For a long time, the thinking was the same. To make a career in medical research, it was critical to pick a promising area of study. That often meant steering clear of ALS.
Short for amyotrophic lateral sclerosis, ALS is a progressive and fatal illness that causes nerves to break down. The disease was first discovered more than a century ago, but became widely known only after famed baseball player Lou Gehrig was diagnosed with it in the late 1930s.
Today, estimates hold that about 30,000 people in the U.S. have ALS, with 5,000 new cases annually. These patients desperately need new treatments; yet, the complicated biology of their disease has thwarted most attempts at developing effective medicines. The Food and Drug Administration has approved only three so far, and each has limitations. ALS patients still live about four years on average once they're diagnosed.
Experts say there are reasons for hope, though. Scientific and technological breakthroughs have given drug hunters better tools to understand and potentially combat ALS. Patients may soon have another treatment, a pill shown to modestly slow people's decline and help them live longer, and could see more options arrive in the next several years if more advanced approaches pan out.
"The science is really exciting, and I think that's driving a lot of companies to have programs," said Merit Cudkowicz, director of the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital.
"I remember people telling me it was a dead-end career to go into ALS research," she added. Now, "it's a hot time to be an ALS scientist. They all want you."
But as with many diseases of the brain, much about ALS remains unclear. The vast majority of cases are "sporadic," for example, meaning their cause isn't fully understood.
For drugmakers hoping to crack the disease, these uncertainties create major roadblocks. In the last year alone, experimental treatments from Brainstorm Therapeutics, Alexion Pharmaceuticals and Biogen — the world's largest biotech focused on neuroscience — have all faltered in late-stage clinical trials, tempering enthusiasm among doctors, patients and investors.
And for patient advocates, these continued setbacks have only intensified calls for companies to accelerate research and for drug regulators to work more flexibly.
"The drug development process takes a long time. And when you're looking at one year, two years, three years of life left, you just don't have time," said Larry Falivena, who serves on the board of trustees of The ALS Association, a patient advocacy group, and who was diagnosed with a slower progressing form of the disease in 2017.
A big year for ALS drugs
In the U.S., patients with ALS have few treatment options. There's one called riluzole, which was approved in 1995 and has been shown to extend survival by a few months. There's also Nuedexta, which was cleared in 2011 to treat a symptom of the disease. And then there's Radicava, which was greenlit in 2017 as a way to slow the physical decline associated with ALS.
About four in five U.S. patients take riluzole, according to Cudkowicz, as it appears to consistently extend people's lives without harsh side effects.
Far fewer are on Radicava, largely because of the way it's administered. The drug is given as an hourlong infusion each day for about a third of every month. That inconvenience, coupled with its often small effect, has led many patients to not consider it worthwhile.
"In any one patient, you don't really notice the difference whether they're on the drug or not. It's that type of benefit you only really see in trials," said Stephen Scelsa, a neurologist at Mount Sinai Hospital in New York City.
Another option could be on the horizon, though.
In 2019, Amylyx Pharmaceuticals, a small Cambridge, Massachusetts-based company, announced that a drug it has been developing appeared to slow ALS in a placebo-controlled clinical trial. Results later published in The New England Journal of Medicine showed those who took the drug, known as AMX0035, scored a couple points better on average on a scale used to evaluate how well ALS patients speak, walk, breathe and perform other essential functions.
Further analysis found early signs the drug kept people alive longer, too. Looking at 135 study participants, those treated with AMX0035 lived a median of just over two years — about six and a half months longer than those who received a placebo.
Experts note that, while positive, the effect of Amylyx's drug is still modest. Patients who took it continued to decline, and the chances of them living up to two years after enrolling in the study were about 50%. The study also found AMX0035 didn't do significantly better than the placebo on secondary tests that looked at health measures like breathing, hospitalization rates and overall muscle strength.
Amylyx's founders acknowledge their drug's limitations. But they, along with others, argue it's a step in the right direction.
"I do think it's incremental, but it's an important increment," said Cudkowicz, who helped lead the investigation of AMX0035. "It is really the first drug to slow loss of function but also prolong survival. That is a big step."
Amylyx has asked regulators in Canada and the U.S. to approve its drug, and plans to do the same in Europe before the end of the year. The FDA has yet to decide whether it will review AMX0035, but if it does, an approval verdict would come sometime in 2022.
"We're really proud of the data we generated," said Justin Klee, one of Amylyx's co-founders. "But there's also so much else to do, and so many other opportunities."
Companies are already at work exploring some of these opportunities. Swiss pharmaceutical giant Novartis is investigating a drug designed to block a protein involved with inflammation in the nervous system. Another drug, from the neuroscience company Alector, targets a protein that performs critical duties for cells both in and outside the brain. That drug is being tested across multiple neurodegenerative disorders, including ALS.
Biogen and its longstanding partner Ionis Pharmaceuticals have attracted attention as well, with one of the few experimental medicines to have moved to the final stage of human testing.
Called tofersen, the medicine was created with a technology that, while not new, has been increasingly validated thanks to a string of recent FDA approvals in other diseases. Tofersen is also the byproduct of a flood of research aimed at the role genes play in ALS.
A recent setback, however, has raised doubts about its chances at ever becoming available outside of clinical trials.
Genes in focus
The human genome has been an invaluable source of information in the fight against disease. DNA was first sequenced in the mid-1970s. Less than a decade later, Huntington's disease — which is also characterized by the progressive breakdown of nerve cells — became the first illness traced back to changes in a specific chromosome.
The first gene associated with ALS, named SOD1, was identified in 1993. Scientists have since uncovered at least several dozen more that look to have some effect on the disease.
These discoveries have encouraged ALS researchers and doctors, especially as technological advances in drugmaking have made it easier to target genes. Tofersen, for example, is a type of precision medicine known as an antisense therapy, meaning it blocks the body's cells from acting on the genetic instructions used to make certain proteins. Specifically, it's designed to inhibit the activity of the SOD1 gene.
"I do think the genetic forms, since we know the targets, will have some of the first big breakthroughs, where we find treatments that really modify the disease," Mount Sinai's Scelsa said.
But, nearly three decades after SOD1 was identified, researchers are still hunting for those breakthroughs. In many cases, drug developers aren't yet sure how best to target these genes, or how to regulate them in a way that positively impacts function or survival. Just two months ago, Biogen and Ionis disclosed results from a late-stage study of tofersen, and while the drug did substantially lower levels of SOD1 protein along with another chemical marker associated with ALS, it wasn't any better than a placebo at slowing down the disease.
Biogen said it will discuss the data with regulators and the broader ALS community to determine tofersen's future.
"Technology has advanced so much … it's easy to identify a target," said Kuldip Dave, vice president of research at The ALS Association. "But then, can we really manipulate the target? I think that's the first challenge, the first transition: from target identification to target validation."
Moreover, the mutations tied to ALS have only been observed in a tiny fraction of patients. That fraction could grow with additional genetic research; but in the meantime, it's estimated that at least 90% of cases don't have a known cause.
For those patients, new treatments may be harder to come by.
"In the case of sporadic ALS, we really don't know," said Raymond Roos, director of the University of Chicago's ALS and Motor Neuron Disease Clinic. "We don't know whether there are multiple genes plus environment, or which genes and which environment. We're struggling."
Researchers aren't giving up, though. A search of a federal clinical trial database shows at least five dozen that are evaluating potential ALS drug treatments and currently recruiting participants. Many of these studies are enrolling people with sporadic disease.
Similar to how the treatment of cancer and certain genetic diseases like cystic fibrosis evolved over the past decade, the hope is that therapies like those or like Amylyx's, which was tested against both sporadic and genetic ALS, will improve patients' daily lives and help keep them alive until more specialized drugs are developed.
Technology that's been used in a more targeted fashion may also prove valuable to broader populations. Biogen, for one, is sponsoring a small study of a different antisense therapy aimed at preventing the buildup of a toxic protein observed in many ALS patients.
"The whole field finds that exciting," Cudkowicz said, "because it's basically learning from the tools and technologies for the familial form of the illness [to then have] something that could also be for sporadic disease."
The road ahead
As with other neurodegenerative diseases, researchers seem to agree that the best treatments for ALS will involve a mix of drugs. Yet, identifying and testing these combination therapies can be difficult, as Amylyx found with AMX0035, which itself is a pairing of two drugs.
"As we proceeded, we realized just how many things developing a combination drug makes more challenging," said Josh Cohen, Amylyx's other co-founder.
"With a single drug you have to worry about dose. For a combination drug you have to worry about dose squared," he said. "You have to worry about the levels of A and the levels of B, and the interaction between [them]. And that pervades everything" from toxicology studies to manufacturing.
Another obstacle is that, while many researchers believe treating patients earlier could lead to better outcomes, ALS is hard to diagnose even after symptoms start to show.
Falivena of The ALS Association knows this obstacle well. While training for a marathon, the now 53-year-old said he noticed weakness in his left arm that later spread to his leg. Despite numerous tests and doctor's visits, it took a few years before Falivena was officially diagnosed.
"It's not like you can just take a blood test," he said, "it's more a process of: 'we have to eliminate everything else.' I'm sure no doctor wants to tell a patient they have a terminal disease with no cure, so it makes sense they want to eliminate everything else. But it can be frustrating."
As scientists attempt to work through these problems, one source of hope among patients has been clinical trials.
At the Healey Center, for example, a first-of-its kind "platform" trial testing five experimental therapies at once has enrolled volunteers two- to three-times faster than is typical for an ALS study, according to Cudkowicz.
"It used to be that it was hard to find people to be in trials," she said. "We now have [situations] where the sites can't keep up with the waitlist. And it's not only because we're doing this platform trial; there's so much patient advocacy that's getting the word out."
Patients like Falivena, who participated in the tofersen study and has since enrolled in a subsequent "open-label" investigation of the drug, have found these trials valuable even when they don't succeed.
"There's so much about this disease that makes you feel like you have no control," he said. "This is a level of control; it's a level of hope, positivity, which in itself can help people live better."
And yet, there is also some resentment toward drug developers, which are often reluctant to broaden enrollment in their clinical trials beyond narrowly defined groups they see as most likely to benefit. Biogen, for one, was heavily pressured to expand access to tofersen and eventually did so after initially resisting.
Patient advocates have criticized the FDA as well for not moving fast enough to make promising yet unproven ALS treatments available to patients. The ALS Association even called out the agency earlier this year, after it looked as though Amylyx would have to conduct another clinical trial before asking for approval of AMX0035.
The FDA has since reversed course, allowing Amylyx to submit its drug before completing the additional trial. Falivena said he's optimistic the agency's change of heart means it was listening to patients.
Patients could have more trials to choose from, too, if recent moves by drug companies are any indication. In just the past year and a half, big-name companies like Merck & Co., Bristol Myers Squibb, GlaxoSmithKline and CRISPR Therapeutics have teamed up with smaller biotechs or research institutions in an effort to discover new treatments for ALS.
And on a broader scale, investors have demonstrated a renewed interest in battling brain diseases. Venture capitalists last year poured more than $2 billion into young biotechs focused on neuroscience, a 10-year high, according to data compiled by the trade group BIO. A bill passed last week by the U.S. House of Representatives, meanwhile, would provide $500 million in funding for ALS research via federal grants.
"The number of companies that are calling and having advisory boards is overwhelming," Cudkowicz noted.
While these investments are welcome, time will tell if they actually lead to treatments that improve the lives of ALS patients.
"Sometimes things take longer than one wants," said Roos from the University of Chicago.
"I've been surprised in my scientific career — in the sense I thought, 'We're going to have a cure in Huntington's, it's around the block, we know what the mutation is,'" Roos added. "That was a while ago, and we're still working on it. Things are difficult."