What are the latest updates on onasemnogene abeparvovec (Zolgensma) for the treatment of spinal muscular atrophy (SMA)?

Latest Updates on Onasemnogene Abeparvovec (Zolgensma) for Spinal Muscular Atrophy

Onasemnogene abeparvovec remains the only FDA-approved one-time gene replacement therapy for pediatric patients less than 2 years of age with SMA and bi-allelic SMN1 mutations, with recent 2025 FDA label updates emphasizing critical liver monitoring protocols and corticosteroid management strategies. 1

Current FDA-Approved Indication and Limitations

• Approved for: Pediatric patients less than 2 years of age with SMA and bi-allelic mutations in the SMN1 gene 1
• Not evaluated in: Patients with advanced SMA (complete paralysis of limbs, permanent ventilator dependence) 1
• Repeat administration: Safety and effectiveness have not been established 1

Mechanism and Clinical Rationale

Onasemnogene abeparvovec delivers a functional copy of the SMN gene via AAV9 vector, replacing the malfunctioning survival motor neuron gene with a single intravenous infusion 2. This one-time treatment has demonstrated the ability to halt disease progression and enhance patient prognosis by restoring motor neuron function 2.

Updated Dosing and Administration Protocol (2025)

Dosing

• Standard dose: 1.1 × 10^14 vector genomes per kg body weight 1
• Administration: Single-dose intravenous infusion over 60 minutes 1
• Postpone treatment: If active infection present until resolved and patient clinically stable 1

Critical Corticosteroid Protocol (Updated February 2025)

• Start: One day prior to infusion 1
• Initial dose: Systemic corticosteroids equivalent to oral prednisolone 1 mg/kg/day for 30 days 1
• At day 30: Check liver function by clinical examination and laboratory testing 1
  • If unremarkable: Taper gradually over 28 days 1
  • If abnormalities persist: Continue 1 mg/kg/day until unremarkable, then taper over 28+ days 1
  • If abnormalities persist ≥2× ULN after 30 days: Promptly consult pediatric gastroenterologist or hepatologist 1
• Never stop corticosteroids abruptly 1

Boxed Warning: Serious Liver Injury (Updated 2025)

Cases of acute liver failure with fatal outcomes have been reported. 1

Pre-Treatment Assessment

• Assess liver function in all patients by clinical examination and laboratory testing before infusion 1
• Patients with preexisting liver impairment are at higher risk 1

Post-Treatment Monitoring

• Monitor liver function for at least 3 months after infusion 1
• Continue monitoring at other times as clinically indicated 1

Additional Safety Warnings (Updated 2024-2025)

Thrombocytopenia (Updated 2025)

• Monitor platelet counts before infusion 1
• Monitor at least weekly for first month 1
• Monitor every other week for second and third months or until return to baseline 1

Thrombotic Microangiopathy (TMA) (Updated 2024)

• Can result in life-threatening or fatal outcomes 1
• If clinical signs, symptoms, or laboratory findings occur: Immediately consult pediatric hematologist and/or pediatric nephrologist 1

Elevated Troponin I (Updated 2025)

• Increases in cardiac troponin I levels have occurred following infusion 1
• Consider cardiac evaluation after infusion and consult cardiologist as needed 1

Clinical Efficacy Data

STR1VE Phase 3 Trial Results

• Independent sitting (≥30 seconds): 59% (13/22 patients) achieved at 18 months vs. 0% in untreated cohort (p<0.0001) 3
• Survival without permanent ventilation: 91% (20/22 patients) at 14 months vs. 26% in untreated cohort (p<0.0001) 3

Speed of Motor Function Improvement

Recent pooled analysis (2025) of START, STR1VE-US, and STR1VE-EU trials (n=67) demonstrated rapid motor gains: 4

• 1 month post-dose: Mean CHOP INTEND increase of 7.0 points 4
• 2 months post-dose: Mean increase of 9.7 points 4
• 3 months post-dose: Mean increase of 11.8 points 4
• 6 months post-dose: 91.5% (54/59) achieved clinically significant ≥4-point improvement; mean score 44.3 points (baseline: 29.3 points) 4

Real-World Experience and Practical Considerations

Weight-Based Risk Stratification

Australian real-world data (2022) showed significantly greater incidence of moderate/severe transaminitis in infants weighing ≥8 kg compared to <8 kg (p<0.05) 5. This necessitates more intensive monitoring in heavier infants receiving higher vector loads 5.

Prolonged Corticosteroid Duration

Real-world practice shows mean prednisolone duration of 87.5 days (range 57-274 days), substantially longer than initial protocols 5. Proactive clinical and laboratory surveillance is essential for individualized risk management 5.

Combination Therapy Experience

• 90.4% (19/21) of treated children in Australian cohort had previous nusinersen 5
• 76% (16/21) gained at least one WHO motor milestone after onasemnogene abeparvovec 5
• 95.2% (20/21) showed stabilization or improvement in bulbar or respiratory function 5

Common Pitfalls to Avoid

1. Do not administer to patients with active infection – postpone until infection resolved and patient clinically stable 1
2. Do not stop corticosteroids abruptly – always taper gradually per protocol 1
3. Do not delay hepatology consultation – if liver abnormalities persist ≥2× ULN after 30 days of corticosteroids, promptly consult specialist 1
4. Do not overlook platelet monitoring – weekly checks for first month are mandatory 1
5. Do not miss TMA signs – immediate specialist consultation required as outcomes can be fatal 1
6. Do not assume single monitoring protocol fits all – infants ≥8 kg require more intensive surveillance 5

Importance of Early Intervention

Early diagnosis and treatment are essential for timely restoration and preservation of motor neurons and maximal motor function improvement 4. The rapid motor gains observed within 1-3 months post-treatment underscore the critical window for intervention in symptomatic SMA type 1 4.