What is the comparison between Risdiplam (Risdiplam) and Spinraza (Nusinersen) for treating spinal muscular atrophy (SMA)?

Risdiplam vs Spinraza for Spinal Muscular Atrophy

For patients with spinal muscular atrophy, risdiplam offers a significant practical advantage as the only oral therapy with demonstrated efficacy across SMA types 1-3, while nusinersen (Spinraza) requires repeated intrathecal injections but has longer-term safety data.

Key Differences in Administration and Access

Route of administration fundamentally distinguishes these therapies:

• Risdiplam is administered orally once daily at 5.00 mg for patients ≥20 kg or 0.25 mg/kg for those <20 kg, making it non-invasive and suitable for home administration 1, 2
• Nusinersen requires repeated intrathecal injections, which necessitate medical facility visits and carries procedural risks 1, 3

The oral route provides broader systemic tissue penetration compared to intrathecal delivery, potentially offering more comprehensive SMN protein restoration across affected tissues 3

Efficacy Evidence

Risdiplam Clinical Data

In the SUNFISH trial (type 2 and non-ambulant type 3 SMA), risdiplam demonstrated statistically significant motor function improvement:

• At 12 months, the least squares mean change in Motor Function Measure was 1.36 points with risdiplam versus -0.19 with placebo (treatment difference 1.55, p=0.016) 2
• Motor function generally improved in younger patients and stabilized in older patients 2
• Benefits were maintained through 2 years of treatment 1

For type 1 SMA infants, risdiplam showed significant motor function improvements in phase 2/3 trials, with sustained benefits over 2 years 1

Comparative Context

Direct head-to-head trials between risdiplam and nusinersen do not exist in the provided evidence. The JEWELFISH study evaluated risdiplam in patients previously treated with nusinersen, showing that risdiplam was safe and well-tolerated in this population, with SMN protein increases comparable across all ages 4

Safety Profile

Risdiplam Adverse Events

Common adverse events with risdiplam include:

• Pyrexia (21% vs 17% placebo) 2
• Diarrhea (17% vs 8% placebo) 2
• Rash (17% vs 2% placebo) 2
• Photosensitivity was universal in one adult cohort 5
• Pneumonia occurred more frequently (8% vs 2% placebo) 2

Serious adverse events occurred in 20% of risdiplam-treated patients versus 18% with placebo, with generally similar rates except for pneumonia 2

Tolerability in Previously Treated Patients

In the JEWELFISH study of 174 patients previously treated with other SMA therapies:

• Upper respiratory tract infection and pyrexia were most common (17% each) 4
• Pneumonia was the most frequent serious adverse event (2%) 4
• Adverse event rates decreased in the second 6-month period compared to the first, suggesting improving tolerability over time 4

Clinical Application Algorithm

When to Choose Risdiplam

Prioritize risdiplam for:

1. Patients aged ≥2 months with type 1,2, or 3 SMA who require non-invasive administration 1
2. Patients with difficult intrathecal access due to spinal fusion, scoliosis, or anatomical barriers 3
3. Infants and young children where repeated lumbar punctures pose significant burden 3
4. Patients previously treated with nusinersen who need treatment continuation but face access barriers 4

When to Consider Nusinersen

Consider nusinersen when:

• Longer-term safety data (beyond 2 years) is prioritized, as nusinersen has been available longer
• Concerns exist about systemic exposure effects, as intrathecal delivery provides more targeted CNS delivery 3

Practical Considerations

Risdiplam provides meaningful patient-reported benefits:

• Adults reported improvements in overall strength, sense of wellbeing, and speech quality 5
• Quality of life measures (QOLM) improved significantly (p=0.027) 5
• Virtual monitoring is feasible for most assessments 5

The broader systemic effect of oral risdiplam requires ongoing safety monitoring, particularly given its mechanism affecting SMN2 splicing throughout the body 3

Common Pitfalls to Avoid

Do not assume oral administration means inferior efficacy - risdiplam demonstrated statistically significant motor function improvements in controlled trials 2

Do not overlook photosensitivity counseling - all adult patients in one series experienced this adverse effect, requiring sun protection measures 5

Do not expect immediate respiratory function changes - respiratory parameters did not change significantly at 6-9 months in adult studies, though other functional measures improved 5

Monitor for pneumonia risk, which appears elevated compared to placebo, particularly in the first 6 months of treatment 2, 4