ALS: how close are we to a cure?


The hunt for amyotrophic lateral sclerosis (ALS) drugs has advanced over the past decade, with seven drugs approved by American regulators. One of them is multinational Biogen’s Qalsody, which was recommended for approval by the European Medicines Agency (EMA) in February, and may now be on its way to a regulatory win. As more and more ALS drug trials press forward, are we inching towards a cure?

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    How does ALS affect people?

    ALS, also known as Lou Gehrig’s disease after the famous 1930s American baseball player, is a neurodegenerative disorder characterized by death of motor neurons resulting in paralysis of voluntary muscles and eventual respiration failure. In the U.S., about 5,000 people are diagnosed with ALS every year, according to MedlinePlus. Most ALS cases are sporadic, while about 8–10% are inherited. 

    While the average survival time after an ALS diagnosis is three years, still, about 20% of people with ALS live for five years or more, and 5% of people diagnosed with ALS have a life expectancy beyond 20 years. A well-known example for the slow progression of the disease was Stephen Hawking, renowned theoretical physicist and cosmologist at Cambridge University in the U.K., who was diagnosed with ALS in 1963.

    The impact of the Ice Bucket Challenge on ALS awareness and research

    Thanks to the 2014 ice bucket challenge, ALS recently gained new public awareness. Fueled by social media, the campaign prompted millions of people to post videos of themselves dumping cold water on their heads and drove hundreds of millions of dollars to the ALS Foundation. Even if drug developments typically take decades rather than years, these donations spurred new developments in ALS research.

    The road to an ALS cure: recent research breakthroughs

    One of the key breakthroughs in ALS research was identifying genetic mutations linked to the disease, according to Amy Reichelt, chief innovation officer of Canadian biotech PurMinds NeuroPharma. Mutations in genes like SOD1, C9orf72, and FUS, among others have helped understand the underlying mechanisms of ALS, and have led to the development of animal models as well.

    “Research into ALS has evolved significantly over the years, driven by advances in technology, increased understanding of the disease mechanisms, and collaborative efforts within the scientific community,” said Reichelt, whose company is currently screening HDAC6 inhibitors, which have emerged as a potential therapeutic approach for treating ALS. 

    Moreover, the discovery of C9orf72 mutations has shed light on a link between ALS and frontotemporal dementia. A study conducted by Case Western Reserve University School of Medicine in the U.S., found that when the IL-17A gene was blocked in mouse models with the C9orf72 mutation, brain inflammation reduced and mobility got better. While IL-17A inhibitors have been approved by the U.S. Food and Drug Administration (FDA) for treating autoimmune diseases like psoriasis and rheumatoid arthritis, further research into these drugs could potentially help slow or reverse disease progression in people with ALS.

    Another late-stage clinical trial for ALS is ATLAS, a phase 3 randomized, placebo-controlled study born out of a collaboration between American biotech Ionis Pharmaceuticals and Biogen after Qalsody’s FDA success. The gene therapy candidate tofersen/Qalsody is being studied in patients with ALS who have a mutation in the SOD1 gene but do not show any signs of the disease yet. Tofersen is meant to delay ALS in people as well as slow the progression of the disease in patients. As an antisense oligonucleotide, it binds to components in RNA, to prevent the production of toxic SOD1 proteins.

    In previous trials, tofersen has been found to bring down SOD1 protein levels in cerebrospinal fluid by 35% after eight weeks of treatment. Eventually, it halved levels of neurofilaments, a biomarker for neurodegeneration, which can cause neuron damage when present abundantly. 

    The HEALY ALS platform trial: paving the way towards an ALS cure?

    Meanwhile, the first-ever ALS platform trial aims to accelerate drug discovery and development for ALS. A platform trial is a random, adaptive trial that tests and compares multiple interventions against a control over a period of time. The HEALEY ALS platform trial is increasing patient participation by 67%, and cutting down on research expenses by 30% as it tests multiple therapies at once. 

    Run by the Healey & AMG Center for ALS at the Massachusetts General Hospital, along with Tackle ALS, the trial is assessing the safety and efficacy of investigational drugs such as zilucoplan, verdiperstat, and pridopidine.

    Zilucoplan, a drug developed by Belgian biopharma UCB, is designed to prevent inflammation and tissue damage in people with ALS. This is done by inhibiting the target protein complement component 5. Previously, zilucoplan has shown efficacy in a phase 2 trial for myasthenia gravis, a disease that causes muscles to feel weak and get tired quickly. 

    U.S.-based Biohaven Pharmaceuticals’ verdiperstat is also part of the trial. Verdiperstat binds to an enzyme called myeloperoxidase, which is a driver of neuroinflammation, and inhibits it. In phase 1 and 2 trials, the candidate was evaluated in 250 people, and was found to be safe and well-tolerated.

    Another candidate, pridopidine, is being assessed in the platform trial as well. The candidate, which is owned by Prilenia Therapeutics, is being studied as a potential treatment for a number of neurodegenerative conditions including ALS and Huntington’s disease. It is a highly selective sigma-1 receptor (S1R) agonist that activates S1R. The receptor regulates cellular pathways that tend to be compromised in ALS, and neurodegeneration in general. Pridopidine was the first drug to ever maintain functional capacity like day-to-day activities, in a phase 2 trial in patients with Huntington’s disease. So, its neuroprotective effects are hoped to manage ALS as well.

    Other candidates being trialed in the HEALEY study are Clene Nanomedicine’s CNM-Au8, Seelos Therapeutics’ trehalose, ABBV-CLS-7262, which is a partnership between pharma giant AbbVie and Calico Life Sciences – currently recruiting participants for the clinical trial – and Denali Therapeutics’ DNL343, which aims to slow ALS progression by suppressing the build-up of the protein TDP-43 associated with the condition. 

    Can stem cell therapy help manage ALS symptoms? 

    A key area of therapeutic interest also lies in stem cell research. Lauded as a breakthrough for cancer, diabetes, and arthritis treatments, ongoing studies look to address ALS through stem cell therapy.

    “Stem cell technology has emerged as a promising avenue in ALS research. Induced pluripotent stem cells (iPSCs) derived from ALS patients’ cells have enabled researchers to model the disease in the laboratory, screen potential drug candidates, and investigate disease mechanisms in patient-specific cellular models,” said Reichelt.

    The approach to replace diseased nerve cells that contribute to neuron death and can lead to paralysis has been taken by Cedars-Sinai’s ALS Clinic. Researchers have engineered said nerve cells called astrocytes, which are star-shaped cells that support nerve function, to release glial cell line-derived neurotrophic factor (GDNF), a growth factor that safeguards neurons. 

    A phase 1/2A study demonstrated that when the stem cells were injected into the region in the spinal cord that controls movement in the leg, the cells put the brakes on disease progression in most patients, however, it failed to achieve overall statistical significance. To add to that, the patients who can enroll for the trial are those people who experience early stages of paralysis, meaning that they would not be able to “regain long-term function of their bodies,” according to the press release.

    “This is a protective strategy and it’s definitely about timing,” said Clive Svendsen, executive director of the Board of Governors Regenerative Medicine Institute, in the press release.“If all the motor neurons are dead, no matter how much progenitor cells and GDNF we deliver, they’ve got nothing to act on. In the future, we can intervene earlier in the disease, and that’s when we might start slowing the progression.”

    To add to that, the Foundation for the National Institutes of Health (FNIH) is on a quest to track down biomarkers that will facilitate the discovery of new therapeutic targets. This initiative is in partnership with agencies like the FDA and the National Institute of Neurological Disorders and Stroke, as well as the ALS Association and pharma giants like Biogen, Abbvie, Lilly and Takeda.

    FDA approved ALS drugs: the early days

    ALS research has come a long way over the years. The first-ever FDA-approved drug was Rilutek, nearly three decades ago. It acts as a glutamate inhibitor, preventing hyperexcitability and neuron damage caused by the accumulation of glutamate in the synaptic gap. But along with hampering glutamate, it also temporarily lowers the number of white blood cells in the blood, increasing the chance of getting an infection. So, staying away from people with infections is recommended during that period.

    Following Rilutek’s clearance, the second drug to be given the FDA nod was more than twenty years later. Edaravone, sold under the brand name Radicava, uses a different neuroprotective mechanism. As a synthetic free radical scavenger, it is designed to reduce oxidative stress, another possible cause of ALS. Similar to riluzol, the active ingredient in Rilutek, it slows down the progression of the disease, although it does not cure it. 

    Since then, oral drugs RELYVRIO and Nuedexta, as well as other forms of riluzol, have secured FDA consent.

    Challenges in the pursuit of an ALS cure

    While research is moving at a pace quicker than ever before, it is not without its drawbacks. 

    “Numerous therapeutic strategies have been explored in ALS research, including neuroprotective agents, anti-inflammatory drugs, gene therapies, and stem cell-based therapies. While many of these approaches have shown promise in preclinical studies, translating them into effective treatments for ALS patients remains challenging,” said Reichelt.

    One of these challenges is the lack of knowledge about how sporadic mutations in ALS come into play. As biotechs like Alexion Pharmaceuticals and Brainstorm Therapeutics have faltered in the past, with the former bidding goodbye to its ALS candidate because it wasn’t effective enough, back in 2021, and the latter’s ALS therapy being voted against by the FDA late last year, it is not customary for ALS drugs to always make it to the market.

    Nevertheless, as different kinds of therapies seem to be on the horizon at present, it is more likely that with the ramped up research, drug trials will prove more fruitful than before. 

    “Although many trials have not yielded successful outcomes, they provide valuable data that contribute to our understanding of the disease and guide future research efforts,” said Reichelt.

    And, while a lot of research is yet to be done to ultimately find a cure for ALS, according to Reichelt, the significant progress made in recent times signals that things may be moving in the right direction.

    This article was originally published by Ute Boronowsky in October, 2017, and has since been updated.

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