A new international study has shown that treating babies with spinal muscular atrophy before symptoms appear can dramatically improve outcomes.
Emily and Mitch still remember the afternoon they learnt their newborn son, Xavier, had screened positive for spinal muscular atrophy (SMA).
"We had Mitch's family over to see Xavier at home for the first time when I took the phone call. It was from a neurologist at the Sydney Children's Hospital," Emily said. "They told us Xavier's newborn screening was positive for SMA. It left us completely numb and confused."
SMA is a rare genetic condition that causes progressive muscle weakness due to the degeneration of motor neurons in the spinal cord. In its most severe forms, babies cannot sit up and rarely live beyond their first birthday.
At the time, treatment options were limited. Xavier could begin a lifelong regimen of spinal injections or join a clinical trial testing an oral medication called risdiplam.
"We were honestly torn and didn't know what to choose for Xavier. The hospital team were so supportive and knowledgeable, and with the help of our family, we decided we wanted Xavier to be on the trial," Emily said.
A new approach to SMA treatment
Xavier was one of 26 infants enrolled in the international RAINBOWFISH trial, which tested the safety and efficacy of risdiplam in presymptomatic babies diagnosed with SMA. Findings from the first two years of the five-year study have been published in the New England Journal of Medicine .
Professor Michelle Farrar , from UNSW Sydney's School of Clinical Medicine and the Sydney Children's Hospital, Randwick , co-led the study, which included infants from Australia, the United States, Belgium, Brazil, Poland, Russia and Taiwan.
"The really exciting thing about this is that it's an oral drug which can be taken at home and be initiated as soon as the diagnosis is made," Prof. Farrar said. "It is important to start treatment as soon as possible to preserve strength from the very start. Every day counts when there is irreversible loss of motor neurons."
Risdiplam helps the body produce more of an essential protein that is deficient in SMA, known as Survival Motor Neuron (SMN) protein. The drug works by switching on a backup gene (SMN2) so it can produce enough of the functional protein.
Significant results in early treatment
The babies were between 16 and 41 days old when they received their first dose of risdiplam, ahead of the approved two-month threshold set by the US Food and Drug Administration at the time. A third of the trial participants were from Australia, all of whom were treated at Sydney Children's Hospital, Randwick.
"The rationale for this trial was that the impact of the medicine would be greatest if it was given before symptoms started to emerge as a baby grows," Prof. Farrar said.
The drug's impact was significant, with the children reaching development milestones that would have been otherwise out of reach.
Of the 26 children, 25 could sit unsupported at 12 months, and 21 were walking alone at two years. The majority did not need any respiratory or feeding support, and many showed improvements in overall muscle function, with increases in compound muscle action potential (CMAP) amplitude observed over the two-year period.
"The fact these children are surviving to two years and beyond, are hitting motor milestones, being able to breathe and swallow on their own, is just completely unprecedented. It's a very significant outcome," Prof. Farrar said.
Regulatory impact and future directions
The findings from the RAINBOWFISH trial prompted regulators to expand the approved use of risdiplam to include neonates aged 0 to 8 weeks.
"Starting treatment earlier can make a lifetime of difference," Prof. Farrar said. "It means we can better enable those with SMA to be independent, to function and move on their own, and can improve outcomes for swallowing and breathing too."
The study will continue for a total of five years, with researchers now exploring longer-term outcomes and broader impacts on feeding, learning and development.
"We're continuing to follow the children that have been treated to understand its impact over a longer period," Prof. Farrar said.
"We're also looking at combination therapies and new treatment targets. This treatment targets the 'S' in SMA - the spinal part - but we're now involved in new clinical trials targeting the 'M' and the 'A', so the muscle atrophy. The idea is, if you have a healthy nerve, but the muscle is weak and atrophied, if we add another treatment in, it may help the muscle grow and improve strength and weakness."
Xavier today
Now nearly five years old, Xavier is thriving. He attends preschool, takes swimming lessons, and enjoys climbing, dancing and playing with his brother and friends.
"He is confident and determined and will always try to do new things or try to achieve what he wants in a brave way," Emily said.
While the results are promising, Prof. Farrar is clear that the journey is ongoing.
"SMA is not solved," Prof. Farrar stressed. "The story is not over. We continue to look at how we can optimise outcomes through therapies and understanding the disease."
