Experimental drug for ALS, dreamed up in a dorm room, offers patients glimmer of hope

An experimental drug for amyotrophic lateral sclerosis, or Lou Gehrig’s disease, slowed the neurological decline of volunteers in a closely watched clinical trial, according to researchers, offering a glimmer of hope for a patient population that desperately needs new treatment options.

Patients who took the medication — initially dreamed up over beers and obsessive internet searching in a Brown University dormitory — retained a higher level of certain motor functions than those given a placebo, according to the researchers’ study, published Wednesday in the New England Journal of Medicine. The company developing the drug, Cambridge, Mass.-based biotech Amylyx, released outlines of the data in December, but the new paper details how effective the treatment was in slowing progression of the disease.

While researchers involved in the study said it marked a watershed moment in the fight against ALS, an accompanying editorial in NEJM called the data from the Phase 2/3 study only “tantalizing.” It said the benefit appeared to be modest — and stressed a Phase 3 trial would be important to validate the conclusions.

Any additional treatments would be welcome by the ALS community. There is no cure for the disease, and only a couple of available treatments.

“We’re thrilled to be part of the charge to change the care for patients with ALS — a disease that’s been unanswered for far too long,” Justin Klee, a co-founder and co-CEO of Amylyx, said in an interview. “We hope that we and everyone else in this field can change the face of this horrible disease.” 

The exact cause for ALS is still unknown, but motor neurons in the brain slowly begin to stop functioning and die off; they ultimately stop transmitting commands to the rest of the body. About 10% of the cases have clear genetic roots, but the remaining cases have no clear cause. It’s hypothesized that unknown genetic mutations, or certain environmental exposures, trigger the kind of nerve cell death associated with ALS. 

Regardless, the disease, broadly, follows a similar course: Individuals begin feeling muscle stiffening and over time — typically two to three years — progressively lose the ability to move, speak, eat, and even breathe. 

A rigorous study

Amylyx’s double-blinded, randomized study, called the CENTAUR trial, tracked 137 patients with ALS over the course of six months. It recruited patients with particularly fast-progressing illness, and for every patient receiving placebo, two were given the Amylyx drug — a combination of sodium phenylbutrate and taurursodiol. 

Outcomes were measured on what is known as the ALS Functional Rating Scale, a questionnaire that evaluates a patient’s ability to continue with daily activities — such as climbing stairs, holding a fork, or swallowing food. 

On the 48-point scale, patients taking the Amylyx drug saw their condition decline on average about 2.9 points less than those taking placebo over that six-month period. Outcomes varied by patient, but overall most saw improvement in fine motor function — without seeing improvements in their ability to breathe. Most patients started out at around 36 points at the beginning of the study, and the placebo arm dropped to around 26 by the end of the six months. Those receiving the Amylyx drug combination scored, on average, closer to 29 points, said Sabrina Paganoni, an ALS researcher at Harvard Medical School who was the principal investigator of the Amylyx trial. 

“Even a small change in a couple of points can mean a large change in what daily life looks like,” Paganoni said. “A two-point change could mean the difference between eating successfully or requiring a feeding tube — or between walking and using a wheelchair.” 

About 25% of volunteers dropped out of the trial, though that’s standard for ALS trials as patients’ illness progresses, said Merit Cudkowicz, chief of neurology at Massachusetts General Hospital, and the study’s senior author. Amylyx is continuing this study in an open-label extension — meaning volunteers are told whether they are getting the treatment or placebo. Researchers hope to track patients over a longer term for further insights into how the treatment affects neurological decline — and survival. 

Some researchers not involved in the study found the medication’s benefits to be marginal. Matthew Kiernan, chair of neurology at the University of Sydney, described the study as a “small benefit for ALS patients” — pointing out that he sees no improvement in survival or a patients’ ability to breathe. He considered the trial well-designed, however, and plans to track Amylyx’s drug in future trials. 

Still, ALS patients are clamoring for better treatment options, and will likely demand fast access to the Amylyx drug based on this mid-stage data, said Neil Thakur, chief mission officer of the ALS Association — an organization that helped fund Amylyx’s work. He thinks it’s important that this drug is quickly offered to ALS patients as an option, as there are so few treatment options currently available. The ALS Association plans on putting out a public petition, to help fast-track expanded access of the drug — or even approval — without the standard Phase 3 trials, which would take several more years.

Certain cancer drugs are approved after mid-stage trials, in patient populations who desperately need treatment. But that pathway doesn’t exist for ALS patients, even though it’s also a terminal disease, Cudkowicz said. 

“I think this is going to be a challenge for the FDA, who will feel pressure to be both bold and conservative,” Thakur said. “We want them to take the side of ALS patients.”

An unconventional origin story

In 2013, Klee and Joshua Cohen, then undergraduates at Brown, were pondering why brain cells die in neurodegenerative diseases. 

The two shared a passion for tunneling through dense academic literature at night. And so, after an exhaustive literature search, they came upon sodium phenylbutrate and taurursodiol, which they believed could help protect diseased neurons.

They had learned that neuronal health is regulated, in part, by two types of structures in the cell: the mitochondria, known as the “powerhouse” of cells, and the endoplasmic reticulum, which plays a major role in the creation, modification, and transport of proteins. So they theorized that the substances might help boost mitochondrial and ER function, and protect nerves from degenerating. Sodium phenylbutrate has been long used for other diseases, particularly those involving kidney dysfunction, and a form of taurursodiol is available for sale as a supplement — but they’ve never been used in combination to treat neurodegeneration.

Cohen and Klee’s thought, back then, was that the drug combination might ultimately help stave off the degeneration associated with Alzheimer’s disease. They contacted Rudy Tanzi, a prominent Alzheimer’s researcher at Mass. General — who took a liking to Cohen and Klee immediately, and decided to give them a hand with their hypothesis. 

“When they first wrote to me in June 2013, they were just kids,” Tanzi recalled. “I thought it was a pretty naive idea, to be honest, but thought I’d go through this exercise with them — throw them some hard-to-do science. And now here we are, today, with a paper coming out.” 

At the time, most work in the neurodegeneration space focused on the beta-amyloid hypothesis, but Klee and Cohen’s line of thinking was that inflammation played a role in nerve cell death. 

Tanzi helped Klee and Cohen design a laboratory study that could test if sodium phenylbutrate and taurursodiol might protect against oxidative stress and damage — which ultimately leads to neuroinflammation. 

“I thought, ‘Let’s test these two whippersnapper undergrads, show them how hard science really is,” Tanzi said. “I was 100% sure it would fail.” 

It didn’t. 

When they came back with results, a few months later, they showed that hydrogen peroxide did indeed kill the cultured neuron cells. But when sodium phenybutrate alone was added, they saved 30% of the cells, and when taurursodiol alone was added, they saved 30% of the cells. The two drugs together, however, saved 90% of the neurons, Tanzi said. 

He thought it was a fluke, and directed Klee and Cohen to do it all over again. The second go-round, they saved 95% of the neuronal cells in the preclinical study. 

At the time, Cohen was a senior in college — and crammed all his classes into one day per week, so he could spend the rest of his time focused on the fledgling company. Klee had recently graduated, so Tanzi hired him to work in his lab, studying Alzheimer’s disease. Klee also taught swim lessons and volunteered for neuroimaging studies in Boston (“it’s an expensive city, and those studies pay the most,” Klee said) in order to fund the preclinical tests. Klee and Cohen outsourced all of the lab work to clinical research organizations.

The results continued to be strong, so Tanzi connected Klee and Cohen with his colleagues at Mass. General — which ultimately led to the clinical studies. The company — which received some early and important funding from the Ice Bucket Challenge, a viral social media effort that raised ALS awareness in 2014 — has raised more than $75 million to date. Amylyx is testing the sodium phenylbutrate-taurursodiol combination in Alzheimer’s disease, and has identified other compounds preclinically that could also be neuroprotective.

When the CENTAUR trial results came back, Klee and Cohen called Tanzi well past midnight — ordering him to grab a drink. So Tanzi poured himself a scotch, and listened: 

“They didn’t say anything about money. They didn’t say anything about how their biotech company was going to be a success,” Tanzi said. “They told me, ‘Guess what: Amylyx is going to help ALS patients.’”