The drug's beginnings, according to the two former students there to see them, were quite humble.

About a decade ago, Justin Klee and Josh Cohen were undergraduates at Brown University. They had no funding, no lab space and no knowledge of the biotechnology industry. What they did have was an idea — that, by combining a specific pair of chemicals, they could combat diseases in which the brain and nervous system break down.

After years of testing, Klee and Cohen's drug is now up for approval in the U.S., Europe and Canada as a treatment for Lou Gehrig's disease, known more formally as ALS or amyotrophic lateral sclerosis. If cleared by the Food and Drug Administration, it would be the first new ALS medicine to reach the market in five years, adding to a short list of available therapies.

Before issuing a verdict on the drug, which carries the name AMX0035, the FDA has requested input from a group of experts who specialize in neuroscience and drug development. The group is set to meet Wednesday to vote on whether Klee, Cohen and the company they built, Amylyx Pharmaceuticals, have generated enough evidence to support the approval of AMX0035.

The FDA typically follows the recommendations of its expert advisors, but not always. Last year, for instance, the agency granted a bold, first-of-its-kind approval for an Alzheimer's disease drug developed by Biogen. The decision was controversial for several reasons, not least of which being that advisors, as well as the FDA's own statisticians, argued strongly against the drug, which is now sold as Aduhelm.

AMX0035 might not spark as much debate. Yet, Wednesday's meeting could cause a stir nonetheless, as some have questioned the strength of Amylyx's data along with the ways the company ran and analyzed its clinical trials.

The FDA's stance on the drug hasn't been entirely clear either, potentially raising the stakes of the advisory meeting. Last April, Amylyx said the agency wanted it to run another large clinical trial before submitting AMX0035, a disclosure that received great pushback from patients and advocacy organizations. But not long after, the FDA met with ALS advocates and, by September, had amended its requirements, allowing Amylyx to run the additional study while simultaneously filing an approval application.

The FDA does appear to have significant reservations about Amylyx’s drug, though. In briefing documents released ahead of this week’s advisory meeting, agency scientists argued that the main evidence Amylyx gathered "was not exceptionally persuasive." The staff also said it was "challenging to interpret" how the drug performed in a key clinical study, as, among other issues, Amylyx made "potentially incorrect assumptions" when assessing the data.

Shares in Amylyx, which had accumulated a market value greater than $1 billion, fell by more than 50% Monday on news of the FDA's views.

The origins of an ALS drug

Klee and Cohen established Amylyx in 2013, around the time they were wrapping up degrees in neuroscience and biomedical engineering.

The company's origins, and, by extension, those of its flagship drug, started with a broad goal. "I'm an engineer by background, so I often think about things in an extremely over-simplistic way," Cohen told BioPharma Dive in December. "The idea was: so long as the neurons remain connected and are shooting electricity, you should be OK."

But how to do that, especially in diseases hallmarked by the death and decay of neurons, remained a mystery. At the time, there was only one medicine specifically approved for ALS, and it offered only a small survival benefit.

Cohen and Klee pored over research, mapping out on a sheet of paper the various ways in which neural cells degrade. They ended up with a web of interconnected proteins, and set out to identify where a drug could have the most impact. With limited resources, Cohen said they opted to "look in the literature to see if any compounds exist that credibly target those targets we want to hit. That's really how we came across AMX0035."

Amylyx's drug is actually a combination of two chemicals, sodium phenylbutyrate and taurursodiol, which animal studies have suggested can protect neural cells. Cohen said the first experiment of the drug involved exposing rat neurons to hydrogen peroxide at a high enough dose to kill most of them. The neurons were also treated with the combination, and the result, according to Cohen, was that nearly all the cells were "rescued," giving him and Klee confidence that they were onto something promising.

With those better-than-expected results in hand, Klee and Cohen concluded they didn't need to optimize their drug further. They sped through preclinical work and, after getting clearance from the FDA, pushed AMX0035 into human testing, running a small, early-stage study in tandem with a larger, mid-stage trial dubbed CENTAUR, which would come to be the crux of Amylyx's approval application.

A 'big step' in treating ALS?

CENTAUR kicked off in June 2017, and ultimately enrolled close to 140 patients with rapidly progressing ALS that either had a known genetic link or was "sporadic," meaning doctors weren't sure exactly what caused it.

The primary phase of the study ran for a little more than two years. Results became publicly available in September 2020, when they were published in The New England Journal of Medicine. Researchers found patients declined a bit slower when given Amylyx's drug compared to a placebo, as measured by a scorecard that evaluates the severity of ALS through patients' ability to perform essential functions like breathing, speaking, walking and writing.

Further analyses would show those who took the drug also lived a median of six to seven months longer. (That difference was smaller, about five months, when more data was considered in the calculations, the FDA's documents show.)

"I do think it's incremental, but it's an important increment," said Merit Cudkowicz, one of the principal investigators in the study and the director of the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital. "It is really the first drug to slow loss of function but also prolong survival. That is a big step."

While deemed a success by both Amylyx and doctors, the study and its results weren't entirely positive. Amylyx's drug didn't perform significantly better than the placebo on additional tests focused on health measures like hospitalization rates and overall muscle strength. Patients on AMX0035 also continued to decline, and the chances of them living up to two years after enrolling in the study were about 50%.

In an editorial also published by NEJM, two neuroscience experts, Michael Benatar and Michael McDermott, argued that the "lack of convincing supporting evidence" in the study raises questions about the effectiveness of AMX0035.

FDA scientists voiced similar concerns in the documents made available Monday. They viewed the data related to functional decline as weak and potentially compromised by how it was measured. There was also considerable missing data, which FDA staff noted could change the study’s conclusions if included.

As for the proposed survival benefit, FDA staff didn't find the supporting evidence to be compelling.

"The overall lack of statistical persuasiveness of the survival benefit, as well as the lack of replication of the results raises concern that the modest survival benefit seen may potentially be due to underlying disease heterogeneity rather than an effect of the drug," they wrote.

Klee and Cohen acknowledge the limitations of their drug, as do others.

"It looks promising," said Steve Scelsa, a neurologist at Mount Sinai Hospital and one of the researchers in CENTAUR, in an interview late last year. "But even treatments like this, the effect is extremely modest. It could be the difference at six months between maybe needing a cane versus a walker, but still having trouble waking; the difference between being able to still cut your food or needing someone to help you."

Cudkowicz, too, has said there is "less science" behind AMX0035 compared to other ALS therapies in development.

"I don't know that people would have predicted the success they had in the trial," Cudkowicz told BioPharma Dive. Even so, "that also says that you can think you know everything, and you can be really wrong."

A difficult position for the FDA

For patients and their caregivers, Amylyx's drug has become a source of hope in a research area marred by disappointments. In just the past few years, experimental ALS treatments from Biogen, Alexion Pharmaceuticals, Cytokinetics and Brainstorm Cell Therapeutics have failed closely watched clinical trials.

Modest benefits, meanwhile, can still be meaningful for patients facing an exceedingly difficult prognosis with only few other treatment options available.

So, when Amylyx disclosed last spring that the FDA wanted to see data from an additional clinical trial before reviewing the company's drug, the response from patient advocacy groups was quick and forceful.

"We have asked the FDA to approve AMX0035 as soon as possible. So far, those calls have been ignored," said Calaneet Balas, president and CEO of The ALS Association, in a statement issued shortly after Amylyx's announcement. (The nonprofit group, along with other organizations, has provided Amylyx with about $2 million to help fund development of AMX0035 and lists the biotech as a corporate partner on its website.)

Against this backlash, the FDA allowed Amylyx to ask for approval while simultaneously running that extra trial. The documents released Wednesday show that, despite notable reservations about Amylyx's data, the agency invited the company to submit an application so it might review the data more thoroughly.

Analysts at the investment bank Evercore ISI argued in a recent note to clients that it was pressure from advocates that spurred the FDA's reversal.

In the weeks ahead of Wednesday's meeting, hundreds of comments have been submitted to the FDA, including many that argue in support of Amylyx's drug and the impact even modest benefits could have on people diagnosed with ALS.

In addition to testimony from Amylyx and FDA staff, the agency's advisers will hear from the public at the meeting, which is the last major step in the FDA's review.

A final verdict from the regulator should arrive by June 29.