Plate Nº 90 · recorded October 10, 2026
Health & Medicine ResearchReported finding
High-dose nusinersen improves motor function in SMA trial
A high-dose nusinersen regimen improved motor function scores by 15.1 points in infants with severe SMA versus an 11.1-point decline in matched untreated controls, the phase 3 DEVOTE trial reports.
By Priya Raman4 min read775 words
In brief
- DEVOTE met its primary endpoint with a 26.19-point CHOP-INTEND gap (95% CI: 20.7–31.74, P<0.0001) at day 183.
- Higher-dose nusinersen cut plasma neurofilament levels by 94% versus 32% in matched sham controls (P<0.0001).
- The trial enrolled 139 participants across 44 sites in 18 countries between November 12, 2020 and August 8, 2023.
- Fatal adverse events occurred in 20% of high-dose patients versus 24% on standard dose and 55% in matched sham controls.
- Results were published in Nature Medicine on February 3, 2026 (registration NCT04089566).
Infants with the most severe form of spinal muscular atrophy who received a higher dose of nusinersen gained an average of 15.1 points on a standard motor function test after six months, while matched untreated infants lost 11.1 points — a 26.19-point gap that met the primary goal of the global phase 2/3 DEVOTE trial, researchers reported in Nature Medicine on February 3, 2026.
What did the trial compare?
The DEVOTE study tested whether a higher dose of nusinersen could slow neurodegeneration more aggressively than the current standard. Participants in the higher-dose arm received 50 milligrams as a loading dose, followed by 28 milligrams every few months for maintenance ("50/28 mg"). The standard arm received the approved 12/12 mg regimen.
In Part B, 75 treatment-naive participants were randomized 2:1 to high-dose or standard-dose nusinersen. The pivotal infantile-onset subgroup included 50 infants on the higher dose and 25 on the standard dose, with outcomes compared against 20 matched sham-procedure controls from the earlier ENDEAR trial. A separate later-onset cohort of 24 treatment-naive individuals (16 high-dose, 8 standard) was included as supportive evidence. Part C enrolled 40 patients already on standard nusinersen for at least a year who transitioned to the higher dose.
How large was the motor function benefit?
The primary endpoint measured change in the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) at day 183. Results showed:
- High-dose group: +15.1 points (95% CI: 12.4–17.8)
- Matched sham group: −11.1 points (95% CI: −15.9 to −6.2)
- Joint-rank test difference: 26.06 (95% CI: 17.9–34.2, P<0.0001)
The high-dose group also showed significantly larger gains on the Hammersmith Infant Neurological Exam (HINE-2) at day 183 (P<0.0001) and a lower risk of death or permanent ventilation (hazard ratio 0.322, nominal P=0.0006).
Did the drug slow underlying nerve damage?
Researchers tracked plasma neurofilament light chain (NfL), a blood biomarker of nerve cell injury, as a key secondary endpoint. Higher-dose nusinersen cut NfL levels by 94% at day 183, compared with a 32% reduction in the matched sham group (P<0.0001). The high-dose group also showed faster NfL reductions than the 12/12 mg group at day 64 (88% versus 77%, nominal P=0.0075).
What about patients already on standard nusinersen?
Part C enrolled 40 patients aged 4–65 who had received the 12/12 mg regimen for a median of 3.9 years before switching to the higher dose. After transition, they gained an average of 1.8 points on the Hammersmith Functional Motor Scale Expanded (HFMSE), with adults gaining 2.3 points on average. About 53% of participants showed HFMSE improvements from baseline by day 302.
Did side effects increase with the higher dose?
No new safety signals emerged. Across Parts B and C, most adverse events were mild to moderate and consistent with the natural history of SMA or with lumbar puncture procedures. Serious adverse events occurred in 60% of high-dose patients, 72% of standard-dose patients, and 95% of matched sham controls. Fatal events were lowest in the high-dose group (20%) versus the standard-dose group (24%) and sham controls (55%).
What are the study's limitations?
The DEVOTE team acknowledged several caveats:
- The trial was not powered to compare 50/28 mg with 12/12 mg directly, only against a matched historical sham group from ENDEAR.
- Use of matched historical controls, rather than a placebo arm, introduces uncertainty from differences in standard of care across the 44 trial sites in 18 countries.
- The later-onset SMA cohort was small (n=24), producing variable results over time.
- Traditional motor scales were designed a decade ago and may be insensitive to differences between dosing regimens.
Why does the dose matter?
Before DEVOTE, 12 mg was the highest tested dose of nusinersen in SMA patients — substantially lower than antisense oligonucleotide doses used in other diseases. Pharmacokinetic modeling and primate safety studies supported testing a higher dose. CSF trough concentrations roughly doubled after one 50 mg dose compared with one 12 mg dose.
What's next?
The DEVOTE trial was sponsored by Biogen and led by Richard S. Finkel of St. Jude Children's Research Hospital, with Stephanie Fradette of Biogen as co-corresponding author. An ongoing extension study called ONWARD (NCT04729907) will track longer-term outcomes. The researchers argue future SMA trials should incorporate more sensitive biomarkers like neurofilament alongside traditional motor scales, to better evaluate new dosing regimens and combination therapies.
via clinicaltrials.gov (Original)
More from Priya Raman
Show full bio
Senior reporter covering industry trends and analytics at SciBeat.
207 articles