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The hunt for amyotrophic lateral sclerosis (ALS) drugs has advanced over the past decade, with six drugs approved by American regulators. One of them is multinational Biogen’s Qalsody, which was approved by the European Medicines Agency (EMA) last year. However, trial results have been a mixed bag of late, with several therapies failing in the clinic. As more and more ALS drug trials press forward, are we inching towards a cure or is this a pipe dream? 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 the death of motor neurons, resulting in paralysis of voluntary muscles and eventual respiratory 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. On average, people with ALS survive three years after diagnosis, but about 20% live five years or longer, and 5% have a life expectancy exceeding 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. Thanks to the 2014 ice bucket challenge, ALS 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. 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. Relyvrio, however, was pulled from the market last year owing to a failed phase 3 trial. 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 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 improved. 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 significant breakthrough has been in recognizing how hormone therapy could treat sleep disruption caused by ALS. According to a study conducted by the University of Strasbourg in France and the University Hospital of Ulm in Germany, the insomnia drug suvorexant and melanin-concentrating hormone were both able to increase REM sleep in mice models of ALS. Neurons are involved in regulating sleep but, in ALS patients, they become degraded. So halting this degradation with the help of the two medicines decreased wakefulness. Moreover, the melanin-concentrating hormone managed to curb the loss of motor neurons in the spine. This makes way for clinical studies to evaluate these medicines further. Meanwhile, a $415 million deal between big pharma Lilly and Alchemab Therapeutics to advance the preclinical antibody ATLX-1282 to the clinic, signed in May, points towards therapeutic progress. The HEALY ALS platform trial: a swing and a miss In the clinic, however, ALS therapies have been on a bumpy road. A much-anticipated study was the first-ever ALS platform trial called the HEALEY ALS platform trial. A platform trial is a random, adaptive trial that tests and compares multiple interventions against a control over a period of time. It was meant to increase patient participation by 67%, and cut down on research expenses by 30% as it tests multiple therapies at once. However, four candidates that were trialed failed their late-stage studies earlier this year. Run by the Healey & AMG Center for ALS at the Massachusetts General Hospital, along with Tackle ALS, the trial assessed the safety and efficacy of the investigational drugs zilucoplan, verdiperstat, CNM-Au8, and pridopidine, among others. Zilucoplan, a drug developed by Belgian biopharma UCB, failed to meet the endpoint, and the trial was prematurely halted as it “demonstrated futility,” according to UCB in a press release. Zilucoplan is designed to prevent inflammation and tissue damage in people with ALS. This is done by inhibiting the target protein complement component 5. It has been greenlit by regulators in Japan, the U.S., and the E.U. to treat myasthenia gravis, an autoimmune condition that causes muscles to feel weak and get tired quickly. U.S.-based Biohaven Pharmaceuticals’ verdiperstat also saw disappointing results as it failed to meet the primary endpoint. Verdiperstat is designed to bind to an enzyme called myeloperoxidase, which is a driver of neuroinflammation, and inhibit it. But there were no signs of a major difference between placebo and treatment group outcomes. The other drug that missed its mark was pridopidine. Owned by Prilenia Therapeutics, it has been seen as a strong candidate for a number of neurodegenerative conditions. The sigma-1 receptor (S1R) agonist that activates S1R is designed to regulate 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. But in the HEALEY trial, it failed to impact disease progression. Finally, Clene Nanomedicine’s CNM-Au8, which is an oral gold-based nanocrystal therapy, came up short in the platform trial after it was found to reap no benefit for patients with ALS. Still, there is hope amidst trials. While zilucoplan and verdiperstat will not graduate to phase 3 studies, pridopidine and CNM-Au8 will still move up, as both have signaled efficacy in treating ALS in the past. ALS therapies in the clinic: on a losing streak? The HEALEY trial also previously saw AbbVie and California-based Calico Life Sciences’ ABBV-CLS-7262 as well as Denali Therapeutics’ DNL343 flunk ALS studies. The pharma giant’s small molecule did not meet the study’s primary endpoint of disease progression for either the primary or the exploratory high dose. As for DNL343, which targets eukaryotic initiation factor 2B (eIF2B) – a key regulator of the integrated stress response – did not hit the primary endpoint either. Late last year, New Jersey-based PTC Therapeutics’ utreloxastat was discontinued after it did not achieve statistical significance in patients, or slow disease progression. Even preclinical treatments such as the gene therapy candidate VY9323 have stumbled, but for different reasons. Massachusetts-based Voyager Therapeutics reported that its SOD1 gene-silencing candidate can’t proceed to the clinic until it has found an alternate payload to “achieve the desired product profile.” ALS therapeutics: what’s currently in the pipeline? Meanwhile, Corcept Therapeutics’ ALS drug dazucorilant also failed the clinic, but there might be a silver lining. While the cortisol modulator was unsuccessful in mitigating the decline in motor skills in people with ALS in a phase 2 trial, recent survival data looks more optimistic. Patient survival significantly improved in the 83 people who were in the 300 mg dosage cohort. Moreover, the biotech took the fact that none of the patients had died after 24 weeks of treatment as a win, as two patients in the 150 mg arm and five patients who received placebo had died. It also showed an “acceptable safety profile,” according to the company. So, Corcept hasn’t given up on its ALS drug yet. Similarly, Brainstorm is forging ahead despite several failed attempts at snagging FDA approval. The regulator voted against its cell therapy NurOwn two years ago, which cited that there wasn’t enough evidence supporting the therapy’s efficacy. After the blow, Brainstorm was forced to withdraw its Biologics License Application (BLA). But now, the New York-based company has vowed to shore up enough data with a phase 3 trial to build its case to the FDA. NurOwn is made up of stem cells that generate neurotrophic factor-secreting cells (MSC-NTF cells). This is supposed to deliver targeted signals that modulate neuroinflammation and promote neuroprotection. Can stem cell therapy help manage ALS symptoms? As seen with NurOwn, a key area of therapeutic interest 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,” Clive Svendsen, executive director of the Board of Governors Regenerative Medicine Institute, had said in the press release. “If all the motor neurons are dead, no matter how many 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. Challenges in the pursuit of an ALS cure While research is moving at a pace quicker than ever before, it is, of course, not without its drawbacks, as seen with the many clinical failures. “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 down 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.