Compared to No Treatment for SMA Type 1, Outcomes Better With Evrysdi
Compared to what would be expected without treatment, the approved oral therapy Evrysdi (risdiplam) led to marked benefits in survival and motor outcomes for babies with spinal muscular atrophy (SMA) type 1, according to a comparison of clinical trial data.
“Untreated infants with Type 1 SMA … reached death or permanent ventilation, required feeding/nutritional support and respiratory/ventilatory support at time points comparable to those reported in other natural history studies. Similarly, they did not achieve or retain most motor milestones, which is consistent with historical cohorts,” the researchers wrote.
“These outcomes markedly contrasted with those achieved by [Evrysdi]-treated infants,” they said.
The study, “Natural history of Type 1 spinal muscular atrophy: a retrospective, global, multicenter study,” was published in the Orphanet Journal of Rare Diseases. The work was funded by Roche, which markets Evrysdi.
Type 1 SMA is a severe form of the disease marked by symptoms manifesting in the first few months after birth. In recent years, several disease-modifying therapies have been developed that are dramatically improving clinical outcomes for babies with SMA.
The clinical study ANCHOVY was launched in 2008, prior to the availability of treatments for SMA. The study included 60 untreated children with SMA type 1 from nine countries across Asia, Europe, and North and South America.
“ANCHOVY provides meaningful additions to previously published natural history studies by including data from countries outside Europe and the USA, such as Brazil and Russia, that had not previously been represented,” the researchers wrote.
Among these children, symptoms became apparent between one and three months after birth, with the most common initial symptom being low muscle tone (hypotonia) in nearly all patients. All children with available genetic data had only two copies of the SMN2 gene that can partially compensate for mutations in the SMN1 gene that cause SMA.Â
No patients with available data had any form of head control or sitting ability by age 1, though some babies showed head control “wobbles” at earlier ages, and one was able to sit supported at age 9 months.
Most of the babies had difficulty swallowing that appeared within the first year of life, and most babies with available data required a feeding tube by age 1.
The median age at requiring permanent ventilation was just over 1 year, and the median age at death was 41.2 months (less than 3.5 years). The median age at reaching either of these endpoints was 7.3 months.
Consistent data
Overall, these data “are consistent with data reported in previous natural history studies of Type 1 SMA,” the researchers wrote.
The team next conducted a battery of analyses comparing outcomes from this natural history trial with results from a two-part clinical trial called FIREFISH (NCT02913482), in which babies with SMA type 1 were treated with Evrysdi starting in the first months of life.
Part 1 of the trial assessed the safety of two different doses of risdiplam in 21 babies (median age about 7 months) and determined that the higher dose was the optimal dose for the trial’s second part. Part 2 is evaluating this dose’s safety and effectiveness in another 41 type 1 infants, who began treatment at median age of 5.3 months.
“Comparing the key baseline [starting] and SMA disease characteristics for ANCHOVY and FIREFISH Part 2 demonstrated that the populations are similar,” the researchers wrote.
In FIREFISH, 85% of children treated with Evrysdi were still alive and free of ventilation at 18 months of age. In the ANCHOVY natural history study, only 10% of children were alive and ventilator-free at age 18 months.
“This great disparity demonstrates the robust differentiation of event-free survival between the two studies,” the researchers wrote.
Also of note, 61% of children in FIREFISH have achieved some level of sitting ability, with nearly one in four (24%) sitting unassisted after a year on Evrysdi. Only 26% of children in FIREFISH required a feeding tube at age 1, while the remaining 74% were fed exclusively by mouth.
“While demographic and baseline disease characteristics were comparable between the ANCHOVY and FIREFISH Part 2 studies, the marked difference in event-free survival, achievement of motor milestones and initiation of feeding support for FIREFISH Part 2 participants compared with ANCHOVY patients further supports the benefit of [Evrysdi] in patients with Type 1 SMA,” the scientists concluded.
The researchers noted this study is limited by its retrospective design, and also by missing data and potential biases. For example, they noted that motor assessments sometimes were not performed in patients whose health was declining, making it difficult to assess trends over time.
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