Escalating Dose and Randomized, Controlled Study of High Dose Nusinersen in Spinal Muscular Atrophy; Study Design of the DEVOTE (232SM203) Study


Clinical Trials

Poster Number: 51


Richard Finkel, MD, John Day, MD, PhD, Nancy Mitchell-Sweeney, Richard Foster, Peng Sun, Ishir Bhan, Daniela Ramirez-Schrempp, Boris Kandinov, Wildon Farwell, MD, MPH


1. Nemours Children’s Hospital, University of Central Florida College of Medicine, 2. Stanford, 3. Biogen, 4. Biogen, 5. Biogen, 6. Biogen, 7. Biogen, 8. Biogen, 9. Biogen

Background: The long-term safety profile of nusinersen provides the basis to explore whether higher doses can offer even stronger clinical outcomes.

Objectives: DEVOTE (NCT04089566) is a 3-part, Phase 2/3 study to examine the safety, tolerability, efficacy and pharmacokinetics (PK) of nusinersen administered intrathecally at higher doses in participants with 5q spinal muscular atrophy (SMA).

Approach: Part A is an open-label safety evaluation of 6 participants with later onset SMA (age 2-15 years inclusive; SMA onset age >6 months) who will receive 3 loading doses of 28mg at 14-day intervals followed by two 28mg maintenance doses every 4 months. After safety evaluation, Part B will enroll ~125 participants with infantile-onset (age ≤7 months; 2 SMN2 copies; SMA onset age ≤6 months) or later-onset SMA (age 2-<10 years; SMA onset age >6 months; sat but not walking independently; HFMSE score ≥10 to ≤54). Part B is a pivotal, double-blind, active-controlled trial with participants randomized (1:2 ratio) to receive the approved dose (4 loading doses with 12mg maintenance doses every 4 months), or 2 loading doses of 50mg 15 days apart with two 28mg maintenance doses every 4 months. After Part B Day 29 safety evaluation, Part C will enroll ~20 participants of any age/SMA type on approved nusinersen dose ≥1 year who will receive a single bolus dose of 50mg 4 months after the most recent 12mg dose, with 2 maintenance doses of 28mg (Days 121 and 241).

Results: Primary objective is to evaluate the clinical efficacy of nusinersen administered at higher and less frequent loading doses. Key endpoints will include, for infantile-onset SMA: CHOP INTEND, HINE-2 motor milestones and event-free survival; for later-onset SMA: HFMSE, RULM and WHO motor milestones. Secondary and exploratory objectives include examination of safety and tolerability, biomarker assessment, QoL and PK.

Conclusions: Enrollment is planned to begin in February 2020 with ~150 participants from ~50 centers globally.

Study Support: Biogen; encore submission; previously presented