Promising results for a disease-modifying treatment for spinal muscular atrophy (SMA) were presented at the 5th Annual Congress of the European Academy of Neurology (EAN) in Oslo, Norway, last week.
SMA is a group of hereditary neuromuscular disorders characterised by degeneration of motor neurons and consequent, progressive muscular weakness and atrophy.1 Although the most common cause of SMA has long been known to be decreased production of the survival motor neuron (SMN) protein, it has been extremely challenging to treat.1 At EAN, interim results were shown from the NURTURE trial, which investigates the anti-sense oligonucleotide (ASO) nusinersen (Spinraza®) for treatment of SMA.2 Nusinersen is designed to increase protein levels of SMN and thereby decrease degeneration of motor neurons.1
In this ongoing, multi-centre, open-label phase II trial, the safety and efficacy of multiple intrathecal doses of nusinersen are being investigated in infants with SMA.2 Enrolled infants are less than six weeks old at the time of first dose, clinically pre-symptomatic, genetically diagnosed with SMA, with two or three copies of the SMN2 gene.2 Thus far, 15 infants with two copies of the SMN2 gene and 10 infants with three copies of the SMN2 gene have been enrolled.2 Disease severity is determined by the copy number and expression level of the SMN2 gene – a paralog which produces variable amounts of functional SMN protein.3
With respect to the primary outcome – time to death or respiratory intervention – all infants are alive and none have required permanent respiratory intervention at the time of interim analysis 2–4 years after the first dose. Four out of 25 infants required respiratory interventions during acute, reversible illness.
Furthermore, all infants achieved the World Health Organization (WHO) motor milestone of sitting without support, 88% achieved walking with assistance and 77% achieved walking alone. Some differences were noted between infants with two versus three copies of the SMN2 gene. All infants with three copies of the SMN2 gene are achieving maximum scores on the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP- INTEND), indicating that a ceiling effect occurs when measuring the motor performance of the infants. Five infants with two copies of the SMN2 gene have yet to achieve the maximum score. Infants with three copies of the SMN2 gene also appear to perform better on suckling and swallowing tests.
In addition, the trial is investigating the value of a biomarker, phosphorylated neurofilament heavy chain (pNF-H), for predicting motor outcomes. Preliminary results indicate that low plasma levels of pNF-H may predict an earlier achievement of walking alone.
Considering that no new adverse events were reported, these data add to the evidence from over 7,000 patients already treated with nusinersen worldwide, and indicate a benefit for early, pre-symptomatic treatment with nusinersen.
- Wurster C.D. and Ludolf A.C. Nusinersen for spinal muscular atrophy. Ther Adv Neurol Disord. 2018;11:1756285618754459.
- Sansone V, et al. Nusinersen in infants who initiate treatment in a presymptomatic stage of spinal muscular atrophy (SMA): interim results from the phase 2 NURTURE
Presented at the 5th annual congress of the European Association of Neurology, 1 July 2019.
- Prior TW. Perspectives and diagnostic considerations in spinal muscular atrophy. Genet Med. 2010;12(3):145-52.