SMA progression in types 2 and 3 varies without treatment: Study
Natural history data used began being collected before DMTs available
In the absence of treatment, the long-term progression of spinal muscular atrophy (SMA) types 2 and 3 is highly variable and seems to be influenced by factors including a patient’s age and functional status, according to four years of data in a natural history study.
Generally, those with better functional abilities at their first assessment saw faster motor declines than people who had already lost many abilities when first evaluated.
Researchers said these long-term findings highlight the importance of looking at patient subgroups to get the clearest picture of how SMA progresses. Ultimately, these natural history data could serve as a reference for clinical studies looking at how SMA treatments influence disease progression.
The study, “Long-term natural history in type II and III spinal muscular atrophy: a 4-year international study on the Hammersmith Functional Motor Scale Expanded,” was published in the European Journal of Neurology.
Natural history studies help to establish a therapy’s ability to alter disease course
Over the last decade, the emergence of disease-modifying therapies (DMTs) that directly address the underlying cause of SMA has substantially altered the disease course for patients.
Treatment benefit has been most obvious in infants with SMA type 1, a severe form. While these babies would not normally survive into childhood without treatment, real-world evidence shows they’re living longer and achieving previously unattainable developmental milestones.
In SMA type 2 and type 3, which are generally milder, disease progression can be significantly more variable. But with DMTs now available, fewer natural history studies are looking at long-term outcomes in untreated patients.
Without a good natural history group for comparison, it’s more difficult to clearly establish how DMTs are altering the disease course across patient groups.
An international team of scientists reported four-year findings from a large international study looking at disease progression over time in untreated people with SMA types 2 and 3.
The analysis included 388 patients seen at centers in Belgium, Italy, Spain, the U.K., and the U.S. Among them, 226 people had SMA type 2 and 162 had SMA type 3. Each center was in one of three natural history networks, which began collecting data in 2003, 2006, and 2015.
Disease progression was monitored with the Hammersmith Functional Motor Scale Expanded (HFMSE), a validated measure of functional abilities across 33 items. Ranging from zero to 66, a higher score reflects better motor function.
Largest motor declines seen in children with greater initial abilities
Among those with SMA type 2, who had a mean age at their first assessment of 11.41 years, HFMSE scores over the entire four-year period declined by a mean of 2.2 points.
In the SMA type 3 group, where the mean age was 19.48 years at the first assessment, HFMSE score declined by a mean of 2.75 points.
Still, disease progression was highly variable across those with each SMA type. In general, subgroups of people who had better functional abilities at the first assessment (baseline) tended to see the largest declines in HFMSE scores over time.
Among those with SMA type 2, the greatest declines in HFMSE scores occurred in children ages 5-14, who still retained their ability to sit up on their own at baseline.
Conversely, the smallest changes were observed in the oldest patients and those who weren’t able to sit up at baseline.
Likewise, within the SMA type 3 group, faster disease progression was observed in children, ages 7-14, who were still able to walk at baseline.
Slower declines were observed in children younger than 7 years old and in patients older than age 15, particularly those with SMA subtype 3a, in which initial symptoms emerge before age 3.
Consistently, statistical analyses indicated that a person’s baseline HFMSE scores and age were significant clinical predictors of four-year disease progression.
Study of value as fewer SMA patients now without a disease-modifying therapy
“Our data confirm the broad variability of findings observed in both SMA type II and type III with the largest changes observed in the more able subgroups … who have relatively high [HFMSE] scores that are progressively lost over time,” the researchers wrote.
“In the less able subgroups, such as those who have lost sitting, changes are limited by their very low HFMSE scores at baseline,” they added.
The scientists noted that for subgroups who’ve already lost many functional abilities, other clinical scales may help to capture more nuanced changes in disease progression.
For the most part, data collected in the study were obtained before DMTs became available. With the vast majority of patients now being treated, collecting natural history data is more difficult. The scientists expect, for this reason, that their findings will be an important resource for future clinical studies.
“Our findings … provide reference data that can be used for future comparisons and facilitate the interpretation of long-term clinical trial results and real-world data,” they concluded.
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