MDA 2025: High-dose Spinraza safe, effective in DEVOTE study
Biogen has sought approval for higher dosing regime in US, Europe
A higher dose of Spinraza (nusinersen) may be more effective than the currently approved dosing schedule in people with spinal muscular atrophy (SMA) for maintaining motor function, according to data from the DEVOTE clinical trial.
Results from the study, which was sponsored by Spinraza’s maker Biogen, were presented at the annual meeting of the Muscular Dystrophy Association (MDA) in the poster, “Exploring higher doses of nusinersen in spinal muscular atrophy (SMA): final results from Parts B and C of the 3-part DEVOTE study.”
Biogen has sought approval for the higher dosing regime in the U.S. and Europe based on the outcomes from DEVOTE.
Spinraza is an approved SMA treatment that boosts levels of the SMN protein. SMA is chiefly caused by mutations that lead to low levels of SMN protein, which causes the nerve cells that control movement to sicken and die, driving disease symptoms. Spinraza became the first widely approved treatment for SMA after clinical trials proved it could slow disease progression.
It’s given by injection into the spinal canal, a procedure known as an intrathecal injection. Under the approved dosing schedule, patients first receive four loading doses of 12 mg, the first three every 14 days and the fourth 30 days later. After that, patients switch to maintenance treatment with 12 mg injections every four months.
The DEVOTE clinical trial (NCT04089566) tested an alternate dosing schedule where patients received two 50 mg loading doses 14 days apart, then 28 mg maintenance doses every four months.
“The question was raised: is there still efficacy to be had from a higher dose? [The approved dose] is so safe, why not try more?” said Thomas Crawford, MD, a study investigator at Johns Hopkins Hospital, who led the presentation.
The main arm of DEVOTE included 75 children with infantile-onset SMA who hadn’t received previous treatment. The children were randomly assigned to Spinraza at the high dose or the approved dosing schedule. Data from these patients were compared against patients who received a sham treatment in ENDEAR (NCT02193074), an earlier Spinraza trial that helped form the basis for its original approval.
The safety profile of Spinraza was comparable for both dosing regimens, data showed.
“The higher dose was just as well tolerated as the [approved dose] … There’s essentially no difference,” Crawford said.
Comparing Spinraza doses
Results from DEVOTE showed that patients given the high-dose regimen had significantly better motor function outcomes than those undergoing a sham procedure in ENDEAR. For example, after nearly six months, average scores on a measure of motor function called the CHOP-INTEND showed improvements of about 15 points with high-dose Spinraza, which contrasted with worsening of about 11 points with the sham procedure. The high-dose regimen also was linked with a lower risk of dying or needing a ventilator.
Comparisons of motor function data between the high-dose regimen and the standard regimen in the main trial group tended to favor the high-dose regimen, though the differences weren’t statistically significant, meaning it’s mathematically plausible they could be random chance. The high-dose therapy tended to lead to a sharper drop in levels of neurofilament light chain (NfL), a marker of nerve damage.
Patients given the high-dose regimen also were less likely to die or need a ventilator than those given standard dosing, though again this difference wasn’t statistically significant. Rates of hospitalizations also were lower.
There is “substantial evidence to suggest that the higher dose actually is better [than standard dosing], but … it’s complicated,” said Crawford, who added the higher dose “is incredibly safe, so there’s almost no reason not to imagine that we’ll be transitioning to a higher dose.”
The DEVOTE study also included a separate group of 40 children and adults with SMA who’d previously been on the standard regimen of Spinraza, but switched to the high dose as part of the trial. Results in these patients showed that motor function tended to improve after the switch. Specifically, after about 10 months on the high dose, average scores on the Hammersmith Functional Motor Scale Expanded (HFMSE), a measure of overall motor function, improved by 1.8 points, while scores on the Revised Upper Limb Module (RULM), a measure of arm and hand function, improved by 1.2 points, on average.
“Collectively, these data demonstrate the safety and efficacy of the 50/28mg regimen of [Spinraza],” the researchers wrote.
Note: The SMA News Today team is providing live coverage of the 2025 MDA Clinical & Scientific Conference March 16-19 in Dallas. Go here to see the latest stories from the conference.
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