As identified by the ALS Canada Research Team, here are the most newsworthy research stories of 2021 and a look ahead to 2022 with hope for what is to come.

A possible third treatment for ALS under review by Health Canada        

AMX0035 is an oral drug that contains two small molecules thought to help preserve motor neuron health in combination. Results from the Phase 2 study showed that AMX0035 was safe and slowed functional decline by approximately 25% compared to those on placebo. A follow-up analysis of long-term data from the trial’s open-label extension demonstrated that early treatment with AMX0035 may also extend survival in people living with ALS.

In August 2021, Amylyx announced Health Canada accepted its New Drug Submission (NDS) for AMX0035 as a treatment for ALS. This step triggered a thorough regulatory review of the therapy which is currently underway. A decision regarding its approval is expected by mid-2022. You can learn more about how drugs become available in Canada here.

In October 2021, the Canadian Agency for Drugs and Technology in Health (CADTH) posted a call for patient input on AMX0035. This step is key to helping ensure the realities of ALS are understood by the decision-makers at CADTH, the agency that ultimately recommends whether public drug plans should cover a drug if it is approved by Health Canada. In December 2021, after surveying over 600 people affected by the disease, ALS Canada delivered the patient input submission to CADTH, which can be read here. Additionally, for the first time ever with an ALS therapy under review, there was also a call for clinician input on AMX0035. ALS Canada supported the Canadian ALS Research Network (CALS) to develop their submission for the therapy.

A global Phase 3 clinical trial of AMX0035 is currently underway to further explore the drug’s effectiveness. The PHOENIX trial will enroll approximately 600 participants at 65 sites across the United States and Europe. Amylyx also recently submitted marketing applications to two other regulatory agencies, including the FDA in the United States and the EMA in Europe.

As our community knows all too well, there is an urgent need for people living with ALS to have access to proven, effective therapies. A concurrent Health Canada and CADTH review is just one step of many in aligning the drug access processes. We hope to see this momentum for AMX0035 carried through to future ALS therapies currently in the pipeline.

Biogen announces results from Phase 3 study of tofersen

Tofersen is an experimental drug being evaluated for the treatment of a genetic form of ALS caused by mutations in the gene SOD1. After promising results in a Phase 1/2 clinical trial, the ALS community eagerly awaited results from the Phase 3 VALOR study, which were announced in October 2021.

Although the results did not show a statistically significant change in disease progression as assessed by the ALSFRS-R scale, multiple secondary and exploratory measures (including respiratory function, muscle strength and quality of life) suggested that the treatment may have a positive effect.

It is clear to the scientific and medical community that further analysis of the trial data will be necessary to fully understand the complex results and assess whether tofersen can have a clinically meaningful effect in people with SOD1-ALS. In the meantime, however, Biogen has expanded eligibility for its ongoing early access program to all people with SOD1-ALS.

Biogen has also initiated the ATLAS study, which will look at whether early treatment with tofersen can significantly delay the onset of clinical symptoms. Never clinically tested before, early intervention has long been considered a key area for study in ALS. The ATLAS trial is an important next step not only in the evolution of tofersen for SOD1-ALS but also in paving the way for future ALS clinical trials.

Two Phase 3 clinical trials in ALS fail to meet expectations

Last year, Alexion Pharmaceuticals and Orphazyme both announced negative results from their Phase 3 studies of Ultomiris (ravulizumab) and arimoclomol, respectively.

Ultomiris (also referred to as ravulizumab) is an antibody-based drug that targets a specific protein within the immune system, called C5, that was thought to play a role in ALS. Researchers had hoped that by blocking this protein in cells they may be able to slow disease progression. A global Phase 3 clinical trial to study Ultomiris, called CHAMPION-ALS, launched in early 2020, enrolled 382 participants, and was set to run for a total of 50 weeks. However, an analysis of interim data by the trial’s data monitoring committee revealed that the drug was not effective at slowing disease progression and so in August 2021, the trial was stopped early due to a lack of efficacy.

In May 2021, Orphazyme announced the outcomes of their Phase 3 clinical trial of arimoclomol in ALS. One of the defining characteristics of ALS and other neurodegenerative diseases is that proteins can become misfolded and clump together, potentially damaging nerve cells. Arimoclomol is an oral drug that increases the production of a group of proteins called heat shock proteins (HSPs) that work to prevent protein misfolding in cells. The Phase 3 study of arimoclomol, however, unfortunately failed to meet its primary and secondary endpoints meaning the drug was unable to significant delay the progression of disease or extend survival in people living with ALS.

With any new ALS therapy, we always hope to see positive results and so like the rest of the community, ALS Canada was disappointed by these outcomes. However, as with all trials, the data, insights and learnings achieved will prove valuable in work toward a future without ALS.

Additional developments in ALS clinical research

In December 2021, Mitsubishi Tanabe Pharma America announced results from their global Phase 3 clinical trial testing an oral formulation of edaravone for the treatment of ALS. Edaravone, or Radicava, was originally approved by Health Canada in October 2018 and is typically delivered through intravenous (IV) infusion. Preliminary results from the new Phase 3 clinical trial studying the oral formulation of the drug revealed that it is safe and appears to have a similar ability to reach the spinal cord as the IV form. Due to the relatively intensive dosing regimen recommended for edaravone, a treatment option that can be taken orally could significantly improve quality of life for people living with ALS. ALS Canada has been in contact with Mitsubishi Tanabe Pharma Canada for many years and expects Canada to be a priority location for seeking approval of oral edaravone.

Last year, Clene Nanomedicine also announced topline results from their Phase 2 clinical trial of CNM-Au8, called RESCUE-ALS. CNM-Au8 is an oral liquid suspension of gold nanocrystals thought to improve motor neuron function and survival by increasing energy production in cells and lowering oxidative stress. Although the clinical trial did not meet the primary and secondary endpoints, the company indicated they were pleased with the results which showed a potential for effectiveness and as such feel it is important to confirm the results in a larger clinical trial. CNM-Au8 is also currently being tested in the HEALEY ALS Platform trial with topline results expected in the second half of 2022. We look forward to hopefully gaining a better of the potential benefits of CNM-Au8 later this year.

Finally, trial data from the Phase 3 study of NurOwn®, sponsored by BrainStorm Cell Therapeutics, was published late last year in the peer-reviewed journal Muscle and Nerve. As previously announced, the data did not demonstrate a statistically significant benefit for those treated with NurOwn® compared to placebo, however, continued analysis of the published data within the scientific and medical community will help to determine if there is any value in further pursuing this therapy.

New opportunities for stronger relationships within the Canadian ALS community 

Each year, ALS Canada convenes the brightest minds in ALS research across Canada at a two-day Research Forum to discuss their work and build capacity for more discoveries in this rapidly changing field. After the pandemic cancelled our plans to host the event in 2020, we brought the community together safely in 2021 in a virtual format.

More than 300 people participated in the virtual event, which featured presentations on the latest in fundamental, translational and clinical ALS research taking place across the country. For the first time, we were pleased to also welcome 13 Community Fellows identified through an application and evaluation process. This pilot program made it possible for people affected by ALS to have insight into the breadth of ALS research underway in Canada and connect with those who are leading it.

In 2021, ALS Canada also launched the inaugural Canadian ALS Learning Institute. Informed by and developed for people affected by ALS, the Learning Institute provides attendees with an online, small-group learning experience to understand the Canadian ALS landscape, clinical research and therapy development, and how new therapies become approved and accessible to Canadians. Participating in the institute gave attendees the opportunity to learn more about the ALS research process and how to advocate effectively for access to Health Canada approved therapies.

We are so grateful to have had these opportunities to bring the Canadian ALS community together in 2021 to support knowledge sharing and capacity building between researchers, clinicians, people living with ALS and their caregivers, and look forward to continued interactions in 2022.

Funding secured to support development of CAPTURE ALS platform

In April 2021, ALS Canada and Brain Canada announced they had joined forces with Alnylam Pharmaceuticals and Regeneron to support CAPTURE ALS, a Canadian platform conceived to unite patients, physicians and researchers to study ALS.

CAPTURE ALS provides the systems and tools necessary to collect, store, and analyze vast amounts of information about ALS, creating the most comprehensive biological picture of people with ALS. Understanding why ALS is different in each person – or the clinical variability– is vital in effectively treating the disease.

Led by a team of world-renowned fundamental and clinician ALS scientists, CAPTURE ALS will combine all the data collected from patients with ALS and healthy individuals with a goal of identifying unique subtypes of ALS, providing important new data to the global study of biomarkers, and to create insights that will inform personalized medicine efforts in the future.

The $2.85M Platform Support Grant awarded to CAPTURE ALS will support enrollment of the first 100 people living with ALS (and related diseases) and 25 healthy controls. The Calgary Flames Foundation donated an additional $240K to CAPTURE ALS in December 2021, to support recruitment of an additional 20 people with ALS to participate. It is thanks to generous sponsors like these the platform will open for recruitment early this year. Interested participants can learn more here.

Promising new ALS clinical trials underway

Pharmaceutical company Cytokinetics has launched a global Phase 3 clinical trial evaluating reldemsetiv in ALS. Reldesemtiv is an oral, muscle-activating drug designed to increase the ability for a muscle to contract with reduced nerve stimulation. The development of this drug follows a previous Phase 2 clinical trial which showed that reldesemtiv may help to slow rates of functional and respiratory decline in people living with ALS. The trial, which has 11 Canadian sites, is currently enrolling participants.

For the first time ever, there are also several clinical trials underway aimed at targeting specific genetic forms of the disease. These include Ionis Pharmaceuticals’ Phase 3 study of ION363 which targets the FUS gene, Biogen’s ATLAS study of tofersen in presymptomatic individuals with SOD1-ALS and Wave Life Sciences Phase 1b/2a study of WVE-004 in people with ALS who carry a C9ORF72 mutation.

Apellis Pharmaceuticals, Eledon Pharmaceuticals and Annexon are three companies currently running separate Phase 2 clinical trials at various Canadian sites aimed at inhibiting certain aspects of inflammatory mechanisms within the body thought to contribute to the progression of disease. Calico Life Sciences is also sponsoring an ongoing Phase 1 study in ALS evaluating ABBV-CLS-7262, an oral experimental treatment shown to have a neuroprotective effect in mouse models of ALS.

This year, in partnership with Sanofi, Denali Therapeutics also plans to launch a Phase 2 clinical trial studying SAR443820 in ALS. SAR443820 is an experimental treatment designed to block a specific protein called RIPK1 which has been linked to inflammation in the brain. The trial, called HIMALAYA, is expected to begin in the first quarter of 2022.

To learn more about clinical trials that are active at sites across Canada, please visit our website here.

 A strong research pipeline providing hope for the future   

More than 2,500 research studies related to ALS were published in peer-reviewed journals in 2021, breaking the 2020 record for the most ever. In the face of laboratory shutdowns during the early stages of the pandemic, scientists were able to continue their work by analyzing data and writing research articles, which is reflected in the breadth of work published.

These studies have not only advanced our understanding of ALS but have also identified multiple new treatment targets and biomarkers in the laboratory that we expect will soon advance to clinical studies. And with hundreds of pharmaceutical companies now invested in clinical development for ALS, there is tremendous hope for treatment breakthroughs in the not-so-distant future.

ALS Canada’s ongoing commitment to invest in ALS research

Thanks to generous support from donors and partners, ALS Canada will be able to announce the recipients of the 2021 ALS Canada-Brain Canada Discovery Grant competition next month. This program will support nine new research projects from multidisciplinary research teams focused on either identifying causes of, or treatments for ALS, or on improving quality of life through symptom management.

In the coming weeks we will also be announcing the recipients of the 2021 ALS Canada Clinical Research Fellowship, one with funding support from Mitsubishi Tanabe Pharma Canada (MTP-CA), and Trainee Award competitions which provide salary support to promising young clinicians and researchers. These competitions are designed to attract the brightest minds to Canadian ALS research and build capacity for the future.

Looking forward to 2022, we are excited to announce that we will be running four new grant competitions in partnership with Brain Canada, while also providing continued support for the Canadian ALS Research (CALS) Network, as part of our ongoing commitment to both fundamental and clinical ALS research in Canada.

Bringing you the latest news on advancements in ALS research, the ALS Canada research team regularly summarizes the most significant discoveries throughout the year.

Note: We have included links to the publications because we know you may be interested in the original source papers. While abstracts are always available, many journals are subscription based, and in some cases, full papers may only be accessed at a cost.

Posted in: Research