What is the mechanism of action of this treatment?

Tofersen targets the SOD1 mutation by reducing the production of the abnormal SOD1 protein, which is believed to contribute to motor neuron degeneration in ALS. Riluzole works by inhibiting glutamate release, thereby reducing excitotoxicity, which is a harmful process where excessive glutamate leads to neuron damage. Edaravone acts as an antioxidant, reducing oxidative stress and slowing functional decline. Sodium phenylbutyrate-taurursodiol reduces neuronal cell death by targeting cellular stress pathways. These treatments are crucial for ALS patients as they aim to slow disease progression, preserve motor function, and improve quality of life.

What side effects are associated with this type of intervention?

The most common treatments for Amyotrophic Lateral Sclerosis (ALS) include edaravone and riluzole. Edaravone is generally well-tolerated but can cause side effects such as bruising, gait disturbance, and headaches. Riluzole may lead to side effects like nausea, weakness, decreased lung function, and liver enzyme abnormalities. For treatments targeting specific mutations like Tofersen, which targets the SOD1 mutation, side effects are still being studied, but similar investigational drugs often report mild to moderate adverse effects such as injection site reactions, fatigue, and elevated liver enzymes.

What prior FDA approvals exist?

The FDA has approved several treatments for Amyotrophic Lateral Sclerosis (ALS), though specific approvals for drugs targeting the SOD1 mutation, like Tofersen, are limited. Riluzole and Edaravone are two primary FDA-approved drugs for ALS. Riluzole is believed to reduce damage to motor neurons by decreasing the release of glutamate, while Edaravone is thought to act as an antioxidant, reducing oxidative stress. Tofersen, currently under investigation, specifically targets the SOD1 mutation, which is a genetic cause of ALS, aiming to reduce the production of the toxic SOD1 protein.

What other types of research exist?

Promising novel alternatives to Tofersen for ALS patients include: 1) Reldesemtiv, a fast skeletal muscle troponin activator that aims to improve muscle function and strength. 2) AMX0035, a combination of sodium phenylbutyrate and taurursodiol, which targets cellular stress pathways. 3) NurOwn, a stem cell therapy that delivers neurotrophic factors to support neuron survival. 4) Tofacitinib, a JAK inhibitor being investigated for its potential to reduce neuroinflammation in ALS.

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Antisense Oligonucleotide

Tofersen for ALS (ATLAS Trial)

Phase 3

Recruiting

Research Sponsored by Biogen

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Participants who are clinically presymptomatic for ALS (i.e., must not have clinically manifest ALS).

Participants who are clinically presymptomatic for ALS (i.e., must not have clinically manifest ALS)

Must not have

Treatment with riluzole, edaravone, and/or sodium phenylbutyrate/taurursodiol (also known as ursodoxicoltaurine). If the participant has been on riluzole, edaravone, and/or sodium phenylbutyrate/taurursodiol, the medication(s) must be discontinued for at least 5 half-lives prior to Screening

Treatment with another investigational drug (including investigational drugs for ALS through compassionate use programs), biological agent, or device within 1 month or 5 half-lives of study agent, whichever is longer. Specifically, no prior treatment with small interfering RNA, stem cell therapy, or gene therapy is allowed

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 5.6 years

Awards & highlights

Pivotal Trial

Summary

This trial is testing a medication called tofersen in adults who have a genetic mutation that can lead to ALS, a serious nerve disease. These individuals show early signs of nerve damage. Tofersen works by lowering harmful proteins in the body to protect nerves and potentially delay or prevent the disease.

Who is the study for?

This trial is for adults who carry a specific gene mutation (SOD1) linked to ALS but don't yet show symptoms. They must have low neurofilament levels and not be on certain ALS treatments or other clinical trials. People with severe mental health issues, active infections like HIV or hepatitis, or those at risk of bleeding complications can't participate.

What is being tested?

The study tests Tofersen's effectiveness in delaying the onset of ALS symptoms in people with an SOD1 mutation. Participants will either receive Tofersen or a placebo without knowing which one they're getting to compare outcomes fairly.

What are the potential side effects?

While the side effects aren't detailed here, similar studies suggest potential reactions could include injection site reactions, liver enzyme changes, and flu-like symptoms. The trial aims to monitor safety closely.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I do not show any symptoms of ALS.

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I do not show any symptoms of ALS.

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My ALS is due to a specific SOD1 mutation confirmed by experts.

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My ALS is due to a specific SOD1 mutation confirmed by experts.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I have stopped my ALS medications for enough time before screening.

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I haven't taken any experimental drugs or treatments recently.

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I am using treatments not officially approved for ALS.

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I am at high risk for bleeding during or after surgery.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 5.6 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 5.6 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to 5.6 years for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Secondary study objectives

Parts B and C: Change in ALS Functional Rating Scale (ALSFRS-R) Total Score

Parts B and C: Percentage of Participants with Outcome as Death or Permanent Ventilation Based on Time to Death or Permanent Ventilation Analysis

Awards & Highlights

Pivotal Trial

The final step before approval, pivotal trials feature drugs that have already shown basic safety & efficacy.

Trial Design

4Treatment groups

Experimental Treatment

Active Control

Group I: Part D: Open-Label TreatmentExperimental Treatment1 Intervention

Participants from Part A who develop clinically manifest ALS prior to randomization in Part B may be eligible to participate in Part D. During Part D, participants will receive tofersen100 mg via IT injection on Days 1, 15, 29, and every 28 days thereafter for up to 2 years.

Group II: Part C: Open-Label ExtensionExperimental Treatment2 Interventions

Participants from Part B who develop clinically manifest ALS may be eligible to participate in Part C. During Part C, participants who received placebo in Part B will receive tofersen 100 mg via IT injection on Days 1, 15, 29, and every 28 days thereafter up to the final maintenance dost visit. Participants who received tofersen during Part B will receive tofersen 100 mg on Days 1, 29, and every 28 days thereafter up to the final maintenance dost visit, with a dose of placebo on Day 15 to maintain the study blind. The combined duration of Part B and Part C is up to approximately 5.6 years.

Group III: Part B: Randomized, Double-Blind, Placebo-ControlledExperimental Treatment2 Interventions

Participants from Part A who meet the protocol-defined NfL threshold and remain presymptomatic may be eligible to participate in Part B. During Part B, participants will receive tofersen 100 milligram (mg) or placebo via intrathecal (IT) injection on Days 1, 15, 29, and every 28 days thereafter for up to approximately 5.6 years.

Group IV: Part A: Natural History Run-inActive Control1 Intervention

Participants enrolled in Part A will undergo blood draws approximately once every 28 days to assess neurofilament light chain (NfL) levels.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Placebo

1995

Completed Phase 3

~2670

Tofersen

2018

Completed Phase 3

~330

0 / 8Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Tofersen targets the SOD1 mutation by reducing the production of the abnormal SOD1 protein, which is believed to contribute to motor neuron degeneration in ALS. Riluzole works by inhibiting glutamate release, thereby reducing excitotoxicity, which is a harmful process where excessive glutamate leads to neuron damage. Edaravone acts as an antioxidant, reducing oxidative stress and slowing functional decline. Sodium phenylbutyrate-taurursodiol reduces neuronal cell death by targeting cellular stress pathways. These treatments are crucial for ALS patients as they aim to slow disease progression, preserve motor function, and improve quality of life.