TY - JOUR
T1 - Validation of serum neurofilaments as prognostic and potential pharmacodynamic biomarkers for ALS
AU - Benatar, Michael
AU - Zhang, Lanyu
AU - Wang, Lily
AU - Granit, Volkan
AU - Statland, Jeffrey
AU - Barohn, Richard
AU - Swenson, Andrea
AU - Ravits, John
AU - Jackson, Carlayne
AU - Burns, Ted M.
AU - Trivedi, Jaya
AU - Pioro, Erik P.
AU - Caress, James
AU - Katz, Jonathan
AU - McCauley, Jacob L.
AU - Rademakers, Rosa
AU - Malaspina, Andrea
AU - Ostrow, Lyle W.
AU - Wuu, Joanne
N1 - Funding Information:
The CReATe Consortium (U54 NS090291) is part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), National Center for Advancing Translational Sciences (NCATS). CReATe is funded through collaboration between NCATS and the National Institute of Neurologic Disorders and Stroke. CReATe is also supported by a Clinical Trial Readiness Grant from NIH (U01NS107027). Supplementary support for the CReATe Biorepository was provided by the ALS Association (Grant ID 16-TACL-242). Target ALS provided support to Quanterix and Iron Horse to cover assay costs as well as a grant to Joanne Wuu. This work was also supported by CTSA grants (UL1TR002366 and UL1TR000001) from NCATS awarded to the University of Kansas.
Funding Information:
M. Benatar reports grants from NIH, the ALS Association, the Muscular Dystrophy Association, the Centers for Disease Control and Prevention, the Department of Defense, and Target ALS during the conduct of the study; personal fees from Mitsubishi Tanabe Pharma, AveXis, and Gen-entech, outside the submitted work; has a provisional patent titled “Determining onset of amyotrophic lateral sclerosis”; and serves as a site investigator on clinical trials funded by Biogen and Orphazyme. L. Zhang reports no relevant disclosures. L. Wang reports grants from the NIH during the conduct of the study. V. Granit reports no relevant disclosures. J. Statland reports grants from NIH, MDA, and the FSH Society during the conduct of the study and personal fees from Fulcrum, Acceleron, Strongbridge, Sarepta, and AveXis, outside the submitted work. R. Barohn reports grants from the NIH during the conduct of the study; grants from FDA/OOPD, the ALS Association, the Muscular Dystrophy Association, Sanofi/Genzyme, Biomarin Pharmaceuticals, IONIS Pharmaceuticals, Teva Pharmaceuticals, Cytokinetics Pharmaceuticals, Eli Lilly and Company, PTC Therapeutics, Orphazyme, Neuraltus Pharmaceuticals, Alexion Pharmaceuticals, Sarepta Therapeutics, and The Marigold Foundation outside the submitted work; personal fees from NuFactor, Momenta, and Plan 365; and other support from Novartis Pharmaceuticals, Option Care, Platform Q Health Education, and Ra Pharma; and patents on the MG-ADL and QMG with royalties paid. A. Swenson reports grants from the University of Iowa during the conduct of the study and other support from Amylyx Pharmaceuticals, FlexPharm, and Cytokinetics outside the submitted work. J. Ravits reports personal fees from MT Pharma and AveXis, outside the submitted work; and serves as a site investigator on a clinical trial funded by Biogen. C. Jackson reports grants from the NIH, Cytokinetics, and Mitsubishi Tanabe Pharma America during the conduct of the study and personal fees from Mallinckrodt, Brainstorm, Mitsubishi Tanabe Pharma America, ITF Pharma, and Anelixis outside the submitted work. T.M. Burns reports no relevant disclosures. J. Trivedi reports grants from NIH, Sanofi-Genzyme, and CSL Behring during the conduct of the study as well as personal fees from CSL Behring outside the submitted work. E.P. Pioro reports grants from NIH and Centers for Disease Control and Prevention during the conduct of the study; grant support from the ALS Association and CDC/NIH outside the submitted work; as well as personal fees from Avanir Pharmaceuticals, Inc., Biohaven Pharmaceuticals, Inc., Cytokinetics, Inc., ITF Pharma, Inc., MT Pharma America, Inc., and Otsuka America, Inc. J. Caress reports grants from NIH, Amylyx Pharmaceuticals Inc., Orion Corporation, Cytokinetics Inc., Flex-Pharma, and Neurology Clinical Research Initiative TCZALS-001, outside the submitted work. J. Katz, Jacob L. McCauley, R. Rademakers, and A. Malaspina report no relevant disclosures. L.W. Ostrow reports grants from The Target ALS Foundation and the ALS Association during the conduct of the study. J. Wuu reports grants and funding from NIH, the ALS Association, the Centers for Disease Control and Prevention, the Department of Defense, and Target ALS during the conduct of the study. Go to Neurology.org/N for full disclosures.
Publisher Copyright:
© 2020 American Academy of Neurology.
PY - 2020/7/7
Y1 - 2020/7/7
N2 - ObjectiveTo identify preferred neurofilament assays and clinically validate serum neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) as prognostic and potential pharmacodynamic biomarkers relevant to amyotrophic lateral sclerosis (ALS) therapy development.MethodsIn this prospective, multicenter, longitudinal observational study of patients with ALS (n = 229), primary lateral sclerosis (n = 20), and progressive muscular atrophy (n = 11), biological specimens were collected, processed, and stored according to strict standard operating procedures (SOPs). Neurofilament assays were performed in a blinded manner by independent contract research organizations.ResultsFor serum NfL and pNfH measured using the Simoa assay, there were no missing data (i.e., technical replicates below the lower limit of detection were not encountered). For the Iron Horse and Euroimmun pNfH assays, such missingness was encountered in ∼4% and ∼10% of serum samples, respectively. Mean coefficients of variation for NfL in serum and CSF were both ∼3%. Mean coefficients of variation for pNfH in serum and CSF were ∼4%-5% and ∼2%-3%, respectively, in all assays. Baseline serum NfL concentration, but not pNfH, predicted the future Revised ALS Functional Rating Scale (ALSFRS-R) slope and survival. Incorporation of baseline serum NfL into mixed effects models of ALSFRS-R slopes yields an estimated sample size saving of ∼8%. Depending on the method used to estimate effect size, use of serum NfL (and perhaps pNfH) as pharmacodynamic biomarkers, instead of the ALSFRS-R slope, yields significantly larger sample size savings.ConclusionsSerum NfL may be considered a clinically validated prognostic biomarker for ALS. Serum NfL (and perhaps pNfH), quantified using the Simoa assay, has potential utility as a pharmacodynamic biomarker of treatment effect.
AB - ObjectiveTo identify preferred neurofilament assays and clinically validate serum neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) as prognostic and potential pharmacodynamic biomarkers relevant to amyotrophic lateral sclerosis (ALS) therapy development.MethodsIn this prospective, multicenter, longitudinal observational study of patients with ALS (n = 229), primary lateral sclerosis (n = 20), and progressive muscular atrophy (n = 11), biological specimens were collected, processed, and stored according to strict standard operating procedures (SOPs). Neurofilament assays were performed in a blinded manner by independent contract research organizations.ResultsFor serum NfL and pNfH measured using the Simoa assay, there were no missing data (i.e., technical replicates below the lower limit of detection were not encountered). For the Iron Horse and Euroimmun pNfH assays, such missingness was encountered in ∼4% and ∼10% of serum samples, respectively. Mean coefficients of variation for NfL in serum and CSF were both ∼3%. Mean coefficients of variation for pNfH in serum and CSF were ∼4%-5% and ∼2%-3%, respectively, in all assays. Baseline serum NfL concentration, but not pNfH, predicted the future Revised ALS Functional Rating Scale (ALSFRS-R) slope and survival. Incorporation of baseline serum NfL into mixed effects models of ALSFRS-R slopes yields an estimated sample size saving of ∼8%. Depending on the method used to estimate effect size, use of serum NfL (and perhaps pNfH) as pharmacodynamic biomarkers, instead of the ALSFRS-R slope, yields significantly larger sample size savings.ConclusionsSerum NfL may be considered a clinically validated prognostic biomarker for ALS. Serum NfL (and perhaps pNfH), quantified using the Simoa assay, has potential utility as a pharmacodynamic biomarker of treatment effect.
UR - http://www.scopus.com/inward/record.url?scp=85088209639&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85088209639&partnerID=8YFLogxK
U2 - 10.1212/WNL.0000000000009559
DO - 10.1212/WNL.0000000000009559
M3 - Article
C2 - 32385188
AN - SCOPUS:85088209639
VL - 95
SP - 59
EP - 69
JO - Neurology
JF - Neurology
SN - 0028-3878
IS - 1
ER -