Identification

Name
Nusinersen
Accession Number
DB13161
Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Gene Therapies
Antisense oligonucleotides
Description

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.

Synonyms
Not Available
External IDs
ASO-10-27 / ISIS 396443 / ISIS SMNRx / ISIS-396443 / ISIS-SMNRx
Product Ingredients
IngredientUNIICASInChI Key
Nusinersen sodium4CHB7QQU1QNot AvailableNot applicable
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
SpinrazaSolution2.4 mgIntrathecalBiogen2017-08-29Not applicableCanada
SpinrazaInjection, solution2.4 mg/1mLIntrathecalBiogen2016-12-23Not applicableUs
Categories
UNII
5Z9SP3X666
CAS number
1258984-36-9

Pharmacology

Indication

Indicated for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients.

Associated Conditions
Pharmacodynamics

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.

TargetActionsOrganism
ASurvival motor neuron protein
antisense oligonucleotide
Human
Absorption

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%

Metabolism

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.

Half life

The mean terminal elimination half-life is estimated to be 135 to 177 days in CSF, and 63 to 87 days in plasma [Label].

Clearance

Slow clearance is observed

Toxicity

Single injection to adult monkeys produced apparent acute neurological impairment.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

General References
  1. 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. [PubMed:26823478]
  2. CENTER FOR DRUG EVALUATION AND RESEARCH [Link]
External Links
PubChem Substance
347911437
Wikipedia
Nusinersen
AHFS Codes
  • 92:92.00 — Other Miscellaneous Therapeutic Agents
FDA label
Download (531 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentSpinal Muscular Atrophy (SMA)3
1, 2CompletedTreatmentSpinal Muscular Atrophy (SMA)1
2Active Not RecruitingPreventionSpinal Muscular Atrophy (SMA)1
2Active Not RecruitingTreatmentSpinal Muscular Atrophy (SMA)1
2CompletedTreatmentSpinal Muscular Atrophy (SMA)1
3CompletedTreatmentSpinal Muscular Atrophy (SMA)2
3Enrolling by InvitationTreatmentSpinal Muscular Atrophy (SMA)1
Not AvailableAvailableNot AvailableInfantile-onset Spinal Muscular Atrophy / Infantile-onset Spinal Muscular Atrophy (SMA)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, solutionIntrathecal2.4 mg/1mL
SolutionIntrathecal2.4 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US6166197No2000-12-262017-12-26Us
US7101993No2006-09-052023-09-05Us
US8361977No2013-01-292030-05-27Us
US7838657No2010-11-232027-07-11Us
US8110560No2012-02-072025-12-05Us
US6210892No2001-04-032018-10-07Us
US8980853No2015-03-172030-11-24Us
US9717750No2017-08-012030-06-17Us
US9926559No2018-03-272034-01-09Us

Properties

State
Solid
Experimental Properties
Not Available

Taxonomy

Classification
Not classified

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antisense oligonucleotide
General Function
Not Available
Specific Function
Rna binding
Gene Name
SMN2
Uniprot ID
B4DP61
Uniprot Name
Survival motor neuron protein
Molecular Weight
24380.21 Da

Enzymes

Kind
Protein
Organism
Enterobacteria phage lambda
Pharmacological action
Yes
Actions
Substrate
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
exo
Uniprot ID
P03697
Uniprot Name
Exonuclease
Molecular Weight
25908.385 Da

Drug created on December 30, 2016 10:53 / Updated on November 20, 2018 01:01