FDA approves first ALS drug in 5 years after pleas from patients

The Food and Drug Administration on Thursday overcame doubts from agency scientists and approved a fiercely debated drug for ALS, a move that heartened patients and advocates who pushed for the medication but raised concerns among some experts about whether treatments for dire conditions receive sufficient scrutiny.

“It’s a huge deal,” said Sunny Brous, 35, who was diagnosed with ALS seven years ago after she had trouble closing her left glove while playing softball. She plans to begin taking the drug as soon as she can.

“Anything that shows any amount of efficacy is important,” the resident of Pico, Tex., added. Even a small change, Brous said, “might be the difference between signing my own name and someone else signing it for me.”

The newly approved therapy, which will be sold under the brand name Relyvrio, is designed to slow the disease by protecting nerve cells in the brain and spinal cord destroyed by ALS — amyotrophic lateral sclerosis. The ailment gradually paralyzes patients, robbing them of their ability to walk, talk and eventually breathe. Patients typically die within three to five years, though some live much longer with the condition. It is sometimes called “Lou Gehrig’s disease,” for the renowned baseball player diagnosed in 1939.

In a memo about the approval, the FDA said the drug showed “a statistically significant treatment benefit” and met its clinical-trial goal, a slowing of decline in patients with ALS. It also said the drug provided a survival benefit and that there were no safety concerns.

The agency acknowledged “limitations” to the findings that resulted in some uncertainty about the drug’s degree of effectiveness but said that was “acceptable in this instance” and that the use of “regulatory flexibility is appropriate.”

Officials from Amylyx, the Cambridge, Mass., biotech company that makes the drug, said they plan to move as quickly as possible to make the drug available. They said a final decision on the price has not been made.

Patients, advocates and ALS specialists hailed what they called a landmark approval, saying the drug represents the kind of modest advance needed to make progress against the disease. About 30,000 people in the United States have ALS, with 6,000 new cases diagnosed every year. Two other drugs are approved for the ailment but have extremely limited effectiveness.

Some drug policy experts, however, said insufficient evidence exists that the drug works. The FDA cleared the medication based on a single trial with 137 patients plus follow-up data and analyses. A trial with 600 patients won’t be completed until late 2023 or early 2024.

“There is some evidence to support the efficacy of the product, but I don’t think it hits the bar that the FDA typically requires,” said G. Caleb Alexander, an internist and epidemiologist at the Johns Hopkins Bloomberg School of Public Health who serves on the FDA advisory committee that reviewed the drug. “How much should the FDA lower the bar — if at all — for products for a devastating disease” that lacks effective treatments?

Diana Zuckerman, president of the of National Center for Health Research, a think tank, agreed.

“How many ineffective ALS drugs do we need?” Zuckerman said. “It would be better to have one that has been proven to make a meaningful difference to live longer.”

But Jinsy A. Andrews, an associate professor of neurology and director of neuromuscular clinical trials at Columbia University, applauded the approval and said she plans to start prescribing the drug as soon as it is available. Other ALS specialists agreed.

“I see patients living with this disease, and I diagnose them every day,” Andrews said. “So to have another therapy for the tool kit is helpful.” Andrews is an investigator in the large trial for the drug now underway.

AMX0035, as the drug has been called during development, is the first new therapy approved for ALS in five years, consists of two components - a prescription drug called sodium phenylbutyrate used to treat rare liver disorders and a nutritional supplement called taurursodiol. The drug comes in a powder that is dissolved in water and can be swallowed or given through a feeding tube.

Two Brown University undergraduates came up with the idea for the therapy almost a decade ago, initially thinking it would be for Alzheimer’s disease. Justin Klee and Josh Cohen went on to found Amylyx.

ALS advocates said the approval shows the importance of patients and advocates getting involved in efforts to bring drugs to the market.

“We still have a lot of work to do to cure ALS, but this new treatment is a significant step in that fight,” said Calaneet Balas, president and chief executive of the ALS Association.

In 2014, the organization raised $115 million in six weeks from the Ice Bucket Challenge and provided $2.2 million of that to help pay for testing AMX0035. The drug is the first funded by the organization to receive FDA approval. Amylyx has agreed to use proceeds from sales of the medication to repay the organization 150% of its investment.

In 2019, Brian Wallach, a staffer in the Obama White House, and his wife founded a group named I AM ALS after Wallach was diagnosed. That organization made getting the Amylyx drug onto the market a priority.

The two groups pressed the FDA to be faster and more flexible in clearing ALS drugs, saying patients would accept treatments with increased safety risks in return for even a small benefit — a viewpoint incorporated into the agency’s 2019 guidance to the pharmaceutical industry on developing ALS therapies. In 2020, the two ALS organizations submitted more than 50,000 signatures to the FDA calling for approval of AMX0035.

In a do-it-yourself effort, some ALS patients in the United States already are taking the ingredients of AMX0035. Because sodium phenylbutyrate was already approved, doctors may prescribe it off-label to ALS patients. The nutritional supplement taurursodiol, also called TUDCA, can be bought online.

Steve Kowalski, 58, who lives in Boston and takes the components of AMX0035, along with the other two approved ALS drugs, credits the regimen for slowing his deterioration. With careful planning and the help of his three adult children, he can still go see his beloved Red Sox but is exhausted when he gets home, he said.

Kowalski welcomed the FDA action on the drug. He prefers to get a high-quality, approved version of the medication rather than having to buy a supplement online.

The company’s application to the FDA was based largely on a single 24-week clinical trial and follow-up data from an “open label” study in which all trial participants were offered the drug. Amylyx said the data showed the drug was safe, prolonged survival by several months and slowed by 25% a decline in essential functions, such as walking, talking and cutting food.

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 be sufficient if the study demonstrates a “clinically meaningful and statistically very persuasive effect” on extending survival or some other aspect of the disease.

In March, however, the FDA staff issued a mostly negative assessment of the clinical trial and the drug, and its advisers agreed, voting 6-4 to recommend against FDA approval. Patients and advocates flooded the agency with more than 10,000 emails pleading for approval, advocates said.

In a rare move, the FDA held a second advisory meeting this month to consider additional analyses submitted by the company. Once again, the FDA staff suggested in a memo that there was not enough evidence of effectiveness to approve the drug.

But the tone of the meeting differed markedly from that of the first session. At the outset, Billy Dunn, director of the FDA’s Office of Neuroscience, acknowledged the data for the drug raised numerous questions, but also stressed the “tremendous unmet medical need” for ALS and the seriousness of the disease. He said the agency had the legal authority to be flexible. And in a highly unusual move, Dunn asked the Amylyx officials whether they would voluntarily withdraw the drug from the market if the large trial failed; they said they would.

With a few of the outside experts on the advisory committee changing their position, the panel recommended approval 7-2.

The debate over the drug has echoes of the battle over Aduhelm, the controversial Alzheimer’s drug approved by the agency in June 2021. Critics said there was scant evidence of efficacy for that medication, and Medicare declined to cover it except in trials. The drug collapsed in the marketplace, never gaining traction with patients or physicians.

But ALS doctors insist the ALS drug is different. It reached its primary goal in the trial, even if the benefit was modest, they noted.

Canada recently approved AMX0035 on a conditional basis. Amylyx can sell the drug there, as long as the treatment’s benefits are confirmed by the larger trial. But the FDA’s approval processes are somewhat different from Canada’s.