Abstract Details

Title Escalating Dose and Randomized, Controlled Study of Nusinersen in Participants with Spinal Muscular Atrophy; Study Design of the Phase 2/3 DEVOTE (232SM203) Study to Explore High Dose Nusinersen

Topic General Neurology

Presentation(s) S12 - General Neurology: Neurotherapeutics and Clinical Trials (3:42 PM-3:54 PM)

Poster/Presentation
Number 002

Objective 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 SMA.

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

Design/Methods 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 supported by: Biogen

Authors/Disclosures
Richard S. Finkel, MD, FAAN (St. Jude Children's Research Hospital) PRESENTER	Dr. Finkel has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for AveXis. Dr. Finkel has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Finkel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Catabasis. Dr. Finkel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Capricor. Dr. Finkel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for ReveraGen. Dr. Finkel has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Finkel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Scholar Rock. Dr. Finkel has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier. The institution of Dr. Finkel has received research support from AveXis. The institution of Dr. Finkel has received research support from Biogen. The institution of Dr. Finkel has received research support from Capricor. The institution of Dr. Finkel has received research support from Catabasis. The institution of Dr. Finkel has received research support from ReveraGen. The institution of Dr. Finkel has received research support from Roche. The institution of Dr. Finkel has received research support from Scholar Rock. Dr. Finkel has received intellectual property interests from a discovery or technology relating to health care. An immediate family member of Dr. Finkel has received intellectual property interests from a discovery or technology relating to health care. Dr. Finkel has received personal compensation in the range of $0-$499 for serving as a Speaker in workshop with National Academy of Sciences. Dr. Finkel has a non-compensated relationship as a advisor with n-Lorem Foundation that is relevant to AAN interests or activities. Dr. Finkel has a non-compensated relationship as a Board Member with EveryLife Foundation that is relevant to AAN interests or activities.
John W. Day, MD, PhD (Stanford University School of Medicine)	Dr. Day has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis Gene Therapy. Dr. Day has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Day has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche/Genentech. Dr. Day has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sarepta. Dr. Day has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Avidity. Dr. Day has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for PepGen. Dr. Day has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Epirium Bio. Dr. Day has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Solid Biosciences. Dr. Day has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Muscular Dystrophy Association. The institution of Dr. Day has received research support from Astellas Pharma. The institution of Dr. Day has received research support from Novartis Gene Therapy. The institution of Dr. Day has received research support from Biogen. The institution of Dr. Day has received research support from Roche/Genentech. The institution of Dr. Day has received research support from Sanofi/Genzyme. The institution of Dr. Day has received research support from Sarepta. The institution of Dr. Day has received research support from Scholar Rock. The institution of Dr. Day has received research support from AMO Pharma. The institution of Dr. Day has received research support from AnnJi. Dr. Day has received research support from CureSMA. The institution of Dr. Day has received research support from Muscular Dystrophy Association. The institution of Dr. Day has received research support from Ionis Pharmaceuticals. The institution of Dr. Day has received research support from NMD Pharma. The institution of Dr. Day has received research support from SMA Foundation. Dr. Day has received intellectual property interests from a discovery or technology relating to health care.
	No disclosure on file
	No disclosure on file
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	No disclosure on file
Boris Kandinov	No disclosure on file
Wildon Farwell, MD	Dr. Farwell has received personal compensation for serving as an employee of Biogen. Dr. Farwell has received stock or an ownership interest from Biogen.

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