Introduction
Spinraza (nusinersen) is a revolutionary antisense oligonucleotide therapy developed by Biogen for the treatment of spinal muscular atrophy (SMA). Approved by the FDA in December 2016, it represents the first disease-modifying therapy for this previously untreatable genetic neuromuscular disorder. Spinraza works by targeting the underlying molecular mechanism of SMA, offering hope to patients across the SMA spectrum.
Mechanism of Action
Spinraza is an antisense oligonucleotide that modifies pre-mRNA splicing of the survival motor neuron 2 (SMN2) gene. In SMA, patients have mutations in the SMN1 gene but retain copies of the SMN2 gene. However, SMN2 primarily produces truncated, non-functional SMN protein due to alternative splicing that excludes exon 7.
Nusinersen binds to a specific site in SMN2 pre-mRNA, promoting inclusion of exon 7 during splicing. This results in increased production of full-length, functional SMN protein, addressing the fundamental protein deficiency in motor neurons that causes SMA.
Indications
Spinraza is indicated for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients. This includes:
- SMA Type 1 (infantile-onset, Werdnig-Hoffmann disease)
- SMA Type 2 (intermediate form)
- SMA Type 3 (juvenile-onset, Kugelberg-Welander disease)
- Presymptomatic SMA patients with genetic diagnosis
- Adult-onset SMA
Dosage and Administration
Loading Dose: 12 mg per administration- First three doses administered at 14-day intervals
- Fourth loading dose administered 30 days after the third dose
- Administered via intrathecal injection by qualified healthcare professionals
- Requires lumbar puncture procedure
- Should be diluted in preservative-free 0.9% Sodium Chloride Injection, USP
- Renal impairment: Use with caution; no specific dosage adjustment recommendations
- Hepatic impairment: No dosage adjustment necessary
- Pediatric patients: Same dosing as adults based on clinical trials
Pharmacokinetics
Absorption: Administered directly into the cerebrospinal fluid (CSF) via intrathecal injection, bypassing systemic absorption barriers. Distribution:- Widely distributed throughout the CNS
- CSF concentrations substantially higher than plasma concentrations
- Limited systemic exposure with intrathecal administration
- Half-life in CSF: Approximately 135-177 days
- Elimination primarily via urinary excretion
- Systemic clearance: Approximately 12 L/hr
Contraindications
- History of serious hypersensitivity reaction to nusinersen or any component of the formulation
- Active bacterial meningitis or other CNS infections (relative contraindication until resolved)
Warnings and Precautions
Thrombocytopenia and Coagulation Abnormalities:- Increased risk of bleeding complications
- Monitor platelet counts before dosing and periodically during treatment
- Cases of renal toxicity, including potentially fatal glomerulonephritis, have been reported
- Monitor urinary protein and renal function
- May occur during treatment; usually asymptomatic
- Lumbar puncture-related complications including post-dural puncture headache, back pain, vomiting, and meningitis
- Reported in clinical trials; typically resolves with symptomatic treatment
Drug Interactions
Anticoagulants and Antiplatelet Agents:- Increased bleeding risk when combined with Spinraza due to thrombocytopenia risk
- Consider temporary discontinuation before procedures
- Potential additive renal toxicity when combined with other nephrotoxic agents
- NSAIDs, SSRIs, and other drugs affecting platelet function may increase bleeding risk
Adverse Effects
Most Common Adverse Reactions (≥20% of patients):- Upper respiratory tract infection
- Lower respiratory tract infection
- Constipation
- Headache
- Back pain
- Post-lumbar puncture syndrome
- Thrombocytopenia (5%)
- Coagulation abnormalities
- Renal toxicity (including glomerulonephritis)
- Aseptic meningitis
- Increased CSF protein
- Decreased platelet count
- Increased urinary protein
- Elevated transaminases
Monitoring Parameters
Before Each Dose:- Complete blood count with platelet assessment
- Coagulation parameters (PT/INR, PTT)
- Urinalysis for proteinuria
- Renal function tests (serum creatinine, BUN)
- Neurological assessment
- Regular monitoring of platelet counts (baseline, before each dose, and periodically)
- Renal function monitoring every 4-6 months
- Neurological function assessment using appropriate SMA scales
- Monitoring for signs of bleeding or bruising
- Vital signs during and after lumbar puncture
- Signs of post-dural puncture complications
Patient Education
Treatment Expectations:- Explain that treatment requires regular intrathecal injections
- Discuss potential benefits and realistic expectations
- Emphasize the importance of adherence to the dosing schedule
- Educate about signs of bleeding (unusual bruising, bleeding gums, blood in urine/stool)
- Report any neurological changes, headaches, or back pain
- Monitor for signs of infection
- Discuss what to expect during lumbar puncture procedure
- Post-procedure care instructions
- Hydration importance to prevent post-lumbar puncture headache
- Importance of regular monitoring appointments
- Coordination with multidisciplinary care team
- Genetic counseling for family members
References
1. FDA prescribing information: Spinraza (nusinersen) injection. December 2016. 2. Finkel RS, Mercuri E, Darras BT, et al. Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy. N Engl J Med. 2017;377(18):1723-1732. 3. Mercuri E, Darras BT, Chiriboga CA, et al. Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy. N Engl J Med. 2018;378(7):625-635. 4. Chiriboga CA, Swoboda KJ, Darras BT, et al. Results from a phase 1 study of nusinersen (ISIS-SMN(Rx)) in children with spinal muscular atrophy. Neurology. 2016;86(10):890-897. 5. Aragon-Gawinska K, Seferian AM, Daron A, et al. Nusinersen in patients older than 7 months with spinal muscular atrophy type 1: a cohort study. Neurology. 2018;91(13):e1242-e1247. 6. ClinicalTrials.gov: ENDEAR, CHERISH, and NURTURE studies.