How a 'Niche' ALS Drug Reached the FDA Review Threshold

According to two former students who were present at the time, the drug's origins were quite modest.

About a decade ago, Justin Klee and Josh Cohen were undergraduates at Brown University. They had no funding, no laboratory space, and knew nothing about the biotechnology industry. All they had was an idea—that by combining a specific pair of chemicals, they might be able to combat degenerative diseases of the brain and nervous system.

After years of testing, the drug developed by Klee and Cohen is now seeking approval in the United States, Europe, and Canada to treat amyotrophic lateral sclerosis (ALS), commonly known as 'Lou Gehrig's disease.' If approved by the U.S. Food and Drug Administration (FDA), it would be the first new ALS drug to reach the market in five years, adding to the currently sparse treatment options.

Before ruling on the drug, named AMX0035, the FDA has invited a panel of experts in neuroscience and drug development to provide input. The panelis scheduled to meet on Wednesdayto vote on whether Klee, Cohen, and their company, Amylyx Pharmaceuticals, have gathered enough evidence to support the approval of AMX0035.

The FDA typically follows the advice of its expert advisors, but not always. For example, last year the agencyapproved an Alzheimer's drug developed by Biogena bold, first-of-its-kind decision. The decision was controversial for multiple reasons, notably because advisors and the FDA's own statisticiansstrongly opposed the drug—now sold under the name Aduhelm.

AMX0035 may not spark the same intense debate. However, Wednesday's meeting could still cause ripples, as questions have been raised about the strength of Amylyx's data and the way the company conducted and analyzed its clinical trials.

The FDA's stance on the drug is also not entirely clear, which may raise the stakes of this advisory meeting. In April of last year, Amylyxstatedthat the FDA wanted it to conduct another large clinical trial before submitting AMX0035, a disclosure that drew strong opposition from patients and advocacy groups. But shortly after, the FDAmet with ALS advocatesand by September hadmodified its requirementsallowing Amylyx to conduct supplementary studies while submitting its approval application.

However, the FDA has indeed shown clear reservations about Amylyx's drug. In thebriefing documents released before this week's advisory meetingthe agency's scientists considered the primary evidence collected by Amylyx to be 'not particularly persuasive.' Staff also said that interpreting the drug's performance in a key clinical study was 'challenging' because, among other issues, Amylyx made 'potentially incorrect assumptions' when evaluating the data.

Amylyx's market value had previously accumulated to over $1 billion, but its stock price fell more than 50% on Monday after the FDA's comments were released.

The origins of an ALS drug

Klee and Cohen founded Amylyx in 2013, as they were about to complete their degrees in neuroscience and biomedical engineering.

The company's origins, and the story of its flagship drug, began with an ambitious goal. 'My background is in engineering, so I tend to think in extremely simplified ways,' Cohen told BioPharma Dive in December of last year. 'The idea was: as long as neurons stay connected and keep firing, you should be fine.'

But how to achieve that, especially in diseases characterized by neuronal death and decline, remained a mystery. At the time, only one drug was specifically approved for ALS, and it offered onlya small survival benefit。

Cohen and Klee carefully reviewed the research literature, mapping out on a piece of paper the various pathways of neuronal degradation. They eventually arrived at an interconnected network of proteins and set out to identify the targets where a drug would most likely have an impact. With limited resources, Cohen said they chose to 'look at the literature to see if there were compounds that could reliably act on the targets we wanted. That's how we found AMX0035.'

Amylyx's drug is actually a combination of two chemicals—sodium phenylbutyrate and taurursodiol,animalstudiessuggest they can protect nerve cells. Cohen said that in the drug'sfirst experimentsrat neurons were exposed to hydrogen peroxide at levels sufficient to kill most of the cells. These neurons were also treated with the combination drug, and according to Cohen, nearly all the cells were 'rescued,' convincing him and Klee that they were working on something promising.

With results exceeding expectations, Klee and Cohen concluded they didn't need to further optimize the drug. They accelerated their preclinical work and, after receiving FDA clearance, advanced AMX0035 into human testing, running a small early-stage study alongside a larger mid-stage trial called CENTAUR—which would become the centerpiece of Amylyx's approval application.

A 'big step' in treating ALS?

CENTAUR launched in June 2017 and ultimately enrolled nearly 140 ALS patients with rapidly progressing disease, who either had known genetic links or were 'sporadic' cases—meaning doctors were unsure of the exact cause.

The main phase of the study lasted just over two years. Results were made public in September 2020, when they werepublished in the New England Journal of MedicineThe researchers found that patients taking Amylyx's drug experienced a slightly slower rate of functional decline compared to placebo—measured using a rating scale that assesses ALS severity by examining patients' ability to perform basic functions like breathing, speaking, walking, and writing.

Further analysis showed that those taking the drug had a median survivalextended by six to seven months(FDA documents show that when more data were included in the calculation, the difference narrowed to about five months.)

'I think it's incremental, but it's an important increment,' said Merit Cudkowicz, one of the study's principal investigators and director of the Sean M. Healey & AMG ALS Center at Massachusetts General Hospital. 'This is really the first drug that both slows functional loss and extends survival. It's a big step.'

Although Amylyx and physicians considered the study a success, the trial and its results were not entirely positive. In additional tests measuring health indicators like hospitalization rates and overall muscle strength, Amylyx's drug did not significantly outperform placebo. Patients taking AMX0035 continued to deteriorate, with about a 50% chance of surviving up to two years after enrollment.

In aneditorial published alongside the NEJM studytwo neuroscience experts, Michael Benatar and Michael McDermott, argued that the 'lack of compelling supportive evidence' in the study raised questions about AMX0035's effectiveness.

FDA scientists expressed similar concerns in documents released Monday. They considered the data on functional decline to be weak and potentially compromised by how it was measured. There was also a substantial amount of missing data, and FDA staff noted that including it in the analysis could change the study's conclusions.

As for the proposed survival benefit, FDA staff found the supporting evidence unconvincing.

'The survival benefit lacks statistical persuasiveness overall, and the lack of reproducibility of the results raises concerns that the modest survival benefit observed may stem from underlying disease heterogeneity rather than a drug effect,' they wrote.

Klee and Cohen acknowledge the drug's limitations, as do others.

'It looks promising,' said Steve Scelsa, a neurologist at Mount Sinai Hospital and one of the CENTAUR investigators, in an interview late last year. 'But even with such treatment, the effect is extremely limited. The difference at six months might be going from needing a cane to needing a walker, but still having difficulty walking; or from being able to cut your own food to needing help.'

Cudkowicz also said that compared to other ALS therapies in development, AMX0035 has 'less scientific rationale' behind it.

'I don't know if people would have predicted the success they had in the trial,' Cudkowicz told BioPharma Dive. Even so, 'it shows that you might think you know everything, but you could be completely wrong.'

The FDA's difficult position

For patients and their caregivers, Amylyx's drug has become a source of hope in a research area marked by repeated setbacks. In just the past few years, experimental ALS therapies fromBiogen、Alexion Pharmaceuticals、CytokineticsandBrainstorm Cell Therapeuticshave all failed in high-profile clinical trials.

Meanwhile, for patients facing an extremely difficult prognosis and few treatment options, even modest benefits can still be significant.

So when Amylyx disclosed last spring that the FDA wanted to see additional clinical trial data before reviewing its drug, the response from patient advocacy groups was swift and strong.

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

Facing this backlash, the FDA allowed Amylyx to apply for approval while conducting additional trials. Documents released Wednesday show that despite the FDA's clear reservations about Amylyx's data, the agency invited the company to submit its application so the data could be reviewed more thoroughly.

Analysts at investment bank Evercore ISI argued in a recent report to clients that it was pressure from advocates that prompted the FDA to change its stance.

In the weeks leading up to Wednesday's meeting, hundreds of commentswere submitted to the FDAmany supporting Amylyx's drug and emphasizing the impact even modest benefits could have on people diagnosed with ALS.

In addition to testimony from Amylyx and FDA staff, the agency's advisors will also hear public comments at the meeting, which is one of the last major steps in the FDA review process.

The regulator's final decision is expected by June 29.