Table 1. Clinical Safety and Efficacy.

Author (Year)	Groups Studied and Intervention	Results and Findings	Conclusions
Chiriboga C. et al. (2016)47	Phase I, open-label dose-escalation study. Participants (n = 28) were patients with SMA types 2 or 3, aged 2–14 years. Nusinersen was given in 1, 3, 6, and 9 mg doses. The authors monitored adverse events and examined the pharmacokinetics of the drug in CSF and plasma. HFMSE scores were evaluated at 3 months and 9–14 months post-dose.	No serious adverse events were reported, and the safety of the drug was established. Plasma and CSF drug levels were dose-dependent, and the drug had a half-life in CSF of 4–6 months. Significant increases from baseline in HFMSE for the 9 mg dose cohort were observed at 3 months post-dose (3.1 points; p = 0.016) and 9–14 months post-dose (5.8 points; p = 0.008).	Nusinersen was safe, well-tolerated, and showed promising preliminary clinical outcome data.
Darras B. et al. (2019)49	Phase Ib/IIa, open-label, multicenter, multiple-dose, dose-escalation study. Participants (n = 28) were patients with SMA types 2 or 3, aged 2–15 years. 3 doses of 3, 6, 9, or 12 mg nusinersen were administered intrathecally over three sessions, and safety was monitored throughout the trial. The extension involved 4 doses of 12 mg administered at 6-month intervals. Measures of motor function were evaluated.	Mean HFMSE scores, ULM scores, and 6MWT distances had improved (HFMSE: SMA type II, +10.8 points; SMA type III, +1.8 points; ULM: SMA type II, +4.0 points; 6MWT: SMA type III, +92.0 meters). Mean CMAP values remained relatively stable, and no children discontinued treatment due to adverse events.	Nusinersen yielded clinically significant improvements in motor function for patients with later-onset SMA.
Finkel R. et al. (2016)51	Phase II, open-label, multiple-dose dose-escalation study. Participants (n = 20) were patients with SMA type 1. 3 doses of 6 or 12 mg nusinersen were administered over three sessions. Safety was assessed throughout the trial. Event-free survival, measures of motor function, and pharmacokinetics of the drug in autopsy tissue were evaluated.	Authors observed incremental achievements of motor milestones (p < 0.0001), improvements in CHOP-INTEND motor function scores (p = 0.0013), and increased compound muscle action potential amplitude of the ulnar nerve (p = 0.0103) and peroneal nerve (p < 0.0001), compared with baseline. Autopsy showed the distribution of the drug in motor neurons in the spinal cord. Adverse events were reported, but authors considered them unrelated to the study drug.	Nusinersen is safe for use in patients with infantile-onset SMA, has pharmacokinetics consistent with its mechanism of action, and shows promising clinical efficacy.
De Vivo D. et al. (NURTURE, 2019)53	Phase II, open-label. Participants (n = 25) were asymptomatic, but all were documented to have homozygous deletions of the SMN1 gene with variable numbers of SMN2 gene copies. Four doses of 12 mg nusinersen were administered, followed by maintenance dosing every 119 days. Achievement of motor milestones, event-free survival, and need for ventilation was analyzed ~2.9 years after the trial began.	Four participants with two SMN2 copies utilized respiratory support for ≥ 6 h/day for ≥ 7 consecutive days that was initiated during acute, reversible illnesses. All 25 participants achieved the ability to sit without support, 23/25 achieved walking with assistance, and 22/25 achieved walking independently. Eight infants had adverse events considered possibly related to nusinersen by the study investigators.	Treatment of pre-symptomatic SMA with nusinersen has an acceptable safety level, and evidence from the trial supports its efficacy.
Finkel R. et al. (ENDEAR, 2017)54	Phase III, multicenter, double-blind, placebo-controlled. 121 symptomatic infants (nusinersen group, n = 80; placebo group, n = 41) were enrolled. Four doses of 12 mg nusinersen were administered over 4 sessions. Motor milestone achievements and event-free survival were compared between the drug group and placebo group.	A significantly higher percentage of infants in the nusinersen group vs. the control group had a motor response (51% vs. 0%), and the likelihood of survival was also higher (hazard ratio 0.53, p = 0.005). Participants with a shorter duration of illness at the onset of treatment were more likely to derive benefit.	Nusinersen is effective in the treatment of type 1 and type 2 SMA. Early detection may be critical for optimal treatment outcomes.
Aragon-Gawinska K. et al. (EAP, 2018)55	Phase III, extension trial for SMA type 1 patients older than 7 months. 33 children between 8.3 and 113.1 months of age were enrolled. Survival, respiratory, and nutritional data were collected.	Median progress on the modified HINE-2 score was 1.5 points after 6 months of treatment (p < 0.001). The need for respiratory support significantly increased over time.	Nusinersen is also effective for SMA type 1 in later stages of the disease.
Mercuri E. et al. (CHERISH, 2018)56	Phase III, double-blind, placebo-controlled. Participants (n = 126; n = 84 for the nusinersen group, n = 42 for the control group) all had symptom onset after 6 months of age and received 4 doses of 12 mg nusinersen or 4 sham procedures over 4 sessions. Changes from the baseline of HFMSE scores were evaluated.	The least-squares mean an increase in HFMSE score from baseline to month 15 was 4.0 in the nusinersen group and -1.9 in the control group. 57% of the nusinersen group had an increase in HFMSE score of ≥ 3 points, in contrast to only 26% of the control group (p < 0.001)	Nusinersen is effective in the treatment of later-onset (types 2 and 3) SMA.