SPINRAZA-Antisense Oligonucleotide For Treatment of Spinal Muscular Atrophy (SMA)

SPINRAZA (nusinersen) injection, for intrathecal use

Nusinersen is a modified antisense oligonucleotide, where 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. Nusinersen binds to a specific sequence in the intron downstream of exon 7 of the SMN2 transcript.

The molecular formula of SPINRAZA is C234H323N61O128P17S17Na17 and the molecular weight is 7501.0 daltons.

Mechanism of Action
 SPINRAZA is an 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, SPINRAZA was shown to increase exon 7 inclusion in SMN2 messenger ribonucleic acid (mRNA) transcripts and production of full-length SMN protein. 

Intrathecal injection of SPINRAZA into the cerebrospinal fluid (CSF) allows nusinersen 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. 
Autopsy data from patients (n=3) showed that SPINRAZA administered intrathecally was distributed within the CNS and peripheral tissues, such as skeletal muscle, liver, and kidney. 
Nusinersen is metabolized via exonuclease (3’- and 5’)-mediated hydrolysis and is not a substrate for, or inhibitor or inducer of CYP450 enzymes.
Excretion The mean terminal elimination 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 chain-shortened metabolites. At 24 hours, only 0.5% of the administered dose was recovered in the urine.

Initial U.S. Approval: 2016

SPINRAZA is a survival motor neuron-2 (SMN2)-directed antisense oligonucleotide indicated for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients

  • SPINRAZA is administered intrathecally 
  • The recommended dosage is 12 mg (5 mL) per administration 
  • Initiate SPINRAZA treatment with 4 loading doses: the first three loading doses should be administered at 14-day intervals; the 4 th loading dose should be administered 30 days after the 3 rd dose. A maintenance dose should be administered once every 4 months thereafter.
Important Preparation and Administration Instructions
  • Allow to warm to room temperature prior to administration
  • Administer within 4 hours of removal from vial 
  • Prior to administration, remove 5 mL of cerebrospinal fluid
  • Administer as intrathecal bolus injection over 1 to 3 minutes
Laboratory Testing and Monitoring to Assess Safety
  • At baseline and prior to each dose, obtain a platelet count, coagulation laboratory testing, and quantitative spot urine protein testing
  • Injection: 12 mg/5 mL (2.4 mg/mL) in a single-dose vial

  • Thrombocytopenia and Coagulation Abnormalities: Increased risk for bleeding complications; testing required at baseline and before each dose and as clinically needed.
  • Renal Toxicity: Quantitative spot urine protein testing required at baseline and prior to each dose
The most common adverse reactions that occurred in at least 20% of SPINRAZA-treated patients and occurred at least 5% more frequently than in control patients were:
  •  lower respiratory infection and constipation in patients with infantile-onset SMA
  •  pyrexia, headache, vomiting, and back pain in patients with lateronset SMA 
Reference: FDA product Inserts