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