About one year of treatment with Spinraza (nusinersen) gradually and significantly improves motor function in adults with spinal muscular atrophy (SMA) type 3 — especially those unable to walk without assistance, according to a large and real-life study in Italy.
Adults with type 2 disease, in turn, showed only a trend toward significant motor improvements at 14 months, suggesting that stabilization is more likely for those with more severe or advanced disease and lower residual motor function at Spinraza initiation.
But too few type 2 patients (13) were in the study to draw definite conclusions, its researchers noted, and larger and longer real-world studies are needed to confirm the extent of Spinraza’s benefits across adults with SMA.
The study, “Nusinersen safety and effects on motor function in adult spinal muscular atrophy type 2 and 3,” was published in the Journal of Neurology, Neurosurgery, and Psychiatry.
Spinraza, a disease-modifying therapy developed by Biogen, was the first approved treatment for all types of SMA in children and adults. It is administered directly into the spinal canal at a recommended regimen of four doses (12 mg each) in the first two months, followed by maintenance treatment at the same dose every four months.
Since its approval was based on clinical trials of infants and young children with SMA, data on Spinraza’s effectiveness in adults is currently limited to one large real-life study in Germany and several smaller case series in the U.S., and Germany.
These studies have reported motor function stabilization or improvements in adult SMA patients treated with Spinraza, meeting most of their expectations.
Now, researchers in Italy evaluated Spinraza’s safety and effectiveness in 116 adults (68 men and 48 women) with SMA, followed across 18 Italian SMA centers.
Patients’ median age at disease onset was 3 (range, 0.5–17 years), and they received the first Spinraza dose at a median age of 34 (range, 18–72 years). Thirteen (11.2%) patients had SMA type 2 disease, and 103 (88.8%) had the milder type 3 disease, representing “the largest adult SMA3 [group] investigated to date,” the researchers wrote.
Adults with SMA type 3 were classified as ‘walkers’ (52 patients) if they were able to take at least a few steps without the assistance of others, and as ‘sitters’ (51 patients) if they were not.
The team retrospectively analyzed patients’ clinical data at Spinraza initiation and after six months (all patients), 10 months (84 patients), and 14 months (54 patients) — corresponding to the first three maintenance doses.
Motor function was mainly 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 SMA type 3 ‘walkers’ only.
Responders were defined as patients who showed improved motor function by at least 3 HFMSE points, 2 RULM points, or 30 meters in the 6MWT — widely considered clinically meaningful changes. Lung function was evaluated through forced vital capacity (FVC), the total volume of air that can be blown forcefully following a full inhalation.
Results showed that 53% of all adults were considered responders at six months, increasing to 63% at 10 months and to 69% at 14 months (little over a year). Type 3 patients had higher response rates at all time points (56% at six months, 64% at 10 months, and 70% at 14 months).
Nevertheless, clinically meaningful responses were also observed in a large proportion of those with type 2 over time: 23% at six months, 56% at 10 months, and 60% at 14 months.
At six months, adults with SMA type 3 showed significant motor function improvements in all three measures, which were maintained and further increased with time for both HFMSE and RULM.
This suggested that Spinraza’s effectiveness in these patients “may be cumulative, at least throughout the first 14 months of treatment,” the researchers wrote.
Moreover, ‘sitters’ showed greater motor improvements than ‘walkers’ in both HFMSE and RULM. The observed smaller RULM improvement among ‘walkers’ was likely associated with the fact that their RULM scores were close to the maximum at all time points, suggesting that this may be a less sensitive measure of benefit for these patients.
In contrast, type 2 patients showed no significant gains in motor function, despite a positive trend for RULM at 14 months.
“The small size of our [SMA type 2] subgroup does not allow definite conclusions, but considering available natural history data, we cannot exclude that the stabilization of motor function over the follow-up period may be considered as a positive effect of [Spinraza],” the researchers wrote.
In addition, “patients with less advanced disease at baseline showed greater motor improvement,” the team wrote, noting that it emphasizes the “relevance of residual motor function at baseline in predicting response to [Spinraza].”
Lung function was also significantly improved in type 3 patients at 14 months, particularly among ‘walkers’; conclusions in adults with type 2 disease were not possible due to their limited number.
Spinraza was generally safe in adults, with most adverse events being exclusively associated with spinal injections rather than the treatment itself. Post-injection headache (37%) was the most common adverse event, and only two (1.7%) adults discontinued treatment due to a poor benefits/tolerability balance.
These findings strongly support Spinraza’s safety and effectiveness in adults with SMA type 3, particularly in those unable to walk but with some residual upper limb function, the researchers concluded.
They also noted that most findings were consistent with those reported in the previous larger German study, but recommended further studies to better investigate Spinraza’s long-term effects in this adult patient population.
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September 23, 2020 at 10:23PM
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