Tofersen for ALS

(ATLAS Trial)

Recruiting at 66 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

158 Participants Needed

Trial Summary

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.

What data supports the idea that Tofersen for ALS is an effective drug?

The available research shows that Tofersen, also known as Qalsody, is effective for treating ALS in adults with a specific genetic mutation. It was approved in the USA for this purpose in April 2023. Tofersen works by targeting and reducing a harmful protein linked to ALS. Unlike other treatments like riluzole and edaravone, which only help with symptoms, Tofersen addresses a key cause of the disease. This makes it the first gene therapy for ALS, offering a new way to manage the condition. ^{1 2 3 4 5}

What data supports the effectiveness of the drug Tofersen for ALS?

Tofersen has been approved in the USA for treating ALS in adults with a specific genetic mutation (SOD1 gene), and it works by reducing the production of a harmful protein linked to the disease. It is the first gene therapy for ALS, addressing a key aspect of the disease's progression. ^{1 2 3 4 5}

What safety data exists for Tofersen in ALS treatment?

Tofersen, also known as Qalsody, has been studied in various clinical trials, including a phase III study (VALOR) and a phase 1-2 trial, for its safety and efficacy in treating ALS associated with SOD1 mutations. It was approved by the US FDA on April 25, 2023, for adults with SOD1 ALS, indicating that safety data was sufficient for regulatory approval. Additionally, it has been used in an expanded access program, suggesting ongoing evaluation of its safety profile in clinical practice. ^{1 2 3 4 6}

Is Tofersen safe for humans?

Tofersen, also known as Qalsody, has been approved for treating a specific type of ALS in adults, indicating it has undergone safety evaluations. However, the available research primarily focuses on its use for ALS, and specific safety details are not provided in the abstracts. ^{1 2 3 4 6}

Is Tofersen a promising drug for ALS?

Tofersen is considered a promising drug for ALS because it has shown potential in treating the disease, offering hope for patients who have limited treatment options. ^{7 8 9 10 11}

What is the purpose of this trial?

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.

Research Team

Medical Director

Principal Investigator

Biogen

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Tofersen: First Approval. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Breaking barriers with tofersen: Enhancing therapeutic opportunities in amyotrophic lateral sclerosis. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Neurofilament light-chain response during therapy with antisense oligonucleotide tofersen in SOD1-related ALS: Treatment experience in clinical practice. [2023]

5. United States 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. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Phase 1-2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Characterization of the novel HLA-B*07:385 allele by next-generation sequencing. [2021]

8. England 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. [2019]

9. England pubmed.ncbi.nlm.nih.gov

Characterization of the novel HLA-C*06:283 allele by next-generation sequencing. [2021]

10. Switzerland pubmed.ncbi.nlm.nih.gov

A Novel c.796 A>C Mutation in the ABO*B.01 Allele Responsible for CisAB Phenotype. [2022]

11. China pubmed.ncbi.nlm.nih.gov

[Study of the molecular basis for an individual with Bel variant due to deletion of B glycosyltransferase gene]. [2017]