We are proud to share the pre-print of a Duke microbiome study led by Richard S. Bedlack, MD, that was funded, in part, by Augie’s Quest to Cure ALS. The scientists found that there are significant differences in the oral and gut microbiomes of fast vs. slow progressing patients with ALS. Slow progressing patients have much more of an organism called P. Vulgatus in their gut microbiome. This gives clear direction for future trials targeting the gut microbiome, and different probiotics.
The gut microbiota modulates the rate of ALS progression
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that can progress at varying rates; however, the factors influencing progression rates in ALS patients remain unknown. In this study, we report distinct microbiome and metabolomic signatures associated with ALS progression rates. Rapid progression rates were transferable to a genetic mouse model of ALS following a fecal microbiota transplant (FMT) from patients exhibiting rapid disease progression. By focusing on microbial and metabolic markers shared between the FMT donors and mouse recipients, we identified Phocaeicola vulgatus as a microbial biomarker for slow progression. Additionally, we found strain-level differences in P. vulgatus among ALS patients and isolated a strain that partially alleviated disease in mice that received microbiota linked with rapid progression. Identifying microbiota that accelerates ALS progression, along with strains of P. vulgatus and correlated metabolites that mitigate such accelerated diseases, reveals new avenues for potential therapeutic interventions.
Cocktail of drugs. Original public domain image from Wikimedia Commons
There are currently no treatments to stop the progression of amyotrophic lateral sclerosis (ALS). However, there are now three drugs available that provide some benefits to people living with ALS. Two drugs have been approved in the US for use by all people with ALS: riluzole and edaravone (Radicava). An additional drug, tofersen (Qalsody), was approved in early 2023 for use by people with SOD1-related genetic ALS. An additional drug, Relyvrio, received approval in the US and conditional approval Canada based on results from a phase 2 study, but was voluntarily removed from the market in 2024 after its phase 3 trial failed to meet its primary or secondary endpoints.
Riluzole
Riluzole, currently sold under the brand names Rilutek, Tiglutik, and Exservan became the first drug approved in the US for the treatment of ALS in 1995. These three brand names represent different formulations of the drug respectively as a tablet, a liquid suspension, or a film that can dissolve in the mouth. The drug reduces the level of glutamate, an amino acid that acts as a neurotransmitter in the brain and spinal cord, by blocking its release from nerve terminals. While glutamate is essential to neural function, above-normal levels of the amino acid have been observed in ALS.
Trial Results: There were two pivotal trials that led to the approval of riluzole, one with 155 participants, and the second with 959 participants. These trials showed a two to three-month survival benefit for people with ALS that received active drug. More recently, a 2020 publication evaluating real world evidence of Riluzole’s effectiveness indicated a median survival benefit for people taking riluzole could range from 6 to 19 months.
Edaravone
Edaravone, sold under the brand name Radicava, was approved for use in ALS in 2017. It had previously been used since the 1980s as a medication for stroke in Japan. For most of this time, it was available only as an intravenous infusion. However, in 2022 an oral formulation was approved for people with ALS in the US and Canada. Edaravone’s mechanism of action in ALS is not fully understood, but it is known to be an antioxidant and thus may reduce oxidative stress in motor neurons.
Trial Results: Radicava was approved following a phase 3 trial conducted in Japan by Mitsubishi Tanabe Pharma. Researchers observed a reduction in participants’ rates of disease progression with a difference of 2.49 ALSFRS-r points between the active treatment and placebo groups over 24 weeks. The inclusion criteria for this pivotal trial were based on a post-hoc analysis from a previous trial of the drug. Trial participants were required to have a FVC breathing score of at least 80%, less than 2 years duration of ALS symptoms, at least 2 points on each of the ALSFRS-r items, as well as a decline of 1-4 ALSFRS-r points over 3 months prior to randomization.
Trial Results: Although the phase 3 trial with 108 participants did not meet its primary functional endpoint, this drug was approved for use by people with SOD1 ALS in early 2023 based on reductions in levels of neurofilament light chain (NfL), a blood-based biomarker that is related to neurodegeneration, in participants on active drug. This approval was secured through the FDA’s accelerated approval pathway, which allows the agency to approve treatments based on “surrogate endpoints” for severe diseases that lack treatments. A surrogate endpoint is a measure in a clinical trial that scientists believe is likely to predict a clinical benefit, even if a clinical benefit is not directly observed in the trial.
In addition to the reduction in NfL, in post hoc analyses of data from participants that continued to the open label extension (OLE), at 52 weeks, there was a slowing of loss of function, based on ALSFRS-r, for those that received active drug from the beginning of the trial compared to those that began on placebo. There was also less decline in breathing function and strength when comparing these groups at 52 weeks. Additionally, some participants stayed on OLE for 3-7 years, providing long term data on the drug’s performance in people with ALS.
While Relyvrio is still currently approved for ALS in the US as of January, 2025, Amylyx has announced they will voluntarily remove it from market after its Phase 3 trial did not meet primary or secondary endpoints.
It is available as a powder which is dissolved in water and either swallowed or placed in a feeding tube.
Trial Results: A phase 2 trial sponsored by Amylyx Pharmaceuticals in 137 people with ALS demonstrated evidence of a decline in the rate of progression, a difference of 2.32 ALSFRS-r points, between the active treatment and placebo groups over 24 weeks. A post-hoc analysis of the open label extension data, where participants could choose to receive active treatment following the placebo controlled part of the trial, showed a potential increase in survival of 5 months when comparing those that began active treatment from the start of the trial to those that received placebo. In 2022, the drug was approved for use in the US and received conditional approval in Canada, where it is sold under the brand name Albrioza.
On March 8, 2024, Amylyx announced topline results for its Phase 3 trial, PHOENIX, sharing that the study “did not meet pre-specified primary or secondary endpoints.” Four weeks later, Amylyx announced their intention to voluntarily remove the drug from market. People who were prescribed Relyvrio in the US and Canada before this point will be allowed to access the drug through a free drug program if they choose to do so.
ALS TDI: Our Work to Find More Treatments for Everyone with ALS
The approval of all these treatments – including two in the last year – is an immensely important step for the ALS community. However, at the ALS Therapy Development Institute (ALS TDI), we know it will take many more treatments to end ALS for everyone with the disease. That’s why every day we’re working to identify effective treatments for the disease. As the Drug Discovery Engine for ALS, it is our mission to continue this work until there are effective treatments for the disease.
This year has been a challenging one for our Quest with the loss of our inspiration and co-founder, Augie Nieto.
Our mission to find a cure for ALS (Amyotrophic Lateral Sclerosis) and improve the lives of those affected by this devastating disease remains our top priority.
We’re proud of the progress made this year at the Augie’s Quest Translational Research Center. Here are just some of the ways your support has made a tangible impact:
1) Using advanced cell biology techniques, the Augie’s Quest Translational Research Center (AQ TRC) initiated collaborative studies to explore two new drug targets – medicine intervention points – in motor neurons from people with ALS grown in the the lab.Developed new techniques for growing and studying axons – the long connections between neurons and muscles – in the lab. These long connections break down in ALS. Understanding how they break down and discovering ways to stop that is important for developing effective treatments.
2) Initiated important studies of the how cells from people with ALS handle or mishandled critical RNA molecules. RNA molecules carry the instructions from human genes to the rest of the cell so that the cells can function properly. This is impaired in ALS and will likely need to be repaired. Scientists in the AQ TRC are exploring treatments that might address this dysfunction.As the end of 2023 approaches, we urge you to make your tax-deductible donation and help change the future for countless people living with ALS, their families, caregivers, and friends.
Incurable is Unacceptable. Together, we can create a future without ALS.
The ARC expansion includes three key changes: Doubling the Size of the Study – allowing us to gain new insights into ALS by gathering data from a larger and more diverse population.
Inclusion of Asymptomatic ALS-Related Gene Carriers – which has the potential to provide us with new insights into processes that delay or accelerate ALS disease onset or progression.
Integration of Electronic Health Records (EHRs) – enabling us to fill in information gaps and gain profound insights into the development and progression of ALS Read the full announcement to learn more about these important updates.
On October 14, 2022, the ALS Therapy Development Institute scientists and guest presenters gathered at the ALS TDI Summit to provide the community with updates on research from the past year.
Dr. Fernando Vieira, CEO/CSO of TDI, emphasized how far we have come in ALS research – with more papers published about ALS in the past 9 years than in all of previous history and the recent approval of a new treatment for the disease.He also highlighted how little we still understand about ALS – and the need for more research and more effective treatments. “We’re proud to be the top funder of the ALS Therapy Development Institute’s critical work,” said Lynne Nieto, who attended the Summit with Augie’s Quest President, Shannon Shryne.
5/31/22: Eledon Pharmaceuticals announced positive topline results today from their Phase 2 trial of tegoprubart (formerly AT-1501) demonstrating safety, target engagement, and biomarker response in patients with ALS. Eledon’s release stated:
Tegoprubart was well-tolerated, with no drug-related serious adverse events
Dose dependent target engagement was demonstrated, and ALS associated pro-inflammatory biomarkers were both observed and significantly reduced in a dose dependent manner
Target engagement and level of pro-inflammatory biomarker reduction were associated with a trend in the slowing of disease progression as measured by ALSFRS slope when compared to a cohort from the ALS PRO-ACT database
Biomarkers significantly reduced included biomarkers also associated with IgA nephropathy and kidney allograft transplant rejection
“I’m proud to be the Chairman at Augie’s Quest to Cure ALS and ALS TDI, and excited to see the next phase of development for tegoprubart – as our work is far from finished. This milestone showcases ALS TDI’s ability to create quality therapeutics in their lab, and Augie’s Quest is proud to fund this critical science. Together, we will find a cure for ALS.” said Augie Nieto. Augie’s Quest has been the lead funder of this critical science granting over $72 million to ALS TDI under Augie’s leadership.
Tegoprubart is an antibody therapeutic targeting CD40L, a well-validated biologic target with a broad therapeutic potential. The Phase 2a trial was a 12-week, open label, dose escalating, safety, and biomarker study. The endpoints of the study were safety and tolerability, and changes in pro-inflammatory biomarkers.
“Neuroinflammation is a driving force in the pathogenesis and progression of ALS. The ability to suppress inflammatory responses may translate into clinical benefit,” said Stanley H. Appel, MD, Co-Director of the Houston Methodist Neurological Institute and Chair of the Stanley H. Appel Department of Neurology at Houston Methodist. “These results reinforce the exciting potential of tegoprubart as a promising therapy for patients with ALS.”
After being invented at ALS TDI with funding from Augie’s Quest to Cure ALS, tegoprubart (previously called AT-1501) was licensed to Anelixis Therapeutics, a for-profit biotech company that oversaw the completion of a Phase 1 safety trial in 2019 (Augie Nieto was chairman of Anelixis). In 2020, Anelixis was acquired by Eledon Pharmaceuticals, a for-profit clinical-stage drug development company. Eledon is developing precision therapies that target the CD40 Ligand pathway for use in organ and cellular transplantation, and for the treatment of autoimmune and neurodegenerative disease (including ALS).
“We are excited by the results from the phase 2 trial and by tegoprubart’s emerging clinical profile. The positive data represent a significant step in the development of tegoprubart as a potential treatment for people living with ALS,” said Steve Perrin, President and Chief Scientific Officer at Eledon Pharmaceuticals. “We thank all of the patients and families, as well as the investigators, who have supported us over the years for their commitment to finding a novel therapeutic option for ALS.”
Ending ALS will require many treatments to meet the needs of every individual living with this disease, and Augie’s Quest will continue to raise the funds and awareness urgently needed to advance cutting-edge research, fast-track effective treatments and ultimately, find a cure for ALS.
Watertown, MA – The ALS Therapy Development Institute (ALS TDI) and Augie’s Quest to Cure ALS are proud to honor the commitment of Liz Bodine to facilitate more effective ALS drug discovery at ALS TDI, the world’s most comprehensive drug discovery lab dedicated solely to ALS.
In recognition of a recent $1.5 million grant from Augie’s Quest, coupled with a $650,000 grant from 2019, ALS TDI has installed a plaque in the Discovery Biology Suite that honors Liz Bodine, the many generous and committed friends who donated in her honor, and Augie’s Quest to Cure ALS.
“We are indebted to Liz for her dedication in supporting our effort to find effective treatments for ALS that will meaningfully slow the progression of the disease. The way her friends and family rallied around our cause in her honor is a testament to the light and love she shared with everyone she touched,” said Augie Nieto, Chairman of Augie’s Quest to Cure ALS.”
ALS, also known as Motor Neuron Disease (MND), Lou Gehrig’s Disease, and Charcot’s disease, is a progressive neurodegenerative disease which attacks motor neurons in the brain and spinal cord resulting in the wasting away of muscle and loss of movement. Every 90 minutes, someone is diagnosed with the disease, and the average lifespan is 3-5 years.
“On behalf of my beloved wife, Liz, I would like to express our deep gratitude to Augie’s Quest and ALS TDI for this honor,” said Murray Bodine. “Liz was deeply inspired by the work being funded by Augie’s Quest at the Institute and it gave her purpose and comforted her to know that she was able to contribute to the efforts to find a cure for ALS. She, of course, shares this honor with her many friends and her family who lovingly stood by her and supported her during these past few years.”
ALS TDI’s CEO and Chief Scientific Officer, Fernando Vieira M.D., says that the discovery of new drug targets is vital to the development of effective treatments for ALS. “I am thankful I had the honor of meeting Liz’s husband, Murray, and so many of the friends that made this donation possible last October,” he added.
The Discovery Biology Team will work to strengthen existing and future research efforts by studying mechanisms of clinical ALS and using the knowledge to facilitate more effective drug development in ALS at the Discovery Biology Suite
Dedicated scientists at ALS TDI are working every day to invent and discover the many treatments that will be needed to cure ALS. ALS TDI’s work has enabled multiple therapies for ALS to move forward into human clinical development, and they will continue to discover drugs until there are effective treatments for everyone with ALS. Augie’s Quest to Cure ALS has been the lead funder of their work since 2005.
About ALS Therapy Development Institute
As the Drug Discovery Engine for ALS, the ALS Therapy Development Institute (ALS TDI) discovers and invents ALS treatments and partners to advance them into clinical trials. It is the first and largest nonprofit biotech focused 100% on ALS research. ALS TDI incorporates all aspects of drug discovery under one roof to find treatments as quickly as possible.
Based in Watertown, MA, ALS TDI employs a team of industry trained, drug development experts with more than 300 years of combined experience. ALS TDI is internationally recognized as a leader in preclinical and translational ALS research, and partners with pharmaceutical companies and biotech organizations all around the world. Rated a four-star nonprofit on Charity Navigator, ALS TDI spends 87 cents of every dollar raised on finding effective treatments and cures for ALS. Visit www.als.net for more information.
About Augie’s Quest to Cure ALS
Augie’s Quest to Cure ALS is a nonprofit committed to changing the experience of people living with ALS by fast-tracking cutting-edge research to advance effective treatments and an ultimate cure. The organization is galvanizing thousands to join this fight, confronting ALS in an entirely new way, and driving innovative research forward, and at an accelerated pace. Augie’s Quest was founded in 2005 byAugie Nieto, the successful fitness industry mogul behind Lifecycle and Life Fitness who has been living with ALS since 2005 and whose life story was chronicled in the award-winning film, Augie. Please join our Quest at www.augiesquest.org.
Watertown, MA – The ALS Therapy Development Institute (ALS TDI) and Augie’s Quest to Cure ALS are proud to honor the commitment of Liz Bodine to facilitate more effective ALS drug discovery at ALS TDI, the world’s most comprehensive drug discovery lab dedicated solely to ALS.
