FDA Approves SPINRAZA (Nusinersen) for the Treatment of Spinal Muscular Atrophy in Pediatric and Adult Patients
On December 23, 2016, the U.S. Food and Drug Administration (FDA) approved SPINRAZA (nusinersen), the first drug approved for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients. The approved recommended dosage of SPINRAZA injection is 12 mg (5 mL) per intrathecal administration. SPINRAZA treatment is initiated with 4 loading doses, the first 3 administered at 14-day intervals, followed by the 4th administered 30 days after the 3rd loading dose. A maintenance dose of SPINRAZA should be administered once every 4 months thereafter. SPINRAZA is administered intrathecally over 1 to 3 minutes by, or under the direction of, healthcare professionals experienced in performing lumbar punctures. Important preparation and administration instructions can be found in the full prescribing information at the link below.
Mechanism of Action (MOA), General Pharmacokinetics (PK), and Pharmacodynamics (PD)
MOA: SPINRAZA is an antisense oligonucleotide designed to treat SMA caused by mutations in chromosome 5q that lead to survival motor neuron protein deficiency.
Absorption: Median plasma Tmax values ranged from 1.7 to 6.0 hours following intrathecal administration.
Dose Proportionality: Mean plasma Cmax and AUC values increased approximately dose-proportionally up to a dose of 12 mg.
Distribution: SPINRAZA administered intrathecally was distributed within the CNS and peripheral tissues, such as skeletal muscle, liver, and kidney.
Elimination: The mean terminal elimination half-life is estimated to be 135 to 177 days in CSF, and 63 to 87 days in plasma.
Metabolism: Nusinersen is metabolized via exonuclease (3’- and 5’)-mediated hydrolysis.
Excretion: 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.
Drug Interaction Potential
Nusinersen is not a substrate for, or inhibitor or inducer of CYP450 enzymes.
Efficacy and Safety
The efficacy of SPINRAZA was demonstrated in a double-blind, sham-procedure controlled clinical trial of symptomatic infantile-onset SMA patients ≤ 7 months of age at the time of first dose. In an interim analysis, a greater percentage of patients achieved a motor milestone response in the SPINRAZA group, 21/52 (40%) compared to the sham-control group, 0/30 (0%), p<0 .0001.="" 15="" 30="" 3="" 40="" 42="" 8="" a="" abilities="" able="" age="" ages.="" ages="" and="" at="" baseline="" be="" by="" clinical="" conducted="" days="" do="" dose.="" dose="" expected="" first="" for="" from="" function="" had="" improvement="" in="" infantile-onset="" less="" lost="" maintained="" milestones="" motor="" nbsp="" of="" on="" open-label="" or="" otherwise="" p="" patients.="" patients="" presymptomatic="" ranged="" scale="" sham-control="" sit="" sma="" so="" some="" spinraza="" stand="" supported="" survived="" symptomatic="" than="" the="" these="" they="" time="" to="" trial="" trials="" unassisted="" uncontrolled="" unexpected="" vs.="" walk="" was="" were="" when="" who="" with="" worsening="" would="" years="">
In the controlled study, the most common adverse reactions that occurred in at least 20% of SPINRAZA-treated patients (n=80) and occurred at least 5% more frequently than in control patients (n=41) were lower respiratory infection (43%), upper respiratory infection (39%), and constipation (30%). Serious adverse reactions of atelectasis were more frequent in SPINRAZA-treated patients (14%) than in control patients (5%).
Coagulation abnormalities, thrombocytopenia, and renal toxicity have been observed after administration of some antisense oligonucleotides. Therefore, conduct platelet count, prothrombin time, activated partial thromboplastin time, and quantitative spot urine protein testing at baseline and prior to each dose of SPINRAZA and as clinically needed.
Full prescribing information is available at http://go.usa.gov/x92FZ.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/
The Office of Clinical Pharmacology (OCP) regulatory reviews for new drugs or biologics are often available for viewing shortly following approval at the website http://go.usa.gov/x92FT.
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This burst was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.
FDA/Center for Drug Evaluation and Research (CDER)
Office of Translational Sciences
Office of Clinical Pharmacology
Email: ocp@fda.hhs.gov
Office of Translational Sciences
Office of Clinical Pharmacology
Email: ocp@fda.hhs.gov
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