The term spinal muscular atrophy (SMA) describes a range of genetic, neuromuscular disorders that are characterised by progressive muscle wasting and subsequent loss of function. The first cases of the condition were described in the 1890s by Werdnig and Hoffman, whose autopsies revealed severe loss of alpha-motor neurons in the anterior horn of the spinal cord and skeletal muscle atrophy.1 SMA is a rare autosomal recessive disorder affecting between 1 in 6000 to 1 in 10,000 live births2 with a carrier frequency between 1 in 40 and 1 in 60.3
There are several phenotypes of SMA, the most common being infantile onset SMA (see Table 1). Initial symptoms in those with infantile onset SMA include hypotonia/floppiness, inability to lift the head and or poor head control with reduced motor activity. In addition, patients experience difficulty swallowing and clearing of oral secretions by one year of age. The clinical course of the disease is characterised by progressive, symmetrical limb and trunk paralysis due to muscular atrophy,4 leading to low muscle tone and proximal muscle weakness, which affects the legs more than the arms.
During normal development, infants would be expected to sit by six months and learn to walk at 12 months but, as shown in Table 1, some of these motor milestones are not achieved in those with SMA and are lost as the disease progresses. Furthermore, although those with less severe disease can expect to have a normal lifespan, the disease places a considerable burden on both patients and their carers.5
SMA is caused by insufficient levels of a protein called survival motor neuron (SMN), which is produced by the survival motor neuron gene located on chromosome 5. Humans have two nearly identical copies of this gene termed SMN1 and SMN2. Though both genes produce SMN protein, SMA occurs when there is a defect in the SMN1 gene and patients have to rely on the protein produced by the SMN2 gene. Unfortunately, during transcription from the SMN2 gene, one of the exons (exon 7) is not copied by RNA and 80–90% of the resultant SMN protein is shorter than normal, unstable and quickly degrades in cells. Although the remaining SMN protein made from the SMN2 gene is normal, it is insufficient to compensate for the lack of SMN protein formed by the SMN1 gene.6
However, as shown in Table 1, SMA has at least four different subtypes, which vary in disease severity. The presence of these subtypes is attributed to the fact that patients have more than one copy of the SMN2 gene and those with a higher number of copies have a better prognosis.
Patients with SMA are managed through supportive care according to comprehensive guidance produced in 2007. These guidelines offer advice on diagnosis (via genetic testing), pulmonary, gastrointestinal, orthopaedic and palliative care issues.7 Pulmonary disease is a major cause of morbidity and mortality in those with infantile onset SMA, due to an impaired cough reflex and therefore poor clearance of airway secretions owing to weakness of the inspiratory and expiratory muscles. Patients thus require ventilator support, without which many would die before the age of two years.
Gastrointestinal complications involve difficulty in swallowing and aspiration pneumonia. Finally, muscle weakness limits motor function, leading to contracture formation, spinal deformity, limited mobility (many children with SMA are wheelchair bound) and at an increased risk of osteopenia and fractures.
Nusinersen is an antisense oligonucleotide that contains 18 nucleotides. The drug binds to the intron downstream of exon 7 and this attachment modifies the splicing of the SMN2 gene to include exon 7, thereby producing normal length and functional survival motor neuron protein.8
The European Medicines Agency (EMA) granted a marketing authorisation in the EU for the treatment of patients with SMA in May 2017.9 Spinraza is available as a single dose use, intrathecal injection containing 12mg of nusinersen. According to the Summary of Product Characteristics, the drug should be administered as early as possible after diagnosis with four loading doses on days 0, 14, 28 and 63 with a maintenance dose once every four months thereafter.10
Early in vitro work and transgenic animal models have shown that nusinersen led to the inclusion of exon 7 in SMN2-derived transcripts, leading to full length SMN protein.8 This work formed the basis for several clinical studies in patients either prior to the development of SMA (NUTURE), those with infantile onset (ENDEAR) and type 2 and 3 (CHERISH). The details of these studies are shown in Table 2 and a brief description of the outcome measures used in the trials, given in the box. The results of the NUTURE trial are not yet available but may provide important insight into the role of nusinersen for the prevention of SMA.
ENDEAR was a multicentre trial involving 13 countries and at the pre-planned interim analysis, only the primary outcome measure, the proportion of milestone responders (based on HINE) was assessed. At this time point:
- 41% of patients assigned to nusinersen were deemed to be motor milestone responders compared with none of those in the sham procedure group
- At the end of the study, the proportion of responders assigned to nusinersen had increased to 51% yet again none of those in the sham procedure became responders
- At the study end, all participants were given the opportunity to enter an open-label extension trial termed SHINE.
The results for the second primary end-point, assessed at the study end, are shown in Table 3, illustrating a significantly prolonged event-free survival (hazard ratio 0.53, p < 0.05) in those given nusinersen.
The results for the change in primary outcome at the study end (15 months) are shown in Figure 1. These data represent the proportion of patients who achieved a 3 or more-point increase in the HFMSE score (that is, a clinically meaningful change).
The data from CHERISH clearly show that children assigned to nusinersen achieved a clinically meaningful change in motor function compared to those given the sham procedure.
To date no results have been made available for the NUTURE study. The effect of nusinersen has also been explored in several other Phase II trials.9
The most commonly reported adverse effects that occurred in at least 20% of nusinersen treated patients and which were reported at least 5% more frequently than in controls during the ENDEAR trial, are shown in Table 4.
Place in therapy
Nusinersen represents an important advance in the management of patients with SMA being the only effective treatment for the disease and the drug has been approved by the FDA for the treatment of patients with subtypes 1, 2 or 3.
In the UK, the drug is available through an expanded access programme but the National Institute for Health and Care Excellence has yet to decide upon the wider availability of the drug. However, the National Centre for Pharmacoeconomics has already decided that nusinersen is not cost-effective at the submitted price although the Scottish Medicines Consortium has accepted nusinersen for restricted use within NHS Scotland but only for patients with symptomatic type 1 SMA (infantile onset).11
While the clinical evidence is convincing, what remains unclear is the extent to which the drug has a lasting effect on patients. Hopefully future trials will provide that much-needed evidence.
1 Calder AN, Androphy EJ, Hodgetts KJ. Small molecules in development for the treatment of spinal muscular atrophy. J Med Chem 2016;59(22):10067–83.
2 D’Amico A et al. Spinal muscular atrophy. Orphanet J Rare Dis 2011;6(1):1–10.
3 Maharshi, Vikas, Hasan S. Nusinersen: The first option beyond supportive care for spinal muscular atrophy. Clin Drug Investig 2017;37:807–17.
4 Lefebvre S et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell 1995;80(1):155–65.
5 Qian Y et al. Understanding the experiences and needs of individuals with spinal muscular atrophy and their parents: a qualitative study. BMC Neurol [Internet]. 2015;15:1–12 (accessed July 2018).
6 Arnold, WD, Kassar, D, Kissel J. NIH Public Access. Muscle Nerve 2015;51(2):157–67.
7 Wang CH et al. Consensus statement for standard of care in spinal muscular atrophy. J Child Neurol [Internet]. 2007;22(8):1027–49.
8 Hoy SM. Nusinersen: First global approval. Drugs. 2017;77(4):473–9.
National Centre for Pharmacoeconomics. Cost-effectiveness of nusinersen (Spinraza) for the treatment of 5q spinal muscular atrophy (SMA) [Internet]. www.ncpe.ie/drugs/nusinersin-spinraza/
(access July 2018).