Nusinersen is a medication used to treat spinal muscular atrophy.
- Brand Names
- Generic Name
- DrugBank Accession Number
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.
- Approved, Investigational
- Biologic Classification
- Gene Therapies
- External IDs
- ISIS 396443
- ISIS SMNRx
Indicated for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients.Accelerate your drug discovery research with the industry’s only fully connected ADMET dataset, ideal for:Accelerate your drug discovery research with our fully connected ADMET dataset
- Associated Conditions
- Contraindications & Blackbox Warnings
- Contraindications & Blackbox WarningsWith our commercial data, access important information on dangerous risks, contraindications, and adverse effects.Our Blackbox Warnings cover Risks, Contraindications, and Adverse Effects
Autopsy samples from patients (n=3) had higher levels of SMN2 messenger ribonucleic acid (mRNA) containing exon 7 in the thoracic spinal cord compared to untreated SMA infants. Cardiac Electrophysiology: In 121 patients with spinal muscular atrophy who received either nusinersen or sham-control, QTcF values >500 ms and change from baseline values >60 ms were observed in 5% of patients receiving nusinersen. Compared to the sham-control, there was no increase in the incidence of cardiac adverse reactions associated with delayed ventricular repolarization in patients treated with nusinersen.
- Mechanism of action
Nusinersen is a survival motor neuron-2 (SMN2)-directed antisense oligonucleotide (ASO) designed to treat SMA caused by mutations in chromosome 5q that lead to SMN protein deficiency. Using in vitro assays and studies in transgenic animal models of SMA, nusinersen was shown to increase exon 7 inclusion in SMN2 messenger ribonucleic acid (mRNA) transcripts and production of full-length SMN protein. Nusinersen acts to replace the SMN protein deficit which causes SMA, by increasing the splicing efficiency of the SMN2 pre- mRNA. More specifically, nusinersen in an 18-mer 2’-MOE phosphorothioate antisense oligonucleotide that acts as a splice-altering oligonucleotide. Nusinersen was designed to pair with a specific target sequence on the SMN2 pre-mRNA to displace heterogeneous ribonucleoproteins (hnRNPs) at the intronic splice silencing site-1 (ISS-1) between exons 7 and 8 to allow for more complete translation of SMN protein from the paralogous gene SMN2. Further reinforcing this concept, SMA phenotype is closely tied to SMN2 copy number. SMN2 serves to produce SMN protein, however at a greatly reduced rate because of differential splicing caused by the binding of the hnRNPs at the ISS-1.
Target Actions Organism ASurvival motor neuron proteinantisense oligonucleotide Humans
Intrathecal injection of nusinersen into the cerebrospinal fluid (CSF) allows it to be distributed from the CSF to the target central nervous system (CNS) tissues. Following intrathecal administration, trough plasma concentrations of nusinersen were relatively low, compared to the trough CSF concentration. Median plasma Tmax values ranged from 1.7 to 6.0 hours. Mean plasma Cmax and AUC values increased approximately dose-proportionally up to a dose of 12 mg.
- Volume of distribution
CSF: 0.4 L Plasma: 29 L
- Protein binding
CSF: < 25% Plasma: >94%
Nusinersen is metabolized via exonuclease (3’- and 5’)-mediated hydrolysis primarily at the 3' end of the oligonucleotide. It is not a substrate for, or inhibitor or inducer of CYP450 enzymes. N-1 metabolites of the drug can be detected in the cerebrospinal fluid while N-1,2,3 metabolites can be predominantly detected in the plasma 2.
- Route of elimination
Excreted by the kidney as chain-shortened oligonucleotides, which are not considered pharmacologically active.
The mean terminal elimination half-life is estimated to be 135 to 177 days in CSF, and 63 to 87 days in plasma Label.
Slow clearance is observed
- Adverse Effects
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Single injection to adult monkeys produced apparent acute neurological impairment.
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.Not Available
- Food Interactions
- No interactions found.
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- Product Ingredients
Ingredient UNII CAS InChI Key Nusinersen sodium 4CHB7QQU1Q Not Available Not applicable
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Spinraza Solution 2.4 mg / mL Intrathecal Biogen 2017-08-29 Not applicable Spinraza Injection, solution 2.4 mg/1mL Intrathecal Biogen 2016-12-23 Not applicable Spinraza Injection, solution 12 mg Intrathecal Biogen Netherlands B.V. 2020-12-16 Not applicable
- ATC Codes
- M09AX07 — Nusinersen
- Drug Categories
- Not classified
- Affected organisms
- Humans and other mammals
- CAS number
- General References
- Hache M, Swoboda KJ, Sethna N, Farrow-Gillespie A, Khandji A, Xia S, Bishop KM: Intrathecal Injections in Children With Spinal Muscular Atrophy: Nusinersen Clinical Trial Experience. J Child Neurol. 2016 Jun;31(7):899-906. doi: 10.1177/0883073815627882. Epub 2016 Jan 27. [Article]
- CENTER FOR DRUG EVALUATION AND RESEARCH [Link]
- FDA Approved Drug Products: Spinraza (nusinersen) for intrathecal injection [Link]
- AHFS Codes
- 92:18.00 — Antisense Oligonucleotides
- FDA label
- Download (531 KB)
- Clinical Trials
Phase Status Purpose Conditions Count 4 Recruiting Treatment Muscular Atrophy, Spinal 1 3 Active Not Recruiting Treatment Spinal Muscular Atrophy (SMA) 1 3 Completed Treatment Spinal Muscular Atrophy (SMA) 1 3 Enrolling by Invitation Treatment Muscular Atrophy, Spinal 1 3 Terminated Treatment Spinal Muscular Atrophy (SMA) 1 2 Active Not Recruiting Prevention Spinal Muscular Atrophy (SMA) 1 2 Completed Treatment Spinal Muscular Atrophy (SMA) 1 2 Terminated Treatment Spinal Muscular Atrophy (SMA) 1 2, 3 Recruiting Treatment Muscular Atrophy, Spinal 1 1 Completed Treatment Spinal Muscular Atrophy (SMA) 3
- Not Available
- Not Available
- Dosage Forms
Form Route Strength Injection, solution Intrathecal 12 mg Injection, solution Intrathecal 2.4 mg/1mL Injection, solution Intrathecal; Parenteral Solution Intrathecal 2.4 mg / mL Solution Intrathecal 2.4 mg
- Not Available
Patent Number Pediatric Extension Approved Expires (estimated) Region US6166197 No 2000-12-26 2017-12-26 US7101993 No 2006-09-05 2023-09-05 US8361977 No 2013-01-29 2030-05-27 US7838657 No 2010-11-23 2027-07-11 US8110560 No 2012-02-07 2025-12-05 US6210892 No 2001-04-03 2018-10-07 US8980853 No 2015-03-17 2030-11-24 US9717750 No 2017-08-01 2030-06-17 US9926559 No 2018-03-27 2034-01-09 US10266822 No 2019-04-23 2025-12-05 US10436802 No 2019-10-08 2035-09-11
- Experimental Properties
- Not Available
- Enterobacteria phage lambda
- Pharmacological action
- General Function
- Metal ion binding
- Specific Function
- Facilitates phage DNA recombination through the double-strand break repair (DSBR) and single-strand annealing pathways. Also important for the late, rolling-circle mode of lambda DNA replication.
- Gene Name
- Uniprot ID
- Uniprot Name
- Molecular Weight
- 25908.385 Da
Drug created on December 30, 2016 17:53 / Updated on June 13, 2021 16:25