Prognostic clinical and biological markers for amyotrophic lateral sclerosis disease progression: validation and implications for clinical trial design and analysis.

Autor:	Benatar M; Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA. Electronic address: mbenatar@miami.edu., Macklin EA; Departments of Neurology and Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Malaspina A; UCL Queen Square Motor Neuron Disease Center, UCL Queen Square Institute of Neurology, University College London, Queen Square, London, UK., Rogers ML; Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia., Hornstein E; Department of Molecular Genetics and Molecular Neuroscience, Weizmann Institute of Science, Israel., Lombardi V; UCL Queen Square Motor Neuron Disease Center, UCL Queen Square Institute of Neurology, University College London, Queen Square, London, UK., Renfrey D; Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia., Shepheard S; Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia., Magen I; Department of Molecular Genetics and Molecular Neuroscience, Weizmann Institute of Science, Israel., Cohen Y; Department of Molecular Genetics and Molecular Neuroscience, Weizmann Institute of Science, Israel., Granit V; Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA., Statland JM; Department of Neurology, University of Kansas Medical Center, Kansas City, KS, USA., Heckmann JM; Division of Neurology, Department of Medicine, University of Cape Town, South Africa., Rademakers R; VIB Center for Molecular Neurology, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., McHutchison CA; School of Philosophy, Psychology, and Language Sciences, The University of Edinburgh, Edinburgh, UK; Euan MacDonald Centre for Motor Neuron Disease Research, The University of Edinburgh, Edinburgh, UK., Petrucelli L; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., McMillan CT; Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA., Wuu J; Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA. Electronic address: jwuu@miami.edu.
Jazyk:	angličtina
Zdroj:	EBioMedicine [EBioMedicine] 2024 Oct; Vol. 108, pp. 105323. Date of Electronic Publication: 2024 Sep 12.
DOI:	10.1016/j.ebiom.2024.105323
Abstrakt:	Background: With increasing recognition of the value of incorporating prognostic markers into amyotrophic lateral sclerosis (ALS) trial design and analysis plans, there is a pressing need to understand which among the prevailing clinical and biochemical markers have real value, and how they can be optimally used. Methods: A subset of patients with ALS recruited through the multi-center Phenotype-Genotype-Biomarker study (clinicaltrials.gov: NCT02327845) was identified as "trial-like" based on meeting common trial eligibility criteria. Clinical phenotyping was performed by evaluators trained in relevant assessments. Serum neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH), urinary p75 ECD , plasma microRNA-181, and an array of biochemical and clinical measures were evaluated for their prognostic value. Associations with functional progression were estimated by random-slopes mixed models of ALS functional rating scale-revised (ALSFRS-R) score. Associations with survival were estimated by log-rank test and Cox proportional hazards regression. Potential sample size savings from adjusting for given biomarkers in a hypothetical trial were estimated. Findings: Baseline serum NfL is a powerful prognostic biomarker, predicting survival and ALSFRS-R rate of decline. Serum NfL <40 pg/mL and >100 pg/mL correspond to future ALSFRS-R slopes of ∼0.5 and ∼1.5 points/month, respectively. Serum NfL also adds value to the best available clinical predictors, encapsulated by the European Network to Cure ALS (ENCALS) predictor score. In models of functional decline, the addition of NfL yields ∼25% sample size saving above those achieved by inclusion of either clinical predictors or ENCALS score alone. The prognostic value of serum pNfH, urinary p75 ECD , and plasma miR-181ab is more limited. Interpretation: Among the multitude of biomarkers considered, only blood NfL adds value to the ENCALS prediction model and should be incorporated into analysis plans for all ongoing and future ALS trials. Defined thresholds of NfL might also be used in trial design, for enrichment or stratified randomisation, to improve trial efficiency. Funding: NIH (U01-NS107027, U54-NS092091). ALSA (16-TACL-242). Competing Interests: Declaration of interests MB reports grants from the NIH (U01NS107027, U54NS092091) and the ALS Association (16-TACL-242) in support of this work. He is also an unpaid member of the Board of Trustees for the ALS Association. He has served as a consultant to Alector, Alexion, Annexon, Arrowhead, Biogen, Cartesian, Denali, Eli Lilly, Horizon, Immunovant, Novartis, Roche, Sanofi, Takeda, UCB, and UniQure. EAM reports grants from the NIH (U01NS107027, U54NS092091). He also serves as a consultant to Annexon, Biogen, Bial Biotech, Cortexyme, Chase Therapeutics, Enterin, nQ Medical, Partner Therapeutics, Stoparkinson Healthcare, and UCB. He has served on DSMBs for NeuroSense Therapeutics, Novartis, and Sanofi. AM reports grants from the NIH (U01NS107027). He has also provided consulting services to Roche, Pfizer, and Accure Therapeutics. MLR reports support from grants from the NIH (U01NS107027, U54NS092091) and FightMND. EH has nothing to declare. VL has nothing to declare. DR has nothing to declare. SS has nothing to declare. IM has nothing to declare. YC has nothing to declare. VG currently is an employee of Biohaven Pharmaceutical Inc. JS receives research funding from the NIH < MDA, FSHD Society, Friends of FSH Research, and FSHD Canada. He also serves as a consultant or on scientific advisory boards for Avidity, Fulcrum, Dyne, Armatus, Epic Bio, Roche, Lupin, and Entrada. JH has nothing to declare. RR reports grants from the NIH (U54NS092091) in support of this work. She is also an unpaid member of the Medical Advisory Board of the Association for Frontotemporal Dementias (AFTD) and a paid member of the Scientific Advisory Board of the Kissick Family Foundation FTD Grant Program. CAM reports funding from the ALS Association and the NIH (U54NS092091). LP reports support from the Mayo Clinic Foundation and grants from the National Institute on Aging (5P30AG0062677, U19AG063911) the National Institute of Neurological Disorders and Stroke (U54NS123743, R35NS097273, P01NS084974) and Target ALS Foundation. CM reports grants from the NIH (AG066597, AG076411, AG066152, AG072979, NS109260, NS092091), Department of Defense, and support from the Penn Institute on Aging, Decrane Family PPA Fund, and Newhouse Fund.2. JW reports funding from the NIH (U01NS107027, U54NS092091) and the ALS Association (16-TACL-242) in support of this work. The CReATe Consortium (U54NS092091) is part of the NIH Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), NCATS. This Consortium is funded through a collaboration between NCATS and the NINDS. This work was also supported by a Clinical Trial Readiness grant (U01NS107027) from NINDS and by a grant from the ALS Association to support the CReATe Biorepository (grant ID 16-TACL-242). (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu