“A Period of Rapid Change.” How the ALS Association Shepherded a New Treatment to Market

In the summer of 2014, the ALS Ice Bucket Challenge went viral on social media, prompting people all over the world to dump ice water on their heads to promote awareness of amyotrophic lateral sclerosis (ALS). Within six weeks, the ALS Association, which funds research and advocates for people with the disease, received $115 million in donations.

In the following years, ALS Association directed a total of $2.15 million in funding raised during the Ice Bucket Challenge to develop Amylyx Pharmaceuticals’ Relyvrio, a drug that is designed to slow disease progression. It earmarked $750,000 for research and $1.4 million for clinical trial support, providing Amylyx with access to trained personnel and trial sites.

The association also launched an advocacy campaign making the case for the drug. These efforts intensified this fall after an FDA panel voted against the treatment in March, citing its ineffectiveness, before reversing course six months later, prompting some experts to argue that the committee acquiesced to advocacy groups. The drug’s proponents countered that the potential benefits of approving Relyvrio outweighed the risks, as most people with ALS die within three to five years after symptoms first appear.

The FDA approved Relyvrio in late September. The announcement, which capped an eight-year process beginning with the Ice Bucket Challenge, underscores how a mix of private dollars earmarked for research and advocacy can shepherd a treatment to market in a field where patients have limited options. “We’re funding a lot of infrastructure that touches more drugs,” the ALS Association’s chief mission officer, Neil Thakur, told me. “Relyvrio happened to be the first, but I don’t think that it’s going to be the last treatment that we’re involved with.”

An ALS overview

ALS is a progressive neurodegenerative disease that affects nerve cells in the brain and spinal cord. Over time, the disease adversely impacts the patient’s ability to speak, swallow, move and breathe. In 90% to 95% of all cases, there’s no family history of the disease or presence of a genetic mutation linked to ALS. Military veterans are more likely to be diagnosed with ALS than the general public, although researchers do not know why this is the case. About 30,000 people in the U.S. have the disease.

The ALS Association, meanwhile, was founded back in 1985. For the fiscal year ending January 31, 2022, it had $91 million in net assets, $39.8 million in total revenues, and $44.6 million in expenses. Of that latter amount, $14.2 million — or 38% of the total — flowed to research, followed by patient and community services ($11.8 million), public and professional education ($5.7 million), fundraising ($8.4 million) and administration ($4.5 million).

Thakur has led the ALS Association’s research, care services and advocacy programs since 2018. Prior to joining the association, he served in the National Institutes of Health (NIH) Office of the Director and as assistant director of Health Services Research and Development at the Department of Veterans Affairs.

The Ice Bucket Challenge’s impact

In terms of sheer dollars, the Ice Bucket Challenge was a game-changer. A 2019 report by consulting firm RTI International found that funding from the Ice Bucket Challenge allowed the ALS Association to commit $81.2 million across 275 research grants in the U.S. and $8.5 million internationally between 2014 and 2018. The report also found that since the challenge, the NIH invested $415.9 million in researchers funded by the association, including $208.6 million in follow-on funding. See the association’s own account of its Ice Bucket Challenge commitments here.

The association and its partners realized some significant wins in the advocacy space, as well. In 2020, the ALS Disability Insurance Act became law, waiving a five-month waiting period that previously applied to people with ALS looking to access Social Security Disability Insurance and Medicare benefits — since the disease has no cure and progresses rapidly.

“In almost every complex disease I’ve worked in — and certainly in ALS — there’s always two disease systems that you need to work with,” Thakur said. “One is, in our case, motor neuron. It’s a biological system. But the other disease system is the American health system, and that never seems to come into the conversation when we talk about finding new treatments and cures. And so I think that if we take that more holistic approach, there will be a lot of people who will be a lot better off than they are today.”

A “livable disease” by 2030

While the ALS field benefited from the torrent of funding that came with the Ice Bucket Challenge, that was eight years ago. Thakur said there’s still “not enough money in this philanthropy space to get the treatments we need, so we have to be really clear about our partnership strategy and our shepherding approach.”

When the association maps out its research strategy, leaders look at what the NIH and its philanthropic partners are funding. “In a lot of cases, we collaborate and joint-fund proposals,” Thakur said. “We collaborate on data archives, resource sharing — and when we’re not co-funding, we’re sharing notes, because that’s the only way to be as efficient as possible.”

Last year, the association laid out its plan to make ALS a “livable disease” by 2030. The hope is that in eight years, anyone with ALS will have access to life-extending treatments and experience fewer physical, emotional and financial burdens. The plan also envisions a future when researchers can identify risk factors to prevent people from getting ALS.

The association’s plan acknowledges how much we still don’t know about the condition. “We’re going to have to make this fundamental change in the experience of people living with ALS without having a full and clear understanding of how it works,” Thakur said. In the absence of that, the plan adopts what Thakur calls “radical incrementalism,” where multiple small changes can lead to a transformative outcome. To this end, the plan calls for funding for more clinical trials and research, improving and delivering state-of-the-art care, and preventing or delaying harms associated with the condition.

“One thing I discovered when I came into this space is that there’s a lot of energy around basic science and drug development, but other parts, like prevention or addressing the complications that come with ALS, like the poverty and the isolation, weren’t getting a lot of attention,” Thakur said. “With a more holistic plan, we think we can get better impacts faster.”

Ramping up advocacy efforts

All of which brings me back to the FDA’s approval of Relyvrio. Since the ALS Association receives support from pharmaceutical companies, it doesn’t take a stance on the effectiveness of a treatment without first soliciting independent advice. “We asked Amylyx to give us data under a confidentiality agreement and then asked independent reviewers to look at the data, which they did, and we relied on their advice,” Thakur said.

The ALS Association also recoups much of the money it grants out to pharmaceutical companies that develop successful drugs. The association’s research contracts have “payback provisions” in which the grant recipient (Amylyx, in this case) reimburses back the grant amount — and then some — should the FDA approve the drug. The association then funnels the proceeds toward more research. “We were clear about those payback provisions on our website when we talked about our role with Amylyx,” Thakur said.

In November 2020, the association and the advocacy group I AM ALS submitted a petition with over 50,000 signatures to the FDA calling on the agency and Amylyx to make and approve Relyvrio as soon as possible. In the ensuing months, association representatives met with FDA officials and organized a “We Can’t Wait Action Meeting” in May 2021, during which ALS patients shared their experiences with the agency.

Then, in March of this year, the FDA’s Peripheral and Central Nervous Systems Drugs Advisory Committee (PCNSDAC) voted 6-4 that Amylyx’s trial did not show that Relyvrio was effective. ALS patients flooded the FDA commissioner’s office with emails challenging the committee’s determination. ALS clinical scientific leaders spoke out in defense of the drug. And ALS Association President and CEO Calaneet Balas issued a statement saying, “The FDA has a choice to make — whether it will approve a drug that has been proven safe that will help people living with ALS today, or whether it will delay approval and require more evidence while more people with ALS die.”

“Things are moving fast”

In June, Canada conditionally approved Relyvrio under the name Albrioza. The PCNSDAC held its second public meeting on the drug three months later. Prior to the meeting, the association filed comments with the FDA arguing that “the safety and efficacy evidence are sufficient within the context of this disease.”

Dr. Billy Dunn, who directs the FDA’s Office on Neuroscience, told committee members that for serious diseases like ALS, “the maximum degree of regulatory flexibility is operational.” ALS patients desperate for new treatment options testified that they would be willing to try the drug. Amylyx reps said that if the FDA approved Relyvrio and the Phase 3 trial results proved inconclusive, they would consider pulling the drug from the market.

The PCNSDAC then voted again, this time 7-2 in favor of approval. Reflecting on the decision, Holly Fernandez Lynch, an assistant professor of medical ethics and health policy at the University of Pennsylvania, told NPR, “The very cynical version of this is that there was some kind of goal of manipulating the advisory committee to vote in a different way.” (The vote came a few months after three members of PCNSDAC resigned from the committee after the FDA approved the Alzheimer’s drug Aduhelm, citing unconvincing data.)

The FDA approved Relyvrio on September 29. Amylyx is expected to complete the Phase 3 trial in late 2023 or early 2024, putting a bookend on a saga that began, in a sense, almost a decade earlier, following a fundraising challenge that went viral.

Before we signed off, Thakur asked me if I had heard of Moore’s Law, which claims that roughly every two years, the number of transistors on microchips will double. I told him I had. Thakur then asked me if I’d heard of “Seroom’s Law.” After I asked him to repeat the question, I told him I hadn’t.

He explained that “Seroom’s Law” — that’s “Moore” spelled backward — posits that drug discovery is becoming slower and more expensive due to rising R&D costs and the challenge of bringing a treatment to market when it’s only an incremental improvement over existing options. It’s a trend that’s manifesting itself in fields like psychiatry and antibiotics, where successive generations of drugs have yielded similar levels of effectiveness.

“We are having the opposite issue in the ALS space,” Thakur said. “We’ve gone from a long period of relatively stable treatment to a period of rapid change, which means more people to serve, more people to train, and more payers to educate. Growth brings its own challenges, and we need to be prepared, because things are moving fast.”

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