• Skip to primary navigation
  • Skip to main content
  • Skip to primary sidebar
  • Skip to footer
  • Email
  • Facebook
  • LinkedIn
  • Twitter
  • YouTube

International Alliance of ALS/MND Associations

  • Members' Login
  • Contact
  • Join the Alliance
  • Donate
  • What is ALS/MND
  • Find a Member Association
  • Support for PALS & CALS
    • Fundamental Rights for People with ALS/MND and Caregivers
    • Research
      • Voice Preservation
      • Open Science
      • Expanded Access
      • Understanding ALS/MND Research
      • Improving Regulatory Pathways
      • Right to Try
      • US FDA Orphan Drug Designation
      • Unproven (Off-Label) Treatments
      • Open Label Extension
    • Advocacy
      • Advocacy Toolkit
      • Emergency Preparedness Toolkit
      • Equitable Access to Therapies
      • Recommendations for Trial Sponsors
    • Clinical Care
      • Genetic Counselling & Testing
      • Mental Health Support
      • Nursing and Symptom Management
      • Nutrition and Swallowing
      • Occupational Therapy and Activities of Daily Living
      • Physiotherapy and Mobility
      • Respiratory Care
      • Speech Therapy and Communication
      • Support for Family & Caregivers
      • Technology
      • Global Clinic Locator
    • Drugs in Development
      • AB Science – Masitinib
      • BrainStorm Cell Therapeutics – NurOwn
      • Clene Nanomedicine – CNM-Au8
      • Collaborative Medicinal Development – CuATSM
      • ILB – Tikomed
      • Kadimastem – AstroRx
      • Mitsubishi Tanabe Pharma America – Oral Edaravone
      • Neuronata-R/Lenzumestrocel
      • NeuroSense – PrimeC
      • Neuvivo – NP001
      • Prilenia Therapeutics – Pridopidine
      • SOD1 Therapies & Trials
      • T Regulatory Cell Therapies
      • Ulefnersen – Ionis Pharmaceuticals
    • Approved Drugs
      • Nuedexta
      • Radicava/Edaravone
      • Riluzole/Tiglutik
      • Rozebalamin/Methylcobalamin
      • Tofersen/Qalsody
    • Drugs No Longer in Development
      • Amylyx – AMX0035
      • Collaborative Medicinal Development – CuATSM
      • Cytokinetics – Reldesemtiv
      • Orphazyme – Arimoclomol
      • TUDCA Trial
  • Support for Health Professionals
    • Breaking the News in ALS/MND
    • Diagnostic Delay (in development)
  • Events/Programs
    • Calendar of Events/Programs
    • Alliance Meeting
    • Allied Professionals Forum
    • Alliance Webinars
    • ALS/MND Connect
    • Global Day Calendar
    • March of Faces
    • Patient Fellows Program
    • Global CRLI
    • International Symposium
  • About
    • Who We Are
    • ALS/MND Health Literacy Map
    • Board of Trustees
    • Advisory Councils/Committees
      • Scientific Advisory Council
      • PALS and CALS Advisory Council
      • Innovation and Technology Council
      • Advocacy and Public Policy Forum
      • Research Directors Forum
      • Governance Committee
      • Finance Committee
    • Staff
    • History
    • Archives
      • Newsletters
      • Meetings
    • Awards
      • Forbes Norris Award
      • Humanitarian Award
      • Allied Health Professional Award
      • Student Innovation Award
  • Members
    • Member Registration
    • Forgot Password

SOD1 Therapies & Trials

Background

In 1993, mutations in the cytosolic copper-zinc superoxide dismutase 1 (SOD1) gene were discovered to be associated with ALS/MND (Ref: Rosen et al., 1993) accounting for roughly 2% of all ALS/MND cases and approximately 15-20% of ALS/MND with familial history. The SOD1 gene contains the instructions needed to produce the SOD1 protein, an abundant enzyme within cells that serves to keep them safe from metabolic waste. Mutations in the SOD1 gene cause an accumulation of defective SOD1 protein in patients’ cells. These defective proteins create a toxic environment and result in motor neuron death (Ref: Bunton-Stasyshyn et al., 2014). 

To date both the Food and Drug Administration (FDA) and the European Medicine Agency (EMA) granted extraordinary approval to Qalsody (tofersen) to treat patients affected by ALS/MND associated with a mutation in SOD1 (SOD1-ALS). Qalsody is an antisense oligonucleotide (ASO) directed against SOD1 messenger RNA (mRNA), which encodes the SOD1 protein. By targeting the SOD1 mRNA, this ASO reduces the overall expression of the SOD1 protein, limiting its toxic activity in people with SOD1-ALS. Qalsody is administered through an injection in the spinal fluid (intrathecally) every 28 days (Ref: FDA). More information on trial design and outcomes that determined FDA approval can be found at als-mnd.org (Biogen-tofersen).

The ATLAS Trial

Early intervention has long been considered as likely optimal in ALS/MND, though it has never been clinically tested. The ability to initiate experimental and proven treatments upstream of clinical symptom onset is a milestone that requires a biological indicator (biomarker) of underlying disease processes being triggered.

In recent years, a significant amount of work has yielded the protein called neurofilament light chain (NfL) as a potential blood biomarker to indicate that nervous system damage has occurred. While this is not specific for ALS/MND, when combined with known, disease-causing genetic mutations, it may provide an opportunity to visualize the pre-clinical triggering of ALS/MND processes.

Given tofersen’s efficacy and safety profile, and the hypothesized advantage of early therapeutic intervention in ALS/MND, Biogen started a global pre-symptomatic trial in ~150 individuals who carry selected SOD1 mutations linked to rapid disease progression but have not yet shown any ALS/MND symptoms. This is a Phase 3 randomized, placebo-controlled trial, and results are expected in 2027. The leading hypothesis for this trial is that by reducing production of toxic SOD1 protein in people with SOD1 mutations, the drug will either delay symptoms from appearing or prevent symptoms altogether. Participants are monitored monthly for change in ALS/MND Functional Rating Scale (ALSFRS-R) total score, change from baseline in percent predicted Slow Vital Capacity (SVC), adverse events and plasma and CSF-based biomarkers. Specifically, participants are monitored monthly for any change in plasma-based biomarkers called neurofilament light (NfL), which indicates early stage of disease up to a year prior symptom onset. If in any of the subjects’ treated with placebo in the people who show symptoms within a year. All individuals on placebo will be provided open label tofersen upon an ALS/MND diagnosis, which still results in earlier access to the treatment than any of the individuals affected by SOD1-ALS treated to date (Ref: ClinicalTrials.gov, ID: NCT04856982).

The novel primary measure of evaluation will be the proportion of participants who develop clinical symptoms of ALS/MND within one year of randomization. Given that the participants will have SOD1 mutations associated with rapid progression, if a significant number do not have clinical symptoms after one year, it would suggest that tofersen is able to delay the disease process. Participants will be treated for up to two years as part of the study.

Fig1. ATLAS trial design overview

It is hoped that the ATLAS trial will pave the way for more pre-symptomatic trials in the future. Should therapies become proven as effective for other known genetic mutations, these pre-symptomatic studies may indicate the next logical step and will have learned from ATLAS in the effectiveness of using NfL as a trial initiation biomarker in practice.

For cases where there is no identifiable mutation in a known ALS/MND gene, researchers will need to identify additional biomarker(s) that can differentiate between nervous system damage indicating ALS/MND versus that of many other conditions. As of 2024, there is nothing fitting this criterion that is close to clinical use, but a strong effort is underway in labs around the world.

Other SOD-1 Targeting Therapies

In addition to the above, three other companies are developing more therapeutics to target SOD1:

  1. UniQure has developed a one-time intrathecally administered gene therapy (AMT-162), composed by a viral vector (AAVrh10) that expresses a micro ribonucleic acid (miRNA) designed to decrease the expression of SOD1. As of 2024, the FDA has cleared the investigational new drug (IND) application for AMT-162 and granted Orphan Drug and Fast Track designations. UniQure expects to initiate patient dosing in the first quarter of 2024 for a Phase 1/2, multi-center, three-part study (Ref: UniQure Website and ClinicalTrials.gov ID: NCT06100276).
  2. In 2022 Alnylam Pharmaceuticals published a novel small interfering RNA (siRNA) technology to enhance delivery to the central nervous system (CNS). The publication showed uptake of SOD1 targeting siRNA in the CNS and subsequent lower expression of SOD1 by 75% in a mouse model system (Ref: Brown at al., 2022, Alnylam Pharmaceutical Website). Alnylam is currently collaborating with Regeneron to start a proof-of-concept study in SOD1-ALS in 2024 (Ref: Regeneron JPM 2024 presentation)
  3. AviadoBio has recently acquired rights for Neurgian Technologie’s novel approach to deliver gene therapies directly to the spinal cord through a ‘subpial’ injection. This technique allows to get through the membrane that surrounds the spinal cord, resulting in the need for lower doses of compound though a minimally invasive procedure (Ref: Miyanohara et al., 2016, ALS News Today). AviadoBio is aiming to use this method to deliver a short hairpin RNA (shRNA) directed against SOD1 to repress gene expression. Neurgian Technologies showed that in rodents one subpial injection with a virally delivered shRNA resulted in the prevention of the disease in SOD1 carriers and improvement of the disease in symptomatic mice. In pigs and non-human primates, one injection produces homogeneous delivery in the whole spinal cord (Ref: Bravo-Hernandez et al., 2019).

Summary

Therapies that lower the total amount of SOD1 are believed to be an effective strategy against SOD1-ALS. It is expected that we will see an optimization of these therapies, such as earlier intervention or improvement of drug delivery to the CNS. There is still much to learn about the long-term implication of lowering of SOD1 levels and to what extent it can safely be lowered. Furthermore, strategies to lower only the abnormal SOD1 are also a possibility, which would be more specific to SOD1 toxicity in ALS/MND.

It is important to note that there are many areas of the world where tofersen is not a therapeutic option due to different reasons. We hope that as more SOD1 targeting therapies are developed, this will give individuals affected by SOD1-ALS an option to receive the new SOD-1 targeting therapeutics through clinical trials. The Alliance is actively working to create clinical trial networks in geographic regions where they do not already exist to facilitate the diffusion of promising therapies without geographic restrictions.

To date, therapies that lower the total amount of SOD1 protein have only been tested in individuals affected by SOD1-ALS or preclinical models of SOD1-ALS. Therefore, none of the therapies mentioned here are currently indicated for people with ALS/MND who do not carry SOD1 genetic variants. Tofersen is the only FDA and EMA approved drug for the treatment of people affected by ALS/MND associated with a genetic variant in SOD1.

International Alliance of ALS/MND Associations
September 2024


The original language of communication is English and any translation cannot be guaranteed for accuracy of messaging.

SOURCES

Rosen et al., 1993 – https://pubmed.ncbi.nlm.nih.gov/8446170/

Bunton-Stasyshyn et al., 2014 – https://doi.org/10.1177/1073858414561795

FDA – https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-treatment-amyotrophic-lateral-sclerosis-associated-mutation-sod1-gene

ClinicalTrial.gov (ATLAS) – https://clinicaltrials.gov/study/NCT04856982#participation-criteria

Businesswire (press release) –  https://www.businesswire.com/news/home/20230412005207/en/Arrowhead-Pharmaceuticals-to-Host-RD-Day-on-Pipeline-of-RNAi-Therapeutics

Uniqure website – https://www.uniqure.com/programs-pipeline/als-sod1

ClinicalTrial.gov ID: NCT06100276 – https://clinicaltrials.gov/study/NCT06100276?cond=ALS&term=SOD1&rank=6

Brown at al., 2022 – https://www.nature.com/articles/s41587-022-01334-x

Alnylam Pharmaceuticals Website (press release) – https://investors.alnylam.com/press-release?id=26761

Regeneron JPM 2024 presentation – https://investor.regeneron.com/static-files/7dfdabe2-05d1-4145-b5c5-342cec0ce9c4

Miyanohara et al. 2016 – https://www.ncbi.nlm.nih.gov/pubmed/27462649

ALS News Today – https://alsnewstoday.com/news/aviadobio-acquires-delivery-technology-als-gene-therapies/

Bravo-Hernandez et al., 2019 – https://www.nature.com/articles/s41591-019-0674-1  

Primary Sidebar

Drugs in Development

  • AB Science – Masitinib
  • BrainStorm Cell Therapeutics – NurOwn
  • Clene Nanomedicine – CNM-Au8
  • Collaborative Medicinal Development – CuATSM
  • ILB – Tikomed
  • Kadimastem – AstroRx
  • Methylcobalamin
  • Mitsubishi Tanabe Pharma America – Oral Edaravone
  • Neuronata-R/Lenzumestrocel
  • NeuroSense – PrimeC
  • Neuvivo – NP001
  • Prilenia Therapeutics – Pridopidine
  • SOD1 Therapies & Trials
  • T Regulatory Cell Therapies
  • Ulefnersen – Ionis Pharmaceuticals

  • Kirsty Gerlach, MND New Zealand, Diagnosed 2017

    Kirsty Gerlach, MND New Zealand, Diagnosed 2017

  • Shera Mukherjee, Diagnosed 2013,  Asha Ek Hope Foundation, India

    Shera Mukherjee, Diagnosed 2013, Asha Ek Hope Foundation, India

  • Teddy Hanono Annie, Apoyo Integral Gila A.C., Diagnosed 2018, Mexico

    Teddy Hanono Annie, Apoyo Integral Gila A.C., Diagnosed 2018, Mexico

  • Nicholas (Nic) Bowman, MND Association of South Africa,  Diagnosed 2016,  Australia

    Nicholas (Nic) Bowman, MND Association of South Africa, Diagnosed 2016, Australia

  • Dawn Morton, Diagnosed 2014 , MND Scotland, UK

    Dawn Morton, Diagnosed 2014 , MND Scotland, UK

  • Ian Gale, MND Australia

    Ian Gale, MND Australia

  • Amparo Muriel Engativa, Colombia

    Amparo Muriel Engativa, Colombia

  • IMG_1211

    IMG_1211

  • 83

    83

  • Dorette Lüdi, Diagnosed 2014 , ALS Schweiz, Switzerland

    Dorette Lüdi, Diagnosed 2014 , ALS Schweiz, Switzerland

  • Francisco Perez Palop, Diagnosed 2013 , FUNDELA, Spain

    Francisco Perez Palop, Diagnosed 2013 , FUNDELA, Spain

  • Phil Rossall, MND-Association, UK

    Phil Rossall, MND-Association, UK

  • Richard Clark, MND New Zealand,  Diagnosed 2011

    Richard Clark, MND New Zealand, Diagnosed 2011

  • Shay Rishoni, Diagnosed 2011 - Prize4Life, Israel

    Shay Rishoni, Diagnosed 2011 – Prize4Life, Israel

  • Anthony (Tony) Lynch, MND New South Wales, Diagnosed 2016, Australia

    Anthony (Tony) Lynch, MND New South Wales, Diagnosed 2016, Australia

  • Soledad Rodriguez, FUNDELA, Diagnosed 2013, Spain

    Soledad Rodriguez, FUNDELA, Diagnosed 2013, Spain

  • Carlos Alberto Báez Murillo, ACELA, Colombia

    Carlos Alberto Báez Murillo, ACELA, Colombia

  • Jan Zuring, Diagnosed 2010 , The Netherlands

    Jan Zuring, Diagnosed 2010 , The Netherlands

  • Sam Hayden-Harler, Motor Neurone Disease (MND) Association, UK

    Sam Hayden-Harler, Motor Neurone Disease (MND) Association, UK

  • Willi Klein

    Willi Klein

  • Fabio Carvalho

    Fabio Carvalho

  • Mauril Bélanger, Diagnosed 2015 , ALS Canada

    Mauril Bélanger, Diagnosed 2015 , ALS Canada

  • Margarita Pizarro, Asociacion ELA Argentina, Diagnosed 2017, Argentina

    Margarita Pizarro, Asociacion ELA Argentina, Diagnosed 2017, Argentina

  • Ailsa Malcolm-Hutton, Diagnosed 2013,  MND Association of England, Wales and N Ireland

    Ailsa Malcolm-Hutton, Diagnosed 2013, MND Association of England, Wales and N Ireland

  • Eddy LeFrançois, Diagnosed 1992,  ALS Canada

    Eddy LeFrançois, Diagnosed 1992, ALS Canada

  • Sanjay Kumar Srivastava, Asha Ek Hope Foundation for ALS/MND, Diagnosed 2018, India

    Sanjay Kumar Srivastava, Asha Ek Hope Foundation for ALS/MND, Diagnosed 2018, India

  • Catherine Pearce, Australia

    Catherine Pearce, Australia

  • Aida Trzmiel de Guterman, Asociacion ELA Argentina, Diagnosed 2007, Argentina

    Aida Trzmiel de Guterman, Asociacion ELA Argentina, Diagnosed 2007, Argentina

  • Horacio Fritzer, Argentina

    Horacio Fritzer, Argentina

  • Imelda Arenas, ACELA, Colombia

    Imelda Arenas, ACELA, Colombia

  • Claudette Sturk, ALS Society of Canada

    Claudette Sturk, ALS Society of Canada
    Picture2

  • Claudia Gotti, Brazil

    Claudia Gotti, Brazil

  • Fabrice Kamp, Germany

    Fabrice Kamp, Germany

  • Steven Spencer, Diagnosed 2014 , MND New Zealand

    Steven Spencer, Diagnosed 2014 , MND New Zealand

  • Hanne Stenmose, Muskelsvindfonden, Denmark

    Hanne Stenmose, Muskelsvindfonden, Denmark

  • Kirsten Harley,  Diagnosed 2013,  Australia

    Kirsten Harley, Diagnosed 2013, Australia

  • Bruno Leanza Mantegna, Diagnosed 1999 , AISLA Onlus, Italy

    Bruno Leanza Mantegna, Diagnosed 1999 , AISLA Onlus, Italy

  • Stephanie Christiansen Hall, Canada

    Stephanie Christiansen Hall, Canada

  • Jose Rivero Muñoz, Diagnosed 2015, FYADENMAC, Mexico

    Jose Rivero Muñoz, Diagnosed 2015, FYADENMAC, Mexico

  • Guido De Mets, Belgium

    Guido De Mets, Belgium

  • Oliver Juenke, Germany

    Oliver Juenke, Germany

  • Sally Pauls, Diagnosed 2006 , Les Turner ALS Foundation

    Sally Pauls, Diagnosed 2006 , Les Turner ALS Foundation

  • Steve

    Steve

  • Hans Dieter Olszewski, Diagnosed 2010 , DGM, Germany

    Hans Dieter Olszewski, Diagnosed 2010 , DGM, Germany

  • Jon Newsome, Les Turner ALS Foundation, USA

    Jon Newsome, Les Turner ALS Foundation, USA

  • Joanne Pratt, Diagnosed 2011 , MND Australia

    Joanne Pratt, Diagnosed 2011 , MND Australia

  • Yolanda Armendariz, Diagnosed 2017 , FYADENMAC, Mexico

    Yolanda Armendariz, Diagnosed 2017 , FYADENMAC, Mexico

  • Maurice Leclerc, Canada

    Maurice Leclerc, Canada

  • Danny Reviers, Diagnosed 1979 , ALS Liga België, Belgium

    Danny Reviers, Diagnosed 1979 , ALS Liga België, Belgium

  • Susan Anderson, Diagnosed 2014 , Hope Loves Company,  USA

    Susan Anderson, Diagnosed 2014 , Hope Loves Company, USA

Learn more about the March of Faces

Latest Tweets

  • Just now

Footer

Subscribe to our Bi-Monthly Newsletter

Sign up to receive updates and to hear what's going on in the International Alliance of ALS/MND Associations.

"*" indicates required fields

 
This field is for validation purposes and should be left unchanged.
  • Email
  • Facebook
  • LinkedIn
  • Twitter
  • YouTube
Return to top of page

Contact | Disclaimer | Privacy Notice & Cookies | Sitemap

Copyright © 2025 The International Alliance of ALS/MND Associations. All rights reserved.


Registered in England: Charity Number 1079504 · Site built by graphics.coop · Powered by WordPress · Members' login