ABOVE: ALS attacks the nerve cells needed for walking and speaking. © iStock.com, Koto_Feja

A panel of independent advisers to the US Food and Drug Administration voted Wednesday (September 7) to recommend the agency approve a novel therapy to treat amyotrophic lateral sclerosis, otherwise known as Lou Gehrig’s disease. The drug, called AMX0035, had previously been rejected by the same group earlier in the year, but new evidence presented by the company that developed it, Massachusetts-based Amylyx Pharmaceuticals, prompted a surprising reversal that also comes amid an aggressive lobbying campaign by ALS patients and their families.

“We applaud and thank the FDA advisory committee for their vote to support approval of AMX0035 and we urge the FDA to swiftly approve,” the ALS Association says in a statement shared with the media. “Americans living with ALS cannot wait. We are grateful for the support of thousands of members of the ALS community who have strongly advocated for approval of AMX0035.”

ALS, a debilitating neurodegenerative disease that attacks the nerve cells needed for functions such as walking and talking, “moves rapidly, is 100% fatal and has no meaningful treatment,” Ben Wallace, an ALS patient, tells Reuters. On average, ALS patients live for only two to five years following their diagnoses. The FDA has already approved two drugs to treat ALS, but they are minimally effective in slowing the disease’s progression.

Amylyx cofounders Josh Cohen and Justin Klee, who are now cochief executives, first conceived AMX0035 more than a decade ago, The Washington Post reports, when the two were undergraduates at Brown University. AMX0035 combines a compound called sodium phenylbutyrate—used to treat rare liver disorders—alongside a nutritional supplement thought to protect neurons from damage. The treatment is taken orally in water or via a feeding tube.

At the first advisory panel meeting, convened in March by the FDA to discuss AMX0035, the group weighed evidence from a single clinical trial that included just 137 patients. The FDA typically requires at least two late-stage studies for approval, but will sometimes approve drugs with one study showing promising early results for severe illnesses. In that March meeting, Amylyx presented data suggesting that the drug could slow the progression of the disease. The first trial found that the drug was associated with a 25 percent decline in the loss of functions such as walking, talking, and cutting food, while a follow-up study found that patients who took the drug lived an average of six months longer than those who did not, the Post reports. But an internal review by the FDA concluded that the data, along with additional analyses submitted by the company, “may not be persuasive enough to warrant approval,” STAT reports. The final vote was 6-4 against recommending the drug for FDA approval. Health Canada, the regulatory body for food and drug safety in that country, granted conditional approval for AMX0035 in June.

“The data isn’t as strong as we would have hoped it would be,” Liana Apostolova, a professor of neurology at Indiana University School of Medicine and a member of the panel who in March voted no, told STAT at the time. “The good silver lining is you have a trial ongoing that could potentially resolve the uncertainties that this trial presents.”

See “New Drug Combo for ALS Slows Decline in Small Clinical Study

That second trial, which includes 600 patients and is called PHOENIX, is currently at 50 percent enrollment, with results expected in 2023 or 2024, the Post reports. In the advisory panel meeting this week, Amylyx presented new data estimating that AMX0035 could extend life expectancy by nearly 10 months compared with controls, and shared biomarker data from a study in Alzheimer's disease, according to the AP.

Speaking to the Post, Apostolova says the new analyses left her “mildly to moderately” persuaded the drug extends life by at least several months, prompting her to change her earlier “no” vote. “To deprive ALS patients of a drug that might work is not something I feel terribly comfortable with,” she said.

Several outlets have reported on one unique exchange that took place during the latest meeting that led to several members changing their votes, which totaled 7-2 in favor of approval. During his opening remarks when the panel met this week, Billy Dunn, the FDA’s top regulator of neurology drugs, said the agency would apply the “broadest regulatory flexibility” in considering the drug’s approval, given the disease’s rapid progression. “We are highly sensitive to the urgent need for the development of new treatments for ALS,” he added.

At one point, the AP reports, Dunn suggested that the agency may lean in favor of approval if Amylyx would consider voluntarily withdrawing their product if the second trial failed to produce meaningful results. He intimated, according to STAT, that the FDA is also capable of mandating such an action. In response, Klee said that if the trial “is not successful, we will do what is right for patients, which includes voluntarily removing the product from the market.”

Such a public commitment is not binding, and some advisers present at the meeting found the promise hollow. “I think the FDA—with all due respect—significantly understates the complexity and likelihood of their pulling the product from the market,” Caleb Alexander of Johns Hopkins University, one of the two panelists who voted against recommending FDA approval of the drug, tells the AP.

Others, however, were keen to see the drug approved. Speaking to the Post, Vance Burghard, a trial participant who was diagnosed with ALS in 2017 and has been on AMX0035 for three years, called the drug “life-changing,” adding that his condition has since stabilized and he has been able to hike in China and Tibet.

Dean Follmann, a biostatistician with the National Institutes of Health who voted yes, tells the AP that the lack of severe side effects factored into his decision. “The drug is not harmful—it seems like it has a benefit—there’s no safety signal here.”

The FDA is not obligated to act on the advice of its advisory panels, but does typically align with them. A formal regulatory decision is expected by the end of the month. In a statement released after the vote, Cohen and Klee say that "AMX0035 has the opportunity to be a meaningful new treatment option for physicians and the ALS community in the fight against ALS. We look forward to the FDA completing their review.”