Background: The long-term safety profile of nusinersen 12 mg and pharmacokinetic/pharmacodynamic (PK/PD) modelling provide the basis for the DEVOTE study.
Objectives: To explore whether administering higher doses of nusinersen further improves patient outcomes.
Methods: DEVOTE (NCT04089566): a 3-part, Phase 2/3 study evaluating the safety, tolerability, efficacy, and PK of nusinersen administered intrathecally at higher doses in participants with 5q spinal muscular atrophy (SMA). Part A is an open-label safety evaluation which has enrolled 6 later-onset SMA participants who will receive 3 loading doses of 28 mg at 14-day intervals followed by two 28 mg maintenance doses every 4 months. After safety evaluation, Part B will enroll ≤ 126 participants with infantile-onset or later-onset SMA. Part B is a pivotal, double-blind, active-controlled trial with participants randomized (1:2 ratio) to receive the approved 12 mg dose, or two 50 mg loading doses 14 days apart with 28 mg maintenance doses every 4 months thereafter. After Part B safety evaluation, Part C will enroll ~20 participants of any age and SMA type on approved nusinersen dose ≥ 1 year who will receive one 50 mg loading dose with 28 mg maintenance doses every 4 months thereafter.
Results: The first study site was activated in Q1 2020. Updated enrollment data and Part A data will be presented. The primary objective of Part B is to evaluate the clinical efficacy of nusinersen administered at higher doses based on Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) in infantile-onset SMA. Key endpoints include, for infantile-onset SMA: Hammersmith Infant Neurological Examination Section 2 (HINE-2) and event-free survival; for later-onset SMA: Hammersmith Functional Motor Scale – Expanded (HFMSE), Revised Upper Limb Module (RULM), and World Health Organization (WHO) motor milestones. Secondary and exploratory objectives include examination of safety and tolerability, biomarker assessment, quality of life, and PK.
Conclusions: The DEVOTE study has achieved Part A enrollment, with continued progress made toward an overall target enrollment of ~150 participants from ~50 centers globally.