Better Ways of Capturing Progression in Types 2 and 3 Identified in Study

Four measures of motor ability — including one of continuous upper limb activity that can be done at the home — reliably detect significant functional changes over one or two years in people with spinal muscular atrophy (SMA) types 2 and 3, according to a natural history study.

These findings support the use of such measures in future clinical trials to better evaluate disease progression in these patients, and to strengthen a trial’s likelihood of determining, within a reasonably short testing period, if significant therapeutic benefits are being shown, the researchers wrote.

The study, “Natural history of Type 2 and 3 spinal muscular atrophy: 2‐year NatHis‐SMA study,” was published in the journal Annals of Clinical and Translational Neurology.

Natural history studies evaluate how a disease progresses without treatment. Data from such studies in SMA are key for identifying markers of disease progression and outcome measures that best assess a therapy’s benefits both in clinical trials and real-world studies after its approval.

SMA types 2 and 3 progress slowly, however, and detecting decline in motor function over short periods, like a two-year trial, is challenging using current measures.

More sensitive measures are needed to not only capture small functional changes over shorter periods, but also to “reduce the number of patients included to adequately power clinical trials, the risk of false negatives, and the duration of clinical trials,”  the researchers wrote.

More SMA treatment studies are also likely, including those into add-on therapies, with three disease-modifying treatments now available for SMA in the U.S. — Spinraza (nusinersen), Zolgensma, and Evrysdi (risdiplam). Natural history studies of untreated patients, in contrast, are likely to decline and become unviable.

A team of European researchers published findings related to outcome measures used in the multicenter, NatHis-SMA study (NCT02391831) — likely one of the last natural history studies to be undertaken in SMA.

Co-funded by Institut Roche and Association Institut de Myologie, in France, the study’s goal was to characterize the natural disease course of SMA type 2 and 3 over two years, and to identify reliable disease biomarkers and sensitive outcome measures.

It enrolled 81 SMA patients (53 with type 2, and 28 with type 3 disease), ages 2–30, and was conducted at nine neuromuscular disease reference centers across Belgium, France, and Germany between May 2015 and May 2018.

Outcomes assessed at the study’s beginning and every six months thereafter included motor function (using the Motor Function Measure, or MFM, scale), hand strength (via MyoGrip and MyoPinch digital measures), and upper limb activity or walking speed (via an at-home, wearable device called ActiMyo).

Tests of lung function and measures of blood levels of SMN — the protein missing in SMA patients — were also taken.

Wearable devices like ActiMyo are gaining in research interest, as they can capture data across aspects of daily life over a longer timescale. They also allow physicians to follow patients remotely, an advantage during the ongoing COVID-19 pandemic.

Assessments were adjusted for each patient based on age (2–5 year olds, and 6–30 year olds) and walking ability (ambulatory or not). Four functional status groups were also predefined: SMA type 2 sitters (those able to sit) and non-sitters (unable to sit), and type 3 ambulant (who are able to walk) and non-ambulant (unable to walk) patients.

A total of 32 participants (mainly with type 2 disease) discontinued the study between its first and second year, opting to begin using an approved treatment or enroll in a clinical trial.

No significant changes in MFM scores were observed after one year, but motor function in patients ages 6 and older declined significantly over two years, particularly among those with SMA type 2, results showed. (MFM32, a 32-item scale, was used with the age 6 and older patient group, and MFM20, a 20-item scale, with younger patients.)

The lack of motor function changes in type 3 patients may be related to this type’s slower disease progression, or to the smaller number of patients in this group, the team noted.

Both hand grip and pinch strength declined significantly over 12 and 24 months, regardless of SMA type, and a significant drop in upper limb activity was detected after six and 12 months among type 2 patients and non-ambulant type 3s.

Changes in upper limb activity after two years could not be assessed, due to the small number of patients — one — still being evaluated at that time. No significant changes in walking speed were observed among ambulant participants during the two-year study period.

Forced vital capacity, a standard measure of lung health, also declined significantly over the first year, but not over two years, while blood SMN protein levels remained stable during the study.

“We demonstrate that a significant decline over a 12‐ or 24‐month period can be reliably measured in a broad range of SMA patients using the MFM32, MyoGrip, MyoPinch, and ActiMyo,” with the latter allowing for changes to be detected after six months, the researchers wrote.

Notably, these measures showed higher sensitivity scores than current measures — including the six‐minute walk test and Expanded Hammersmith Functional Motor Scale — suggesting that they may “reduce the necessary sample size and study duration of future clinical trials,” they added.

“The collective use of these measures in a therapeutic trial protocol could provide a more holistic evaluation of disease progression in individuals with SMA, potentially improving treatment options for patients,” the researchers concluded.