What are the treatment options for Spinal Muscular Atrophy (SMA)?

Treatment Options for Spinal Muscular Atrophy (SMA)

Three FDA-approved disease-modifying therapies are available for SMA: onasemnogene abeparvovec (gene therapy), nusinersen (antisense oligonucleotide), and risdiplam (oral SMN2 splicing modifier), with onasemnogene abeparvovec offering the advantage of single-dose administration and rapid motor function improvement when given early. 1, 2

FDA-Approved Disease-Modifying Therapies

Onasemnogene Abeparvovec (Zolgensma)

Primary recommendation for early treatment:

• Indicated for pediatric patients less than 2 years of age with SMA and bi-allelic mutations in the SMN1 gene 1
• Administered as a single-dose intravenous infusion at 1.1 × 10^14 vector genomes per kilogram of body weight 1
• Delivers a functional copy of the SMN1 gene via adeno-associated virus vector to motor neuron cells 3
• Most effective when initiated early - rapid motor function improvements observed within 1-3 months post-treatment, with mean CHOP INTEND score increases of 7.0,9.7, and 11.8 points at 1,2, and 3 months respectively 4
• At 6 months post-dose, 91.5% of treated infants achieved clinically significant ≥4-point improvement in CHOP INTEND scores 4

Critical limitations and contraindications:

• Not evaluated in patients with advanced SMA (complete paralysis of limbs, permanent ventilator-dependence) 1
• Safety and effectiveness of repeat administration have not been evaluated 1
• Requires patients to be clinically stable (adequate hydration, nutritional status, absence of infection) prior to infusion 1

Mandatory monitoring protocol:

• Systemic corticosteroids (prednisolone 1 mg/kg/day) must be initiated one day prior to infusion and continued for 30 days to mitigate hepatotoxicity risk 1
• Baseline liver function assessment required before infusion 1
• Monitor liver function for at least 3 months after infusion - acute liver failure with fatal outcomes has been reported 1
• Baseline testing for anti-AAV9 antibodies required 1, 5
• Obtain baseline creatinine, complete blood count including hemoglobin and platelet count 1

Risdiplam (Evrysdi)

Oral alternative for all ages:

• Indicated for treatment of SMA in pediatric and adult patients 2
• Administered orally once daily with or without food 2

Age and weight-based dosing:

• Less than 2 months: 0.15 mg/kg daily 2
• 2 months to less than 2 years: 0.2 mg/kg daily 2
• 2 years and older weighing less than 20 kg: 0.25 mg/kg daily 2
• 2 years and older weighing 20 kg or more: 5 mg daily (available as tablet or oral solution) 2

Administration considerations:

• Available as oral solution or tablets (5 mg dose only) 2
• Can be administered via nasogastric or gastrostomy tube if oral solution formulation is used 2
• If dose missed, administer within 6 hours; otherwise skip and resume regular schedule next day 2

Nusinersen

• Antisense oligonucleotide therapy that has demonstrated efficacy in clinical trials 5
• May be used as initial therapy or in combination strategies 5
• Limited motor function improvement compared to gene therapy in some cases 5

Treatment Selection Algorithm

For symptomatic infants <2 years with SMA Type 1:

1. First-line: Onasemnogene abeparvovec if patient meets criteria (clinically stable, no advanced disease, negative or low anti-AAV9 antibodies) 1, 4
2. Consider risdiplam if onasemnogene contraindicated or patient preference for non-invasive route 2
3. Nusinersen as alternative if gene therapy not feasible 5

For pre-symptomatic patients identified through newborn screening:

• Onasemnogene abeparvovec is optimal - early treatment associated with rapid age-appropriate motor milestone achievement and maximal motor function preservation 3, 4

For patients ≥2 years or adults:

• Risdiplam is the only FDA-approved option for this age group 2

For patients with prior nusinersen treatment:

• Transition to onasemnogene abeparvovec is feasible if patient meets eligibility criteria and shows limited response to nusinersen 5

Critical Safety Considerations

Hepatotoxicity with onasemnogene abeparvovec:

• Acute liver failure with fatal outcomes reported - patients with preexisting liver impairment at higher risk 1
• Transient transaminase elevations occur in all patients 6
• Prophylactic prednisolone generally mitigates risk but does not eliminate it 3, 7

Cardiac monitoring:

• Troponin-T elevations observed in 100% of patients prior to treatment with fluctuations in 57% thereafter 6

Hematologic effects:

• Transient decrease in platelet count observed in all patients 6
• Monitor complete blood count regularly 1

Expected Outcomes and Realistic Expectations

Motor function improvements:

• SMA Type 1 patients show mean CHOP INTEND score increases of 28.1 points from baseline with onasemnogene abeparvovec 6
• 50% of SMA Type 1 patients still require nutritional support and 17% require night-time ventilation at follow-up 6
• 67% develop scoliosis despite treatment - orthopedic monitoring remains essential 6

Long-term considerations:

• Durable efficacy maintained up to median of approximately 5 years with onasemnogene abeparvovec 3
• Long-term benefits and risks beyond 5 years not yet determined 7

Common Pitfalls to Avoid

• Delaying treatment while awaiting "optimal" conditions - early intervention provides best outcomes; motor neuron loss is irreversible 4
• Failing to assess anti-AAV9 antibody status before onasemnogene administration - high titers may preclude treatment 1, 5
• Administering onasemnogene to patients with active infection - postpone until infection resolved and patient clinically stable 1
• Inadequate liver function monitoring post-gene therapy - continue for minimum 3 months 1
• Assuming treatment eliminates need for supportive care - nutritional support, respiratory management, and orthopedic monitoring remain necessary 6