Skip to content
Original article published 24th April 2019

Darras and colleagues have recently released information on the longer-term results of the nusinersen trials. The results showed significant differences between treated and untreated groups in their ability to perform tasks over an almost three-year period. This article summarises their findings.

Over time more studies have been published regarding the effects of nusinersen in treatment of SMA. These have ranged from pre-clinical trials (on the effect on cells and animals) to human trials looking at treatment before and after symptoms develop in SMA Type 1, and in SMA Types 2 and 31-8. There are many things not known about nusinersen, although it has been talked about within the SMA community for seemingly a long time, in medical practice it is very new and isn’t yet a standard treatment for SMA. The NICE committee in the England met in 2018 to discuss whether nusinersen should be paid for by the NHS9, they recommended that it shouldn’t be made available yet. Their reasoning was partly on grounds of cost compared to the potential benefits, but also because:

“Clinical trial evidence shows that nusinersen improves a range of outcomes that are important to patients. However, there is no long-term evidence, so the long-term benefits are highly uncertain.”

Darras and colleagues have published in the prestigious medical journal “Neurology” the longer-term findings of the first trials that used nusinersen in treatment of SMA10. In the context of the refusal to fund nusinersen treatment on the NHS in this first consultation, this study is especially important to provide evidence of long-term effects of the medication.

Darras and colleagues followed up 28 children with SMA Type 2 (11 children) or Type 3 (17 children) from their enrolment in the early phase studies (see levels of evidence). Early phase studies look primarily at safety and effect of medications in small numbers of participants, before going on to give the medication to larger numbers in later phase trials.

All participants received nusinersen via an injection in the spine (intrathecal) at regular time points of Day 1, a month, then at about three months. In the first part of the study the medication was given in different dosages to ensure it was safe then all participants were given the highest dose (12mg) for each injection. Of the original 28 children who took part in the first part of the trial, 27 went on to have all of the doses in the second, longer part of the study, where participants received treatment after 1 year (from the beginning of the trial), then about every six months. The trial ended in January 2017, and participants were followed up after this.

The study was most interested in how the participant motor function changed over time and compared this to a different study which followed up untreated children with SMA (natural history). Motor function is assessed by the ability of a participant to perform actions or activities as assessed by a physiotherapist. The tools used included the Hammersmith Functional Motor Scale expanded (HFMSE), the 6 minute walk test (how far you can walk in six minutes on the flat), and the Upper Limb Module (which assesses only the function of the arms).

Darras and colleagues found that the greatest difference in the HFMSE was seen in the participants with SMA Type 2. More than three points improvement on the HMFSE is considered to be clinically significant (i.e. participants will notice a significant improvement in function). Improvements were seen in the HMFSE score from the first assessment of almost 11 points, with the majority (9/11) participants having a clinically significant improvement in function (>3 points improvement) by the end of the study. Participants with SMA Type 3 had a less impressive improvement in function of 1.8 points on average (from their first assessment). Only 4/11 participants with SMA Type 3 had a clinically significant increase in function (>3 points improvement).

Infants with SMA Type 2 are not expected to walk according to their medical classification; one infant did begin walking over the age of 2 and managed to walk 180 meters by the end of the study. In those with SMA Type 3, the average improvement in walking distance was 92 meters by the end of the study, two children who had lost the ability to walk by the beginning of the study regained the ability to walk before the end of the study.

The participants with SMA Type 2 were seen to progressively improve in their upper limb scores, with all those with SMA Type 3 achieving the maximum score by the end of the study.

The study also looked at safety, no side effects were though to be due to the drug itself, although there were a number of participants who reported side effects (such as headache) due to the way the medication is given (via injection in the spine).

Compared to natural history studies which looked at untreated children with SMA, this study found significant improvements in the ability of children to perform tasks and to walk distances. Their findings also highlight that a minority of children may regain or gain developmental milestones that they would otherwise not have gained. Darras and colleagues are unable to say why these improvements may have happened and suggest further preclinical studies to work out why.

The study highlights there is a difference in terms of potential benefit to participants with different SMA Types, with Type 2 seemingly benefitting more. In previous studies it has been suggested that earlier treatment with nusinersen may have more effect than later treatment. It may be the case that those with SMA Type 3 were older and therefore this led to a lesser treatment effect. These findings add further support for the development of a newborn screening programme to allow earliest treatment with nusinersen.

The findings of this study suggest that in treatment of SMA Types 2 and 3 with nusinersen, there may be long term (2-3 years) of positive effects on muscle function. Nusinersen treatment appears to have few side effects except those related to the administration.

1. Singh NK, Singh NN, Androphy EJ, Singh RN. Splicing of a critical exon of human Survival Motor Neuron is regulated by a unique silencer element located in the last intron. Mol Cell Biol 2006; 26: 1333–46.

2. Hua Y, Vickers TA, Okunola HL, Bennett CF, Krainer AR. Antisense masking of an hnRNP A1/A2 intronic splicing silencer corrects SMN2 splicing in transgenic mice. Am J Hum Genet. 2008; 82: 834–48.

3. Porensky PN, Mitrpant C, McGovern VL, et al. A single administration of morpholino antisense oligomer rescues spinal muscular atrophy in mouse. Hum Mol Genet. 2012; 21: 1625–38.

4. Finkel RS, Chiriboga CA, Vajsar J, et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet 2016; 388: 3017–26.

5. Finkel RS, Mercuri E, Darras BT, et al. Nusinersen versus sham control in infantile-onset spinal muscular atrophyN Engl J Med 2017; 377: 1723–32.

6. Chiriboga CA, Swoboda KJ, Darras BT, et al. Results from a phase 1 study of nusinersen (ISIS-SMN(Rx)) in children with spinal muscular atrophyNeurology 2016; 86: 890–7.

7. Mercuri E, Darras BT, Chiriboga CA, et al. Nusinersen versus sham control in later-onset spinal muscular atrophyN Engl J Med 2018; 378: 625–35.

8. Bertini E, Hwu W-L, Reyna SP, et al. Efficacy and safety of nusinersen in infants with presymptomatic spinal muscular atrophy (SMA): interim results from the NURTURE study. Eur J Paediatr Neurol 2017; 21 (Suppl. 1): e14.

9. accessed on the 8th of May 2019

10. Darras BT, Chiriboga CA, Iannaccone ST, et al. Nusinersen in later-onset spinal muscular atrophyNeurology, 2019, DOI: 10.1212/WNL.0000000000007527