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The Lancet: Experimental drug for spinal muscular atrophy shows promising early results, prompting phase 3 clinical trial

The Lancet

A new drug for spinal muscular atrophy has shown promising early results in a phase 2 trial involving 20 babies with infantile-onset spinal muscular atrophy. The study, published in The Lancet, found that nusinersen was safe and improved muscle function and nerve activity in most babies. While the drug does not represent a cure, the findings are an important first step and have prompted a larger phase 3 clinical trial.

Spinal muscular atrophy is a genetic disease that affects around one in every 11000 births. It affects the nerve cells in the spinal cord that connect to the muscles, causing them to waste away resulting in progressive muscle weakness and difficulties breathing and eating.

Infantile-onset is the most severe form of the disease, affecting 60% of those diagnosed with spinal muscular atrophy. It affects babies under six months old and less than a quarter of those diagnosed will live to two years old without major feeding and breathing support. Until now there has been no effective treatment for the disease other than providing permanent supportive care.

In the study of 20 babies aged one to seven months, researchers tested the safety, effectiveness and mechanism of action of the nusinersen drug, which is designed to modify the way the body reads the SMN2 gene to increase the production of SMN protein in these infants and children with spinal muscular atrophy. The trial did not include a control group and was 'open-label', meaning that doctors and parents knew the babies were being given the drug.

"While our results are promising this drug does not represent a cure. 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. 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." said lead author Dr Richard Finkel from Nemours Children's Hospital, USA. "It's important to interpret these findings carefully as our study is relatively small and open-label, but this is an important first step."

The first four patients were given a low dose (6mg) of nusinersen for their first three doses to confirm that it was safe before being given the higher dose (12mg) at each four month treatment visit. The next 16 patients were given the higher dose throughout the trial. The drug was injected directly into the spinal fluid via a lumbar puncture.

Four babies died of their disease during the study including one who died too early to be included in the analysis. All participants experienced adverse events linked to their disease, with 16 babies experiencing 77 serious adverse events such as difficulties breathing or respiratory infections which were considered by the investigators not to be drug-related. One baby developed mild neutropenia (low white blood cell count) and another had mild vomiting possibly linked to the drug.

During the trial the babies' muscle function was assessed using two tests that measured their ability to perform certain tasks (head control, sitting, grasping, kicking, rolling, crawling, standing and walking) and their overall muscle function.

Muscle skills improved in 16 out of 20 babies and the biggest improvements were in their ability to grasp, kick and sit (for 13, nine and eight babies, respectively - see figure 1B). Overall muscle function improved in 14 of 18 babies, for whom measurements were available, with the average muscle function score increasing by 11.5 points (on the 64-point CHOP-INTEND motor function scale) during their treatment time. When babies are not treated this score typically declines by 1.27 points each year, as shown in a comparison study.

The researchers also found that responses generated from the peroneal nerve (located behind the knee) increased for babies given high dose nusinersen, and responses from the ulnar nerve (located at the wrist) increased in 12 of the 15 babies for whom nerve activity measurements were available.

The researchers were unable to calculate an average survival for those on the drug as most babies were still alive - with 16 babies surviving without requirement for permanent breathing support during the trial's treatment period, which ranged from 18 to 32 months.

The study demonstrated that nusinersen, when administed by lumbar puncture (spinal tap), was effectively absorbed from the spinal fluid into the spinal cord and brain tissue and targeted the nerve cells that are most affected in spinal muscular atrophy. This was performed by testing tissue samples from three babies who died during the study, providing proof of the drug's action.

The researchers note that the small number of patients in the trial, the short follow-up period and that it was an open-label study limit the findings of the study. Typically, phase 3 trial results are needed to confirm results from phase 2 clinical trials.

Writing in a linked Comment, Professor Thomas Gillingwater, University of Edinburgh, UK, said "The new open-label, phase 2 clinical study ... represents a major milestone on the journey towards a viable therapy... Whilst these findings need to be interpreted cautiously in the context of the obvious limitations of a small, open-label interventional trial, they should generate significant encouragement that elevating SMN protein levels is likely to be of therapeutic benefit to spinal muscular atrophy patients."

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NOTES TO EDITORS

The study was funded by Ionis Pharmaceuticals Inc and Biogen. It was conducted by researchers from Nemours Children's Hospital, Columbia University Medical Center, University of Toronto, Stanford University and Ionis Pharmaceuticals. A declaration of interests is available in the Article.

[1] Quote direct from author and cannot be found in the text of the Article.

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