Months before the US Food and Drug Administration (FDA) approved aducanumab (Aduhelm), the first medication thought to modify the progression of Alzheimer’s disease, on June 7, Jay Reinstein had already made the decision to try it.
Reinstein, 60, was the assistant city manager of Fayetteville, NC, when he was diagnosed with early-onset Alzheimer’s disease in 2018 at the age of 57. “I was devastated,” he says. “My first thought was ‘What does this mean for me and for my family’s future?’”
An outgoing person who had thrived in his job in local government, Reinstein became involved with the Alzheimer’s Association, joining its National Early-Stage Advisory Group and working to dispel stigma about the disease. “I speak a lot in front of small groups, large groups, and conferences,” he says. “It’s been a blessing to me. I find it very therapeutic, because talking about it helps me.”
When he initially heard that aducanumab was in clinical trials, Reinstein says, he knew right away he wanted to take it. “At my age, I want to have more time with my family. I’m married, with two daughters and a son and four grandkids, and my parents are still alive. I want to see my other daughter and son get married, to have more summers with my grandkids—that’s what I’m hoping for.”
While he didn’t participate in the clinical trials, Reinstein was one of six patients who spoke at a patient listening session with the FDA about aducanumab last January. He felt the event was a chance to have a personal impact—to share the realities of patients’ lives.
The conversation about aducanumab (the first Alzheimer’s treatment to gain FDA approval since 2003) has been heated partially because patients and families are desperate for effective treatments. An estimated 6 million people in the United States have Alzheimer’s disease; it is the nation’s sixth leading cause of death. Alzheimer’s disease primarily affects people age 65 and older, and the oldest members of the huge baby-boom generation have just turned 75.
Reinstein’s decisiveness about trying the new drug is one type of response physicians across the country are already hearing from patients. Other responses run the gamut from enthusiasm and curiosity to hesitancy or outright refusal. But many questions about the drug—Who is eligible? What are the side effects? Is it covered by insurance? What are the risks and benefits in diverse populations?—have yet to be answered.
The Road to Approval
Aducanumab works by clearing beta-amyloid plaques—clumps of protein that are a hallmark of Alzheimer’s disease—from the brain. It was developed initially by the Cambridge, MA, biotech firm Biogen, with Japanese pharmaceutical company Eisai joining the project in 2017.
Although the drug reduces levels of beta-amyloid in the brain, clinical trials did not show that such changes reliably decrease symptoms of dementia for patients. Two trials of the drug, at different doses, studying nearly 3,500 patients in total, were stopped in March 2019 when an independent data-monitoring committee found that the chances of them meeting their efficacy targets were too slim. Both trials resumed seven months later.
The controversy over aducanumab became more public in November 2020, when an expert advisory committee to the FDA recommended almost unanimously (with one vote of “uncertain”) against approval of the drug. In addition to lack of evidence of clinical benefit, the committee noted that more than one-third of patients developed a major complication called amyloid-related imaging abnormalities (ARIA), involving swelling and possible bleeding in the brain.
Yet seven months later, the FDA stunned the research world by granting aducanumab “accelerated approval.” This type of approval, typically granted to therapies for cancer and HIV, is for drugs that treat serious conditions, fill an unmet medical need, and achieve a “surrogate endpoint”—a biomarker, like the level of beta-amyloid that is reduced with treatment. Under accelerated approval, that marker is accepted as a sign of the drug’s effectiveness, rather than the usually required clinical benefit in the form of a measurable change in patients’ symptoms.
No Alzheimer’s treatment had ever been granted accelerated approval before. In the days following the FDA’s announcement, three members of the expert advisory committee resigned in protest: Joel Perlmutter, MD, FAAN, endowed professor of neurology at Washington University in St. Louis’ Hope Center for Neurological Disorders; David S. Knopman, MD, FAAN, professor of neurology at Mayo Clinic in Rochester, MN; and Aaron Kesselheim, MD, professor of medicine at Harvard Medical School and director of the Program on Regulation, Therapeutics, and Law at Brigham and Women’s Hospital in Boston.
Aducanumab was tested only in patients with mild cognitive impairment (MCI) or in early stages of Alzheimer’s disease, but the FDA’s initial “label” (its formal statement about who should receive the drug) recommended it to treat patients with Alzheimer’s at any stage of the illness. Under criticism and amid revelations that even some senior FDA staffers had been caught off guard by the breadth of the initial label, the agency reversed course a month after announcing approval, clarifying on July 8 that prescribing should follow the composition of the trial.
The controversy escalated the next day, with acting FDA director Janet Woodcock calling for a federal investigation by the Department of Health and Human Services’ acting inspector general into whether the agency’s interactions with Biogen to secure aducanumab’s approval “were inconsistent with FDA policies and procedures.” The request followed press reports of accusations of an off-the-books meeting between the FDA official overseeing the aducanumab approval process and a top official at Biogen in May 2019, shortly after the drug trials had been halted.
Unexpected Price Tag
Only hours after the drug’s approval, Biogen and Eisai announced that the medication would cost $56,000 a year. The price has already provoked calls for congressional hearings and questions about whether aducanumab could reenergize efforts toward drug pricing reform. The Institute for Clinical and Economic Review, which analyzes drug price levels based on clinical evidence, calculated that aducanumab should cost between $3,000 and $8,300 per year, or up to $23,100 based on the most favorable trial results.
Guidance is still pending on whether or to what degree Medicare or private insurers would cover the medication. At press time, the Centers for Medicare and Medicaid Services (CMS), which oversees Medicare, had started a national coverage determination process, which may limit coverage of aducanumab. Some private insurers like Blue Cross Blue Shield have decided that the drug isn’t medically necessary. And three major medical centers—the Cleveland Clinic in Ohio, Mount Sinai Health System in New York, and Providence Health in Reston, VA—said they wouldn’t administer the drug to patients.
Without adequate coverage, the majority of Americans would be unable to afford the drug. Most patients on Medicare are responsible for 20 percent of the cost of their prescriptions; for aducanumab, that would come to about $11,200 per year. While Biogen and Eisai have created patient assistance programs to reduce out-of-pocket expenses, actual patient costs won’t be clear until CMS has issued guidance on coverage. The Kaiser Family Foundation estimates that if even 1 million of the estimated 1.5 million Americans eligible for treatment actually received the drug under Medicare, it could cost Medicare $57 billion per year—$20 billion above what Medicare Part B spent on all drugs combined in 2019.
The medication’s cost is just the start of its overall expense. In order to prescribe the drug, doctors must provide documentation of patients’ beta-amyloid plaques, which could be done with a PET scan—an imaging procedure that costs more than $6,000 and is not covered by Medicare outside of clinical trials—or a lumbar puncture. Because of the risk of brain swelling or bleeding, patients will need to be monitored with MRI scans before starting the drug and at regular points during treatment and follow-up. Since aducanumab is given by monthly intravenous infusion, there is also the cost of visits to an infusion center or hospital or home visits from a specialized nurse.
“The Alzheimer’s Association believes the price is unacceptable,” says Kristen Clifford, chief program officer at the association, which has otherwise applauded the drug’s approval. “It poses a huge barrier for many families impacted by Alzheimer’s and can really complicate long-term, sustainable access to the treatment, and even potentially deepen existing health inequities.” The Alzheimer’s Association has called on Biogen to change the price and says it is committed to working with CMS and private insurers to make sure that all patients likely to benefit from the drug have access to it.
Neurologists have been fielding many questions from patients about aducanumab. “I try to make it clear that there are a lot of limitations to this unexpected FDA accelerated approval,” says Joel Salinas, MD, endowed assistant professor of neurology at NYU Langone’s Grossman School of Medicine. “I also want to make sure that patients and their families understand that this is a hopeful sign of the future for the treatment of Alzheimer’s disease.”
Physicians also find themselves explaining the finer points of the trials, the drug’s approval process, and the FDA’s initial broad prescribing label. “Not everyone who has Alzheimer’s disease dementia is going to be a candidate for this drug,” says John Morris, MD, FAAN, endowed professor of neurology at Washington University in St. Louis’ Knight Alzheimer Disease Research Center. “There are no data whatsoever as to how the drug may perform in people with more advanced disease.” The trials excluded people who have diabetes or high blood pressure or who are on blood thinners, raising questions about the safety of the drug for the many older people with those conditions. “We don’t know what this looks like in a more typical patient population,” says Dr. Salinas. “For example, in someone who’s at risk of hemorrhage or who has uncontrolled high blood pressure or who is on a mix of different medications.”
Furthermore, doctors may not be able to make specific recommendations for their Black and Hispanic patients, since the trials tested the drug primarily in non-Hispanic White patients, even though Black and Hispanic people have the highest incidence of Alzheimer’s disease nationally. “Non-White patients need to take a leap of faith, knowing the study wasn’t really tailored to them,” says Dr. Salinas. “We’re not sure how generalizable these results are to populations that have more co-occurring conditions related to structural racism, which affects access to quality health care, health education, and healthy food,” he says. The FDA has asked Biogen to conduct confirmatory trials of the drug for evidence of clinical benefit, and many physicians and advocates hope those trials will include a more diverse group of patients.
In the meantime, although few providers are prescribing aducanumab, many patients with early-stage Alzheimer’s disease who may be eligible are talking with their doctors about the drug’s possible benefits and risks. “A minority is really chomping at the bit: ‘When’s it going to be available? When can I get my husband treated?’” says Dr. Morris. “I think the press, in the weeks since the announcement, has been so clear that this is a controversial decision that many other patients and families are uncertain: ‘Is it really the breakthrough we’ve been waiting for?’” Dr. Salinas has heard a similarly mixed response. “Some patients ask, ‘When can we start?’ Others were asking for my opinion,” he says.
“I’ve been telling the families of patients who are contacting me to think about why they’re interested in this medication,” says Zaldy Tan, MD, medical director at the Jona Goldrich Center for Alzheimer’s and Memory Disorders at Cedars-Sinai Medical Center in Los Angeles. “In the best circumstances, the drug will offer modest benefit in terms of function and cognition. It’s not going to stop the disease. And it’s not benign: A third of patients can have complications.” Dr. Tan also notes that taking the drug is complicated, given the monthly infusions and a series of MRIs. “If patients’ expectations and reasoning for wanting the medication are consistent with what we know it can and cannot do and the patient is qualified to receive it, then it may be appropriate to prescribe it.”
The Future of Treatments
Approval of aducanumab could influence research into Alzheimer’s treatments in several different ways. Some critics worry that it could affect both participation in and the content of other trials. In his resignation letter, Dr. Perlmutter asserted, “Approval of an ineffective drug has serious potential to impair future research into new treatments that may be effective for treating Alzheimer’s. For example, new studies may be required to compare an investigational drug to aducanumab instead of a placebo. And people may not be as willing to volunteer for a trial if they think an effective treatment already exists, which is not true.”
Others are far more positive. “While this treatment is not a cure, and it’s not for everyone, it does represent an important step forward,” says Clifford of the Alzheimer’s Association. “History has really shown us what the energy and excitement and invigoration and investments in new treatments can mean in terms of innovation. We’ve seen it happen in other conditions like heart disease, cancer, and multiple sclerosis, where that first treatment spurred additional treatments and advancements and innovation. So it’s an exciting time in that respect.”
It’s also possible that amyloid-clearing medications like aducanumab may become one part of a combination therapy for Alzheimer’s. “With heart disease, for example, we treat high blood pressure, diabetes, hypercholesterolemia—we don’t just give a single treatment to one target,” says Dr. Morris. “We’ll likely need combination therapy for Alzheimer dementia that also addresses multiple targets. Amyloid very probably will be included as one target, but not the only one.” If other anti-amyloid medications already in the FDA pipeline win approval, he says, “we can start designing studies where we add an anti-tau drug, or an anti-inflammation drug, or an anti–oxidative stress drug, or perhaps some combination of all of these.”
Whatever is in the offing, for patients like Jay Reinstein, aducanumab represents hope. “With nothing else out there, and the first drug that’s shown potential to slow down the risk—it’s a no-brainer for me,” Reinstein says. In advising others, he stresses that patients and their families should learn as much as they can before making a decision. “It’s important to have a neurologist and a team you trust, and to have conversations with your family about the risks involved,” he says. “It would be too simple to say it’s a one-size-fits-all answer. It’s not. But I was willing very quickly to say, ‘Yeah, this works for me.’”