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. 2023 Oct 10;13(10):1446. doi: 10.3390/brainsci13101446

Table 2.

Pivotal clinical trials leading to the marketing authorization of nusinersen, onasemnogene abeparvovec, and risdiplam.

Study Study Design Status Eligibility Criteria Exposure Outcome Results
Treatment Group Control Group
Nusinersen
ENDEAR [23] Phase III double-blind, controlled, randomized clinical trial. Completed Patients with homozygous deletions or mutations in the SMN1 gene and with two copies of the SMN2 gene and younger than 7 months at the screening date 80 patients treated with nusinersen at a dose adjusted by cerebrospinal fluid volume, such that the patients 2 years old or older received a dose equivalent to 12 mg. 41 patients treated with a sham procedure

  1. Achievement of a motor milestone (defined based on the Hammersmith Infant Neurological Examination results)

  2. Event-free survival (i.e., death or lifelong use of assisted ventilation)

  1. 51% (37/73) of the patients in the treatment arm achieved at least one motor milestone, compared with 0 out of the 37 patients in the control arm.

  2. 61% (49/80) of the patients did not die or did not require permanent ventilation (compared to 32% [13/41] of the patients in the control group; p = 0.005) at the end-of-trial visit (i.e., day 183, 302, or 394).
Onasemnogene abeparvovec
STR1VE-US [24] Phase III open-label, single-arm clinical trial Completed Patients with SMA type 1, with biallelic SMN1 mutations, with one or two copies of SMN2, and younger than 6 months of age at the date of onasemnogene abeparvovec administration 22 patients treated with a single intravenous administration of onasemnogene abeparvovec, over approximately 60 min: 1.1 × 1014 vg/kg 23 untreated children, aged less than 6 months and with SMA type 1 registered in the Pediatric Neuromuscular Clinical Research dataset (historical controls)

  1. Proportion of patients able to sit unassisted for at least 30 s at the 18 months follow-up visit

  2. Survival to the age of 14 months (i.e., no death or permanent ventilation)

  1. 13 out of the 22 patients (59%) were able to sit unassisted for 30 s or more at 18 months of age (compared with 0 out of the 23 untreated patients in the Pediatric Neuromuscular Clinical Research cohort; p < 0.0001).

  2. 20 out of the 22 patients (91%) survived without a need for permanent ventilation use for up to 14 months (vs. 6/23 [26.1%] of the untreated patients in the Pediatric Neuromuscular Clinical Research cohort; p < 0.0001).
Risdiplam
SUNFISH—Part 2 [25] Phase III double-blind, placebo-controlled, randomized clinical trial Ongoing Patients between 2 and 25 years of age, with type 2 or type 3 SMA 120 patients treated with oral-administered risdiplam (5 mg/day for patients weighing ≥ 20 kg or 0.25 mg/kg/day for patients weighing < 20 kg) 60 placebo-treated patients Variation from the baseline in the 32-item Motor Function Measure’s total score for patients at the 12th month of treatment compared to the placebo group At month 12, the mean change from baseline in the MFM32 score was 1.36 (95% CI: 0.61 to 2.11) in the treatment group and −0.19 (95% CI: −1.22 to 0.84), with a difference of 1.55 (95% CI: 0.30–2.81; p = 0.016) in favor of the treatment with risdiplam.
FIREFISH—Part 2 [26] Phase II/III open-label, single-arm clinical trial Completed Patients aged 1 to 7 months with a type 1 SMA diagnosis and two copies of the SMN2 gene 41 patients treated with risdiplam. The patients older than 5 months received a dose of 0.2 mg/kg/day; the patients younger than 5 months received a dose of 0.04 or 0.008 mg/kg/day, adjusted to 0.2 mg/kg/day within 1–3 months from starting treatment. 16 historical controls derived from the NeuroNEXT study, and 24 historical controls Proportion of patients able to sit without assistance for at least 5 s after 12 months of treatment, based on the 3rd edition of the Bayley Scales of Infant and Toddler Development 12 out of the 41 patients (29%; 95% CI: 16 to 46) were able to sit without assistance for at least 5 s after 12 months of treatment; the percentage was significantly higher than in the historical controls (p < 0.001).

Abbreviations: CI = confidence interval; MFM32 = 32-item Motor Function Measure; SMA = spinal muscular atrophy; SMN = spinal motor neuron; and vg = vector genomes.