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Title: Design of a randomized, placebo-controlled, phase 3 trial of Tofersen initiated in clinically presymptomatic SOD1 variant carriers : the ATLAS study
Author(s): Benatar, Michael
Wuu, Joanne
Andersen, Peter M.
Bucelli, Robert C.
Andrews, Jinsy A.
Otto, Markus
Farahany, Nita A.
Harrington, Elizabeth A.
Chen, Weiping
Mitchell, Adele A.
Ferguson, Toby
Chew, Sheena
Gedney, Liz
Oakley, Sue
Heo, Jeong
Chary, Sowmya
Fanning, Laura
Graham, Danielle
Sun, Peng
Liu, Yingying
Wong, Janice
Fradette, Stephanie
Issue Date: 2022
Type: Article
Language: English
Abstract: Despite extensive research, amyotrophic lateral sclerosis (ALS) remains a progressive and invariably fatal neurodegenerative disease. Limited knowledge of the underlying causes of ALS has made it difficult to target upstream biological mechanisms of disease, and therapeutic interventions are usually administered relatively late in the course of disease. Genetic forms of ALS offer a unique opportunity for therapeutic development, as genetic associations may reveal potential insights into disease etiology. Genetic ALS may also be amenable to investigating earlier intervention given the possibility of identifying clinically presymptomatic, at-risk individuals with causative genetic variants. There is increasing evidence for a presymptomatic phase of ALS, with biomarker data from the Pre-Symptomatic Familial ALS (Pre-fALS) study showing that an elevation in blood neurofilament light chain (NfL) precedes phenoconversion to clinically manifest disease. Tofersen is an investigational antisense oligonucleotide designed to reduce synthesis of superoxide dismutase 1 (SOD1) protein through degradation of SOD1 mRNA. Informed by Pre-fALS and the tofersen clinical development program, the ATLAS study (NCT04856982) is designed to evaluate the impact of initiating tofersen in presymptomatic carriers of SOD1 variants associated with high or complete penetrance and rapid disease progression who also have biomarker evidence of disease activity (elevated plasma NfL). The ATLAS study will investigate whether tofersen can delay the emergence of clinically manifest ALS. To our knowledge, ATLAS is the first interventional trial in presymptomatic ALS and has the potential to yield important insights into the design and conduct of presymptomatic trials, identification, and monitoring of at-risk individuals, and future treatment paradigms in ALS.
Open Access: Open access publication
License: (CC BY 4.0) Creative Commons Attribution 4.0(CC BY 4.0) Creative Commons Attribution 4.0
Sponsor/Funder: Publikationsfonds MLU
Journal Title: Neurotherapeutics
Publisher: Springer
Publisher Place: New York, NY
Original Publication: 10.1007/s13311-022-01237-4
Appears in Collections:Open Access Publikationen der MLU

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