Article In Brief
Academic medical centers are establishing committees and workgroups to develop standards and criteria for determining eligibility for the newly-approved and controversial Alzheimer's drug, aducanumab.
Just a few weeks after the US Food and Drug Administration (FDA) approval on June 7 of the Biogen drug aducanumab (Aduhelm) for Alzheimer's disease (AD) under its accelerated approval pathway, memory disorders programs at academic medical centers across the country have begun to grapple with how to prescribe the controversial therapy.
Indeed, at press time, the Cleveland Clinic and the Mount Sinai Health Center for Cognitive Health stated that they will not prescribe the drug.
In an interview with The New York Times, Samuel E. Gandy, MD, PhD, professor of neurology and psychiatry and the Mount Sinai Chair in Alzheimer's Research, and director of the Mount Sinai Center for Cognitive Health, said aducanumab would not be “considered for infusion into patients on any of its campuses until and unless” an investigation by the inspector general of the Department of Health and Human Services “affirms the integrity of the FDA-Biogen relationship” and then reaffirms the FDA rationale for approving the drug.
At the same time, the American Neurological Association released a statement to its members, recommending that patients being considered for the drug “meet the same or very similar criteria that were utilized in the clinical trials.”
Further, they urged the FDA to ensure that “Biogen complete a phase 4 confirmatory study as soon as possible, preferably within three years, to confirm or not whether clinical efficacy is observed.”
Meanwhile, other medical centers have established workgroups and committees to try to respond to demand for the drug. Who should receive it? How should patients taking the drug be monitored? How should the care team counsel patients and family members about aducanumab's risk/benefit profile? Neurology Today spoke with AD experts at four leading institutions about how they plan to address these and other questions associated with aducanumab.
Amyloid plaques measured by amyloid PET were significantly decreased by aducanumab in both EMERGE and ENGAGE trials of the drug, they agreed. But the FDA approval of aducanumab shocked the field, given that its two phase 3 trials, EMERGE and ENGAGE, were both halted in March 2019 after a futility analysis showed no clinical benefit.
The drug appeared dead in the water until seven months later, when Biogen announced that it would go to the FDA after all. They based this turnaround on new findings from the EMERGE data set that appeared to show that participants who received the higher dose of aducanumab outperformed those getting placebo on the trial's primary outcome, the Clinical Dementia Rating Scale-sum of boxes score, a composite measure with cognitive and functional components including home activities, problem solving, and community engagement.
Those results weren't enough to convince the FDA's panel of outside experts, the Peripheral and Central Nervous System (PCNS) Drugs Advisory Committee, which overwhelmingly voted no to the question of whether EMERGE and ENGAGE provided “strong evidence” that aducanumab is effective for treating AD.
Many experts were also taken aback by the fact that the approval indications simply stated “Alzheimer's disease,” with no reference to disease stage or contraindications. The EMERGE and ENGAGE trials only enrolled patients with either mild cognitive impairment (MCI) or early AD, required a positive amyloid PET scan, and excluded patients who were taking blood thinners or had been diagnosed with a relevant brain hemorrhage, bleeding disorder, or cerebrovascular abnormalities. Amyloid-related imaging abnormalities (ARIA) were common in both trials, and 17 percent of aducanumab patients developed ARIA-H microhemorrhages, compared with 6 percent of controls.
“Originally, there was very little guidance given by the FDA in terms of their approval. No limitations, no contraindications, no indication that you need biomarkers,” said Erik Musiek, MD, PhD, professor of neurology at Washington University School of Medicine in St. Louis, who is coordinating that institution's approach to the approval of aducanumab.
He noted that on July 8, the FDA updated the label to read that treatment with the drug “should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in clinical trials. There are no safety or effectiveness data on initiating treatment at earlier or later stages of the disease than were studied.”
The Review Process
Several institutions have formed multidisciplinary committees and workgroups to address the questions posed by aducanumab's approval. At the Yale School of Medicine, a clinical workgroup led by the department of neurology and including representatives from the department of medicine's geriatrics section and the psychiatry department's division of aging and geriatric psychiatry, is developing a clinical protocol for the screening and selection patients for treatment as well as the ongoing management and safety monitoring of those on treatment.
“We are still establishing our criteria, but we are in agreement that aducanumab will not be offered to all patients with Alzheimer's disease,” said Babar Khokhar, MD, FAAN, vice chair of operations for the department of neurology, chief ambulatory medical officer, and associate dean for clinical transformation.
“Once a patient is placed on treatment, their care will be monitored by a central clinical oversight committee involving neurologists, geriatricians, geriatric psychiatrists, and neurology nurse coordinators and navigators. The members of the workgroup will also serve on the oversight committee and review cases on a monthly basis, or more urgently if needed.”
The workgroup has also been advised by representatives from Yale's Ethics Committee, which recommended that aducanumab be offered to a preselected subset of patients, largely following the enrollment criteria for the trials.
“Our pharmacy also has to decide whether or not to put the drug on the formulary, and put together its own expert panel to decide about whether to move forward,” said Dr. Khokhar. “They haven't made that decision yet, and will proceed with guidance from the protocol developed by the workgroup.”
Yale was a trial site for EMERGE and ENGAGE, so the institution has experience with the drug, and individuals involved in the trials are serving on the expert panels, Dr. Khokhar said. “We are not in complete agreement that it should have been approved, but given that it has been, our concern is that we know patients are going to be seeking access to this medication, so we want to offer a consistent and safe protocol across all delivery networks.”
That's a concern that has also been voiced at Virginia Commonwealth University (VCU), which has also put together a multidisciplinary team with content experts in neurology, geriatrics, pharmacy, and drug information first conducting an evidence-based review to answer the question, “Who should be getting this drug?”
After that is complete, the team will be expanded to include representatives from psychiatry, ethics, radiology, infusion, and general medicine to address other questions such as handling referrals, guidance to the community about risks and cost-effectiveness, and monitoring with PET imaging, lumbar puncture, and MRIs.
“I have not yet seen anyone who has the intestinal fortitude to just say ‘We're not going to give it,’” said Gordon Smith, MD, FAAN, professor and chair of neurology and the Kenneth and Dianne Wright distinguished chair in clinical and translational research in neurology at VCU. “But I've heard the opinion expressed that if people are going to be getting this drug, it's safest in the hands of neurologists rather than primary care providers. A concern I do have is that there may be pressure to provide aducanumab based on a feeling of general obligation rather than a careful analysis of the value it provides relative to cost and risk.”
“I wish the recommendation of the PCNS Drugs Advisory Committee had been followed,” said Dr. Khokhar. “But if the patients are going to get this and most likely look to us as an academic medical center to ensure the right people get it, we want to be sure we are providing options. It's a very difficult place to be in.”
Using the Clinical Trial Criteria
Most experts said they are likely to adopt the same or similar screening protocols as those used in the clinical trials, with MCI and mild AD as the criteria.
“We—and probably, I think, a lot of people—are using the clinical trial that Biogen ran as our guide, at least until we hear from Medicare and private insurers about what they are going to require,” said Dr. Musiek.
“We operate under the assumption that Medicare and private insurers will restrict who will get reimbursement for this drug based on some kind of criteria that are reminiscent of what was done in this trial,” Dr. Musiek continued. “If not, it will be too expensive and the drug will be used in people for whom there is literally no evidence at all that it works. The evidence in people with MCI and mild Alzheimer's disease is controversial, but if no one was even enrolled in the trial with moderate or severe AD, there's absolutely no evidence that this drug works for them.”
That's also the conclusion of experts in the Penn Memory Center at the University of Pennsylvania's Perelman School of Medicine. “We are still establishing our specific protocols, but one thing we are in very strong agreement about is not to go beyond the inclusion/exclusion criteria for the clinical trials themselves, which would include some sort of measure of amyloid status for everyone, as well as MRI imaging for evidence of microhemorrhage,” said the center's co-director, David A. Wolk, MD, FAAN, and an associate professor of neurology in the cognitive neurology division.
“The study also excluded people who had had multiple microhemorrhages. This suggests more active amyloid angiopathy, and these individuals are more likely to have downstream increased ARIA. We are going to be very careful about these kinds of issues.”
The response from patients and families has been more muted than he expected, Dr. Musiek said. “If the data had been more convincing, I think my phones would be blowing up,” he said. “But I've talked to several patients in my own clinic who have heard the news about it and aren't very interested in it.”
“We are not hearing much demand from patients so far,” said Dr. Smith. “I think that perhaps reflects the media coverage, which has been appropriately reflecting the concerns of the experts.”
The Question of Cost
Dr. Smith noted that beyond the discussion of clinical evidence, screening and monitoring, and adverse events, lurks the question of cost. Biogen has priced aducanumab at $56,000 a year—a cost that is massively higher than the value-based price of $3,000 to $8,400 by the Institute for Clinical and Economic Review (ICER).
ICER's draft report on aducanumab, which was updated on June 30, noted that only a hypothetical drug that halts AD entirely would merit a price like the one Biogen has set.
Indeed, at an ICER meeting on July 15, a panel of medical experts voted unanimously—15-to-0—that evidence is lacking to support the drug's benefit to patients.
Speaking on behalf of the AAN at the ICER meeting, Brian Callaghan, MD, MS, FAAN, Fovette E. Dush Early Career Professor of Neurology and associate professor of neurology at University of Michigan,said: “The AAN was heartened to see the FDA update the label to patients with mild cognitive impairment or mild dementia, as this is in line with the recommendations we sent to the FDA prior to aducanumab's approval. However as noted in ICER's revised evidence report, Biogen has set an annual price for aducanumab at $56,000. Unfortunately, patients are likely to bear a significant amount of financial hardship given the rising out-of-pocket costs of many neurologic medications that has occurred over the last several years. Furthermore, the impact on Medicare Part B spending cannot be overstated as aducanumab could cost more than a trillion dollars before its clinical benefit is adequately demonstrated, depending on how many patients take the drug.
“The AAN agrees with ICER that due to the high systemic and out-of-pocket costs, aducanumab could only be administered to a very small number of patients before the need for federal policy changes to address access and affordability. The budget impact on the health care system and individual patients is very concerning, including factors not included in the ICER analysis such as ancillary costs associated with infusions and testing.” The full statement is available at AAN.com/aducanumab.
On June 10, the Kaiser Family Foundation released a report finding that if just one-quarter of the nearly two million Medicare beneficiaries currently taking Alzheimer's treatments covered under Medicare Part D were prescribed aducanumab, total Medicare spending for the drug would exceed $29 billion in a single year—“an amount that far exceeds spending on any other drug covered under Medicare Part B or Part D, based on 2019 spending,” they noted.
At press time, CMS has posted a public comment period on coverage for the drugs, and proposed that a decision memo on covering costs would come in early 2022.
“Even when you restrict the drug to just the populations eligible for the clinical trial, the numbers become staggering, and not just for the cost of aducanumab alone,” Dr. Smith said. “Thousands of patients in our area alone will need amyloid screening, infusions, routine MRI scans, and monitoring for ARIA.”
“If there were a dramatic benefit, as is the case with the direct-acting antivirals that cure hepatitis C in virtually all patients, or Zolgensma [onasemnogene abeparvovec-xioi] and Spinraza [nusinersen] for presymptomatic spinal muscular atrophy, then that's a happy problem to have,” Dr. Smith continued. “These drugs are dramatically effective for the right patient population, in a disease that previously had no treatments. Aducanumab poses a very different problem. Having thought about drug pricing for a long time, it's precisely the storm I was worried about—a modestly effective—if at all—drug for Alzheimer's disease, with a high price tag.”