Abstract Details

Title Association of Phosphorylated Neurofilament Heavy Chain (pNF-H) Levels With Motor Function Achievement in Individuals With Spinal Muscular Atrophy (SMA) Treated With Nusinersen

Topic General Neurology

Presentation(s) S27 - General Neurology: Improving Neurologic Care and the Impact of Therapeutics (2:28 PM-2:39 PM)

Poster/Presentation
Number 009

Background Neurofilaments (NF) are neuronal cytoskeleton components released into interstitial fluid following axonal damage/neuronal degeneration. Elevated NF levels have been detected in neurodegenerative disorders.

Objective To assess phosphorylated neurofilament heavy chain (pNF-H) levels in individuals from nusinersen clinical trials with presymptomatic (most likely to develop Type I/II), infantile-onset (has or most likely to develop Type I/II) or later-onset SMA (has or most likely to develop Type II/III) and volunteers without SMA and investigate the association with motor function (MF) achievement in nusinersen-treated individuals with SMA.

Design/Methods pNF-H plasma levels were evaluated using the ProteinSimple™ SimplePlex ELLA immunoassay. MF responses in infantile-onset SMA included 1) improvement in ≥1 HINE-2 category and more categories improving than worsening or 2) ≥4-point CHOP INTEND improvement. MF responses in later-onset SMA included 1) ≥3-point HFMSE improvement, 2) ≥2-point RULM improvement, or 3) attainment of ≥1 WHO motor milestone. Receiver Operating Characteristic (ROC) curves and logistic regression analyses assessed pNF-H levels and MF achievement associations.

Results Baseline pNF-H levels were higher in individuals with SMA (n=302) than age-matched individuals without SMA (n=34). In nusinersen-treated individuals with SMA, plasma pNF-H levels declined during the nusinersen loading period and then stabilized at lower levels through latest observed visits (infantile-onset SMA: Day 302; later-onset SMA: Day 456). The percentage change from baseline in pNF-H levels at nusinersen loading end (Day 64 or 85) predicted MF response at Day 302 (infantile-onset SMA; HINE-2: AUC=74%, CHOP INTEND: AUC=92%) and at Day 456 (later-onset SMA; HFMSE: AUC=73%, RULM: AUC=76%, WHO: AUC=86%) after controlling for age of first dose and disease duration, respectively.

Conclusions pNF-H levels were elevated at baseline in individuals with SMA; however, nusinersen treatment reduced pNF-H levels to lower levels. The percentage change in pNF-H levels at the completion of nusinersen loading appears to predict subsequent MF response. Further evaluation is warranted.

Authors/Disclosures
Charlotte J. Sumner, MD, FAAN PRESENTER	Dr. Sumner has received personal compensation for serving as an employee of Biogen. Dr. Sumner has received personal compensation for serving as an employee of Avexis. Dr. Sumner has received personal compensation for serving as an employee of Roche/Genentech. Dr. Sumner has received personal compensation for serving as an employee of Ionis Pharmaceuticals. Dr. Sumner has received personal compensation for serving as an employee of Sarepta. Dr. Sumner has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Sumner has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Avexis/Novartis. Dr. Sumner has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche/Genentech. Dr. Sumner has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sarepta. Dr. Sumner has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alnylam. Dr. Sumner has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Proneurotech. Dr. Sumner has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for CMTRF. Dr. Sumner has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Journal Clinical Investigation. Dr. Sumner has received research support from Roche. Dr. Sumner has received intellectual property interests from a discovery or technology relating to health care. Dr. Sumner has received publishing royalties from a publication relating to health care.
Basil T. Darras, MD (Children'S Hosp Boston Harvard Med School)	The institution of Dr. Darras has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amicus. Dr. Darras has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Amicus. The institution of Dr. Darras has received research support from National Institutes of Health/National Institute of Neurological Disorders and Stroke,. The institution of Dr. Darras has received research support from Slaney Family Fund for SMA. The institution of Dr. Darras has received research support from Spinal Muscular Atrophy Foundation. The institution of Dr. Darras has received research support from CureSMA. The institution of Dr. Darras has received research support from Working on Walking Fund . The institution of Dr. Darras has received research support from CHERISH, CS2/CS12 . The institution of Dr. Darras has received research support from Biogen for CS11. The institution of Dr. Darras has received research support from AveXis. The institution of Dr. Darras has received research support from Sarepta Pharmaceuticals. The institution of Dr. Darras has received research support from PTC Therapeutics. The institution of Dr. Darras has received research support from Roche. The institution of Dr. Darras has received research support from Santhera. The institution of Dr. Darras has received research support from Scholar Rock. The institution of Dr. Darras has received research support from Fibrogen. The institution of Dr. Darras has received research support from Summit. Dr. Darras has received publishing royalties from a publication relating to health care. Dr. Darras has received publishing royalties from a publication relating to health care.
Francesco Muntoni, MD (UCL Institute of Child Health)	Dr. Muntoni has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sarepta. Dr. Muntoni has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Pfizer. Dr. Muntoni has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sarepta. Dr. Muntoni has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Biogen. Dr. Muntoni has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. Dr. Muntoni has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. The institution of Dr. Muntoni has received research support from European Commission. The institution of Dr. Muntoni has received research support from Medical Research Council. The institution of Dr. Muntoni has received research support from Biogen. The institution of Dr. Muntoni has received research support from Muscular Dystrophy UK. The institution of Dr. Muntoni has received research support from MDA USA. The institution of Dr. Muntoni has received research support from Sarepta. The institution of Dr. Muntoni has received research support from Association Francoise Myopathies. Dr. Muntoni has received personal compensation in the range of $0-$499 for serving as a Clinical expert with UK NICE Committee.
Thomas O. Crawford, MD (Johns Hopkins Hospital)	Dr. Crawford has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen.
Richard S. Finkel, MD, FAAN (St. Jude Children's Research Hospital)	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.
	No disclosure on file
Darryl C. De Vivo, MD, FAAN (Columbia University)	Dr. De Vivo has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen and Novartis. Dr. De Vivo has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Aspa Therapeutics.
Maryam Oskoui, MD, FAAN (Montreal Children's Hospital - McGill University Health Centre)	Dr. Oskoui has received personal compensation in the range of $500-$4,999 for serving as an officer or member of the Board of Directors for the Association des Neurologues du Quebec. The institution of Dr. Oskoui has received research support from Hoffmann-La Roche Ltd. The institution of Dr. Oskoui has received research support from Muscular Dystrophy Canada. The institution of Dr. Oskoui has received research support from Canadian Institutes of Health Research. The institution of Dr. Oskoui has received research support from Santhera. The institution of Dr. Oskoui has received research support from Novartis. Dr. Oskoui has a non-compensated relationship as a Member of the Medical and Scientific Advisory Committee with Muscular Dystrophy Canada that is relevant to AAN interests or activities.
	No disclosure on file
Monique M. Ryan, MD (Childrens Hospital)	Dr. Ryan 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. Ryan has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for CSL Behring . Dr. Ryan has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Ryan has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Biogen . The institution of Dr. Ryan has received research support from Save our Sons Muscular Dystrophy . The institution of Dr. Ryan has received research support from Muscular Dystrophy Australia. Dr. Ryan has received publishing royalties from a publication relating to health care.
	No disclosure on file
	No disclosure on file
	No disclosure on file
Stephanie Fradette	Stephanie Fradette has received personal compensation for serving as an employee of Biogen. Stephanie Fradette has stock in Biogen.
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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