Tofersen for ALS

(ATLAS Trial)

Not currently recruiting at 74 trial locations

Overseen By Kristen Riley

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Biogen

Must not be taking: Riluzole, Edaravone, Ursodoxicoltaurine, others

Disqualifiers: HIV, Hepatitis B, Hepatitis C, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 4

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines tofersen, a treatment for individuals with a specific genetic mutation linked to ALS, also known as Lou Gehrig’s disease. The main goal is to determine if tofersen can delay or prevent ALS symptoms in those who show no signs of the disease but have high levels of a protein (neurofilament) indicating early nerve damage. The trial also assesses the safety and tolerability of the treatment. It is suitable for individuals who know they carry the SOD1 gene mutation and have not yet developed ALS symptoms. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants an opportunity to contribute to potentially groundbreaking treatment advancements.

Do I need to stop my current medications to join the trial?

Yes, you may need to stop certain medications. If you are taking riluzole, edaravone, or sodium phenylbutyrate/taurursodiol, you must discontinue them for at least 5 half-lives before screening. You also cannot use off-label ALS treatments or other investigational drugs within a specified period before the study.

Will I have to stop taking my current medications?

You may need to stop taking certain medications like riluzole, edaravone, and sodium phenylbutyrate/taurursodiol at least 5 half-lives before the screening. The protocol does not specify about other medications, so it's best to discuss with the study team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that tofersen, a treatment for a specific type of amyotrophic lateral sclerosis (ALS) caused by superoxide dismutase 1 mutations (SOD1-ALS), is already approved for this condition, indicating it has been checked for safety. Earlier studies found that most people tolerated tofersen well, though there were reports of serious side effects affecting the nervous system, such as inflammation of the spinal cord (myelitis), nerve root inflammation (radiculitis), brain lining inflammation (aseptic meningitis), and swelling of the optic nerve (papilledema). These side effects underscore the importance of monitoring during treatment.

In another study, 50 people received tofersen, and it was generally safe. It also helped lower levels of the SOD1 protein linked to ALS. Some patients showed less decline in their ALS symptoms compared to those who did not receive the drug, but these results were not statistically significant, suggesting they might have occurred by chance.

These findings highlight the need for careful consideration and discussion with healthcare providers when considering participation in a clinical trial involving tofersen. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for ALS?

Most treatments for ALS focus on managing symptoms and improving quality of life, but Tofersen works differently by targeting the genetic root of the condition. Tofersen is designed to reduce the production of toxic proteins in people with a specific genetic mutation linked to ALS. Unlike current therapies that rely on oral or intravenous administration, Tofersen is delivered directly into the spinal fluid through intrathecal injections, allowing it to reach the central nervous system more effectively. Researchers are excited because this targeted approach has the potential to slow the progression of ALS rather than just address its symptoms.

What evidence suggests that tofersen might be an effective treatment for ALS?

Research has shown that the drug tofersen, which participants in this trial may receive, can reduce a specific protein in the blood, called neurofilament light chain (NfL), by 40-50% over six months in people with ALS. Lowering NfL is important because high levels are associated with nerve damage. One study found that tofersen also reduced the SOD1 protein in the fluid around the brain and spine, which is crucial for people with the SOD1 mutation. However, tofersen did not improve ALS symptoms over 28 weeks. Despite this, the FDA has approved the treatment, indicating it may help manage certain aspects of ALS. ^{3 6 7 8 9}

Who Is on the Research Team?

Medical Director

Principal Investigator

Biogen

Are You a Good Fit for This Trial?

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.

Inclusion Criteria

I do not show any symptoms of ALS.

I do not show any symptoms of ALS.

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

Exclusion Criteria

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

History of systemic hypersensitivity reaction to tofersen, the excipients contained in the formulation, and if appropriate, any diagnostic agents to be administered during the study

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

Timeline for a Trial Participant

Natural History Run-in

Participants undergo blood draws approximately once every 28 days to assess neurofilament light chain (NfL) levels

Varies

1 visit every 28 days

Randomized, Double-Blind, Placebo-Controlled

Participants receive tofersen 100 mg or placebo via intrathecal injection on Days 1, 15, 29, and every 28 days thereafter

Up to approximately 5.6 years

1 visit every 28 days

Open-Label Treatment

Participants receive tofersen 100 mg via IT injection on Days 1, 15, 29, and every 28 days thereafter for up to 2 years

Up to 2 years

1 visit every 28 days

Open-Label Extension

Participants who develop clinically manifest ALS may receive tofersen 100 mg via IT injection on Days 1, 29, and every 28 days thereafter

Up to approximately 5.6 years

1 visit every 28 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• BIIB067 (Tofersen)
• Placebo
• Tofersen

Trial Overview 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.

How Is the Trial Designed?

Group I: Part D: Open-Label Treatment Experimental Treatment 1 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 Extension Experimental Treatment 2 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-Controlled Experimental Treatment 2 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-in Active Control 1 Intervention

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

BIIB067 (Tofersen) is already approved in United States, European Union for the following indications:

Approved in United States as Qalsody for:

• Amyotrophic lateral sclerosis (ALS) associated with a mutation in the superoxide dismutase 1 (SOD1) gene

Approved in European Union as Qalsody for:

• Amyotrophic lateral sclerosis (ALS) caused by a defective superoxide dismutase 1 (SOD1) protein

Who Is Running the Clinical Trial?

Biogen

Lead Sponsor

Trials

655

Recruited

468,000+

Daniel Quirk

Biogen

Chief Medical Officer

MD

Christopher A. Viehbacher

Biogen

Chief Executive Officer since 2022

Graduated from Queen's University, Kingston, Ontario, Canada

Published Research Related to This Trial

B*07:385 is a variant of B*07:02:01:01, differing by a single nucleotide change at position 660 in exon 4, which may have implications for immune response and disease susceptibility.

Understanding these genetic differences is important for research in immunology and personalized medicine, as they can affect how individuals respond to infections and treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization of the novel HLA-B*07:385 allele by next-generation sequencing. Genebrier, S., Elsermans, V., Texeraud, E., et al.[2021]

In a phase 3 trial involving 108 adults with SOD1 ALS, tofersen significantly reduced levels of the SOD1 protein and neurofilament light chains in cerebrospinal fluid and plasma, indicating its mechanism of action in targeting the disease.

Despite these biochemical reductions, tofersen did not show a significant improvement in clinical outcomes, such as the ALS Functional Rating Scale score, and was associated with common adverse events related to lumbar punctures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS. Miller, TM., Cudkowicz, ME., Genge, A., et al.[2022]

In a case series of six SOD1-ALS patients treated with the antisense oligonucleotide tofersen for an average of 6.5 months, there was a significant reduction in neurofilament light chain (NfL) levels, indicating a potential response to treatment and suggesting disease-modifying activity.

The decline in NfL levels, which are associated with ALS progression, supports the use of NfL as a biomarker for monitoring treatment response in SOD1-ALS, highlighting tofersen's potential efficacy in slowing disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neurofilament light-chain response during therapy with antisense oligonucleotide tofersen in SOD1-related ALS: Treatment experience in clinical practice. Meyer, T., Schumann, P., Weydt, P., et al.[2023]

C*06:283 is a variant of C*06:02:01:01, differing by a single nucleotide change at position 764 in exon 4, which may have implications for its function or association with diseases.

Understanding these subtle genetic differences is important for research in immunology and personalized medicine, as they can affect how individuals respond to treatments or their susceptibility to certain conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization of the novel HLA-C*06:283 allele by next-generation sequencing. Genebrier, S., Elsermans, V., Texeraud, E., et al.[2021]

A novel CisAB allele (c.796A>C mutation in ABO*B.01) was identified in a newborn and his family, marking the first discovery of this allele in the Chinese population.

The study utilized serological tests and genetic sequencing of the ABO gene to confirm the CisAB phenotype in the proband and his relatives, highlighting the genetic basis of this rare blood type.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Novel c.796 A>C Mutation in the ABO*B.01 Allele Responsible for CisAB Phenotype. Li, X., Bi, H., Sun, L., et al.[2022]

The individual studied expressed a very weak B antigen on red blood cells, identified as the Bel variant phenotype, due to a specific mutation in the ABO gene.

The 484delG mutation in the B allele likely disrupts the function of the glycosyltransferase enzyme, leading to reduced enzymatic activity and the observed Bel variant phenotype.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Study of the molecular basis for an individual with Bel variant due to deletion of B glycosyltransferase gene]. Ying, Y., Hong, X., Chen, S., et al.[2017]

Four new HLA Class II alleles were discovered using a reverse hybridization assay, with unique polymorphisms that could impact immune response and disease susceptibility.

The novel alleles include DRB3*0208, which differs from DRB3*0202 by a significant nucleotide change, and DQB1*0614, which shows a change in amino acid, indicating potential evolutionary significance and the mechanisms of gene conversion and mutation in their formation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel DRB3 allele (DRB3*0208), a new allelic variant of DRB1*1502 (DRB1*15023) and two new DQB1 (DQB1*03012 and DQB1*0614) alleles. Hashemi-Tavoularis, S., Ouellet, S., Sengar, DP., et al.[2019]

Tofersen (Qalsody™) is an antisense oligonucleotide that has been approved in the USA for treating amyotrophic lateral sclerosis (ALS) specifically in adults with a mutation in the SOD1 gene.

The approval of tofersen marks a significant milestone in ALS treatment, highlighting the potential of targeted genetic therapies in managing this challenging neurodegenerative disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tofersen: First Approval. Blair, HA.[2023]

Tofersen, the first gene therapy approved for ALS, targets mutant SOD1 mRNA, addressing a key pathological factor in the disease and offering a potential way to slow its progression.

This review highlights that while current treatments like riluzole and edaravone only provide symptomatic relief, tofersen represents a significant advancement in ALS therapy, allowing for better monitoring and treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Breaking barriers with tofersen: Enhancing therapeutic opportunities in amyotrophic lateral sclerosis. Saini, A., Chawla, PA.[2023]

The ATLAS study is the first interventional trial targeting presymptomatic carriers of SOD1 variants in ALS, aiming to evaluate whether the drug tofersen can delay the onset of clinically manifest ALS in individuals showing early biomarkers of disease activity, specifically elevated plasma neurofilament light chain (NfL).

Tofersen is designed to reduce the production of the harmful SOD1 protein by degrading its mRNA, which could provide a novel therapeutic approach for genetic forms of ALS, potentially allowing for earlier intervention before the disease fully manifests.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design of a Randomized, Placebo-Controlled, Phase 3 Trial of Tofersen Initiated in Clinically Presymptomatic SOD1 Variant Carriers: the ATLAS Study. Benatar, M., Wuu, J., Andersen, PM., et al.[2022]

Tofersen, an antisense oligonucleotide, effectively reduced cerebrospinal fluid (CSF) SOD1 concentrations in adults with ALS due to SOD1 mutations, particularly at the highest dose of 100 mg over 12 weeks.

While tofersen showed potential efficacy in lowering SOD1 levels, it was associated with adverse events, including lumbar puncture-related complications and elevated white-cell counts in some participants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1-2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS. Miller, T., Cudkowicz, M., Shaw, PJ., et al.[2022]

Citations

1. ninds.nih.gov ninds.nih.gov/about-ninds/what-we-do/impact/ninds-contributions-approved-therapies/tofersen-qalsodyr-amyotrophic-lateral-sclerosis

Tofersen (Qalsody®) - Amyotrophic Lateral Sclerosis FDA approval of tofersen relied on the treatment's ability to lower blood plasma NfL levels by 40-50% over a six-month period.8 Building on this ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03070119

NCT03070119 | Long-Term Evaluation of BIIB067 (Tofersen) The primary objective of the study is to evaluate the long-term safety and tolerability of BIIB067 (tofersen) in participants with amyotrophic lateral ...

3. als.org als.org/navigating-als/living-with-als/fda-approved-drugs/tofersen

Tofersen A phase 1/2 clinical trial involving a group of 50 people showed that treatment with tofersen was generally safe and lowered levels of the SOD1 protein in ...

4. nejm.org nejm.org/doi/full/10.1056/NEJMoa2204705

Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS Tofersen reduced concentrations of SOD1 in CSF and of neurofilament light chains in plasma over 28 weeks but did not improve clinical end points and was ...

5. qalsody.com qalsody.com/en-us/home/about-qalsody/clinical-studies.html

QALSODY® (tofersen) - Clinical Studies VALOR studied the effectiveness and safety of QALSODY compared to placebo in people with weakness due to amyotrophic lateral sclerosis (ALS)

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40017137/

Serious Neurologic Adverse Events in Tofersen Clinical ... Serious neurologic AEs of myelitis, radiculitis, aseptic meningitis, and papilledema reported in the tofersen clinical trials are described.

7. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/10.1002/mus.28372

Serious Neurologic Adverse Events in Tofersen Clinical ... Tofersen is approved for the treatment of amyotrophic lateral sclerosis (ALS) due to superoxide dismutase 1 mutations (SOD1-ALS).

8. clinicaltrials.gov clinicaltrials.gov/study/NCT02623699

Study Details | NCT02623699 | An Efficacy, Safety, ... This is a 3-part study to examine the efficacy, safety, tolerability, PK, and PD of tofersen. Part A is the single ascending dose (SAD) component of the study, ...

9. qalsodyhcp.com qalsodyhcp.com/en-us/home/clinical-study-information/clinical-results.html

Clinical Study Results | QALSODY® (tofersen) Patients treated with QALSODY experienced less decline from baseline in the ALSFRS-R compared to placebo, but the results were not statistically significant.1.