017-08-25.
- Jump up^ “Spinraza – Zulassung nun auch in der Schweiz” (in German). SMA Schweiz. 2017-09-30.
- Jump up^ Medicinrådet siger nej til lægemiddel til børn med muskelsvind: ‘Urimeligt’ dyrt Retrieved October 13 2017.
- ^ Jump up to:a b Dette er uforståelig og utrolig urettferdig
(nusinersen) Receives Notice of Compliance from Health Canada for the Treatment of 5q Spinal Muscular Atrophy (SMA)”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.
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| Clinical data | |
|---|---|
| Trade names | Spinraza |
| Synonyms | IONIS-SMNRx, ISIS-SMNRx |
| AHFS/Drugs.com | Multum Consumer Information |
| License data | |
| Routes of administration |
Injection into cerebrospinal fluid |
| ATC code | |
| Legal status | |
| Legal status |
|
| Pharmacokinetic data | |
| Metabolism | Exonuclease (3’- and 5’)-mediated hydrolysis |
| Biological half-life | 135–177 days (in CSF), 63–87 days (in plasma) |
| Identifiers | |
| CAS Number | |
| PubChem CID | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| KEGG | |
| Chemical and physical data | |
| Formula | C234H323N61Na17O128P17S17[2] |
| Molar mass | 7501 Da[2] |
| 3D model (JSmol) | |
////////////////Nusinersen sodium, Spinraza, ヌシネルセンナトリウム, FDA 2016, EU 2017, JAPAN 2017
CC1=CN(C(=O)NC1=O)C2C(C(C(O2)CO)OP(=S)(O)OCC3C(C(C(O3)N4C=C(C(=NC4=O)N)C)OCCOC)OP(=S)(O)OCC5C(C(C(O5)N6C=NC7=C6N=CN=C7N)OCCOC)OP(=S)(O)OCC8C(C(C(O8)N9C=C(C(=NC9=O)N)C)OCCOC)OP(=S)(O)OCC1C(C(C(O1)N1C=C(C(=O)NC1=O)C)OCCOC)OP(=S)(O)OCC1C(C(C(O1)N1C=C(C(=O)NC1=O)C)OCCOC)OP(=S)(O)OCC1C(C(C(O1)N1C=C(C(=O)NC1=O)C)OCCOC)OP(=S)(O)OCC1C(C(C(O1)N1C=C(C(=NC1=O)N)C)OCCOC)OP(=S)(O)OCC1C(C(C(O1)N1C=NC2=C1N=CN=C2N)OCCOC)OP(=S)(O)OCC1C(C(C(O1)N1C=C(C(=O)NC1=O)C)OCCOC)OP(=S)(O)OCC1C(C(C(O1)N1C=NC2=C1N=CN=C2N)OCCOC)OP(=S)(O)OCC1C(C(C(O1)N1C=NC2=C1N=CN=C2N)OCCOC)OP(=S)(O)OCC1C(C(C(O1)N1C=C(C(=O)NC1=O)C)OCCOC)OP(=S)(O)OCC1C(C(C(O1)N1C=NC2=C1N=C(NC2=O)N)OCCOC)OP(=S)(O)OCC1C(C(C(O1)N1C=C(C(=NC1=O)N)C)OCCOC)OP(=S)(O)OCC1C(C(C(O1)N1C=C(C(=O)NC1=O)C)OCCOC)OP(=O)(OCC1C(C(C(O1)N1C=NC2=C1N=C(NC2=O)N)OCCOC)OP(=S)(O)OCC1C(C(C(O1)N1C=NC2=C1N=C(NC2=O)N)OCCOC)O)S)OCCOC