The Food and Drug Administration approved a new drug Aduhelm for the treatment of Alzheimer's disease June 7 through its accelerated approval pathway. While some patient advocacy groups and creators of the drug — including several University researchers — see the drug’s approval as a step forward, Aduhelm’s price and approval against the recommendations of advisors have garnered nationwide criticism and sparked a federal investigation into the communications between FDA staff and Biogen, the biotechnology company that developed the drug.
More than six million Americans suffer from Alzheimer's disease, a form of slowly-progressing dementia for which there is no cure. Existing drugs that treat Alzheimer’s mediate symptoms of the disease but do not slow down or reverse the disease process. Since the approval of the last AD drug 18 years ago, patients and healthcare workers alike have waited for stronger treatment options to combat this devastating disease.
As the Baby Boomer generation enters the prime age range susceptible to the disease, the development of effective treatments is “imperative,” said University Professor of Neurology Brian Ott, who served as a principal investigator on several of the Aduhelm trials.
Stephen Salloway, professor of neurology at the Warren Alpert Medical School, also served as a principal investigator for Aduhelm phase one and phase three trials at Butler Hospital.
The new drug Aduhelm consists of monthly intravenous injections of aducanamab, an antibody molecule that fights off the build-up of amyloid beta proteins in the brain — a hallmark feature of AD. Aduhelm is the first drug on the market to directly target these plaques with the goal of slowing disease development in its early stages.
Aduhelm “really represents a turning point in how we approach the treatment of Alzheimer's disease,” Ott said. “This is the first time that physicians will be able to prescribe a disease-modifying drug for Alzheimer's.”
Salloway said that the development of the drug “opens a new treatment era” for Alzheimer’s.
But the FDA’s decision to approve the drug has raised a wave of concerns about its effectiveness, cost and the legitimacy of the FDA’s approval process.
FDA Approval and Backlash
In November 2020, Aduhelm was brought to the FDA Peripheral and Central Nervous System Drugs Advisory Committee, which consists of experts in this area that advise the FDA upon assessment of a proposed drug, where it was almost unanimously rejected.
The panel evaluated data from two Biogen clinical trials designed to test the drug’s effectiveness in treating AD. Although both of these trials were terminated early when Biogen determined that the drug was unlikely to be effective, a retrospective analysis found that one of two trials did produce positive results.
The advisory committee did not believe there was sufficient evidence that the drug would improve clinical outcomes given the conflicting results between trials, wrote Joel Perlmutter, professor of neurology at Washington University in St. Louis and a former member of the FDA advisory committee who resigned after Aduhelm’s approval, in a written statement provided to The Herald. Additionally, the committee expressed concern about brain swelling and bleeding, a side effect observed in approximately 40% of trial participants, Perlmutter wrote.
None of the committee members voted in favor of the drug — ten of the 11 members voted against Aduhelm’s approval, with the last member voting that they were uncertain. Despite the negative recommendation by the committee, Aduhelm was approved through the FDA’s Accelerated Approval Program.
The program allows the FDA to evaluate the efficacy of a drug based on its ability to reach a “surrogate endpoint” — an outcome that predicts clinical benefit — rather than directly measuring clinical benefit. The intention is to expedite the approval process of drugs they feel should be made available to the public urgently by forgoing expensive and time-consuming clinical trials.
By using amyloid plaque reduction in the brain as the surrogate endpoint for Aduhelm, the FDA determined that the drug was effective.
As part of the Accelerated Approval process, Biogen is required to conduct a post-approval study but does not have to produce results for another nine years. The FDA can reverse its decision based on the results of this study, but does not have to.
“In all studies in which it was evaluated, … Aduhelm consistently and very convincingly reduced the level of amyloid plaques in the brain in a dose- and time-dependent fashion. It is expected that the reduction in amyloid plaque will result in a reduction in clinical decline,” the FDA’s director of the Center for Drug Evaluation and Research, Patrizia Cavazzoni, wrote in the FDA’s press release.
But there is little evidence so far to support the idea that clearing amyloid plaques will relieve AD symptoms, according to Perlmutter. He wrote that many studies on experimental drugs targeting these plaques have not shown a clinical benefit for people with non-genetic forms of AD.
“We know that the drug does reduce plaques in the brain,” based on the evidence, Ott said. “But does that make a real difference on the clinical outcomes and patient functionality? That's still up in the air, and another trial needs to be done.”
“I am extraordinarily disappointed that our unbiased advisory committee review was not valued,” Perlmutter wrote in his statement. He resigned from the FDA panel in protest, along with two other committee members, including Mayo Clinic neurologist David Knopman.
Knopman wrote in his resignation letter to the FDA that justifying approval through the reduction of the plaques “in the absence of consistent clinical benefit after 18 months of treatment is indefensible,” and that the approval made a “mockery” of the advisory committee’s role, as reported by The New York Times.
On July 8, the FDA revised Aduhelm’s usage from treating all patients with AD to patients with “mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in clinical trials,” thereby narrowing the population the drug is available to.
In separate emails to The Herald, Salloway and Ott wrote that they approve of this change because it is more consistent with the evidence from the clinical trials. Salloway added that it is highly recommended that patients being offered this treatment have a positive amyloid
Additionally, on July 9, the Acting Commissioner of the FDA Janet Woodcock requested an independent investigation by the Office of Inspector General into the interactions between Biogen representatives and FDA members leading up to the approval.
Ramifications of Aduhelm’s unconventional approval
Aduhelm’s approval has “serious potential to impair future research into new treatments that may be effective at treating AD,” Perlmutter wrote. “Enthusiasm (from either potential volunteer participants or funders) for new treatments may wane due to thinking that we already have an effective treatment, when in fact we do not.”
There is also concern that Aduhelm’s unconventional approval may set a precedent that leads to a less stringent approval process for future drugs, noted Harvard Professor of Medicine Aaron Kesselheim, the third committee member who resigned, as reported by CBSnews.
Biogen has listed Aduhelm at a price of $56,000 a year per patient, but other sources claim that the price will be closer to $61,000 to $62,000 per year when factoring in the average AD patient’s weight, which is greater than the number used for Biogen’s approximation. Biogen’s listed price does not include doctor’s visits, amyloid plaque diagnostic testing and MRIs that will be necessary to monitor for side effects.
“For many, this price will pose an insurmountable barrier to access,” wrote the Alzheimer’s Association in a statement in favor of the drug’s approval but calling for more affordability of the drug. “It complicates and jeopardizes sustainable access to this treatment, and may further deepen issues of health equity.”
At the moment, the Centers for Medicare and Medicaid Services has not said whether the drug will be covered under Medicare and Medicaid. But even with Medicare coverage, patients and their families would have to pay about $11,500 in co-insurance annually, since Medicare does not cover the entire cost.
According to an analysis by the Kaiser Family Foundation, Aduhelm would cost patients and taxpayers more than $29 billion per year. This estimate only accounts for one fourth of the Medicare population currently prescribed Alzheimer’s medication — the real cost would likely be higher. This far exceeds the money spent on any other drug to treat any disease covered by Medicare Part B or Part D.
“In this case, we have a new medication that costs a lot. And what we're getting in return is not entirely clear,” said Eric Jutkowitz, assistant professor of Health Services, Policy and Practice. “We don't want to be spending money on something that doesn't work.”
Spending on Aduhelm would take away from Medicaid and Medicare funds that would otherwise go towards underfunded services like long-term care or the development and testing of new AD treatments, Jutkowitz said.
Future plans for Alzheimer’s research
Still, Aduhelm’s approval has been celebrated by AD advocacy groups who have long-awaited new treatment options.
“Aduhelm is certainly not a cure, but, at long last, it provides many with Alzheimer's disease and their families an effective treatment,” the Alzheimer’s Association wrote in a statement. They hope this drug will help close “the vast unmet need of the Alzheimer's community.”
Salloway said that the FDA approval was “a very wise decision and very much pro-patient” in an interview with The Herald.
Though he “understands the concerns” voiced by critics of the drug, the “totality of evidence” amassed by the researchers — including the drug’s ability to reduce amyloid beta plaques, the positive phase three clinical trial and the clinical benefits observed in the phase two trial — as well as the strong need for innovative Alzheimer’s treatments support the FDA’s decision.
Contrary to the idea that the approval of Aduhelm will quench efforts to develop new drugs, Salloway said that he believes the presence of Aduhelm as a treatment could spur new drug development for Alzheimer's by creating demand for new screening and preventative technologies.
“There's so much that needs to be done and there is no time to waste,” he said. For instance, Salloway cited the ongoing need for new inexpensive diagnostic tools to test for amyloid beta plaque build-up in the brain, and the development of new “combination treatments,” which incorporate multiple medications and lifestyle changes to not only treat AD once it develops but also help prevent it.
Salloway and Ott hope that through a strong partnership with primary care, continued research and a focus on early and preventative treatment, clinicians will develop new care models to better care for Alzheimer’s patients.
With additional reporting by Gabriella Vulakh
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