Incomplete registry data limits value of SMA studies

Registry studies can provide a valuable glimpse into how outcomes are evolving in rare diseases such as spinal muscular atrophy (SMA), but a lack of complete data can limit their usefulness, a study found.

The researchers called for “improved processes and governance for communication and collaboration across registries [and] standards to harmonize and simplify outcome measurements” so that SMA registries can provide the best data possible for future research.

An early-access version of the study, “Use of European registries to characterise the changing landscape of disease progression and treatment of spinal muscular atrophy (SMA): opportunities, pitfalls and challenges,” was published in the Orphanet Journal of Rare Diseases. The work was funded by the European Medicines Agency.

Several disease-modifying treatments targeting the underlying cause of SMA have been widely approved over the last decade, altering the typical course of the disease. With the advent of these therapies, many countries have launched registries to track outcomes for people with SMA.

“Given the changing treatment landscape for SMA, this study leveraged six registries across Europe and aimed to describe the disease progression of patients with SMA, overall and by treatment status and disease type, and to assess treatment utilization over time,” along with “the challenges and limitations of such an approach,” the researchers wrote.

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Analysis covers more than 2,000 patients

SMA is a genetic disorder in which motor neurons, the nerve cells that control movement, sicken and die, leading to muscle weakness and mobility limitations.

SMA types are based on the age when SMA symptoms first appear. In type 1 SMA, symptoms appear before six months; in type 2, symptoms appear between six and 18 months; in type 3, symptoms develop later in childhood. Earlier symptom onset is generally associated with more severe disease and greater long-term mobility limitations.

The six registries covered patients in Belgium, the Czech Republic, Slovakia, Sweden, Germany, Austria, Spain, Ireland, and the U.K., containing data on more than 2,000 SMA patients. Among them, 19.7% had SMA type 1, 41.8% had type 2, and 35.6% had type 3. Other types made up a small fraction of reported cases.

Just over 60% of patients had received a disease-modifying treatment, the most common of which was Spinraza (nusinersen), the first such therapy to be widely approved.

The researchers noted that the use of disease-modifying treatments increased markedly over time. In the mid-2010s, before any therapies were approved, about 2% of patients received treatment through clinical trials. But by 2021, when multiple therapies were available, more than two-thirds of patients (68.4%) were on treatment.

To analyze outcomes following treatment, the researchers used a measure called best functional status, which reflects the motor functions a person is able to perform (sitting independently, walking, etc.).

In SMA type 1, the most common best functional status was “sitter” (36.6%), followed by “non-sitter” (23.6%) and “walker” (12%). In type 2, more than 60% of patients were able to sit independently, and in type 3, nearly 90% were walkers.

The researchers noted that these outcomes were somewhat difficult to interpret due to missing data. Almost none of the patients had a best functional status recorded before starting treatment, making it impossible to compare how functional status had changed after treatment. And among SMA patients who did not receive treatment, best functional status was almost never recorded.

Missing data was also an issue with other variables. For example, SMA is usually diagnosed via genetic testing — but for most patients in these registries, the reason for genetic testing was not recorded.

“The observed lack of data completeness, especially for motor and functional status variables, results in an incomplete picture of this patient population and limits the ability to identify post-diagnostic outcomes of interest or patient prognostic characteristics that may influence treatment decisions,” the researchers wrote.

This lack of data is especially problematic for a rare disease such as SMA, the scientists said. There’s been an increasing push to use registry data from untreated patients as a benchmark for future clinical studies testing new treatments, but comparisons aren’t always reliable because so much data is missing in the registries, they said. They called for greater efforts to standardize data collection in SMA registries so that these studies can provide the most useful data possible.