Plasma Phosphorylated Neurofilament Heavy Chain Levels Over Time in Participants With Infantile-and Later-onset SMA: Data from the SHINE Study (1692)

Objective: To investigate change in plasma phosphorylated neurofilament heavy chain (pNF-H) levels over time in nusinersen trial participants with infantile- or later-onset SMA. Background: NFs are neuronal cytoskeleton components released into interstitial fluid following axonal damage/neuronal degeneration. Elevated NF levels have been detected in neurodegenerative disorders. Design/Methods: Individuals treated with nusinersen or sham-procedure in the Phase 3 ENDEAR and CHERISH studies could transition to the open-label SHINE extension study (NCT02594124). Plasma pNF-H levels were measured at baseline and predose using the ProteinSimple pNF-H ELLA assay. Results: In participants who initiated nusinersen in ENDEAR and continued in SHINE (n=76), the geometric mean (±SD) plasma pNF-H concentration was 14,388 (8326) pg/ml at nusinersen initiation (ENDEAR baseline) and declined to 1261 (993) pg/ml at Day 302 (n=51; 15 October 2018 SHINE data cut). In those who received sham-procedure in ENDEAR and initiated nusinersen in SHINE (n=20), the geometric mean pNF-H concentration was 7556 (6265) pg/ml at nusinersen initiation (SHINE baseline) and declined to 778 (653) pg/ml at Day 183 (n=13). In participants who received nusinersen in CHERISH and SHINE (n=83), the geometric mean plasma pNF-H concentration was 1297 (1261) pg/ml at CHERISH baseline and declined to 439 (374) pg/ml at Day 450 (n=79). In the CHERISH sham-procedure group who initiated nusinersen in SHINE (n=32), the geometric mean pNF-H concentration was 746 (676) pg/ml at SHINE baseline and declined to 382 (204) pg/ml at Day 253 (n=8). Values for later timepoints and the SHINE 2019 data cut will be presented. Conclusions: Plasma pNF-H levels at treatment initiation were higher in participants who initiated nusinersen in ENDEAR or CHERISH (compared with SHINE), consistent with differences attributable to age at treatment initiation and SMA disease characteristics. However, these data demonstrate a similar decline in pNF-H levels over time in nusinersen-treated participants, irrespective of when treatment was initiated. Study supported by: Biogen Disclosure: Dr. Darras has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Biogen, Bristol-Myers Squibb, Cytokinetics, Marathon, PTC Therapeutics, Roche, Santhera, and Sarepta. Dr. Darras has received research support from the National Institutes of Health/National Institute of Neurological Disorders and Stroke, the Slaney Family Fund for SMA, Working on Walking Fund, the SMA Foundation; CureSMA, Ionis Pharmaceuticals, Inc. and Biogen, AveXis, Cytokinetics, Fibrogen, PTC Th. Dr. Sumner has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Consultant for AveXis, Biogen, Cytokinetics, Genentech, Pfizer, PTC, and Roche. Dr. Sumner has received personal compensation in an editorial capacity for Associate editor for the Journal of Clinical Investigation. Dr. Sumner has received research support from Received research funding from Roche. Dr. Muntoni has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Advisory boards for AveXis, Biogen, Cytokinetics, Novartis, Pfizer, PTC, Roche, Sarepta, Summit, and Wave. Dr. Muntoni has received research support from Principal Investigator for ongoing Ionis Pharmaceuticals, Inc./Biogen and Roche clinical trials; funding from Muscular Dystrophy UK, SMA Europe, and SMA Trust UK. Dr. Crawford has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Biogen, Catalyst, Cure SMA, Cytokinetics, Marathon, Muscular Dystrophy Association, Novartis, Roche, Sarepta, Scholar Rock, and the Spinal Muscular Atrophy Foundation. Dr. Finkel has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Advisor fees from Biogen and Ionis Pharmaceuticals, Inc. during ENDEAR and CHERISH; advisor to AveXis, Novartis, and Roche; data safety monitoring board for the AveXis AVX-101 Phase 1 gene transfer study and Roche Moonfish Phase 1b study; advisory capacit. Dr. Finkel has received compensation for serving on the Board of Directors of Royalty payments from Children’s Hospital of Philadelphia for licensing fees obtained for use of the CHOP INTEND motor function scale. Dr. Finkel has received royalty, license fees, or contractual rights payments from Royalty payments from Children’s Hospital of Philadelphia for licensing fees obtained for use of the CHOP INTEND motor function scale. Dr. Finkel has received research support from grants from Biogen and Ionis Pharmaceuticals, Inc. during ENDEAR and CHERISH; grants from AveXis, Cytokinetics, and Roche. Dr. Mercuri has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Advisory boards for SMA studies for AveXis, Biogen, Ionis Pharmaceuticals, Inc., Novartis, and Roche.. Dr. Mercuri has received research support from Principal Investigator for ongoing Biogen/Ionis Pharmaceuticals, Inc. and Roche clinical trials; support from Biogen for a natural history registry; funding from Famiglie SMA Italy, Italian Telethon, and SMA Europe.. Dr. De Vivo has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Advisor/consultant for AveXis, Biogen, Cytokinetics, Ionis Pharmaceuticals, Metafora, Roche, Sanofi-Aventis, Santhera, Sarepta, Scholar Rock, PTC, Ultragenyx, Cure SMA and the SMA Foundation. Dr. De Vivo has received research support from Grants/clinical trial support from Biogen, CureSMA, Hope for Children Research Foundation, Mallinckrodt, the National Institutes of Health, PTC, Santhera, Sarepta, Scholar Rock, the SMA Foundation, Ultragenyx, NINDS, Glut1 Deficiency Foundation, and the U. Dr. Oskoui has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Advisory boards for Biogen; data safety monitoring board for AveXis gene therapy studies. Dr. Oskoui has received research support from Grants from Biogen and Ionis Pharmaceuticals, Inc. during the ENDEAR, CHERISH, and CS11 studies, and from Cytokinetics and Roche. Dr. Tizzano has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Consultant for AveXis, Biogen, Biologix, Cytokinetics, and Roche; scientific/medical advisor to FAME Chile, Familias SMA Argentina, FUNDAME, SMA Europe, and TREAT-NMD. Dr. Tizzano has received research support from Grant support from Biogen and Ionis Pharmaceuticals, Inc.; funding from Fundacion Privada Daniel Bravo Andreu and SMA Europe. Dr. Ryan has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Advisor fees from Biogen, Genzyme, and Pfizer; advisor to and received funding from nonprofit organizations: FSHD Global Research Foundation, Muscular Dystrophy Association, Muscular Dystrophy Foundation, and Save Our Sons Duchenne Foundation. Dr. Ryan has received research support from Grants/advisor fees from Biogen, Genzyme, and Pfizer. Dr. Liu has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Biogen. Dr. Liu holds stock and/or stock options in Employees of and holds stock/stock options in Biogen which sponsored research in which Dr. Liu was involved as an investigator. Dr. Liu holds stock and/or stock options in Holds stock/stock options in Biogen. Dr. Petrillo has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Biogen. Dr. Petrillo holds stock and/or stock options in Holds stock/stock options in Biogen. Dr. Kandinov has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Biogen. Dr. Kandinov holds stock and/or stock options in Holds stock/stock options in Biogen. Dr. Wong has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Biogen. Dr. Farwell has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen. Dr. Farwell holds stock and/or stock options in Biogen.