Although 2020 was an unpredictable and challenging year, the ALS research community continued to push forward with major scientific advances in Canada and internationally. As identified by the ALS Canada Research Team, here are the most newsworthy research stories of 2020 and a look ahead to 2021 with hope for what is to come.

ALS research community continued their relentless work in the face of the COVID-19 pandemic

The COVID-19 pandemic represented unprecedented obstacles to most, including the Canadian and international ALS research communities. Laboratory shutdowns and restrictions on in-person interactions posed challenges for basic and clinical researchers worldwide. In the face of this crisis, researchers adapted quickly to sustain the increased momentum we have seen in ALS research over the past few years.

To support the Canadian ALS research community during this time, the ALS Canada Research Program played a key role in helping to connect researchers virtually. We offered a series of new online learning opportunities, regular calls for basic and clinical researchers to share challenges and best practices, and an online communication platform for trainees to come together to learn and share.

Innovations resulting from opportunities the pandemic created, such as new home monitoring methods for clinical trials or increased telehealth opportunities, are likely to support clinical research and care in the future. In the face of laboratory shutdowns, basic scientists were able to continue their work by analyzing data, writing research articles, applying for grants, and developing experimental plans for future studies. Conferences that typically would have been held in person became virtual, such as the International Symposium on ALS/MND, the largest scientific and medical ALS conference, providing a platform for knowledge sharing and networking. It has been inspiring to see the ALS research community persevere in their work to create a future without ALS.

Publication of the first set of guidelines for care of Canadians living with ALS

In November 2020, the first-ever Canadian ALS Best Practice Recommendations (BPRs) were published in the Canadian Medical Association Journal (CMAJ). A 13-member pan-Canadian working group developed the guidelines’ more than 130 recommendations across 13 areas of focus to provide an update on evolving best practices of care in ALS. In doing so, they assessed thousands of published peer-reviewed articles, and sought the input of people living with ALS in Canada, ALS Societies across the country, as well as other health providers and organizations.

These best practice recommendations establish a national standard for the care and management of people living with ALS and addresses issues relevant in a Canadian context, like medical assistance in dying. They also empower people living with ALS, their families and healthcare providers to make informed and collaborative decisions. You can learn more about the Canadian Best Practice Recommendations for the Management of Amyotrophic Lateral Sclerosis here.

Promising results from Phase 1/2 clinical trial of tofersen

A study published in July 2020 in the New England Journal of Medicine showed that an experimental drug called tofersen has promise for treating a genetic form of ALS caused by mutations in the SOD1 gene.

Results from the Phase 1/2 clinical trial, sponsored by the pharmaceutical company Biogen, revealed that tofersen was safe and able to lower levels of the toxic SOD1 protein thought to contribute to ALS progression. The preliminary data also showed potential for slowing loss of function and preserving neuronal health. Canadian researchers have played a key role in the studies with Dr. Angela Genge (Montreal) and Dr. Lorne Zinman (Toronto) being involved since the beginning of the trial. The positive results from this study led to launch of the Phase 3 VALOR study that will further test the safety and effectiveness of tofersen and is ongoing at a number of sites globally, including at four Canadian sites: Calgary, Edmonton, Toronto and Montreal (Neuro).

If the Phase 3 trial is successful and tofersen moves forward as a new and proven treatment for ALS, it will directly benefit the small percentage of ALS patients who have a mutation in the SOD1 gene. Additionally, the lessons learned from this pivotal study will help researchers when developing future treatments for other forms of ALS.

New drug combination shows promise for treating ALS

Two studies published in 2020 showed that AMX0035, an experimental therapy being developed by pharmaceutical company Amylyx, has promise for slowing progression and extending survival in people living with ALS.

AMX0035 is an oral drug that contains two small molecules thought to help preserve motor neuron health. The Phase 2 clinical trial enrolled 137 participants assessed over a 24-week period, primarily based on the ALS Functional Rating Scale-Revised (ALSFRS-R). Results from the Phase 2 study were published in September 2020 in the New England Journal of Medicine and showed that AMX0035 was safe and slowed functional decline by approximately 25% in participants receiving the active drug when compared to those on placebo. The preliminary data also showed potential benefits in other areas, such as measures of muscle strength, breathing and hospitalization frequency.

A follow-up analysis of long-term data from the clinical trial through its open-label extension was published in the journal Muscle & Nerve in October 2020. The results demonstrated that early treatment with AMX0035 may extend survival in people living with ALS. Since many participants in the trial were already taking riluzole and/or edaravone (Radicava), the researchers believe that the effects observed for AMX0035 were in addition to that for the current standard of care.

While these results are a step in the right direction, larger and longer clinical trials may be necessary to better evaluate the safety and effectiveness of AMX0035 in people living with ALS. Discussions are ongoing between Amylyx and regulatory agencies like the FDA and Health Canada to determine the path forward. ALS Canada has been in contact with Amylyx for many years and continues to advocate to have Canada included as a location for future clinical trials and/or regulatory approval (if applicable).

Two Phase 3 clinical trials in ALS fail to meet expectations

Last year, pharmaceutical companies Orion Corporation and BrainStorm Cell Therapeutics Inc. both announced negative results from their Phase 3 studies of levosimendan and NurOwn, respectively.

Levosimendan is an oral drug shown in previous studies to help muscles (such as the diaphragm) contract more easily. The Phase 3 study enrolled 492 participants across 104 sites in the U.S.A., Canada, Europe, and Australia, and was designed to determine whether levosimendan (ODM-109) can preserve breathing abilities in people living with ALS. In July 2020, Orion Corporation announced that the study did not reach its primary endpoint of preserving lung function in people living with ALS.

In November 2020, BrainStorm Cell Therapeutics Inc. announced the outcomes of their Phase 3 clinical trial of NurOwn, a treatment designed to convert a person’s own mesenchymal stem cells into cells that secrete neurotrophic factors, substances thought to promote and support nerve cell repair. The trial enrolled 189 people living with ALS who were assessed over a 28-week period, primarily based on the ability of NurOwn treatment to change the slope of decline as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R). The study results showed no statistically significant slowing of ALS progression in people treated with NurOwn compared to those on placebo.

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.

Promising new clinical trials underway

The first clinical trial aimed at genetic targeting of non-inherited (sporadic) ALS began in 2020. This clinical research study is the result of preclinical work indicating that abnormalities in the ataxin-2 (ATXN2) gene may represent a risk factor for ALS. A subsequent study showed that reduction of ATXN2 in cells is protective in ALS mouse models. As a result, pharmaceutical company Biogen has begun a Phase 1 clinical trial to test the safety and tolerability of an antisense oligonucleotide targeted at ATXN2 reduction. As we learn more about the complex genetic susceptibilities that underly the majority of ALS cases, more of these types of clinical trials are likely to begin and bring with them the promise for more effective and personalized treatments.

Pharmaceutical company Cytokinetics has set things in motion for a global Phase 3 clinical trial (COURAGE-ALS) of its muscle activating drug, reldesemtiv, that will enroll approximately 555 people living with ALS, with multiple Canadian sites included. Alexion, Apellis and Annexon are three companies with treatments for ALS in clinical trial aimed at inhibiting various aspects of an inflammatory mechanism called the complement pathway. Mitsubishi Tanabe Pharma Development America has also begun testing an oral formulation of edaravone, while long-awaited Phase 3 clinical trials of ibudilast and masitinib are now officially recruiting.

Finally, the HEALEY platform trial started recruiting in 2020, and recently added a sixth therapy to the regimen. In Europe, the MND-SMART platform trial also began recruiting and the TRICALS MAGNET platform trial moved closer to initiation, announcing the addition of an innovative new arm testing people who may be genetic responders to a previously studied drug.

More ALS research studies in 2020 than ever before

More than 2,000 ALS research studies were published in peer-reviewed journals in 2020, the most ever. This is a strong testament to the breadth of work happening around the world that is focusing efforts on better understanding ALS, working toward treatments, and expanding our rapidly evolving knowledge of the disease.

Prominent work demonstrated a key new, potentially druggable, inflammatory pathway that appears to be connected to a number of ALS animal models and is detectable in blood samples of people living with ALS (1,2), large leaps in our understanding of C9ORF72-related ALS, with potential therapeutic implications for individuals with that genetic mutation and others (1,2,3,4,5) and further demonstration of the gut-brain axis/microbiome influence on ALS has been documented. Unique new genetic connections (1,2), novel therapeutic delivery strategies, and a lot of biomarker work were also communicated. These represent only a very small portion of the advances made in 2020, but with the number and quality of ALS studies expanding year-over-year, 2020 has demonstrated that even in times of adversity, there is tremendous hope for treatment breakthroughs in the not-so-distant future.

Pride for our Canadian researchers who continue to move the needle

For decades, Canadian ALS researchers have been strong contributors to the global knowledge of ALS and 2020 was no different. Some of the ways in which Canadian scientists played a big role in advancing our ability to understand and treat ALS include: the introduction of a new mouse model to the field, discovery of a whole new biological system of proteins that could alter how we look at the disease, expertise in the neuromuscular junction (1), and early development of an exciting new therapeutic target. Canadians were also leaders in the area of clinical research, including world-class speech analysis work (1, 2), brain imaging innovations (1, 2), and novel neuropathological contributions. And finally, our researchers regularly collaborate with international peers on important laboratory and clinical/clinical trial studies. ALS Canada is proud of their ongoing accomplishments and looks forward to helping the Canadian ALS research community continue to play a vital role in the worldwide efforts toward a future without ALS.

For additional examples of Canadian ALS research excellence in 2020, be sure to check out these publications: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21

ALS Canada’s ongoing commitment to investment in ALS research

In November 2020, ALS Canada announced a $650,000 investment in three new research projects that will contribute to the development of potential ALS therapies and strengthen ALS clinical care in Canada. The announcement was made following two separate peer-reviewed grant competitions that engaged a panel of scientific experts in prioritizing projects grounded in scientific excellence with the potential to advance the field of ALS research most quickly, contributing to the knowledge base needed for the development of new treatments.

Funding partners for the ALS Canada Research Program’s 2020 grants and awards are the provincial ALS Societies across Canada through , Mitsubishi Tanabe Pharma Canada, and La Fondation Vincent Bourque.

ALS Canada also looks forward to announcing the results from a third grant competition that took place in the fall of 2020. Projects receiving funding through this additional $1 million research investment, made possible thanks to our continued partnership with , through the Canada Brain Research Fund, an innovative partnership between the Government of Canada (through Health Canada) and Brain Canada, will be shared in early 2021.

Continued hope for the future

As we look forward through 2021, there is much progress on the horizon.

Results from the ongoing Phase 3 VALOR study of tofersen in people with SOD1-linked ALS are expected to be released in the second half of 2021, followed by the start of a landmark pre-symptomatic study of tofersen. We are also anticipating results from Orphazyme’s Phase 3 study of arimoclomol, Biogen’s Phase 1 study of an antisense oligonucleotide targeting C9ORF72, the Phase 2 MIROCALS trial of IL-2, the TRICALS Phase 3 study of TUDCA and many more. Undoubtedly, further advancements in our understanding of ALS at the molecular, cellular and clinical level will also bring us new avenues to explore treating the disease more effectively. 2021 brings renewed hope and optimism in ALS research.

Thanks to generous support from donors and partners during the COVID-19 pandemic when health research funding is so challenged, ALS Canada will be able to announce the recipients of the 2020 ALS Canada-Brain Canada Discovery Grant competition early in 2021. This program will support eight 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. We also look forward to running three new grant competitions in 2021, while also providing continued support for the Canadian ALS Research (CALS) Network, as part of our ongoing commitment to both basic 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.

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