Desperate patients want a new ALS drug, but the FDA is not sure it works
The Washington Post September 6, 2022
Steven Kowalski is just 58 but feels decades older. He falls frequently, walks haltingly with leg braces and a cane and has lost most of his muscle mass. "I don't even recognize my body in the mirror anymore," he said.
Yet Kowalski, who has ALS, feels fortunate he has not declined more swiftly — something the Boston resident attributes to a do-it-yourself drug regimen using components of an experimental treatment dreamed up by Brown University undergraduates almost a decade ago.
Today, those former students run the Cambridge-based biotech company Amylyx that is seeking Food and Drug Administration approval for the treatment, known as AMX0035. And Kowalski and other ALS patients are flooding the federal agency with thousands of emails and personal testimonials pleading for its blessing for the drug.
The debate over the therapy is about to take center stage in the often-agonizing world of ALS, or amyotrophic lateral sclerosis, a fatal illness that destroys nerve cells in the brain and spinal cord. The degenerative disease typically paralyzes patients, robbing them of their ability to walk, talk and eventually breathe, often killing them within two to five years of diagnosis.
On Wednesday, the FDA is holding a rare, second meeting with a panel of independent experts to discuss the treatment, and is expected to make a decision on approval by Sept. 29. The agency staff has expressed skepticism about the drug and its single small clinical trial, as have those same advisers who voted narrowly against recommending approval in late March. On Friday, the FDA repeated many of its earlier concerns about the drug's effectiveness, saying additional analyses submitted by the company were flawed and included no new information.
Nevertheless, ALS advocates hold out hope that the FDA will clear the treatment in the face of intense pressure from patients and their families. About 30,000 people in the United States have ALS, sometimes called "Lou Gehrig's disease." Another 6,000 are diagnosed every year. There are two FDA-approved therapies on the market but they have limited effectiveness. The last one was approved five years ago.
Skeptics of the drug warn that if the FDA approves AMX0035, it would be repeating the same mistake it made last year when it cleared a controversial Alzheimer's drug that critics said had little data showing it worked. They say the agency should wait to approve the ALS drug until the manufacturer completes a larger trial with 600 patients in late 2023 or early 2024.
AMX0035 is the latest drug to land at the center of an intense debate over how the agency should handle potential therapies for devastating diseases, such as ALS and Alzheimer's, that lack effective treatments. Faced with newly assertive patient communities with allies in Congress, the FDA has promised to be flexible in dealing with "unmet medical needs."
But flexibility is hard to define, and the agency increasingly finds itself embroiled in highly charged debates that pit patients demanding access to drugs that might slow an implacable disease against the FDA's mission to determine medicine's safety and effectiveness. Often, the evidence is far from clear-cut.
"We don't want the FDA to approve just anything, we don't want to drink bleach," said Brian Wallach, a former staffer in the Obama White House who was diagnosed with ALS five years ago at 37. Relying on an aide to "translate" his severely affected speech, he added, "We have done our homework and we know that this drug can help us."
Wallach said that AMX0035, while not a cure, could slow the disease while serving as a building block for the kind of combination therapies used for cancer and HIV. That could give him more time to spend with his wife and two daughters, the youngest of whom was a week old when he was diagnosed, he said.
In 2019, Wallach and his wife, who met on the first presidential campaign of Barack Obama, founded I Am ALS, a politically connected advocacy organization that has pushed hard for more funding for ALS research and the approval of AMX0035.
The debate over AMX0035 recalls the FDA controversy over the Alzheimer's drug, called Aduhelm. The agency approved the drug amid intense pressure from patients and their families, provoking a fierce backlash from critics. Medicare refused to cover the medicine for most patients and the drug collapsed in the marketplace.
Now, many ALS advocates and physicians worry that debacle could hurt AMX0035's chances.
Jinsy Andrews, director of neuromuscular clinical trials at Columbia University and an investigator in the 600-patient Amylyx study, said there is plenty of evidence enabling the FDA to approve AMX0035 now. And she argues there are big differences between Aduhelm and AMX0035.
While many Alzheimer's specialists opposed the approval of Aduhelm, the Amylyx drug has strong support from ALS physicians, she said. In addition, Aduhelm posed significant safety issues and its trials were ended prematurely because of a lack of efficacy, while AMX0035 is considered safe and reached its primary goal of slowing the decline of everyday functions, she said.
Those opposed to approval of AMX0035 now fear the FDA will clear another drug prematurely because of pressure from the ALS community. "Yes, people are suffering," Michael Abrams, senior health researcher at Public Citizen, acknowledged. "But it doesn't make it any better to give them crappy medications."
Reshma Ramachandran, an assistant professor of medicine and health services researcher at Yale University, agreed. "I want the FDA to say, 'Unless there is something very compelling, we are going to wait'" for the results of the larger study, she said.
The ALS medicine, the brainchild of Amylyx co-founders Joshua Cohen and Justin Klee, is made up of two components — an expensive prescription drug called sodium phenylbutyrate that is used to treat rare liver disorders and a nutritional supplement called taurursodiol — designed to protect neurons from destruction. The treatment comes in a powder that is dissolved in room-temperature water and drunk. It can also be administered through a feeding tube.
The development of AMX0035 was partly financed by the ALS Association, which put up $2.2 million from its "Ice Bucket Challenge." Amylyx has agreed to use sales proceeds of the drug to repay the organization 150 percent of its investment, the ALS Association said.
Because sodium phenylbutyrate is already approved, doctors may prescribe it off label to ALS patients. That's how Kowalski, the Boston ALS patient, gets it. He buys taurursodiol, also called TUDCA, on Amazon, in addition to taking the two ALS medications already approved by the FDA. Kowalski believes the combination is slowing his disease, though he acknowledges the illness affects different people in different ways.
Other ALS patients are pursuing similar DIY regimes. Wallach takes taurursodiol, which he imports from Italy. Both men said they want the FDA to approve the drug to provide access to everyone, and to ensure quality and insurance coverage.
The FDA declined to discuss AMX0035, saying it does not comment on drug applications. Amylyx said in a statement it is looking forward to Wednesday's meeting of FDA advisers, adding, "We believe AMX0035 is an important potential new treatment in the fight against ALS, and we are working against the ALS clock and the ALS community does not have time to wait."
In 2017, Amylyx launched a 24-week clinical trial of AMX0035 involving 137 patients — with two-thirds getting the medication, and the rest receiving a placebo — at more than two dozen medical sites. The goal was to test the drug's safety and its ability to slow a decline in essential functions such as walking, talking and cutting food.
Investigators concluded in fall 2020 that the drug was safe and slowed a worsening of the disease by 25 percent. A follow-on open-label study, in which all participants were offered the drug, showed that patients who received the treatment from the start of the trial lived a median of more than six months longer than those who did not.
Typically, the FDA expects drugmakers to submit "substantial evidence of effectiveness" provided by two well-designed clinical investigations. But the agency says a single trial may suffice if the study demonstrates a "clinically meaningful and statistically very persuasive effect" on extending survival or some other aspect of the disease. The agency also says it has the authority to be flexible in expediting treatments for life-threatening and severely debilitating illnesses.
In the spring of 2021, federal regulators told Amylyx it should not apply for approval until it completed the 600-patient study, sparking an outcry among ALS advocates. Five months later, the FDA changed its mind, giving Amylyx the green light to submit its application, which the company did last November. The FDA scheduled a meeting of its outside advisers on the application for late March of this year.
A few days before that session, the FDA issued a strikingly negative memo for its advisers. The AMX0035 data, it said, was "not exceptionally persuasive and there were analytical and interpretive issues," including an inadequate accounting for deaths during the study. "The data may not be adequate to serve as a single study capable of providing substantial evidence of effectiveness," the FDA said, urging Amylyx to keep moving ahead with its larger study.
During the March advisory committee meeting, ALS patients and their families pleaded for the drug's approval. But the independent experts agreed with the FDA that the evidence of effectiveness was insufficient, voting 6 to 4 against recommending approval.
ALS doctors disputed criticisms of the trial and said many of their patients would be dead by the time the larger study was completed.
"Waiting two to three years for results of a second study is essentially a death sentence," Merit E. Cudkowicz, chief of neurology at Massachusetts General Hospital, and Jeremy M. Shefner, a neurologist at the Barrow Neurological Institute, wrote in an editorial in April that sought to rebut the FDA's arguments. The scientists were involved in the AMX0035 trials.
In May, Amylyx published new analyses of its data that concluded AMX0035 extended median survival several months longer than originally thought, delayed first hospitalizations and reduced severe complications.
In early June, the FDA postponed its deadline for deciding on AMX0035 to Sept. 29, saying it needed more time to evaluate the new analyses. Soon afterward, Canada cleared the drug on a conditional basis, meaning the medication can be sold, but the manufacturer will be required to confirm the treatment is beneficial based on the results from the 600-patient trial.
The FDA does not have a conditional approval process that is identical to Canada's.
In July, the FDA decided to convene a second advisory committee meeting on the drug — the one scheduled for Wednesday — heartening the ALS community. But the mood darkened on Friday after the agency posted its latest memo for its advisers, expressing doubts about the new analyses and restating its concerns about the adequacy of the clinical trial.
On Twitter, Wallach urged his followers to send members of the advisory committee the editorial by Cudkowicz and Shefner and the FDA's 2019 guidance on ALS drugs that talks about the importance of flexibility and patient input.
And in the interview, Wallach said it is time to change the dynamic of ALS. Over and over, he said, newly diagnosed patients hear the same thing: "'There is no treatment, there is no cure.' If this drug is approved, doctors will be able to say, 'I don't have a cure but I am starting to have treatments, and they are safe.' "