The current approved dosing regimen for nusinersen consists of four 12 mg loading doses followed by maintenance doses of 12 mg every four months. Despite this regimen, some patients exhibit functional impairment. Several factors may contribute to this, including: (a) irreversible motor neuron loss occurring prior to treatment; (b) insufficient therapeutic effect during treatment (e.g., inadequate modulation of SMN2 modulation); and (c) comorbid conditions such as scoliosis or joint contractures. DEVOTE trial (Finke et al 2026) evaluated the efficacy and safety of a higher dosing nusinersen regimen (50 mg loading doses and 28 mg maintenance doses). Results from parts B and C have now been reported.
In Part B, 75 treatment-naïve patients with spinal muscular atrophy (SMA) were randomized in a 2:1 ratio to receive either the 50/28 mg or the standard 12/12 mg regimen. The primary endpoint was the change in CHOP-INTEND score at six months in the high-dose group compared with a matched sham-treated cohort (n=20) from the ENDEAR trial. The study met its primary endpoint. At Day 183, the CHOP-INTEND improved significantly in the high-dose group (+15.1 points), while declined in the sham group (−11.1 points), resulting in a total difference of 26.19 points (95% CI: 20.7 to 31.74). Secondary outcomes supported these findings, with greater reductions in neurofilament light (NfL) levels observed in the high-dose group in comparison to sham group at day 183. Additionally, improvements in HINE-2 and prolonged event-free survival were reported. Comparisons between the high-dose and standard-dose groups favoured the high-dose regimen across several outcomes, including respiratory events and need for ventilatory support. However, the study was not powered to detect significant differences between dosing regimens.
Part C was an open-label study enrolling patients previously treated with nusinersen (12/12 mg for more than one year) that transitioned into a high dose regimen. Among 40 participants with a range of SMA phenotypes and ages (2 with infantile-onset and 38 with late-onset SMA), improvements in motor function scores (HFMSE and RULM) were observed. These gains were consistent with those seen in treatment-naïve patients initiating standard-dose therapy and exceeded expectations for a population already treated for a median of 3.9 years.
The study has several limitations. One of them is that variability in access to supportive care (e.g., ventilators or cough assist devices) across regions may have influenced outcomes. Therefore, the study highlights the need for more sensitive and objective outcome measures, and as such may serve NfL.
In conclusion, data from DEVOTE Parts B and C show the potential of high-dose nusinersen (50/28 mg) in comparison to the sham group and support benefits compared with the standard 12/12 mg regimen, while showing a similar safety profile.
Key Points:
- The phase 2/3 DEVOTE trial was designed and powered to assess the primary and key secondary endpoints in the high-dose nusinersen group (50/28 mg), compared with a matched group of patients that received sham as part of the ENDEAR trial. While the study included secondary comparisons between the high-dose and normal-dose nusinersen regimens, it was not powered to detect differences between these groups.
- The study reached its primary endpoint, demonstrating improvement in the CHOP INTEND score in the high-dose group compared with the sham group. Additional findings suggest the potential of the novel 50/28 mg dosing regimen over the standard 12/12 mg dose.
- DEVOTE Part 2/3 highlighted the need for more objective and sensitive secondary outcome measures, as variability in treatment accessibility and differences between study sites may have influenced results.
References:
Finkel RS, Crawford TO, Mercuri E, Sumner CJ, Garcia Romero MDM, Day JW, Montes J, Sun P, Tichler B, Paradis AD, Boesch E, Inra J, Littauer R, Sohn J, Monine M, Gambino G, Foster R, Farewell R, Fradette S. High-dose nusinersen for spinal muscular atrophy: a phase 3 randomized trial. Nat Med. 2026 Mar;32(3):1095-1104. doi: 10.1038/s41591-025-04193-6. Epub 2026 Feb 3. PMID: 41634391; PMCID: PMC13004686.
Publish on behalf of the Scientific Panel on Muscle and NMJ disorders