Alzheimer's disease research faces one of its most pivotal moments this week.
The disease, which affects millions of patients and families, remains notoriously difficult to treat, having thwarted every effort by the world's most powerful pharmaceutical companies to slow or stop its progression. But over the last year, one drug meant to change the course of Alzheimer's has come within striking distance of approval.
Its biggest hurdle yet comes Friday, when a panel of experts tasked with evaluating new treatments for brain diseases will convene, and by the end of the day make a recommendation to the Food and Drug Administration about whether or not to approve the drug, called aducanumab. Though the FDA doesn't have to follow such recommendations, it usually does.
The months leading up to this meeting have been marked by intense debate as doctors, researchers and patients weigh the pros and cons of aducanumab becoming available. A positive opinion from the committee, followed by a green light from the FDA, would help address a desperate need for new Alzheimer's medicines.
Such an outcome could be a "shot in the arm" for Alzheimer's research, according to Eric Reiman, CEO of the Banner Alzheimer's Institute. The most recent treatment to be approved came in 2003, for a combination drug that helps with memory but not the underlying cause of the disease.
It would also be a much needed win for the drug's developer, Biogen, validating a risky decision to bet heavily on aducanumab while competitive threats chip away at its business.
Yet, some fear an approval could have unintended, negative consequences. Drugs that work in the same way as aducanumab have failed again and again in clinical testing, prompting questions — and, at points, criticism — about whether time and resources would be better spent investigating other potential therapies.
There are concerns, too, that aducanumab might not actually be effective, or effective enough to bring substantial improvements to patients' daily lives. If those doubts persist, aducanumab could be met with pushback from the regulators reviewing it and the insurance companies deciding how to cover it, which then might put added obstacles in front of patients looking to access what would likely be an expensive drug.
"I would love to see an effective therapy approved," said Michael Sherman, chief medical officer for the New England-based insurer, Harvard Pilgrim. "But I think there is also skepticism, given the general history as well as the background with this drug, about whether it will be approved and to what degree it will be efficacious."
The skepticism surrounding aducanumab stems from two large clinical studies that were supposed to show it works as intended.
The studies, titled EMERGE and ENGAGE, were identically designed. Each enrolled over 1,600 patients with early Alzheimer's disease, and tested a low dose and a high dose of aducanumab against placebo to see whether patients performed better on a cognitive test after a year and a half of treatment.
By March 2019, an independent committee that was monitoring the studies had concluded neither was likely to succeed, leading Biogen to stop them early. Aducanumab, it seemed, would join the long list of Alzheimer's drugs shelved after too many setbacks.
But then, seven months later, Biogen made an unprecedented reversal. The company announced it would submit aducanumab for approval after additional analyses with more data showed EMERGE had actually succeeded, with patients on the high dose performing significantly better than those in the placebo arm.
ENGAGE, though still a negative trial after further analysis, had data that supported the findings in EMERGE, Biogen claimed.
The company would later propose one possible reason for two almost identical studies having such divergent results: that EMERGE had more patients who were on the high dose for longer amounts of time. Researchers who spoke to BioPharma Dive said that theory is plausible.
Still, Biogen's analyses and the various tweaks made to its studies have raised serious doubts about the reliability of the data. Stakeholders expect the company's defense to be a point of discussion at Friday's meeting.
"You have one positive trial, and you have another trial that's a little bit more difficult to interpret. And I think that's what the committee is really going to have to deal with: how to interpret that ENGAGE trial," said Howard Fillit, chief science officer of the Alzheimer's Drug Discovery Foundation.
In the meantime, the Alzheimer's community remains split on the aducanumab data and Biogen's rationale for pursuing approval. Analysts at the investment bank Stifel recently wrote there's a "significant binary divide" among the experts they've spoken to, with some viewing EMERGE as positive and others taking a more cautious stance.
Importantly, Biogen has had only limited success convincing people that the cognitive test results seen in EMERGE can translate to a noticeable benefit on patients' daily lives.
"The value is less about how you score on a cognitive test, and more what it means for people's ability to function," Sherman of Harvard Pilgrim said. "And if we don't get data on that, it's going to make the discussion around how to cover this — what to pay for, and under what circumstances — that much harder."
Efficacy might not be the only sticking point, either. In both trials, about one in five patients on high-dose aducanumab experienced a kind of brain swelling that caused microhemorrhages. While healthcare providers can manage such events relatively well, the committee could still be uneasy about the safety of the drug.
FDA staff, meanwhile, weren't overly concerned in briefing documents published Wednesday, noting that they would expect any label for the drug to communicate such risks effectively.
Alongside data presentations, Friday's meeting will allow some patients and their families the chance to speak about aducanumab and what its approval could mean to them.
For Tom Hillertz, 63, who was diagnosed roughly two years ago, treatments like aducanumab offer hope of getting back the pieces of life that were stolen by Alzheimer's.
The disease forced Hillertz to leave his "dream job" of 16 years as pastor of his church in Champaign, Illinois. He said it's been hard going from busy days at the church to an empty calendar. And while there is a silver lining in having more time to spend with his wife, children and two-year-old granddaughter, his family can't help but to worry. Hillertz takes medications to help with some of his symptoms, but they carry "really difficult" side effects, he said.
There are also the issues of insurance coverage and paying for the medications, which have been challenging.
"I always called Alzheimer's a thief," Hillertz said. "It steals not only from the patient, which it steals a lot from, but also from other people — my wife, all the members of the congregation."
The dire need for treatments, for Hillertz and millions of others, makes the stakes for Friday's meeting that much higher.
Additionally, it raises the question of whether the FDA, under pressure to get some disease-modifying drug to patients, will base its decision on more than data. Notably, the agency has been scrutinized in the last few years for approving drugs for a rare neuromuscular disease that showed limited effects in clinical testing.
Analysts, though, have argued it's an apples-to-oranges comparison between those drugs and aducanumab, in part because of the sheer number of patients who could conceivably get aducanumab should it come to market. Brian Skorney, an analyst at Baird who's doubted the drug and its approval chances, believes the agency's review will be "precedent-setting."
Researchers who spoke to BioPharma Dive said they have confidence the FDA's approval decision will be rooted in data. That decision is expected by March 2021 at the latest.
Yet, the committee's vote is also likely to factor in.
The panel will have at least 10 members, most of whom are professors of neurology and medicine at large U.S. universities. Until recently, another researcher was included as well. But David Knopman, a professor of neurology at Mayo Clinic, has been recused. Knopman helped conduct clinical trials of aducanumab and has been critical of the drug; this month, the journal Alzheimer's & Dementia published a paper co-authored by Knopman, which argued the data from EMERGE and ENGAGE do not support the conclusion that aducanumab has clinical benefits.
However, Knopman and his co-authors did write that there is enough evidence to warrant running a third large trial testing high-dose aducanumab. It's possible, according to Fillit, that other members of the committee come away from Friday's meeting with a similar stance.
"If the committee declines to approve the drug, I think what they'll probably ask for is a third trial. But, in my mind, I don't see any way where the committee comes out and says, 'This is a reject. Don't come back. Forget the whole thing.'"
The committee vote could be consequential for Alzheimer's research as well.
Aducanumab is an engineered antibody meant to bind to clusters of a protein called amyloid-beta. It's a byproduct of the "amyloid hypothesis," a theory many researchers subscribe to, which holds that these sticky protein clusters destroy neurons and serve as the main cause for functional decline in Alzheimer's patients. To treat the disease, therefore, this accumulated protein needs to be broken down or flushed out.
While amyloid-targeting drugs have received the lion's share of research funding, time and again they've failed in clinical testing. The last few years alone have seen high-profile setbacks from Roche, Merck & Co., Amgen, AstraZeneca, Eli Lilly and other drugmakers, each followed by calls from some in the research community to put more attention elsewhere.
But, should the committee issue a positive opinion for aducanumab, Reiman of the Banner Institute said he doesn't think it will stifle non-amyloid drug development. Neither does Fillit.
Rather, they envision aducanumab's success fueling the broader field of Alzheimer's research. On that front, scientists have been looking into another protein called tau that they believe is tied to neurodegeration, as well as into therapies that target a gene known to be a risk factor for Alzheimer's.
Conversely, Reiman and others said they wouldn't expect a negative vote to sink the amyloid hypothesis. Reiman characterizes amyloid as a kindling that starts the Alzheimer's fire. And while patients will likely need other treatments that can extinguish the fire if and when it ignites, drugs like aducanumab may still help combat the starter materials.
"I can't stress how historical it is, the committee meeting on Friday and the FDA ruling next year. But, it's just one step, it's not a magic bullet," said Eliezer Masliah, director of National Institute of Aging's Neuroscience Division. So, independent of the committee's vote, "the research continues."
Editor's note: This article was updated to include mention of documents published Wednesday by the Food and Drug Administration.