Neurofilament light chain as a biomarker in spinal muscular atrophy

Topic:

Translational Research

Poster Number: 195 M

Author(s):

Stephanie Fradette, PharmD, Biogen, Charlotte Sumner, MD, Johns Hopkins University School of Medicine, Thomas Crawford, MD, Johns Hopkins University School of Medicine, Michelle Farrar, MD, UNSW Sydney, Perry Shieh, MD, University of California Los Angeles, Crystal Proud, MD, Children’s Hospital of the King’s Daughters, Norfolk, VA, USA, Arlene D'Silva, PhD, UNSW Sydney, Peng Sun, PhD, Biogen, Carrie Rubel, PhD, Biogen, Richard Foster, PhD, Biogen, Danielle Graham, PhD, Biogen

Neurofilament proteins are an established biomarker of axonal injury and neurodegeneration, and thus increasingly relevant to therapeutics development in multiple neurodegenerative disorders. For example, in ALS neurofilament levels function (1) as a susceptibility/risk biomarker enabling conduct of the first interventional presymptomatic study, (2) as a prognostic biomarker reducing disease heterogeneity in clinical trials, and (3) as a treatment response biomarker providing an early window into the neurodegenerative process that correlates with clinical outcomes over time. In SMA, pre-treatment levels of phosphorylated neurofilament heavy chain (pNfH) levels are correlated with age and clinical course. Levels of pNfH were robustly reduced following initiation of nusinersen, an intrathecally-administered antisense oligonucleotide designed to increase production of full-length SMN protein.

Neurofilament levels provide an “early look” at the process of neurodegeneration and permit greater power to objectively evaluate treatment response. As we now work to optimize the SMA treatment paradigm, neurofilament levels can unveil benefits of modifications of treatment, higher efficacy therapies, novel routes of administration, combination therapy, etc.

Highly sensitive, low-volume methods have facilitated an integrated analysis of NfL across the nusinersen clinical studies. Cross-study integrated neurofilament light chain (NfL) results will be debuted from the NURTURE, ENDEAR, CHERISH, RESPOND, and DEVOTE studies; these enable evaluation of low and high dose nusinersen in treatment naïve and previously-treated presymptomatic and symptomatic participants. These data further inform the role of NfL as a prognostic and treatment-response biomarker in SMA with the potential to support clinical decision-making in an evolving SMA treatment landscape.

This experience with SMA, ALS, and a range of other genetic and acquired neurodegenerative disorders, and the emerging ability to measure neurofilament in clinical laboratories, herald the emergence of neurofilament levels as a tool in clinical practice decisions.