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The approval was hailed by advocacy groups and some practitioners as a victory for patients and families, as the drug – the first anti-Alzheimer’s agent to reach the market in 18 years – is a potentially disease-modifying therapy, which acts to clear amyloid plaques from the brain.
But several prominent Alzheimer’s researchers lambasted the agency’s decision, citing unclear evidence of benefit, trials that did not meet their primary endpoints, and reliance on a post hoc analysis of a high-dose subgroup of patients in a halted trial to argue that aducanumab (Aduhelm, Biogen, and Eisai), slowed cognitive and functional decline by 22% on one measure. In November 2020, 10 of 11 members of an independent FDA advisory committee voted against aducanumab’s approval, citing holes in the data and concerns about the quality of the evidence. After the agency went on to approve anyway, three members of that committee resigned in protest.
The FDA decision on aducanumab was made using the agency’s accelerated approval pathway, which allows for the use of a surrogate endpoint – in this case imaging that showed amyloid clearance from the brain – to predict clinical benefit. But amyloid clearance, which a number of experimental antiamyloid antibodies have been shown capable of, has not been definitively linked to clinical benefit. Aducanumab, which is delivered by monthly intravenous infusion, will be marketed pending results from a phase 4 clinical trial, which the manufacturer has nearly a decade to complete. The drug’s price was announced at $56,000 per year, underscoring concern over its modest-at-best benefits.
Clinicians prescribing aducanumab must obtain magnetic resonance imaging at baseline and repeatedly during the course of treatment to detect brain edema and microhemorrhages, which occurred in a third of high-dose patients in clinical trials. Beyond this, there are few restrictions. The FDA label allows for its use in any patient deemed to have Alzheimer’s disease, without stipulations as to disease stage or evidence of brain amyloid. Payers, of course, are likely to restrict use to certain patient groups, and to require evidence of amyloid positivity. The FDA offered no guidance on when treatment should be ceased, leaving payers to make that call as well. Whatever aducanumab’s value and role turns out to be, the first-in-class treatment for Alzheimer’s disease is likely to have a major impact on how patients are assessed and treated in the coming years, and embolden manufactures of similar agents to seek FDA approval.
This news organization reached out to researchers, advocates, and specialists in the community to learn how they see this change playing out.
Fielding broad interest
Maria C. Carrillo, PhD, chief science officer of the Alzheimer’s Association, which was a strong proponent of aducanumab’s approval, acknowledged in an interview that the months to come are likely to be confusing for practitioners and families alike as the drug makes its way into community practices.
“We understand that off the bat millions of Americans will not have access to this tomorrow, but over time that will build. And the physician community, the specialists most likely to be prescribing this, over the next few years will even expand further,” Dr. Carrillo said.
For now, those specialists are mostly just struggling to respond responsibly to a deluge of inquiries from patients and their families.
“I’ve gotten like 20 calls in the just the past 2 days,” said neurologist Philip R. Delio, MD, who practices in Santa Barbara, Calif. “This is a longstanding issue that physicians have with patients’ access to information. Patients are getting information about a drug which isn’t available yet. They don’t know that it’s not ready to be sold. They don’t necessarily realize that a biopharma company won’t go into production until the FDA approves the drug.”
Many patients, Dr. Delio said, are aware of the controversy surrounding aducanumab and eager to hear their neurologist’s opinion. “I have tried to let them know that I want to see the trial data and to better understand the FDA’s rationale in approving it. I always caution patients that the devil will be in the details.”
While aducanumab’s label gives physicians remarkably wide latitude in whom to treat, clinicians say that until payers weigh in, the label is all but meaningless. Neurologist Douglas Scharre, MD, of the Ohio State University Wexner Medical Center, and a site investigator on a trial of aducanumab, said that he and his colleagues at the university’s memory center have tried to anticipate who might be deemed eligible by triaging calls.
Dr. Scharre and colleagues have been working under the assumption that payers will support aducanumab only for patients like those who seemed to benefit in the trials – people with mild cognitive impairment (MCI) or in the earliest stages of dementia with evidence of brain amyloid.
“I don’t want to fill up our new patient slots with people who are not even appropriate for this drug,” Dr. Scharre said. “We have a call center, and we have a few triage questions. After that a nurse practitioner collects some more data, and there’s a review process. Only then do we decide whether that person could be a candidate. If we deem that they are, we will want them in and to order an amyloid PET” – a type of brain scan that is seldom used outside research settings and not reimbursed by Medicare.
Dr. Scharre predicts that regardless of payer limitations, “there will be people hounding for the drug who are not appropriate for the drug. There will be very wealthy people who will want to pay for tests and get it no matter what.” Another concern, he said, was that having poorly selected patients on the drug could make definitive trial results even more elusive.
“The label the way it’s written is not going to help the drug in phase 4 trials,” he said. “It’s good to have real-world patient data, but if you have all these people in your cohort who are too early or too late, you won’t have good results.”
The challenge of delivery
Intravenous infusions are new to Alzheimer’s disease and pose all sorts of logistical hurdles. The Alzheimer’s Association’s Dr. Carrillo described the situation as “manageable,” noting that infusions are standard of care for many diseases, and that neurologists now have more than 15 years’ experience with them for multiple sclerosis.
Still, most clinicians treating Alzheimer’s disease in the community – neurologists, geriatricians, psychiatrists, and primary care physicians – do not have infusion centers in their practices. Virtually none have experience with or access to PET-amyloid, or with screening for amyloid-related imaging abnormalities–edema (ARIA-e) on MRI, as required by the FDA.
“I contacted the hospital infusion center we use and said I could end up sending five or six patients a week, can you handle this? They only have so many chairs,” Dr. Delio said. “I am one neurologist in a local community, and I might have 50 candidates for this drug. That’s a lot for them.” Patients with cognitive impairment are also difficult to infuse and may need to be treated at home, he noted.
“MRIs are easy enough to do,” Dr. Delio said. “But do we know what ARIA-e looks like on imaging? You’d have to talk to the radiologists – this is another element of uncertainty. Do we even know what we’re looking for with these scans? Will we recognize this?”
Neurologist Jeffrey L. Cummings, MD, ScD, of the University of Nevada, Las Vegas, a vocal proponent of aducanumab and lead author of a May 2021 paper defending the evidence for it, acknowledged that the field was unprepared for a wide-scale adoption of infusions in dementia treatment, pointing to a Rand Corporation study from 2017 that warned that screening, diagnosis, and availability of infusion chairs would have to be drastically scaled up to meet demand.
“There are few clinicians who know how to identify MCI, too few imaging centers, too few radiologists who know how to identify ARIA-e on MRI, so all of these things will be required to be put into place. The label doesn’t specify any of this, but good clinical practice will require that, and getting this up and running will take 18 to 24 months,” Dr. Cummings said.
Neurologist David S. Knopman, MD, of the Mayo Clinic in Rochester, Minn., a leading critic of the evidence for aducanumab who recently resigned his position on the independent committee that advises the FDA on neurology drugs, said that for large research institutions like his that have served as trial sites, the transition to offering PET-amyloid, MRI, and infusions in clinical practice will be easier.
“We have all this because this is what we do every day. And we have a very extensive understanding of MCI and mild dementia staging,” Dr. Knopman said. “But the amount of infrastructure that is implied by this, and all the extra steps it would take, would be a real challenge for people in general neurology practice.”
In addition to routine use of PET-amyloid and MRI screening for ARIA-e, Dr. Knopman said, clinicians will have to provide genetic screening and counseling before administering aducanumab, as clinical trials showed that treated patients have a higher risk of developing ARIA-e if they have APOE4, a risk variant for Alzheimer’s disease. “And that has real implications for the families and the children of patients,” he said.
Uncertainty over costs
Aducanumab’s true costs, to patients and to taxpayers, remain unknown. The $56,000 per year currently cited by its manufacturer “doesn’t count the PET scans and MRIs,” Dr. Knopman noted. “We’re probably pushing $100,00 a year for the first year of treatment.”
Most of that expense will likely be borne by Medicare, he said, and if not, “that will exacerbate existing health care disparities. People who can pay out of pocket are a pretty limited group.”
Dr. Scharre agreed that the costs of treatment were concerning, and that “at least you should be able to narrow it down and hopefully just use health care dollars for people who might stand to benefit,” he said – namely patients in an earlier stage of disease.
The Alzheimer’s Association’s Dr. Carrillo declined to address the high price of aducanumab or its implications, saying only that the association is “very invested in all aspects of access including covering costs associated with the drug and the rest of treatment.”
Access also means “infrastructure, access to physicians to diagnose, access to diagnostics,” Dr. Carrillo said.
Dr. Cummings said aducanumab’s price would likely come down through negotiations with the Centers for Medicare & Medicaid Services, copayments, and bulk purchases.
The FDA has offered no guidance on how long treatment with aducanumab should last, or what should prompt withdrawal of treatment, meaning that patients could, in theory, stay on it to the end of their lives – raising costs further.
Critics have also noted that a built-in financial incentive under Medicare Part B, which covers infusion drugs, could result in overprescription of aducanumab. Under Medicare Part B, prescribing physicians are reimbursed 6% of a drug’s average sales price.
Geriatricians wary
On social media and in the lay press, geriatricians have been among the most outspoken opponents of the FDA decision and the Alzheimer’s Association’s advocacy of aducanumab.
Eric Widera, MD, a geriatrician at the University of California, San Francisco, said that the specialty might be less likely than others to embrace aducanumab. “I think part of the reasons geriatricians don’t make a lot of money is they have strong commitment to their values,” Dr. Widera said.
The American Geriatrics Society opposed the drug’s approval, citing concerns about evidence, side effects, and cost. “Additional considerations are the unintended consequences of overstressing Medicare’s limited financial reserves, and of challenging health care systems … to divert precious resources to an expensive treatment of uncertain value,” the society’s president, Peter Hollmann, MD, and chief executive officer, Nancy E. Lundebjerg, wrote in a June 2 letter to the FDA.
Dr. Widera said the approval was likely to undermine confidence in the FDA and in the Alzheimer’s Association, which receives significant funding from drug manufacturers, including Biogen and Eisai. “There’s a lot of reasons that the Geriatrics Society could have done what the Alzheimer’s Association did, and yet they came out against it, which I applaud.”
Dr. Widera pointed to a study showing that dementia patients were less likely to be on an antidementia drug if they were treated by a geriatrician, compared with a psychiatrist or a neurologist. But whether the specialty will prove as cautious with aducanumab remains to be seen. Some geriatricians will be tempted to open lucrative infusion centers, he predicted.
What is especially worrisome, Dr. Widera said, is that aducanumab’s label offers no guidance as to when to withdraw treatment. “We’ll probably see something similar to what happened with the cholinesterase inhibitors” – the class of marginally effective antidementia drugs that includes donepezil (Aricept, Pfizer) and rivastigmine (Exelon, Novartis). “No one thinks about deprescribing them. People are prescribed them even in their last months of life. There is no reason to think these infusions won’t be continued for a very long time, well beyond how long people were dosed in the trials.”
“Taking care of someone with dementia is hard enough,” Dr. Widera added. “We can’t even get normal support in the home for someone with dementia. But we are more than happy to throw money to Biogen for a drug they have not yet showed benefit for. Hopefully in 5 years we’ll have a drug that actually works,” Dr. Widera said. “After 5 years of giving this to people at $50,000 a year.”
A fractured research community
Ever since October 2019, when Biogen and Eisai announced that despite two trials halted for futility, they would go ahead and seek FDA approval for aducanumab, the Alzheimer’s research community has been bitterly divided over the drug and the FDA’s accelerated approval process.
Top researchers published critical editorials in journals, with some eventually taking their case to major newspapers as well. The Alzheimer’s Association’s position on the drug has clashed with that of many researchers whose work it supports.
“The Alzheimer’s community has been wonderfully collegial – we all have a common purpose,” Dr. Cummings said. “Now we have people taking extreme positions and I’m hoping this will not result in a permanent fracturing of the community.”
Chief among the critics’ concerns is that the FDA decision ratified the use of antiamyloid therapies based on biomarker evidence, opening the door for makers of similar drugs – those still under development or even those whose development has been halted – to seek approval on weak evidence of clinical benefit.
Whether the approval will chill research into drugs targeting pathways other than amyloid is uncertain.
Dr. Cummings said he felt that while the aducanumab decision would spur other manufacturers of antiamyloid drugs to seek accelerated approval, other classes of Alzheimer’s therapies in development also stand to get a boost. Many Alzheimer’s experts believe that a combination of drugs targeting different elements of the disease pathway – not just amyloid – will be needed in the long run.
Dr. Scharre said that the buzz over aducanumab’s approval will have at least one concrete benefit: people getting into doctors’ offices sooner.
“The people who come into our memory centers represent only a fraction of people walking around with MCI – there are people out there who may have heard that it’s normal aging; they have decreased insight; there’s denial, there’s embarrassment – there’s hundreds of reasons people avoid getting seen,” he said.
“Perhaps they come in and learn that they don’t have any degenerative process but their thyroid is out of whack, or there’s something else causing cognitive impairment. And if they do have a degenerative process, they’ll have time to start [aducanumab], and hopefully get to see a reduction in the decline.”
Dr. Knopman was a site investigator for the Biogen aducanumab trials and has consulted for Samus Therapeutics, Third Rock, Roche, and Alzeca Biosciences. A former member of the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee, he was recused from the Nov. 6, 2020, meeting that voted against aducanumab. Dr. Cummings has consulted for Biogen, Eisai, and other manufacturers. Dr. Scharre reports financial relationships with Biogen, Brain Test, Acadia, and Vascular Scientific. Dr. Widera has no disclosures. Dr. Delio is a speaker for Gore Medical, Allergan, and Biohaven Pharmaceuticals.
The approval was hailed by advocacy groups and some practitioners as a victory for patients and families, as the drug – the first anti-Alzheimer’s agent to reach the market in 18 years – is a potentially disease-modifying therapy, which acts to clear amyloid plaques from the brain.
But several prominent Alzheimer’s researchers lambasted the agency’s decision, citing unclear evidence of benefit, trials that did not meet their primary endpoints, and reliance on a post hoc analysis of a high-dose subgroup of patients in a halted trial to argue that aducanumab (Aduhelm, Biogen, and Eisai), slowed cognitive and functional decline by 22% on one measure. In November 2020, 10 of 11 members of an independent FDA advisory committee voted against aducanumab’s approval, citing holes in the data and concerns about the quality of the evidence. After the agency went on to approve anyway, three members of that committee resigned in protest.
The FDA decision on aducanumab was made using the agency’s accelerated approval pathway, which allows for the use of a surrogate endpoint – in this case imaging that showed amyloid clearance from the brain – to predict clinical benefit. But amyloid clearance, which a number of experimental antiamyloid antibodies have been shown capable of, has not been definitively linked to clinical benefit. Aducanumab, which is delivered by monthly intravenous infusion, will be marketed pending results from a phase 4 clinical trial, which the manufacturer has nearly a decade to complete. The drug’s price was announced at $56,000 per year, underscoring concern over its modest-at-best benefits.
Clinicians prescribing aducanumab must obtain magnetic resonance imaging at baseline and repeatedly during the course of treatment to detect brain edema and microhemorrhages, which occurred in a third of high-dose patients in clinical trials. Beyond this, there are few restrictions. The FDA label allows for its use in any patient deemed to have Alzheimer’s disease, without stipulations as to disease stage or evidence of brain amyloid. Payers, of course, are likely to restrict use to certain patient groups, and to require evidence of amyloid positivity. The FDA offered no guidance on when treatment should be ceased, leaving payers to make that call as well. Whatever aducanumab’s value and role turns out to be, the first-in-class treatment for Alzheimer’s disease is likely to have a major impact on how patients are assessed and treated in the coming years, and embolden manufactures of similar agents to seek FDA approval.
This news organization reached out to researchers, advocates, and specialists in the community to learn how they see this change playing out.
Fielding broad interest
Maria C. Carrillo, PhD, chief science officer of the Alzheimer’s Association, which was a strong proponent of aducanumab’s approval, acknowledged in an interview that the months to come are likely to be confusing for practitioners and families alike as the drug makes its way into community practices.
“We understand that off the bat millions of Americans will not have access to this tomorrow, but over time that will build. And the physician community, the specialists most likely to be prescribing this, over the next few years will even expand further,” Dr. Carrillo said.
For now, those specialists are mostly just struggling to respond responsibly to a deluge of inquiries from patients and their families.
“I’ve gotten like 20 calls in the just the past 2 days,” said neurologist Philip R. Delio, MD, who practices in Santa Barbara, Calif. “This is a longstanding issue that physicians have with patients’ access to information. Patients are getting information about a drug which isn’t available yet. They don’t know that it’s not ready to be sold. They don’t necessarily realize that a biopharma company won’t go into production until the FDA approves the drug.”
Many patients, Dr. Delio said, are aware of the controversy surrounding aducanumab and eager to hear their neurologist’s opinion. “I have tried to let them know that I want to see the trial data and to better understand the FDA’s rationale in approving it. I always caution patients that the devil will be in the details.”
While aducanumab’s label gives physicians remarkably wide latitude in whom to treat, clinicians say that until payers weigh in, the label is all but meaningless. Neurologist Douglas Scharre, MD, of the Ohio State University Wexner Medical Center, and a site investigator on a trial of aducanumab, said that he and his colleagues at the university’s memory center have tried to anticipate who might be deemed eligible by triaging calls.
Dr. Scharre and colleagues have been working under the assumption that payers will support aducanumab only for patients like those who seemed to benefit in the trials – people with mild cognitive impairment (MCI) or in the earliest stages of dementia with evidence of brain amyloid.
“I don’t want to fill up our new patient slots with people who are not even appropriate for this drug,” Dr. Scharre said. “We have a call center, and we have a few triage questions. After that a nurse practitioner collects some more data, and there’s a review process. Only then do we decide whether that person could be a candidate. If we deem that they are, we will want them in and to order an amyloid PET” – a type of brain scan that is seldom used outside research settings and not reimbursed by Medicare.
Dr. Scharre predicts that regardless of payer limitations, “there will be people hounding for the drug who are not appropriate for the drug. There will be very wealthy people who will want to pay for tests and get it no matter what.” Another concern, he said, was that having poorly selected patients on the drug could make definitive trial results even more elusive.
“The label the way it’s written is not going to help the drug in phase 4 trials,” he said. “It’s good to have real-world patient data, but if you have all these people in your cohort who are too early or too late, you won’t have good results.”
The challenge of delivery
Intravenous infusions are new to Alzheimer’s disease and pose all sorts of logistical hurdles. The Alzheimer’s Association’s Dr. Carrillo described the situation as “manageable,” noting that infusions are standard of care for many diseases, and that neurologists now have more than 15 years’ experience with them for multiple sclerosis.
Still, most clinicians treating Alzheimer’s disease in the community – neurologists, geriatricians, psychiatrists, and primary care physicians – do not have infusion centers in their practices. Virtually none have experience with or access to PET-amyloid, or with screening for amyloid-related imaging abnormalities–edema (ARIA-e) on MRI, as required by the FDA.
“I contacted the hospital infusion center we use and said I could end up sending five or six patients a week, can you handle this? They only have so many chairs,” Dr. Delio said. “I am one neurologist in a local community, and I might have 50 candidates for this drug. That’s a lot for them.” Patients with cognitive impairment are also difficult to infuse and may need to be treated at home, he noted.
“MRIs are easy enough to do,” Dr. Delio said. “But do we know what ARIA-e looks like on imaging? You’d have to talk to the radiologists – this is another element of uncertainty. Do we even know what we’re looking for with these scans? Will we recognize this?”
Neurologist Jeffrey L. Cummings, MD, ScD, of the University of Nevada, Las Vegas, a vocal proponent of aducanumab and lead author of a May 2021 paper defending the evidence for it, acknowledged that the field was unprepared for a wide-scale adoption of infusions in dementia treatment, pointing to a Rand Corporation study from 2017 that warned that screening, diagnosis, and availability of infusion chairs would have to be drastically scaled up to meet demand.
“There are few clinicians who know how to identify MCI, too few imaging centers, too few radiologists who know how to identify ARIA-e on MRI, so all of these things will be required to be put into place. The label doesn’t specify any of this, but good clinical practice will require that, and getting this up and running will take 18 to 24 months,” Dr. Cummings said.
Neurologist David S. Knopman, MD, of the Mayo Clinic in Rochester, Minn., a leading critic of the evidence for aducanumab who recently resigned his position on the independent committee that advises the FDA on neurology drugs, said that for large research institutions like his that have served as trial sites, the transition to offering PET-amyloid, MRI, and infusions in clinical practice will be easier.
“We have all this because this is what we do every day. And we have a very extensive understanding of MCI and mild dementia staging,” Dr. Knopman said. “But the amount of infrastructure that is implied by this, and all the extra steps it would take, would be a real challenge for people in general neurology practice.”
In addition to routine use of PET-amyloid and MRI screening for ARIA-e, Dr. Knopman said, clinicians will have to provide genetic screening and counseling before administering aducanumab, as clinical trials showed that treated patients have a higher risk of developing ARIA-e if they have APOE4, a risk variant for Alzheimer’s disease. “And that has real implications for the families and the children of patients,” he said.
Uncertainty over costs
Aducanumab’s true costs, to patients and to taxpayers, remain unknown. The $56,000 per year currently cited by its manufacturer “doesn’t count the PET scans and MRIs,” Dr. Knopman noted. “We’re probably pushing $100,00 a year for the first year of treatment.”
Most of that expense will likely be borne by Medicare, he said, and if not, “that will exacerbate existing health care disparities. People who can pay out of pocket are a pretty limited group.”
Dr. Scharre agreed that the costs of treatment were concerning, and that “at least you should be able to narrow it down and hopefully just use health care dollars for people who might stand to benefit,” he said – namely patients in an earlier stage of disease.
The Alzheimer’s Association’s Dr. Carrillo declined to address the high price of aducanumab or its implications, saying only that the association is “very invested in all aspects of access including covering costs associated with the drug and the rest of treatment.”
Access also means “infrastructure, access to physicians to diagnose, access to diagnostics,” Dr. Carrillo said.
Dr. Cummings said aducanumab’s price would likely come down through negotiations with the Centers for Medicare & Medicaid Services, copayments, and bulk purchases.
The FDA has offered no guidance on how long treatment with aducanumab should last, or what should prompt withdrawal of treatment, meaning that patients could, in theory, stay on it to the end of their lives – raising costs further.
Critics have also noted that a built-in financial incentive under Medicare Part B, which covers infusion drugs, could result in overprescription of aducanumab. Under Medicare Part B, prescribing physicians are reimbursed 6% of a drug’s average sales price.
Geriatricians wary
On social media and in the lay press, geriatricians have been among the most outspoken opponents of the FDA decision and the Alzheimer’s Association’s advocacy of aducanumab.
Eric Widera, MD, a geriatrician at the University of California, San Francisco, said that the specialty might be less likely than others to embrace aducanumab. “I think part of the reasons geriatricians don’t make a lot of money is they have strong commitment to their values,” Dr. Widera said.
The American Geriatrics Society opposed the drug’s approval, citing concerns about evidence, side effects, and cost. “Additional considerations are the unintended consequences of overstressing Medicare’s limited financial reserves, and of challenging health care systems … to divert precious resources to an expensive treatment of uncertain value,” the society’s president, Peter Hollmann, MD, and chief executive officer, Nancy E. Lundebjerg, wrote in a June 2 letter to the FDA.
Dr. Widera said the approval was likely to undermine confidence in the FDA and in the Alzheimer’s Association, which receives significant funding from drug manufacturers, including Biogen and Eisai. “There’s a lot of reasons that the Geriatrics Society could have done what the Alzheimer’s Association did, and yet they came out against it, which I applaud.”
Dr. Widera pointed to a study showing that dementia patients were less likely to be on an antidementia drug if they were treated by a geriatrician, compared with a psychiatrist or a neurologist. But whether the specialty will prove as cautious with aducanumab remains to be seen. Some geriatricians will be tempted to open lucrative infusion centers, he predicted.
What is especially worrisome, Dr. Widera said, is that aducanumab’s label offers no guidance as to when to withdraw treatment. “We’ll probably see something similar to what happened with the cholinesterase inhibitors” – the class of marginally effective antidementia drugs that includes donepezil (Aricept, Pfizer) and rivastigmine (Exelon, Novartis). “No one thinks about deprescribing them. People are prescribed them even in their last months of life. There is no reason to think these infusions won’t be continued for a very long time, well beyond how long people were dosed in the trials.”
“Taking care of someone with dementia is hard enough,” Dr. Widera added. “We can’t even get normal support in the home for someone with dementia. But we are more than happy to throw money to Biogen for a drug they have not yet showed benefit for. Hopefully in 5 years we’ll have a drug that actually works,” Dr. Widera said. “After 5 years of giving this to people at $50,000 a year.”
A fractured research community
Ever since October 2019, when Biogen and Eisai announced that despite two trials halted for futility, they would go ahead and seek FDA approval for aducanumab, the Alzheimer’s research community has been bitterly divided over the drug and the FDA’s accelerated approval process.
Top researchers published critical editorials in journals, with some eventually taking their case to major newspapers as well. The Alzheimer’s Association’s position on the drug has clashed with that of many researchers whose work it supports.
“The Alzheimer’s community has been wonderfully collegial – we all have a common purpose,” Dr. Cummings said. “Now we have people taking extreme positions and I’m hoping this will not result in a permanent fracturing of the community.”
Chief among the critics’ concerns is that the FDA decision ratified the use of antiamyloid therapies based on biomarker evidence, opening the door for makers of similar drugs – those still under development or even those whose development has been halted – to seek approval on weak evidence of clinical benefit.
Whether the approval will chill research into drugs targeting pathways other than amyloid is uncertain.
Dr. Cummings said he felt that while the aducanumab decision would spur other manufacturers of antiamyloid drugs to seek accelerated approval, other classes of Alzheimer’s therapies in development also stand to get a boost. Many Alzheimer’s experts believe that a combination of drugs targeting different elements of the disease pathway – not just amyloid – will be needed in the long run.
Dr. Scharre said that the buzz over aducanumab’s approval will have at least one concrete benefit: people getting into doctors’ offices sooner.
“The people who come into our memory centers represent only a fraction of people walking around with MCI – there are people out there who may have heard that it’s normal aging; they have decreased insight; there’s denial, there’s embarrassment – there’s hundreds of reasons people avoid getting seen,” he said.
“Perhaps they come in and learn that they don’t have any degenerative process but their thyroid is out of whack, or there’s something else causing cognitive impairment. And if they do have a degenerative process, they’ll have time to start [aducanumab], and hopefully get to see a reduction in the decline.”
Dr. Knopman was a site investigator for the Biogen aducanumab trials and has consulted for Samus Therapeutics, Third Rock, Roche, and Alzeca Biosciences. A former member of the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee, he was recused from the Nov. 6, 2020, meeting that voted against aducanumab. Dr. Cummings has consulted for Biogen, Eisai, and other manufacturers. Dr. Scharre reports financial relationships with Biogen, Brain Test, Acadia, and Vascular Scientific. Dr. Widera has no disclosures. Dr. Delio is a speaker for Gore Medical, Allergan, and Biohaven Pharmaceuticals.
The approval was hailed by advocacy groups and some practitioners as a victory for patients and families, as the drug – the first anti-Alzheimer’s agent to reach the market in 18 years – is a potentially disease-modifying therapy, which acts to clear amyloid plaques from the brain.
But several prominent Alzheimer’s researchers lambasted the agency’s decision, citing unclear evidence of benefit, trials that did not meet their primary endpoints, and reliance on a post hoc analysis of a high-dose subgroup of patients in a halted trial to argue that aducanumab (Aduhelm, Biogen, and Eisai), slowed cognitive and functional decline by 22% on one measure. In November 2020, 10 of 11 members of an independent FDA advisory committee voted against aducanumab’s approval, citing holes in the data and concerns about the quality of the evidence. After the agency went on to approve anyway, three members of that committee resigned in protest.
The FDA decision on aducanumab was made using the agency’s accelerated approval pathway, which allows for the use of a surrogate endpoint – in this case imaging that showed amyloid clearance from the brain – to predict clinical benefit. But amyloid clearance, which a number of experimental antiamyloid antibodies have been shown capable of, has not been definitively linked to clinical benefit. Aducanumab, which is delivered by monthly intravenous infusion, will be marketed pending results from a phase 4 clinical trial, which the manufacturer has nearly a decade to complete. The drug’s price was announced at $56,000 per year, underscoring concern over its modest-at-best benefits.
Clinicians prescribing aducanumab must obtain magnetic resonance imaging at baseline and repeatedly during the course of treatment to detect brain edema and microhemorrhages, which occurred in a third of high-dose patients in clinical trials. Beyond this, there are few restrictions. The FDA label allows for its use in any patient deemed to have Alzheimer’s disease, without stipulations as to disease stage or evidence of brain amyloid. Payers, of course, are likely to restrict use to certain patient groups, and to require evidence of amyloid positivity. The FDA offered no guidance on when treatment should be ceased, leaving payers to make that call as well. Whatever aducanumab’s value and role turns out to be, the first-in-class treatment for Alzheimer’s disease is likely to have a major impact on how patients are assessed and treated in the coming years, and embolden manufactures of similar agents to seek FDA approval.
This news organization reached out to researchers, advocates, and specialists in the community to learn how they see this change playing out.
Fielding broad interest
Maria C. Carrillo, PhD, chief science officer of the Alzheimer’s Association, which was a strong proponent of aducanumab’s approval, acknowledged in an interview that the months to come are likely to be confusing for practitioners and families alike as the drug makes its way into community practices.
“We understand that off the bat millions of Americans will not have access to this tomorrow, but over time that will build. And the physician community, the specialists most likely to be prescribing this, over the next few years will even expand further,” Dr. Carrillo said.
For now, those specialists are mostly just struggling to respond responsibly to a deluge of inquiries from patients and their families.
“I’ve gotten like 20 calls in the just the past 2 days,” said neurologist Philip R. Delio, MD, who practices in Santa Barbara, Calif. “This is a longstanding issue that physicians have with patients’ access to information. Patients are getting information about a drug which isn’t available yet. They don’t know that it’s not ready to be sold. They don’t necessarily realize that a biopharma company won’t go into production until the FDA approves the drug.”
Many patients, Dr. Delio said, are aware of the controversy surrounding aducanumab and eager to hear their neurologist’s opinion. “I have tried to let them know that I want to see the trial data and to better understand the FDA’s rationale in approving it. I always caution patients that the devil will be in the details.”
While aducanumab’s label gives physicians remarkably wide latitude in whom to treat, clinicians say that until payers weigh in, the label is all but meaningless. Neurologist Douglas Scharre, MD, of the Ohio State University Wexner Medical Center, and a site investigator on a trial of aducanumab, said that he and his colleagues at the university’s memory center have tried to anticipate who might be deemed eligible by triaging calls.
Dr. Scharre and colleagues have been working under the assumption that payers will support aducanumab only for patients like those who seemed to benefit in the trials – people with mild cognitive impairment (MCI) or in the earliest stages of dementia with evidence of brain amyloid.
“I don’t want to fill up our new patient slots with people who are not even appropriate for this drug,” Dr. Scharre said. “We have a call center, and we have a few triage questions. After that a nurse practitioner collects some more data, and there’s a review process. Only then do we decide whether that person could be a candidate. If we deem that they are, we will want them in and to order an amyloid PET” – a type of brain scan that is seldom used outside research settings and not reimbursed by Medicare.
Dr. Scharre predicts that regardless of payer limitations, “there will be people hounding for the drug who are not appropriate for the drug. There will be very wealthy people who will want to pay for tests and get it no matter what.” Another concern, he said, was that having poorly selected patients on the drug could make definitive trial results even more elusive.
“The label the way it’s written is not going to help the drug in phase 4 trials,” he said. “It’s good to have real-world patient data, but if you have all these people in your cohort who are too early or too late, you won’t have good results.”
The challenge of delivery
Intravenous infusions are new to Alzheimer’s disease and pose all sorts of logistical hurdles. The Alzheimer’s Association’s Dr. Carrillo described the situation as “manageable,” noting that infusions are standard of care for many diseases, and that neurologists now have more than 15 years’ experience with them for multiple sclerosis.
Still, most clinicians treating Alzheimer’s disease in the community – neurologists, geriatricians, psychiatrists, and primary care physicians – do not have infusion centers in their practices. Virtually none have experience with or access to PET-amyloid, or with screening for amyloid-related imaging abnormalities–edema (ARIA-e) on MRI, as required by the FDA.
“I contacted the hospital infusion center we use and said I could end up sending five or six patients a week, can you handle this? They only have so many chairs,” Dr. Delio said. “I am one neurologist in a local community, and I might have 50 candidates for this drug. That’s a lot for them.” Patients with cognitive impairment are also difficult to infuse and may need to be treated at home, he noted.
“MRIs are easy enough to do,” Dr. Delio said. “But do we know what ARIA-e looks like on imaging? You’d have to talk to the radiologists – this is another element of uncertainty. Do we even know what we’re looking for with these scans? Will we recognize this?”
Neurologist Jeffrey L. Cummings, MD, ScD, of the University of Nevada, Las Vegas, a vocal proponent of aducanumab and lead author of a May 2021 paper defending the evidence for it, acknowledged that the field was unprepared for a wide-scale adoption of infusions in dementia treatment, pointing to a Rand Corporation study from 2017 that warned that screening, diagnosis, and availability of infusion chairs would have to be drastically scaled up to meet demand.
“There are few clinicians who know how to identify MCI, too few imaging centers, too few radiologists who know how to identify ARIA-e on MRI, so all of these things will be required to be put into place. The label doesn’t specify any of this, but good clinical practice will require that, and getting this up and running will take 18 to 24 months,” Dr. Cummings said.
Neurologist David S. Knopman, MD, of the Mayo Clinic in Rochester, Minn., a leading critic of the evidence for aducanumab who recently resigned his position on the independent committee that advises the FDA on neurology drugs, said that for large research institutions like his that have served as trial sites, the transition to offering PET-amyloid, MRI, and infusions in clinical practice will be easier.
“We have all this because this is what we do every day. And we have a very extensive understanding of MCI and mild dementia staging,” Dr. Knopman said. “But the amount of infrastructure that is implied by this, and all the extra steps it would take, would be a real challenge for people in general neurology practice.”
In addition to routine use of PET-amyloid and MRI screening for ARIA-e, Dr. Knopman said, clinicians will have to provide genetic screening and counseling before administering aducanumab, as clinical trials showed that treated patients have a higher risk of developing ARIA-e if they have APOE4, a risk variant for Alzheimer’s disease. “And that has real implications for the families and the children of patients,” he said.
Uncertainty over costs
Aducanumab’s true costs, to patients and to taxpayers, remain unknown. The $56,000 per year currently cited by its manufacturer “doesn’t count the PET scans and MRIs,” Dr. Knopman noted. “We’re probably pushing $100,00 a year for the first year of treatment.”
Most of that expense will likely be borne by Medicare, he said, and if not, “that will exacerbate existing health care disparities. People who can pay out of pocket are a pretty limited group.”
Dr. Scharre agreed that the costs of treatment were concerning, and that “at least you should be able to narrow it down and hopefully just use health care dollars for people who might stand to benefit,” he said – namely patients in an earlier stage of disease.
The Alzheimer’s Association’s Dr. Carrillo declined to address the high price of aducanumab or its implications, saying only that the association is “very invested in all aspects of access including covering costs associated with the drug and the rest of treatment.”
Access also means “infrastructure, access to physicians to diagnose, access to diagnostics,” Dr. Carrillo said.
Dr. Cummings said aducanumab’s price would likely come down through negotiations with the Centers for Medicare & Medicaid Services, copayments, and bulk purchases.
The FDA has offered no guidance on how long treatment with aducanumab should last, or what should prompt withdrawal of treatment, meaning that patients could, in theory, stay on it to the end of their lives – raising costs further.
Critics have also noted that a built-in financial incentive under Medicare Part B, which covers infusion drugs, could result in overprescription of aducanumab. Under Medicare Part B, prescribing physicians are reimbursed 6% of a drug’s average sales price.
Geriatricians wary
On social media and in the lay press, geriatricians have been among the most outspoken opponents of the FDA decision and the Alzheimer’s Association’s advocacy of aducanumab.
Eric Widera, MD, a geriatrician at the University of California, San Francisco, said that the specialty might be less likely than others to embrace aducanumab. “I think part of the reasons geriatricians don’t make a lot of money is they have strong commitment to their values,” Dr. Widera said.
The American Geriatrics Society opposed the drug’s approval, citing concerns about evidence, side effects, and cost. “Additional considerations are the unintended consequences of overstressing Medicare’s limited financial reserves, and of challenging health care systems … to divert precious resources to an expensive treatment of uncertain value,” the society’s president, Peter Hollmann, MD, and chief executive officer, Nancy E. Lundebjerg, wrote in a June 2 letter to the FDA.
Dr. Widera said the approval was likely to undermine confidence in the FDA and in the Alzheimer’s Association, which receives significant funding from drug manufacturers, including Biogen and Eisai. “There’s a lot of reasons that the Geriatrics Society could have done what the Alzheimer’s Association did, and yet they came out against it, which I applaud.”
Dr. Widera pointed to a study showing that dementia patients were less likely to be on an antidementia drug if they were treated by a geriatrician, compared with a psychiatrist or a neurologist. But whether the specialty will prove as cautious with aducanumab remains to be seen. Some geriatricians will be tempted to open lucrative infusion centers, he predicted.
What is especially worrisome, Dr. Widera said, is that aducanumab’s label offers no guidance as to when to withdraw treatment. “We’ll probably see something similar to what happened with the cholinesterase inhibitors” – the class of marginally effective antidementia drugs that includes donepezil (Aricept, Pfizer) and rivastigmine (Exelon, Novartis). “No one thinks about deprescribing them. People are prescribed them even in their last months of life. There is no reason to think these infusions won’t be continued for a very long time, well beyond how long people were dosed in the trials.”
“Taking care of someone with dementia is hard enough,” Dr. Widera added. “We can’t even get normal support in the home for someone with dementia. But we are more than happy to throw money to Biogen for a drug they have not yet showed benefit for. Hopefully in 5 years we’ll have a drug that actually works,” Dr. Widera said. “After 5 years of giving this to people at $50,000 a year.”
A fractured research community
Ever since October 2019, when Biogen and Eisai announced that despite two trials halted for futility, they would go ahead and seek FDA approval for aducanumab, the Alzheimer’s research community has been bitterly divided over the drug and the FDA’s accelerated approval process.
Top researchers published critical editorials in journals, with some eventually taking their case to major newspapers as well. The Alzheimer’s Association’s position on the drug has clashed with that of many researchers whose work it supports.
“The Alzheimer’s community has been wonderfully collegial – we all have a common purpose,” Dr. Cummings said. “Now we have people taking extreme positions and I’m hoping this will not result in a permanent fracturing of the community.”
Chief among the critics’ concerns is that the FDA decision ratified the use of antiamyloid therapies based on biomarker evidence, opening the door for makers of similar drugs – those still under development or even those whose development has been halted – to seek approval on weak evidence of clinical benefit.
Whether the approval will chill research into drugs targeting pathways other than amyloid is uncertain.
Dr. Cummings said he felt that while the aducanumab decision would spur other manufacturers of antiamyloid drugs to seek accelerated approval, other classes of Alzheimer’s therapies in development also stand to get a boost. Many Alzheimer’s experts believe that a combination of drugs targeting different elements of the disease pathway – not just amyloid – will be needed in the long run.
Dr. Scharre said that the buzz over aducanumab’s approval will have at least one concrete benefit: people getting into doctors’ offices sooner.
“The people who come into our memory centers represent only a fraction of people walking around with MCI – there are people out there who may have heard that it’s normal aging; they have decreased insight; there’s denial, there’s embarrassment – there’s hundreds of reasons people avoid getting seen,” he said.
“Perhaps they come in and learn that they don’t have any degenerative process but their thyroid is out of whack, or there’s something else causing cognitive impairment. And if they do have a degenerative process, they’ll have time to start [aducanumab], and hopefully get to see a reduction in the decline.”
Dr. Knopman was a site investigator for the Biogen aducanumab trials and has consulted for Samus Therapeutics, Third Rock, Roche, and Alzeca Biosciences. A former member of the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee, he was recused from the Nov. 6, 2020, meeting that voted against aducanumab. Dr. Cummings has consulted for Biogen, Eisai, and other manufacturers. Dr. Scharre reports financial relationships with Biogen, Brain Test, Acadia, and Vascular Scientific. Dr. Widera has no disclosures. Dr. Delio is a speaker for Gore Medical, Allergan, and Biohaven Pharmaceuticals.