SMA type 1 children show lasting benefits after 5 years on oral treatment
Final Evrysdi trial data point to survival, motor, feeding gains
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- After five years of daily Evrysdi treatment, 90% of children with SMA type 1 in the FIREFISH trial were alive.
- Many children reached motor milestones rarely seen without treatment, including sitting without support.
- Most maintained swallowing ability, many continued feeding by mouth, and no new safety findings were reported.
After five years of daily treatment with Evrysdi (risdiplam), 90% of children with spinal muscular atrophy (SMA) type 1 were alive, and most had reached motor milestones, such as sitting without support, that are rarely seen in untreated children with this severe disease.
These are the final published results of the two-part Phase 2 FIREFISH trial (NCT02913482), which tested the safety and effectiveness of Evrysdi in infants with SMA type 1 and two SMN2 copies who were between 1 and 7 months old at enrollment.
The study also found that most children with SMA type 1 maintained their ability to swallow and many continued feeding by mouth, either fully or partly. Some measures of breathing support needs also declined over time. Still, no children in the study learned to walk without assistance.
Final FIREFISH results published
The study, “Efficacy and safety of risdiplam in patients with type 1 spinal muscular atrophy: a 3-year open-label extension of the two-part, phase 2 FIREFISH trial,” was published in The Lancet Child & Adolescent Health.
SMA is a rare, progressive disease of the nerves that control muscles, caused by a shortage of a protein called SMN. SMA type 1 is a severe form, usually appearing within six months of age. Without treatment, children with this condition are never able to sit on their own and typically die from breathing complications at a median age of 10 months.
Evrysdi, taken daily by mouth or via feeding tube, is a medication approved to treat adult and pediatric patients with SMA by helping to increase functional SMN protein levels.
The FIREFISH trial enrolled 62 children with SMA type 1 and two SMN2 copies at 17 medical centers across 12 countries. After two years in the study, 55 children continued Evrysdi treatment into the open-label extension for a further three years. At the time of the study’s completion, 52 children (84%) had completed five years of Evrysdi treatment.
After one year of therapy, most children were alive and did not require permanent ventilation, and many had achieved motor milestones. Evrysdi’s benefits were generally maintained or improved at two, three, and four years.
After five years of treatment, 56 of the 62 children (90%) were alive, and 50 (80%) were alive without needing permanent ventilation.
Breathing support needs tracked over time
Among the 58 children who received the approved dose of Evrysdi, 17 (29%) did not require any invasive or noninvasive breathing support by year five, up from 13 (22%) at year one. The proportion needing noninvasive breathing support for less than 16 hours a day dropped from 55% at year one to 36% at year five.
The children’s motor abilities were tracked using several standard tools, including CHOP-INTEND and HINE-2, which measure motor function and motor milestone development in infants.
Mean CHOP-INTEND scores rose from 22.47 at the study’s start to about 50 by year five, representing “a clear deviation from the natural disease course, in which independent sitting rarely occurs without disease-modifying treatment,” the scientists wrote.
By year five, 36 children (62%) could sit without support for at least five seconds, and 34 (59%) could do so for 30 seconds. Four children (7%) could stand without support, and six (10%) could “cruise,” meaning they could walk while holding onto something for balance. No children were able to walk independently. Most of the gains in motor scores occurred within the first four years, after which scores tended to stabilize rather than continue rising.
By year five, most children maintained their ability to swallow, and many continued to feed by mouth, either fully or partially. Specifically, 46 children (79%) could swallow, 42 (72%) were feeding at least partly by mouth, 37 (64%) were feeding exclusively by mouth, and four (7%) relied entirely on a feeding tube.
Growth patterns for weight, height, and head circumference were consistent with those typically seen in other children with SMA type 1. The rate of hospital stays also declined over time, from 1.24 hospitalizations per patient-year in year one to 0.55 in year five, and 13 children (22%) were never hospitalized during the entire study.
No new safety findings reported
All 62 children experienced at least one adverse event during the study, and a total of 950 adverse events were recorded, most of which were mild or moderate. The most common were fever (65%), upper respiratory infections (63%), and pneumonia (50%), which was also the most frequently reported serious adverse event, occurring in 28 children (45%).
Forty-one adverse events, occurring in 12 children (19%), were considered by study doctors to be related to Evrysdi itself, and no individual treatment-related adverse event occurred in more than 5% of participants. The most common treatment-related adverse event, mild in severity, was blood in the urine, seen in three children.
Seven children (11%) died during the study, six from progressive disease and one from a pneumonia-related adverse event. No deaths occurred after the second year of the study.
No child stopped taking the therapy because of an adverse event linked to the drug. The researchers noted that no retinal findings, which had been observed in earlier animal studies of the drug, were found in any of the children.
Regarding study limitations, the authors noted that children may have reached certain abilities earlier than documented, as milestones were recorded only during clinic visits. Some visits were missed due to COVID-19 restrictions, and those children were counted as not having reached a milestone. The study also did not evaluate cognitive or speech development, nor did it assess the impact of scoliosis (a sideways curvature of the spine) on motor progress.
“FIREFISH provides evidence of long-term safety and efficacy of [Evrysdi] in children with [SMA type 1] through the achievement of motor milestones, maintenance of respiratory and feeding function, and consistent safety findings,” the authors wrote. “Longer-term real-world data are crucial to provide further insights on the enduring impact of [Evrysdi] treatment in [SMA type 1].”
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