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How a long shot ALS drug came before the FDA

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.