About one year of treatment with Spinraza (nusinersen) effectively prevents or reverses motor function decline in children and adults with spinal muscular atrophy (SMA) type 3, according to real-world data from an international registry.
Notably, when compared with an external group of untreated patients, who always showed negative changes in motor function measures from age 8 onward, Spinraza was always associated with positive changes.
These findings expand upon previous real-world studies focused mostly on Spinraza benefits in adults with type 3 disease, thereby showing that the therapy is effective not only in adults, but also in children with this milder type of SMA.
The study, “Nusinersen in pediatric and adult patients with type III spinal muscular atrophy,” was published in the journal Annals of Clinical and Translational Neurology.
A rare genetic disease characterized by progressive muscle weakness and wasting, SMA is divided into main five types (0, 1, 2, 3, and 4) based on age of disease onset and maximum motor function achieved.
SMA type 3 is a late-onset, and generally milder, form of the disease. In these patients, the symptoms become apparent between 18 months (about 1.5 years) and 18 years of age, when all the early motor development milestones, including walking, have been reached at least for some time in life.
It can be divided into types 3a (symptom onset before age 3) and 3b (onset after age 3 and less-severe disease).
Biogen’s Spinraza was the first approved disease-modifying therapy for all SMA types in children and adults. It is administered directly into the spinal canal at a recommended regimen of four doses in the first two months, followed by maintenance treatment every four months.
Given that its approval was based on clinical trials of infants and young children with SMA, data on Spinraza’s effectiveness in older children and adults mainly relies on real-world and case studies.
While some previous studies have reported the therapy’s effects in adults with SMA type 3, data on younger patients with this milder form are lacking.
To fill this knowledge gap, an international team of researchers retrospectively analyzed data from 144 Spinraza-treated children and adults with type 3 disease, mostly participating in the International SMA Consortium (iSMAC) registry.
This Biogen-sponsored registry is following both treated and untreated (natural history) SMA patients across the U.S., the U.K., and Italy.
Patients’ ages ranged from 30 months to 68.3 years, 58% were males, and 74 had type 3a, while 70 had type 3b. More than half (54.9%) could walk unaided (“walkers”), 43.1% could sit without help (“sitters”), and 2.1% were not able to sit independently (“non-sitters”).
No patient had received any prior treatment, and they were followed for a mean of 1.83 years, during which no serious adverse events (side effects) were reported and the most frequent were related to spinal canal injection.
Motor function was assessed with the Hammersmith Functional Motor Scale Expanded (HFMSE), the Revised Upper Limb Module (RULM), and the 6-Minute Walk Test (6MWT), which measures the distance a person is able to walk in six minutes (for “walkers”only).
The team analyzed motor function changes in the 104 patients (72%) who had one-year assessments on at least one measure, as well as the potential effects of different factors in motor changes in the 130 patients (90.3%) with at least six months of follow-up data.
Results showed that after one year of Spinraza treatment, patients had a significant increase in the mean scores of both HFMSE and RULM, indicative of better motor function. “Walkers” also were able to walk more meters during the 6MWT at one year, but this difference did not reach statistical significance.
Changes in the HFMSE achieved statistical significance in both walkers and non-walkers and in type 3b patients, while RULM changes were significant only in sitters and patients with SMA type 3a.
“These results suggest that the different scales should be used in combination as each of them contributes to detect possible changes in different groups of patients,” the researchers wrote.
Notably, none of the scales alone “was able to identify all patients who had a functional improvement, likely reflecting the large variability of the functional characteristics of the individuals studied,” they added.
The researchers then compared one-year HFMSE changes in these patients to those previously published for an external group of untreated 199 SMA type 3 patients across age groups.
While Spinraza-treated patients across all age groups had increases in HFMSE scores after a year, untreated patients older than 7 always showed HFMSE score drops, indicative of motor function decline.
Up to age 7, untreated children showed increases in HFMSE scores, but these were not as pronounced as those observed for the corresponding treated group.
When the team looked at potential influencers of motor improvements in Spiranza-treated patients, they found that age, sex, HFMSE score before treatment, and functional status — but not SMN2 copy number — contributed significantly to observed changes in HFMSE. Of note, SMN2 functions as a “backup” gene that can partly compensate for the loss of SMN1-produced SMN protein, the main cause of SMA. Typically, the more SMN2 gene copies a patient has, the less severe the disease.
“The effect of the different variables was less obvious on the RULM and even less on the 6MWT,” the team wrote, adding that this probably reflects the more restrictive nature of these two scales, as the former is more appropriate for weaker type 3 patients and the latter can be performed only in walkers.
These data from both pediatric and adult type 3 patients “confirm previous findings in adult patients, suggesting that there is a 12-month treatment effect in type III patients irrespective of their [walking abilities] and that the changes can be observed on one or more functional measures, depending on age and functional status,” the researchers wrote.
“As the pattern of changes varies in relation to age and functional severity, the relevance of the response to treatment is better appreciated if the observed changes are compared to the changes observed in untreated patients with similar age and functional status,” the team added.
They also noted that further studies are needed to determine the minimal clinically meaningful difference in these scales in type 3 patients, which would help clinicians present reasonable expectations to patients treated with Spinraza.
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