Long-Term Efficacy and Safety of Nusinersen in Adults With 5q Spinal Muscular Atrophy: A Prospective European Multinational Observational Study

Major Points and Findings:

This paper does not concern stem cells. Its subject is nusinersen (Spinraza), one of the three approved disease-modifying drugs for SMA, given by intrathecal injection. We summarise it here because families considering cell therapy need to know what the approved treatments deliver, and because adults with SMA are often told very little about what to expect from long-term treatment.

The study is the largest prospective study of nusinersen in adults published to date, drawing on 389 screened patients across Germany, Switzerland and Austria who were followed for up to 38 months. Motor scores rose on average and stayed above baseline for more than three years. The average gain was small, however. Roughly 30% of patients showed a clinically meaningful improvement, and a similar proportion got worse.

Aim:

To test whether the benefit of nusinersen in adults holds up over a longer period than the 14 to 16 months covered by earlier studies, and whether patients reach a plateau.

Methods:

This was a prospective, observational, multicentre study within the SMArtCARE registry. Recruitment ran from July 2017 to May 2022.

Participants were adults and older adolescents aged 16 to 71 with genetically confirmed 5q SMA, treated with nusinersen according to the label for at least 14 months. To avoid selection bias, no other inclusion criteria were applied, and everyone at each centre willing to join the registry was included. Of 389 screened, 237 had usable data at 14 months, 171 at 26 months and 120 at 38 months. Mean age was 36. Two thirds had SMA type 3 and a quarter had type 2. In all, 42% could walk and 19% had already had spinal fusion surgery.

Patients received nusinersen 12 mg intrathecally, with a loading phase then maintenance every four months. It was given by lumbar puncture, either plain or guided by fluoroscopy, ultrasound or CT depending on the patient’s spine.

Outcome measures: The primary measure was the Hammersmith Functional Motor Scale Expanded (HFMSE, maximum 66 points, a change of 3 points counts as clinically meaningful) at 14, 26 and 38 months. Secondary measures were the Revised Upper Limb Module (RULM, maximum 37, meaningful change 2 points) and the six-minute walk test (meaningful change 30 metres). Adverse drug reactions were recorded using a standard protocol.

Results:

The average change was positive but small. Mean HFMSE rose by 1.72 points at 14 months (95% CI 1.19 to 2.25), 1.20 at 26 months and 1.52 at 38 months. RULM rose by 0.75, 0.65 and 0.72 points. The six-minute walk distance rose by 30.86 m, 29.26 m and 32.20 m. All of these were statistically significant, but the average HFMSE gain is well under the 3-point threshold for a clinically meaningful change.

Individual responses: At 38 months, 36 of 120 patients (30%) had a clinically meaningful HFMSE improvement, averaging 6.64 points. In the same group, 34 patients (28%) had worsened, and for 16 of them (13%) the worsening was clinically meaningful. Twenty-eight patients who improved meaningfully at 14 months were still holding that gain at 38 months. On the walk test, 48% of those tested improved meaningfully at 38 months while 18% declined by 30 metres or more.

Less severely affected patients gained more. HFMSE rose significantly at all three time points in SMA type 3 but only at 14 months in type 2, and only in ambulatory patients at 26 and 38 months. The reverse held for arm function. RULM improved significantly at all three time points in type 2 and in non-ambulatory patients, but not in those who could walk, where a ceiling effect applies. Patients who had had spinal fusion showed HFMSE gains only at 14 months. Age had almost no relationship with response.

Missing data: A large share of data was missing (39% at 14 months, 56% at 26, 69% at 38). When the authors re-ran the analysis with imputed values for missing data, the mean HFMSE change was 1.43 points at 14 months (still significant), but 0.75 at 26 months and 0.54 at 38 months. Neither of the later values remained statistically significant.

Safety: Across the 389 patients who received at least one injection, 732 adverse drug reactions or procedure-related complications were recorded, and 353 patients (91%) had at least one. Most were post-lumbar-puncture syndrome, headache, back pain and infections. One patient developed aseptic meningitis. Eleven patients stopped nusinersen before the 14-month assessment, four of them switching to risdiplam. There were no cases of hydrocephalus, a complication reported shortly after approval elsewhere, and no new safety signals.

Conclusions:

Nusinersen produced sustained improvement or stabilisation of motor function in most adults over 38 months, which differs from the natural history of the disease. Untreated adults lose roughly 0.5 HFMSE points a year, and type 2 patients lose about 1.5 RULM points over two years. In the more severely affected, the authors argue that stabilisation itself should be read as a benefit.

The authors list several limitations. There was no untreated comparison group, so the study provides real-world evidence and not the evidence of a randomised trial. Missing data were substantial. The motor scales suffer floor effects in severely affected patients and ceiling effects in mildly affected ones, and they do not capture swallowing or breathing at all.

Background Information:

Several findings bear on the practical burden of SMA treatment.

Nusinersen is given into the spinal canal every four months for life. Nine in ten patients reported at least one adverse reaction or procedural complication, mostly related to the lumbar puncture itself. In patients with spinal fusion the procedure needs imaging guidance, and this group showed smaller sustained gains.

The authors state that no biomarker of response to nusinersen has been validated for adults in clinical routine. Motor scales therefore remain the only practical measure, despite their known limitations.

Nusinersen was approved on the basis of trials in infants and children. Evidence in adults has come almost entirely from real-world studies such as this one, and for that reason studies of this kind carry more weight in SMA than they would in a common disease.