Risdiplam Data to New Way of Classifying ‘Types’ Among SMA Europe 2020 Highlights, Advocate Says

Results from a clinical trial of risdiplam in a broad range of people with spinal muscular atrophy were a highlight of SMA Europe’s 2020 conference, a board member of that SMA umbrella patient advocacy group said in an interview.

Also of interest were discussions about a possible paradigm shift in how SMA is classified, Kacper Rucinski, the founder and president of Fundacja SMA in Poland, told SMA News Today.

The conference took place earlier this month in Evry, France.

Asked what he thought “most exciting” of new findings presented, Rucinski highlighted data showing the SUNFISH trial (NCT02908685) met its primary goal — greater improvements in motor function compared to placebo after one year of treatment — in children and young adults (ages 2 to 25) with SMA types 2 and 3. 

These data showed that treatment with oral risdiplam, Roche and Genentech’s investigational therapy, improved or stabilized motor function in a significantly greater portion of patients than those given a placebo.

The greatest improvements in motor function, as assessed by the Motor Function Measure 32 scale (MFM-32), were found in the youngest age group (2 to 5 years old), with 78.1% of treated patients here showing clinically meaningful improvement, compared with 52.9% of the placebo group. MFM-32 is a validated test able to measure motor skills across a range of patients with neuromuscular diseases.

“That was a big thing,” said Rucinski, whose daughter, Lia, has SMA type 2. “People could finally see the results in patients, the real data.”

This trial’s design, as well as other discussions at the conference, are also indicative of a paradigm shift away from the traditional classification system of SMA types. 

Currently, SMA is divided into five types (0, 1, 2, 3, and 4), each based on age of disease onset and symptom severity or likely severity (for newborns). But evidence is surfacing of a “gradual departure” from this framework “in favor of a more functional description,” he said.

This change is critical, he added, because current classifications lend themselves to “confusion and misunderstanding,” and can affect access to treatment.

Rucinski gave as an example two children with SMA, neither of whom are now able to walk. One was never ambulatory, while the other has since lost that ability. Under the current classification system, the first child would be considered SMA type 2, and the second a type 3. 

Yet, even though they’re diagnosed with different types, “currently, they might be exactly the same; they have the same functional level,” he said. 

In the U.K.’s public healthcare system, the child classified as type 2 would be eligible for treatment with Spinraza (nusinersen, by Biogen), while the child marked as a type 3 would not be. This is, in large part, because clinical trials of SMA treatments have historically been stratified by type.

More flexible, functional descriptions instead of the more rigid type classifications could be more useful, Rucinski said. For instance, an individual might be described as a ‘sitter’ or a ‘non-sitter,’ or as a ‘walker’ or a ‘non-walker,’ based on what they are able to do on their own. These descriptions can then be further classified by adding distinctions like age at disease onset (early or late). 

This paradigm is evident in some recent clinical trials.  SUNFISH, for instance, distinguished the type 2 and 3 patients it wanted by walking skills. Its part 1 accepted both ambulatory or non-ambulatory patients, while part 2 was limited to those currently unable to walk. 

Disease type and previous walking ability were less important. “What mattered was their functional level,” Rucinski said. 

“Classification based on types is completely inadequate, especially in the era of having new treatments, where they modify the disease course,” he added. And he noted that a child classified as SMA type 1 might — if treated early enough in this disease’s course — be able to sit up and even walk with current treatments, meeting milestones once considered impossible. 

Other notable SMA Europe 2020 presentations included updated data on clinical trials into Spinraza and the gene therapy Zolgensma (onasemnogene abeparvovec-xioi), marketed by Novartis. According to Rucinski, there were “no big surprises” in data on these two approved and targeted SMA treatments. Rather, new findings were largely in keeping with previous safety and efficacy results. 

Rucinski also mentioned new findings on the disease’s epigenetics — that is, how biochemical modifications to DNA affect genetic activity in the cells of people with SMA. He also noted “promising” early data on potential therapies that aim to improve muscle function.

The congress overall showcased the considerable progress made in SMA research and treatment development in recent years.

“I left [the congress] quite uplifted, quite encouraged,” Rucinski said. 

The scale of this year’s conference was also remarkable. “There were more than a hundred posters, from all over the world, showing what’s happening with SMA research,” he said. 

According to Rucinski, those numbers alone highlight how great demand is for such an event — one focused exclusively on SMA, and one that brings together all stakeholders, including researchers, patients, clinicians, and pharmaceutical companies.

“We did not expect such a high interest,” Rucinski said, noting that the first SMA Europe conference, in Krakow in 2018, drew several hundred people. The 2020 conference was attended by over 600, with about 200 more on a waiting list.

“That was incredible,” Rucinski said. “It does show how much such an event is needed.”  

For the next conference — planned for 2022 — SMA Europe hopes to put aside “enough room to allow everyone to participate,” he added.