#AANAM – Trial Will Evaluate Tofersen in Presymptomatic SOD1 Patients

Editor’s note: The ALS News Today team is providing in-depth coverage of the 2021 Virtual AAN Annual Meeting, April 17–22. Go here to read the latest stories from the conference.

A new clinical trial will seek to determine the optimal timing to begin treatment with the investigational medication tofersen in people who have SOD1 gene mutations, but who do not yet have clinically manifest amyotrophic lateral sclerosis (ALS).

The ATLAS trial is expected to start in the coming months at about 30 sites worldwide.

The trial’s rationale and design were described in a presentation at the 2021 Virtual American Academy of Neurology Annual Meeting (AANAM), in a talk titled, “Design of a Phase 3, Randomized, Placebo-controlled Trial of Tofersen Initiated in Clinically Pre-symptomatic SOD1 Mutation Carriers: The ATLAS Study.”

As many as one in 10 ALS cases are familial, meaning they are associated with an inherited genetic mutation. Mutations in SOD1 are among the most common causes of familial ALS, accounting for up to one-fifth of cases.

These mutations lead to the production of a mutant SOD1 protein that is prone to misfolding and forming clumps, which is thought to interfere with various cellular processes to drive the disease.

Reducing levels of the mutant SOD1 protein “is recognized as a potential therapeutic strategy” in people with these mutations, according to Michael Benatar, MD, PhD, of the University of Miami, who presented the results at AANAM.

Tofersen is an investigational therapy being developed by Biogen that aims to decrease levels of mutant SOD1 protein, and potentially slow disease progression, by targeting its messenger RNA — an intermediate molecule made by cells during the process of producing the protein.

Data from a prior Phase 1/2 clinical trial demonstrated that tofersen, delivered via an injection into the spinal canal, could decrease levels of SOD1 protein in ALS patients and slow functional decline in those with fast progressive disease.

Tofersen is currently being evaluated in a Biogen-sponsored Phase 3 study called VALOR (NCT02623699) and its open-label extension (NCT03070119). If results from that study are positive, they are expected to support applications for regulatory approval, according to Benatar.

“The goal of the ATLAS study is really to better define the optimal timing for initiation of tofersen, and whether it is of value to presymptomatic intervention,” Benatar said.

Presymptomatic ALS, as the name implies, refers to the period during which a person has early signs of ALS, like nervous system damage, but does not have overt clinical signs of the disease.

“In general, we don’t know when somebody will develop clinically manifest ALS, and we can’t predict that based on genotype [specific genetic mutations],” Benatar said. “The challenge with presymptomatic therapeutic intervention is that we need to know who to treat, and when.”

In ATLAS, the optimal time for treatment will be determined with the help of a biomarker called neurofilament light chain (NfL).

NfL is a structural protein found in neurons that is released into the blood and other bodily fluids when nerve cells become damaged. Prior research has suggested that NfL levels start to increase in SOD1 carriers before clinically evident disease manifests.

The ATLAS trial will enroll about 150 adults with SOD1 mutations that are typically associated with rapid disease progression. In the first part of the trial, participants will not receive any treatment, but they will undergo monthly screenings of NfL levels.

If screenings reveal a rise in NfL levels of at least 10 picograms (pg) per mL, such that total levels are at or above 44 pg/mL, participants will be enrolled in the next portion of the study, during which they will be given either tofersen (100 mg) or a placebo.

Individuals who develop clinically manifest ALS during this part of the trial will be allowed to move to an open-label part of the trial during which all participants will receive tofersen.

The study’s primary efficacy endpoint — its main measurement of treatment effectiveness — is the proportion of participants who develop clinically manifest ALS within a year of randomization.

It is conceivable that some people will develop clinically manifest ALS before an increase in NfL levels is evident. These individuals also would be randomized to either tofersen or placebo.

Participants in the study will be treated for up to two years.

The overall objective of ATLAS is “to evaluate whether preysmptomatic initiation of tofersen can delay emergence of clinically manifest ALS and/or slow the decline in function after the emergence of clinically manifest ALS,” Benatar said.

“ATLAS is designed to further our understanding of the optimal timing of tofersen administration, and to enhance our understanding of biomarkers of presymptomatic and early clinical disease,” Benatar concluded.