Plasma Phosphorylated Neurofilament Heavy Chain (pNF-H) Level is Associated with Future Motor Function in Nusinersen-treated Individuals with Later-onset Spinal Muscular Atrophy (SMA) (2248)

Objective: To evaluate the association between plasma phosphorylated neurofilament heavy chain (pNF-H) levels and clinical motor function endpoints in nusinersen-treated individuals with later-onset spinal muscular atrophy (SMA) who participated in the CHERISH/SHINE studies. Background: Neurofilament (NF) isoforms are major structural proteins of the neuronal cytoskeleton and are released into interstitial fluid following axonal damage or neuronal degeneration. Elevated NF levels have been detected in neurodegenerative disorders, including SMA. Design/Methods: Individuals treated with nusinersen in the Phase 3, randomized, double-blind CHERISH study could transition to the open-label SHINE extension study (NCT02594124). Plasma pNF-H levels were measured using the pNF-H SimplePlex ELLA assay (ProteinSimple); motor function was assessed using the Hammersmith Functional Motor Scale – Expanded (HFMSE) and Revised Upper Limb Module (RULM). Linear multivariate regression models were applied to determine any relationship between log pNF-H levels at baseline and change from baseline in HFMSE or RULM to Day 450, 690, 930, 1170, or 1410. Results: pNF-H data were available for up to 75 participants with HFMSE/RULM data. After controlling for age at treatment initiation and baseline motor function, higher baseline log pNF-H level was not significantly associated with change in HFMSE or RULM at Days 450, 690 or 930. Higher baseline log pNF-H level was significantly associated with greater improvements in HFMSE and RULM at Days 1170 and 1410. The relationship between higher baseline pNF-H and improvement in HFMSE and RULM increased over time. Additional analyses will be presented. Conclusions: These results show that participants with higher pNF-H levels at baseline are expected to have higher HFMSE and/or RULM scores relative to baseline at later visits after receiving nusinersen. pNF-H may be a useful indicator of future motor function and warrants further evaluation as a biomarker of treatment response in SMA. Supported by: Biogen Disclosure: Michelle Farrar has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Michelle Farrar has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Michelle Farrar has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Michelle Farrar has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Biogen. Michelle Farrar has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. 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 $500-$4,999 for serving on a Speakers Bureau for Pfizer. Dr. Muntoni has received personal compensation in the range of $500-$4,999 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 Avexis. 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. 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. 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. Dr. Finkel has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neurogene. 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 $5,000-$9,999 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 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 Every Life Foundation that is relevant to AAN interests or activities. Eugenio Mercuri has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sarepta, Santhera, PTC, Pfizer, Roche, Biogen, Avexis Novartis, Scholar Rock, Cytokinetics. Eugenio Mercuri has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Sarepta, Santhera, PTC, Pfizer, Roche, Biogen, Avexis Novartis. The institution of Eugenio Mercuri has received research support from biogen. Xiaotong Jiang has nothing to disclose. Jihee Sohn has nothing to disclose. Marco Petrillo has received personal compensation for serving as an employee of Biogen. Marco Petrillo has received stock or an ownership interest from Biogen. Steve Garafalo has received personal compensation for serving as an employee of Biogen. Steve Garafalo has received stock or an ownership interest from Biogen. Dr. Farwell has received personal compensation for serving as an employee of Biogen. Dr. Farwell has received stock or an ownership interest from Biogen.