New Treatment Benefits Children With Spinal Muscular Atrophy

December 15, 2016

Researchers are reporting positive results with a new treatment for spinal muscular atrophy, the most common genetic cause of childhood mortality.

The condition, which affects around 1 in every 11,000 births, is a progressive motor neuron disorder, causing muscle weakness and difficulties breathing and eating.

About 60% of patients with spinal muscular atrophy are born with the severe form — infantile-onset type I — developing profound limb and trunk weakness before 6 months of age and failing to roll over or achieve independent sitting. Less than a quarter of these infants survive beyond 2 years of age without dependence on ventilation support. There are no approved drug treatments.

The current research, published online in The Lancet on December 6, involves giving an antisense oligonucleotide aimed at increasing concentrations of the key protein — known as survival motor neuron (SMN) protein — which is underexpressed in spinal muscular atrophy.

In the phase 2 open-label study, multiple intrathecal doses of the drug, known as nusinersen (in development by Ionis Pharmaceuticals and Biogen) appeared to show remarkable efficacy, with improvements in motor function, achievement of motor milestones, and permanent ventilation-free survival as compared with published natural history.

"We observed remarkable improvement in muscle function. For instance, some babies undergoing treatment developed the ability to sit and roll over independently and improved their head control, kicking, grasping, standing, and even walking," lead author Richard Finkel, MD, Nemours Children's Hospital, Orlando, Florida, told Medscape Medical News.

He cautioned, however, that while their results are promising, this drug does not represent a cure.

"Although this type of improvement has not been observed before in infants with infantile-onset spinal muscular atrophy, the drug did not restore normal levels of muscle function. It's important to interpret these findings carefully as our study is relatively small and open-label, but this is an important first step."

"A New Dawn"

In an accompanying editorial, Thomas H. Gillingwater, PhD, Euan MacDonald Centre for Motor Neurone Disease Research and Centre for Integrative Physiology, University of Edinburgh, United Kingdom, describes the study as "a new dawn in developing safe and effective therapy options for spinal muscular atrophy that are urgently required."

The new open-label, phase 2 clinical study, he writes, "is a major milestone on the journey towards a viable therapy…. Although these findings need to be interpreted cautiously in the context of the limitations of a small, open-label, interventional trial, they should generate substantial encouragement that raising SMN protein concentrations could be of therapeutic benefit to patients with spinal muscular atrophy."

In the Lancet paper, the researchers explain that spinal muscular atrophy is caused by deletions or mutations in the SMN1 gene, rendering it incapable of generating functional SMN protein. However, there is a similar gene — SMN2 — that can also produce the SMN protein, but this gene has several nucleotide substitutions compared to SMN1 so that only 10% to 25% of SMN2 transcripts can generate functional SMN protein.

The key part of the gene needed to produce the SMN protein is known as exon 7. Nusinersen is an antisense oligonucleotide that binds to repressive sites within SMN2 exon 7, thus promoting exon 7 inclusion and increased production of functional SMN protein.

The current study included 20 infants aged 3 weeks to 7 months who had spinal muscular atrophy symptoms and were known to have SMN1 homozygous gene deletion or mutation. They received loading doses of 6 to 12 mg of nusinersen on days 1, 15, and 85, and then 12-mg equivalent doses on day 253 and every 4 months thereafter, for a total of 18 to 32 months.

All participants were followed up regularly in person, with additional monitoring by telephone for safety and ventilation status.

In terms of safety, 77 serious adverse events were reported in 16 participants, all considered by study investigators not related or unlikely related to the study drug. The most common were respiratory distress or failure or respiratory infections, which the authors say are commonplace in infants with spinal muscular atrophy.

One mild event of transient, asymptomatic neutropenia and one mild event of vomiting were both considered "possibly related to nusinersen."

Significant Efficacy Results

Efficacy results showed incremental improvements in developmental motor milestones on the Hammersmith Infant Neurological Examination-2 (HINE-2) scale in 16 of 19 participants (1 of 4 participants who started with loading doses of 6 mg and in all 15 of those starting on the 12-mg dose) at the last visit compared with baseline.

Change in HINE-2 score from baseline to last visit was significant for both cohorts combined (P =.0002) and for participants in the 12-mg dose group (P < .0001).

Improvements of two or more levels per motor milestone category on at least one category were observed in 13 participants and were most often observed for grasping (13 participants), ability to kick (9 participants), and sitting (8 participants) but were also evident for head control (6 participants), rolling (6 participants), standing (5 participants), crawling (2 participants), and walking (2 participants).

Motor function, assessed by using the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders scale, showed a mean increase of 11.5 points from baseline to last visit overall, with 14 of 18 infants having an improvement.

In the 12-mg group, 12 of 14 participants had an increase from baseline to last visit (mean increase, 15.2 points) compared with a natural history case series of infants with type I spinal muscular atrophy, in which a mean decline of 1.27 points per year was observed.

A score greater than 40, a value rarely observed for symptomatic infants with type I spinal muscular atrophy with two SMN2 gene copies, was observed in none of the 13 infants with two SMN2 gene copies at baseline and increased to 7 of 13 participants at last visit in the 12-mg group, the researchers report.

As of the date of analysis, a median age of death or permanent ventilation had not been reached because most participants were surviving without permanent ventilation. Four infants died of their disease during the study, including one who died too early to be included in the analysis.

Postmortem samples from the infants who died showed proof of target engagement and mechanism, as nusinersen altered SMN2 splicing, with an increase in full-length transcript that includes exon 7, and an increase in SMN protein in spinal cord motor neurons as compared with untreated infants with spinal muscular atrophy as control, the authors report.

The researchers conclude: "Our study shows favourable safety and tolerability, pharmacokinetics, proof-of-concept pharmacodynamics, and a promising clinical response of intrathecal nusinersen." They add that this study provides proof of principle for the use of antisense therapeutics in the treatment of neurologic disorders and that therapies that increase SMN protein might provide clinical benefit to patients with spinal muscular atrophy.

A large phase 3, randomized, sham-controlled study of nusinersen in infantile-onset spinal muscular atrophy is ongoing. Because no safety concerns were identified in the phase 2 study reported here, the phase 3 study has incorporated a more frequent dosing regimen, especially in the first few months of treatment, when infants with spinal muscular atrophy progress rapidly and are particularly vulnerable, the authors note.

They add that presymptomatic treatment might provide an even greater clinical response, and this hypothesis is being examined in an ongoing phase 2 study.

The current study was funded by Ionis Pharmaceuticals and Biogen. Dr Finkel reports grants and personal fees from Ionis Pharmaceuticals during the conduct of the study and grants and advisor fees from Biogen and Roche, outside the submitted work. He also serves in an advisory capacity to the nonprofit organizations the SMA Foundation, Cure SMA, SMA Reach (UK), and SMA Europe and serves on the data safety monitoring board for the AveXis gene transfer study. Professor Gillingwater is chair of the Scientific Advisory Board of the SMA Trust and serves on scientific and clinical advisory boards for SMA Europe and Association Française contre les Myopathies. He is named on a patent application submitted by the University of Edinburgh for the use of β-catenin inhibitors for the treatment of spinal muscular atrophy.

Lancet. Published online December 6, 2016. Abstract, Editorial

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