Shelly Hoover is a bit of an anomaly. The 57-year-old veteran and former middle school principal has ALS, a rare disorder that causes her nerves to break down, taking with them the ability to walk, talk, eat and, eventually, breathe. The disease is fatal, typically within two to five years after symptoms start to show. Hoover, though, has lived with it for almost a decade.
Until recently, the Food and Drug Administration had approved just two main medicines for ALS, or amyotrophic lateral sclerosis, which affects roughly 30,000 people in the U.S. These medicines have been shown to help patients, but doctors consider the benefits offered by each to be small.
In September, the FDA cleared a third drug that’s now sold as Relyvrio. In the clinical trial that led to its approval, Relyvrio appeared to slow the functional decline associated with ALS. The trial also found patients treated with the drug lived a median of five months longer than those given a placebo.
While Relyvrio’s benefits have been called modest, the drug has become a vital source of hope for many ALS patients. “This is a step to keep more of us alive longer until we find more effective treatment,” said Hoover. Because of her advanced disease, she uses an eye-tracking device to speak.
But alongside this optimism are fears that accessing Relyvrio could be difficult, as it has been for other expensive rare disease treatments. Patients and doctors recall how insurance companies were hesitant to cover one of those earlier ALS medicines, Radicava, which was approved in 2017 and is now priced at north of $170,000 per year for an oral version. According to Hoover, who does advocacy work with the group I Am ALS, her healthcare through the Department of Veterans Affairs initially denied Radicava coverage because she didn’t meet certain criteria. She was able to later successfully appeal that decision.
For a disease like ALS, which often progresses rapidly, any delays to treatment are acutely felt. In only a few months time, patients can lose the ability to perform daily functions like writing legibly, cutting up food or dressing without help.
To that end, Relyvrio’s developer, the Massachusetts-based Amylyx Pharmaceuticals, has established an assistance program to address some of the obstacles to access and get patients on treatment faster.
“We have a responsibility to get it to people quickly,” said Justin Klee, who, along with partner Josh Cohen, co-founded Amylyx and now jointly serves as its chief executive. “We know how precious time is for people with ALS, and so every week, every day, every hour matters.”
Still, Relyvrio is expensive, too. Amylyx set its price at $158,000 per year of treatment, putting patients and their caregivers on alert.
Affordability “is a major concern among the community,” said Layne Oliff, 63, a pharmacist by training and former owner of a healthcare marketing firm who started noticing symptoms of ALS in 2012 but wasn’t formally diagnosed until two years ago.
Oliff, who has been approved for Relyvrio therapy, said he was recently told the copay for his first month of the drug would be around $3,800. The amount would go down in subsequent months, but Oliff still expects to hit his insurance plan’s $7,400 cap for annual out-of-pocket costs quickly.
“I’m fortunate, in that I can afford to buy the therapy,” he said. “A lot of people can’t.”
Hoover, meanwhile, has been bracing for a battle with Veterans Affairs over Relyvrio prescribing limitations. The VA this month released criteria it will use when deciding whether a patient should get Relyvrio and, while those criteria could have been stricter, Hoover anticipates many patients will nevertheless be denied access.
“We are desperate for treatment and willing to fight,” she said.
A groundswell of interest
In 2013, the same year of Hoover’s diagnosis, Klee and Cohen were just getting Amylyx off the ground.
At the time, the two were undergraduate students at Brown University completing degrees in neuroscience and biomedical engineering. They had been investigating ways to treat diseases in which nerve cells decay and die, and ultimately found promise in a pairing of two chemicals that, research suggested, might protect those cells.
One of the chemicals, known in shorthand as TUDCA, can be bought online and is used by some ALS patients as a supplement.
Klee and Cohen were able to quickly usher their drug through preclinical studies and into human testing, beginning a trial of about 140 ALS patients in mid-2017. Results were published in The New England Journal of Medicine in September 2020, and served as the primary evidence to support approval two years later.
While relatively fast, Relyvrio’s path to market was also winding. After those positive results were released, Amylyx met with FDA officials who, according to the company, said another study would be needed before the drug could be filed for approval. That decision sparked intense pushback from patient advocacy groups, which criticized the agency for not working hard or fast enough to make new ALS treatments available.
Just a few months later, Amylyx said the FDA had reversed course and encouraged it to submit Relyvrio while conducting that additional study.
The FDA also made the highly unusual choice to twice convene a group of outside experts to weigh Relyvrio’s merits. Most drugs up for approval don’t undergo even one of these so-called advisory committee meetings.
In the first meeting, which took place this past March, FDA staff were critical of the ways Amylyx collected and analyzed data, and the committee narrowly sided against the drug.
Six months later, the second meeting had the opposite outcome. Amylyx had gathered more supportive data, and a majority of the experts ended up voting in the drug’s favor. At the request of a top FDA official, Amylyx agreed in the meeting to pull Relyvrio from the market if confirmatory testing didn’t read out positive.
Now, with approval granted, demand for Relyvrio has been high in ALS treatment centers across the country.
“Every patient that I see wants to take the drug, and many new patients have already heard about it even before I bring it up,” said Cathy Lomen-Hoerth, director of the ALS Center at the University of California, San Francisco, which sees around 400 patients.
In North Carolina, the ALS clinic at Duke University has already processed more than 100 applications for the drug, according to director Rick Bedlack, who has consulted with Amylyx in the past.
“We've had tremendous interest, bigger interest in this than anything I've seen,” he said. Becklack now expects a majority of the 500 patients his clinic follows to go on Relyvrio within the next six months.
Yet, at Duke and elsewhere, initial excitement has stretched resources thin.
To help patients get access to Relyvrio, Amylyx has assembled a special team to assist doctors in obtaining insurance coverage. Patients and their healthcare providers fill out an application and send it to Amylyx, which investigates what insurance will cover, relays that information back and offers support when out-of-pocket costs are high. If coverage is denied, Amylyx provides templated letters of appeal that doctors can use.
The process takes about six weeks, according to Bedlack, who said the work related to these applications has inundated his clinic.
While bureaucratic steps are commonplace in the highly fractured U.S. healthcare system, which is home to thousands of different insurance plans, they’re especially impactful in diseases like ALS where patients are racing against the clock.
Jennifer Scalia, a nurse practitioner and associate clinic director at the Sean M. Healey and AMG Center for ALS at Massachusetts General Hospital, said she worries about the “cost of fighting” with payers.
“It’s a big issue,” Scalia said, “being on hold with the insurance companies, doing the authorization and then the appeal, all because the insurance companies don’t appear to understand ALS.”
“It’s a big chunk of time that’s taking nurses away from helping patients.”
Patients and doctors note how the application process for Relyvrio shares similarities to that of Radicava when it first came to market. Stephen Scelsa, a neurologist at Mount Sinai Health System in New York and director of its ALS center, called them both “equally laborious.” He estimates that his center has sent about 30 requests through Amylyx’s program, but, as of early December, he hadn’t been notified of any approvals from insurers.
A tricky healthcare system
Still, others have found the experience with Relyvrio smoother than with its predecessor. Lomen-Hoerth said she hasn’t run into any major issues getting patients on the drug, while Scalia and her team have seen “a good number of approvals.” In general, healthcare providers say they’ve been impressed by Amylyx’s handling of the drug launch.
“It took a long time to actually get Radicava into the hands of patients. If I remember right, it was probably five or six months,” Bedlack said. “This process, so far, seems a lot more streamlined.”
There have been some rejections, however. A few applications from the Healey Center were denied, according to Scalia, because patients hadn’t yet taken Radicava or the other FDA-approved ALS medication, riluzole.
Such requirements, sometimes known as “step therapy,” are used across a range of diseases by insurers, which argue that they lower costs for patients. Step therapy remains controversial, though, and in the case of ALS contradicts what many experts believe to be more appropriate treatment approaches.
“The intent is to [take the available medications] all at the same time. I don't know if insurance knows that yet,” Scalia said.
There are concerns, too, that some payers will enact strict criteria regarding which patients are allowed to take Relyvrio. For example, the division of the VA that manages pharmacy benefits lists seven exclusion criteria, including if a patient has certain respiratory or heart problems or comorbidities like Parkinson’s disease and dementia.
The committee that decides the VA’s National Formulary believes these finalized criteria are “written in a manner that will allow for equitable access to Relyvrio for Veterans with ALS across the system who are clinically appropriate for use.”
Major commercial insurers, including Aetna, UnitedHealthcare and Cigna, did not respond to repeated requests for comment.
In an email, The Centers for Medicare and Medicaid Services said it is "continuing to review the recent FDA decision and will monitor how the product is used in the patient population over time." An agency spokesperson added that, based on current information, Relyvrio would be considered a Medicare Part D drug "if used for a medically accepted indication.”
“For a plan to say, ‘You need to try step therapy first,’ it’s bad medicine."
The extent to which insurers cover Relyvrio will directly impact out-of-pocket costs, which, healthcare providers say, is a near constant issue when treating ALS.
“ALS is a very expensive disease; there are a lot of things that insurance does not cover — straight down to help in the home,” Scalia said. “Spending more money on a medication that slows things but doesn’t stop, doesn’t reverse them, I find a lot of people have to weigh what makes most sense for them.”
Perhaps further complicating this choice is that Relyvrio’s merits remain up for debate to some experts. Caleb Alexander, an associate professor at the Johns Hopkins University Bloomberg School of Public Health and an FDA advisory committee member, voted against the drug during both meetings because he didn’t feel the evidence backing it was substantial enough.
He and others have also questioned whether Amylyx would indeed pull its drug from the market if confirmatory tests fail.
With that debate ongoing, some patients may be forced to make difficult decisions about whether the potential benefits of Relyvrio, with its six-figure price tag, are worth the costs.
“These are extremely expensive drugs, and that's just the nature of our healthcare system,” said Scelsa, who has advised and received grant funding from Amylyx in the past. “In a rare disease, [developers] have to charge lots of money to make back their investment.”
“It's not just about one drug or one specific piece of the puzzle, it’s about the fact that we need to continue to advocate for better coverage for our patients,” said Sabrina Paganoni, a physician scientist at the Healey Center who also led that key clinical trial which supported Relyvrio’s approval. Paganoni has received research grants from Amylyx and her center has consulted with the company.
To Lomen-Hoerth, one way to lower the cost barrier would be a program that covers copay expenses for a couple months. A program like that, she said, could give patients with high copays time to appeal to or change their insurance, without sacrificing access to Relyvrio.
Amylyx does have a program in place to help patients with their co-pays, but it not available for those on government insurance.
A meaningful new therapy
Amylyx executives believe the questions surrounding costs and access will be ironed out over the coming months.
"Very, very few insurers at this point have formal coverage plans. Everything is done as a one-off," Cohen said. "So you can imagine a system where everything is done as a one-off, there’s just a little bit of complexity, friction in the early days."
How well Amylyx navigates that complexity will have big implications. With no other medicines in human testing, the company's near-term future hinges on the use of Relyvrio. Consensus among Wall Street analysts is that Relyvrio at its peak will generate $900 million to $1 billion in annual sales.
For some patients, the drug, while far from a cure, may offer priceless benefits.
“These are people who have a fatal disease,” Paganoni said. “So anything that's new and can provide even a little bit more time with their families, even a little bit more time with good function, that's certainly something. It's really a matter of life or death.”
Since his diagnosis, Oliff’s symptoms have become more severe. His speech is slowing down, his arms are weaker and he now uses a wheelchair because of increasing balance issues. He can no longer do the trail running, hiking and swimming that he enjoyed just a few years ago.
Oliff previously took what he calls “do-it-yourself” Relyvrio, by buying TUDCA online and having the drug’s other chemical compounded at a local pharmacy. He said he believes the combination has helped stabilize his disease.
Hoover acknowledges that, given her advanced disease, she may not respond to Relyvrio treatment. But she wants to try. She’s motivated by her husband, Steve, two children, David and Lacey, and their grandchildren, all of whom followed Hoover across the country when she and Steve moved from California to North Carolina two years ago.
“I know it’s not a cheap drug, but this is one more little candle of hope that the ALS community has, which they haven't had in the past,” Steve Hoover said. “So I say it's worth fighting for.”