Design of a Randomized, Placebo-Controlled, Phase 3 Trial of Tofersen Initiated in Clinically Presymptomatic SOD1 Variant Carriers: the ATLAS Study

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.

Keywords: Genetic testing; Neurofilament; Phenoconversion; Pre-fALS; SOD1-ALS.

Fig. 1

ATLAS study schematic. Study treatment (tofersen or placebo) is administered via intrathecal injection. The dosing regimen consists of three loading doses administered at 14-day intervals followed by maintenance doses once every 28 days thereafter

Fig. 2

Illustration of decision rules for the primary endpoint

Fig. 3

Trends across matrices (serum and plasma), analytes (NfL and pNfH), and platforms (Quanterix Simoa, Siemens Healthineers, ProteinSimple Ella, Euroimmun) of NF prior to phenoconversion. Dotted horizon lines indicate the 95th percentile for the combined control and presymptomatic carrier group. Biological samples and clinical data were from the Pre-fALS (Pre-Symptomatic Familial ALS) study

Fig. 4

Fitted neurofilament trajectory model (using Siemens Healthineers assay results) to inform the NfL threshold in ATLAS. The black curve represents the fitted model (with 95% prediction bands for the sigmoidal fit shown in gray shading), while the colored lines represent the data. The dotted horizon line indicates the predefined threshold of 44 pg/mL. Biological samples and clinical data were from the Pre-fALS (Pre-Symptomatic Familial ALS) study

Fig. 5

Process for determining the primary endpoint (clinically manifest ALS) in the ATLAS study

Fig. 6

Country-specific privacy and antidiscrimination laws. This figure does not and is not intended to provide a complete or comprehensive description of all country-specific relevant laws, regulations, and practices. This is a starting place to learn the risks and legal protections that individuals undergoing SOD1 genetic testing may face and is limited to the countries planned to participate in ATLAS