Background: Since 2017, the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have approved three drugs for the treatment of SMA. Results of the pivotal trials showed minimally clinically meaningful improvements/differences (MCID) in motor skills in SMA type 1 (especially those with early treatment initiation and ≥2 SMN2 copies), as well as a stabilisation of health status in SMA type 2 to 4 patients. In SMA type 1 patients, while motor skills improved, no changes (sometimes even a deterioration) in the need for ventilation and nutritional support could be observed. The present report aims to synthesize the evidence on mid- and long-term (≥ 12 months) follow-up of the approved drugs as monotherapies or as combination therapies.

Method: Systematic Review. Twenty-two observational studies were included for analysing mid- and long-term outcomes. The included studies reported on 840 SMA patients, of which 289 SMA type 1 patients and 521 SMA type 2 to 4 patients were treated with nusinersen, only 12 SMA type 1 patients with onasemnogene abeparvovec and 18 SMA type 1 patients received a combination therapy.

Results: SMA type 1 patients treated with nusinersen (n=225): Nine patients died despite therapy, six withdrew due to lack of improvement and 35 patients were lost to follow-up. For those children that could be followed-up, many data were lacking. All patients in whom CHOP INTEND was measured reached the MCID. On HINE-2 fewer patients (67-100%) reached the MCID. SMA type 1 patients treated with onasemnogene abeparvovec (n=12): 75% achieved sitting (≥30 s) and 17% standing without support. All patients (n=18) treated with a combination of onasemnogene abeparvovec and nusinersen reached the MCID on CHOP INTEND, but only 40% reached the MCID on HINE-2. 40% learned to sit without support and 20% could control the head or stand. SMA type 2 to 4 patients (n=341) treated with nusinersen: One patient died and nine withdrew due to lack of improvement. Patients achieved a stabilisation or eventually small improvements (mostly below the MCID on HFSME and on RULM), but also some deterioration occurred. In all patient groups, independent of the type of SMA and the drug used, no significant improvements (but in some cases worsening) were reported for the need of respiratory or nutritional support.

Conclusions: The mid-term outcomes support the findings of the pivotal trials. Long-term data published by independent clinicians are not available yet and many open questions remain. Nevertheless, evidence suggests that early treatment in (pre-) symptomatic children, with at least two SMN2 copies and no need for pulmonary support seems to lead to the best outcomes.