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Tãtaru et al. Rare Dis Orphan Drugs J 2024;3:19 https://dx.doi.org/10.20517/rdodj.2024.08 Page 3 of 10

Table 1. Characteristics of 5q SMA types
Type 1 Type 2 Type 3 Type 4
Age of onset of first symptom Before 6 months Between 6-18 months After 18 months Adult age
(> 18 years)
Mobility status without treatment Non-Sitter Sitter Walker Walker
% of Incidence 50%* 25% 22% 3%

*Incidence of type 1 is quite high, but because of the short life expectancy (less than 2 years, median life expectancy 12 months) of this population,
prevalence of type 1 remains quite low.

The published clinical studies results have shown that the effectiveness of all approved treatments is
significantly higher when the child is treated before the onset of the first clinical sign . Three treatments
[5-7]
are approved in Europe, targeting the survival motor neuron gene (SMN1 and SMN2) production:

(1) Spinraza™ (nusinersen), an antisense oligonucleotide (ASO) targeting the SMN2 gene, administered via
intrathecal injection every 4 months ;
[8]

(2) Evrysdi™ (risdiplam), SMN2 splicing modifier overexpressing SMN production, medicine administered
[9]
per os (PO), once per day ;

(3) Zolgensma™ (onasemnogene abeparvovec), gene therapy, adding the SMN1 sequence, single-dose
intravenous infusion .
[10]
Why include SMA in NBS programs?
During the clinical studies preceding the marketing submission or authorization of new treatments, in
addition to symptomatic patients, pharmaceutical companies conducted a series of trials on patients
diagnosed with SMA at birth via genetic screening. Most investigations were focused on patients treated
presymptomatically who had two or three copies of SMN2 and who were predisposed to developing an
early form of the disease. In the NURTURE study, a clinical trial conducted by Biogen, the newborns were
administered intrathecal nusinersen (Spinraza™) during neonatal development, with long-term follow-up to
evaluate the benefits on survival, respiratory interventions, and motor outcomes and if the treatment
guaranteed a favorable safety profile. Interim results from the NURTURE study concluded that, after a
follow-up of 2 years and 9 months, there were clear clinical benefits for the infants with two or three copies
of the SMN2 gene who received treatment, providing an opportunity for early intervention and
improvement of symptoms experienced. The ENDEAR study evaluated the motor-milestone responses and
the event-free survival in infants with SMA treated with nusinersen compared with a control group. An
interim analysis showed a better motor-milestone response in the group treated with nusinersen, which led
to the early termination of the trial. The final analysis showed a significant improvement in motor response
and survival in the arm treated with nusinersen compared with the control group .
[5,8]

A comparable level of efficacy has been demonstrated by Zolgensma (onasemnogene abeparvovec), the gene
therapy medication developed by Novartis Gene Therapies, that was administered in a single-arm SMA
patients trial who had two or three copies of SMN2. The results highlighted that 7 out of 14 (50%) infants
with two SMN2 copies had gross motor performance similar to normal development, while all 14 (100%)
infants had fine motor performance similar to normal development . Moreover, all patients with three
[10]
copies of SMN2 treated presymptomatically achieved the primary endpoint, demonstrating the ability to
stand without support during the 2-year follow-up visit. More recently, Evrysdi (Roche) also showed a
comparable level of efficacy based on the results presented in their publication of the RAINBOWFISH trial