Two weeks after the FDA gave the nod to aducanumab, the aftershocks continue to reverberate. Critics are lambasting the agency, three members of its advisory committee resigned, and the drug’s cost has ignited calls for pricing reform. Meanwhile, Alzheimerologists are split, with some applauding the first disease-modifying therapy and others worrying it could dampen research into other drugs. All bemoan the broad label and agree that the drug’s clinical rollout will be challenging.
Series
Fallout Continues After Aducanumab Approval
Aducanumab Approval Sparks Backlash
Eds. note, 25 Jun 2021: In the three days since this series posted, Senators Elizabeth Warren (D, Massachusetts) and Bill Cassidy (R, Louisiana) have requested the Senate Finance Committee examine how Aduhelm will affect the Medicare budget. Private insurer Point32Health, a merger of Tufts Health Plan and Harvard Pilgrim Health Care that insures some two million people in New England, said it may not cover Aduhelm unless the cost comes down. Meanwhile, the FDA granted breakthrough therapy status to Eisai/Biogen’s lecanemab and Eli Lilly’s donanemab, and Lilly applied for accelerated approval. Gantenerumab developer Roche has said it will continue its Phase 3 program unchanged.
In the two weeks since the Food and Drug Administration approved a license for Biogen’s Alzheimer’s antibody aducanumab, marketed as Aduhelm, controversy over the decision has continued to build. Industry analysts have written numerous scathing editorials. Critical debate reached the U.S. Congress. A watchdog group called for heads to roll at the FDA, and three members of the agency’s advisory committee quit in protest. On the other side, advocacy groups continue to laud the decision, but even they note qualms about the treatment’s price tag (see Part 2 of this series). Among Alzheimer’s researchers and clinicians, reaction remains mixed. Privately, many express unhappiness with the decision and lament a possible chilling effect on other therapeutic research, as well as the logistical challenge of integrating monthly infusions into clinical practice (see Part 3 of this series). Others view it as a first, if faltering, step toward more disease-modifying treatments. They see a bright future ahead. The debate will likely continue as the field grapples with this disruptive change to Alzheimer’s practice.
Recriminations Swirl in Wake of FDA Decision
The approval process for aducanumab has been fraught from the beginning. After skipping Phase 2, Biogen halted its two Phase 3 trials when they failed a futility analysis, but later announced that additional data rendered one of them positive (Mar 2019 news; Dec 2019 news). None of the members of the FDA’s advisory committee considered these conflicting data sufficient for approval (Nov 2020 news; Nov 2020 news).
In its June 7 ruling, the FDA acknowledged uncertainties in the efficacy data but based its decision on aducanumab’s robust clearance of amyloid plaques, noting their expectation that this will lead to a clinical benefit. The agency granted a marketing license using its accelerated approval program, which accepts change on a surrogate biomarker as likely evidence of efficacy but requires a post-market study to prove clinical benefit. Biogen has nine years to conduct such a trial (Jun 2021 news), a time span that sparked outrage for its length.
In the industry press, the decision ignited a firestorm of criticism. Observers lamented the lowering of standards and the precedent this might set for other drug approvals (Bloomberg news; AAAS blog). In a poll of 1,400 biopharma executives and staff, 80 percent thought the FDA should not have approved aducanumab, and 70 percent disagreed with the use of the accelerated approval pathway (Endpoints news).
The FDA’s move led Joel Perlmutter at Washington University in St. Louis, David Knopman at the Mayo Clinic in Rochester, Minnesota, and Aaron Kesselheim at Brigham and Women’s Hospital, Boston, to resign from AdComs (STAT news). Kesselheim later penned a New York Times editorial lambasting the agency. A fourth member, Madhav Thambisetty of the National Institute on Aging in Bethesda, Maryland, felt the need to explain why he was staying on the committee (STAT news).
The Washington, D.C.-based watchdog group Public Citizen, which had earlier criticized the close collaboration between Biogen and the FDA, went so far as to call for the removal of acting FDA commissioner Janet Woodcock, drug evaluation director Patrizia Cavazzoni, and neuroscience director Billy Dunn (Jan 2021 news; Endpoints news). The issue even reached the halls of the U.S. Congress, where Senator Joe Manchin (D, West Virginia) cited the aducanumab approval in his June 17 letter urging President Biden not to appoint Woodcock commissioner of the FDA. The decision also prompted criticism of the agency in the general media (e.g., The Washington Post editorial).
Plaque Removal A Surrogate Marker?
In particular, the FDA’s use of the accelerated approval mechanism raised eyebrows. At the AdComs meeting last November 6, FDA officials explicitly said this pathway was not on the table (Endpoints news). The advisory committee was asked to evaluate the drug based on the efficacy data. After receiving a “no,” the agency pivoted to make its decision on a different basis not discussed by the committee. The FDA never consulted the AdComs about the different pathway it had switched to since the meeting.
Lon Schneider at the University of Southern California, Los Angeles, noted that by using this pathway, the FDA in effect declared that amyloid PET functions as a surrogate marker of efficacy in AD treatment. “This perhaps is the most stunning outcome,” he wrote to Alzforum. Normally, the FDA follows a methodical qualification process, whereby it first establishes the validity of a surrogate marker and issues guidance to the whole field, before using the marker as the basis for approving a specific drug. That did not happen here, giving the de facto validation of plaque removal as a surrogate a sense of sleight of hand.
Many others expressed similar surprise. “This [decision] implies that brain amyloid has achieved the status of blood cholesterol for heart disease, and I don’t believe it has,” John Hardy at University College London wrote to Alzforum (full comment below). AdComs member Thambisetty warned that the aducanumab approval could make it easier for other amyloid-lowering drugs to reach the market without proving efficacy. Jörg Schulz, who chairs the neurology department at RWTH University Medical School in Aachen, Germany, asked if a slew of amyloid-reducing agents from the past will now be re-evaluated under the accelerated approval pathway (see full comment from June 14). In a public defense of her agency’s decision on June 22, Woodcock said future approvals under this pathway would be possible if the magnitude of plaque reduction was great enough.
Marsel Mesulam at Northwestern University, Chicago, believes the agency stepped outside of its purview by declaring amyloid reduction a surrogate marker. “Many of us have wondered whether regulators should be in the business of deciding on hope rather than fact, and whether they should be adjudicating on theories of pathogenesis,” Mesulam wrote (comment below). Jason Karlawish at the University of Pennsylvania, Philadelphia, said, “It raises real concerns about what’s going on at FDA and how they are using their regulatory authority.”
Plaque and Cognition, a Hazy Relationship
One reason for some scientists’ reservations about plaque removal as a surrogate marker is that small reductions in amyloid have not led to cognitive benefit in trials of several different drugs. In a recent meta-analysis, researchers led by Edo Richard at Radboud University Medical Center, Nijmegen, the Netherlands, evaluated data from trials of solanezumab, bapineuzumab, and low-dose gantenerumab, the latter two of which nudged plaque load but not ADAS-Cog scores (Richard et al., 2021).
Researchers led by Maria Glymour at the University of California, San Francisco, cast a wider net, including published studies of all drugs purported to lower amyloid plaque, regardless of their mechanism of action. In addition to the trials studied by Richard et al., Glymour et al. analyzed data from bexarotene, semagacestat, verubecestat, lecanemab Phase 1, and aducanumab Phase 1 trials. Their meta-analysis found no correlation between MMSE score and the small amyloid reduction in these studies (Ackley et al., 2021).
“The idea that we would approve medications on the basis of a biomarker change, i.e., amyloid reduction, when we know that reducing amyloid does not equate to definite benefit for improving people’s lives, i.e., memory and functioning improvements, sets a bad precedent,” Glymour wrote to Alzforum (full comment below).
The connection between amyloid removal and cognitive benefit remains possible, however. These meta-analyses included small trials, e.g. lecanemab; low-dose trials, e.g., gantenerumab; and drugs not primarily designed to lower plaques, e.g., BACE inhibitors, bexarotene. Much more drastic amyloid plaque reduction is being reported for three other anti-amyloid antibodies besides aducanumab. Two of them—donanemab and lecanemab—did tap the brakes on cognitive decline by 20 to 30 percent in well-designed Phase 2 trials, while Phase 3 data on high-dose gantenerumab are expected next year. This renders the agency’s assumption that near-complete amyloid removal may foretell a subsequent cognitive benefit not formally proven but plausible.
And indeed, many scientists focus on the bigger scientific picture in their qualified welcome of the agency’s decision. Bart De Strooper, who leads the U.K. Dementia Research Institute at UCL, thinks it is misleading to set up a dichotomous choice whereby amyloid plaques are seen as either a driver of cognitive decline, or irrelevant to the disease process. “A simplistic cause-consequence relationship between accumulating amyloid and neurodegeneration should have been abandoned more than a decade ago,” he wrote to Alzforum (full comment below). “Amyloid pathology [is] a trigger of a series of disease processes.” In this scheme, often referred to as the amyloid cascade hypothesis, amyloid buildup unleashes tau tangles, which then lead to neurodegeneration and memory problems. Inflammation is an important player, too.
And How About the Tangles?
Takeshi Iwatsubo at the University of Tokyo noted that aducanumab’s effect on tangles may be the key to its apparent slowing of cognitive decline in Biogen’s one positive Phase 3 trial. “The FDA statement emphasized amyloid reduction as a surrogate biomarker, but they should rather have valued the CSF p-tau and tau PET data,” he wrote to Alzforum (full comment below). Biogen ran only tiny substudies on these tau markers; the data they did show indicated normalization in people on high-dose aducanumab.
All four of the anti-amyloid antibodies that clear plaques to below the threshold of brain-wide positivity also seem to dampen tau pathology, as seen by CSF or tau PET. These data often come from substudies and effect sizes are typically small (Mar 2021 conference news; Nov 2018 conference news; Apr 2020 conference news).
For more reaction from Alzheimer’s researchers, see Part 2 of this series.—Madolyn Bowman Rogers
References
Therapeutics Citations
- Aduhelm
- Solanezumab
- Bapineuzumab
- Bexarotene
- Semagacestat
- Verubecestat
- Donanemab
- Leqembi
- Gantenerumab
News Citations
- A New Era of Alzheimer’s Treatment
- Biogen/Eisai Halt Phase 3 Aducanumab Trials
- Exposure, Exposure, Exposure? At CTAD, Aducanumab Scientists Make a Case
- FDA Advisory Committee Throws Cold Water on Aducanumab Filing
- Aducanumab Still Needs to Prove Itself, Researchers Say
- Aducanumab Approved to Treat Alzheimer’s Disease
- Begone 2020: Despite COVID, Alzheimer’s Research Advanced
- Donanemab Confirms: Clearing Plaques Slows Decline—By a Bit
- Second Look at BAN2401 Data Still Positive, Despite Snafu
- In DIAN-TU, Gantenerumab Brings Down Tau. By a Lot. Open Extension Planned
Paper Citations
- Richard E, den Brok MG, van Gool WA. Bayes analysis supports null hypothesis of anti-amyloid beta therapy in Alzheimer's disease. Alzheimers Dement. 2021 Jun;17(6):1051-1055. Epub 2021 May 31 PubMed.
- Ackley SF, Zimmerman SC, Brenowitz WD, Tchetgen Tchetgen EJ, Gold AL, Manly JJ, Mayeda ER, Filshtein TJ, Power MC, Elahi FM, Brickman AM, Glymour MM. Effect of reductions in amyloid levels on cognitive change in randomized trials: instrumental variable meta-analysis. BMJ. 2021 Feb 25;372:n156. PubMed.
External Citations
Further Reading
A New Era of Alzheimer’s Treatment
The Food and Drug Administration’s decision to greenlight aducanumab (trade name Aduhelm) for Alzheimer’s disease has touched off an explosion of criticism and debate (see Part 1 of this series). Some researchers, however, consider the approval an overall positive development that the neurodegeneration field can build on as it seeks combination therapies that slow disease progression. For example, Ken Marek at the Institute for Neurodegenerative Disorders in New Haven, Connecticut, believes the aducanumab decision heralds the beginning of a new era in neurodegenerative disease research, with a focus on therapies that move biomarkers in Alzheimer's and related diseases and slow the march of the underlying pathology (STAT news). Marek leads the Parkinson’s Progression Markers Initiative, which studies biomarkers of PD.
Dawn of Disease Modification?
Some Alzheimer’s researchers, too, see the approval as a step toward disease-modifying therapies. They draw parallels with the history of drug development in other fields. “I think the FDA decision will benefit the AD field greatly, as did the approval of betaferon for the multiple sclerosis field in 1993. It will boost drug development and research in general,” Philip Scheltens at VU University, Amsterdam, wrote to Alzforum (full comment below). Bart De Strooper, who leads the U.K. Dementia Research Institute at UCL, compared the decision to the fast-tracking of the first drugs for AIDS, which had minimal clinical benefit. “This opened the way for further clinical experimentation and trials and brought the AIDS field in two decades to almost curative therapy,” De Strooper wrote.
Others drew a distinction between the messy approval process for aducanumab and its end result. “We all recognize the liabilities of the path to aducanumab approval, which I believe were more a function of trial execution than an intrinsic weakness of the agent or the biology behind it,” Dennis Selkoe at Brigham and Women’s Hospital wrote to Alzforum. “In my view, the strength of the biology and the clarity of aducanumab’s key biomarker endpoint overcame an imperfect clinical dataset,” Selkoe added (full comment below). Marwan Sabbagh, at the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas, went further. “It was a transformative moment in the field. It’s the first step toward taking Alzheimer’s from a terminal to a chronic disease,” Sabbagh said.
Other stakeholders hailed the decision, as well. In addition to positive reaction from advocacy groups such as the Alzheimer’s Association and Us Against Alzheimer’s, the Global Alzheimer’s Platform commended the FDA for its stance, and the National Institutes of Health called the approval a milestone achievement. “The hope is greater than it’s ever been before that we’re going to find increasingly effective interventions,” NIA director Richard Hodes told Alzforum.
The Price Isn’t Right
Even those who agree with the FDA’s decision, however, take issue with Biogen’s planned price of $56,000 per patient per year. In a poll of biopharma executives, 75 percent considered this too high, given the drug’s uncertain efficacy and known safety risks. They warned that given the large number of retirement-age people who might qualify for treatment, aducanumab's cost would blow an enormous hole into the taxpayer-funded budgets of Medicare and the Veteran's Health Administration. A recent analysis by the Kaiser Family Foundation estimated aducanumab could cost Medicare $57 billion per year, roughly the same amount as all other hospital outpatient services combined.
The approval could also deepen inequity in the U.S. health care system, where the well-off typically receive better care. “We know there will be disparities in access because our health care system is riddled with them,” Emily Largent, University of Pennsylvania, Philadelphia, wrote to Alzforum (full comment below). Others fear that hope and desperation may prompt patients whose disease is too advanced for them to benefit from this treatment to spend their life savings on out-of-pocket aducanumab.
“This price is simply unacceptable. … We call on Biogen to change this,” the Alzheimer’s Association wrote in a June 12 statement.
In a June 8 call with investors, Biogen CEO Michel Vounatsos defended the price, noting that aducanumab’s cost is about one-third that of cancer immunotherapies. He said the company is talking to private insurers such as Cigna about using value-based contracts, which set the price of a drug based on how well it performs, but gave no details on how that would work or what performance benchmarks might be used. He also promised not to raise the price for four years.
Meanwhile, Biogen’s chief financial officer Mike McDonnell estimated that U.S. sales of the antibody would ramp up over several years into the multibillion-dollar range. Mainstream and industry press likewise believe Biogen stands to rake in the cash (New York Times news; Endpoints news; STAT news).
Some predicted the antibody’s cost could spur renewed calls for drug pricing reform (Fierce Pharma news; STAT news). One senator has already called for Medicare to have the ability to negotiate cost, specifically citing aducanumab as an example of unjustifiable pricing (Endpoints news). A coalition representing employers and other health care purchasers is advocating for this as well.
Bane or Boon for Alzheimer’s Drug Research?
Many researchers fear the aducanumab approval will complicate their efforts to evaluate better Alzheimer’s drugs. One concern is that patients may prefer to take an approved medication rather than roll the dice on one still in development, especially given that they might end up on placebo. “Once aducanumab becomes commonly available, it’s going to become really hard to recruit for mild cognitive impairment trials,” Sabbagh predicted.
Some worry that participants in ongoing AD trials might drop out to go on aducanumab instead. Researchers at Eli Lilly, who are developing donanemab, among other investigational medicines for AD, did not respond to a request for comment. Roche scientists, meanwhile, expressed confidence in their program. “We are not changing our scientific approach for the pivotal trials of gantenerumab in AD,” Rachelle Doody of Roche wrote to Alzforum. “We're working closely with our investigator network to address any questions they or trial participants may have about continuing in our studies,” she added (full comment below).
Others think the field will adapt. “Finishing current trials will no doubt be more challenging with Aduhelm on the market, but other fields have faced this problem and moved on to add multiple new agents over time,” Selkoe wrote.
A related concern is that the aducanumab approval might lead funding agencies to favor anti-amyloid drugs at the expense of other approaches. The NIH, at least, has no plans to change course. “Right now, the large majority of Phase 1 and 2 [AD] trials are against non-amyloid targets, and this will certainly continue,” Hodes told Alzforum (see Alzforum Therapeutics listing of such trials). Hodes also sees no imperative to change trial designs to compare new drugs against aducanumab as a positive control, given that the antibody has not shown a definitive effect on symptoms.
De Strooper sees ample opportunity in aducanumab’s approval. It will open the door for studies that define the antibody’s benefit in different patient populations and test its efficacy in combination with other drugs. “Alzheimer’s disease and dementia are complicated disorders, and it is unlikely that one simple hypothesis and one golden bullet will explain and treat all,” he wrote.
Many believe this approval will encourage further investment in AD drug research. “History has shown us that approval of the first drug in a new category invigorates the field, increases investments in new treatments, and encourages greater innovation,” wrote Maria Carrillo of the Alzheimer’s Association in a statement. There are already signs of renewed investor interest, with pharma companies reporting a deluge of calls (Fierce Biotech news; related news). In part, investors are lured by the prospect of gaining approval more easily with amyloid reduction data alone.
Retired neurologist Daniel Gibbs of the Oregon Health and Science University, Portland, compared aducanumab to tacrine, the first acetylcholinesterase inhibitor to go on the market in 1993. Tacrine’s efficacy was controversial at the time (Relman, 1991). It was also toxic to the liver and was soon supplanted by other drugs in its class. “Aducanumab may be the tacrine of today: the first drug of its class with likely effectiveness, but it will almost certainly be joined and possibly replaced by other, more effective drugs in the future,” Gibbs suggested.
Selkoe summed up the situation this way: “We have taken a sizeable, albeit controversial, step in the direction of actual disease modification. There’s no going back.”—Madolyn Bowman Rogers
References
News Citations
Paper Citations
- Tacrine as a treatment for Alzheimer's dementia: editor's note. An interim report from the FDA. A response from Summers et al. N Engl J Med. 1991 Jan 31;324(5):349-52. PubMed.
Other Citations
External Citations
Further Reading
How Will Aducanumab Approval Change Clinical Practice?
The U.S. Food and Drug Administration’s green light for aducanumab (Aduhelm) is poised to upend research and clinical practice. In research settings, many scientists wonder if this decision will set a precedent for future approvals without proof of efficacy, and whether it will help or hamper research into additional drugs (see Part 1 and Part 2 of this series). In treatment settings, Alzheimer’s physicians are facing a deluge of calls. They are also facing a sea of unknowns, ranging from which patients qualify for aducanumab treatment to what its contraindications may be and how long patients should stay on it (see Part 4 of this series). And how exactly are they to decide whether the antibody’s benefits outweigh its risks for the patient before them?
The accelerated approval requires Biogen to run a Phase 4 trial to address some of these quandaries, but the nine-year timeframe for this study means answers will not be coming anytime soon. Also up in the air is whether insurers will cover the treatment's steep cost, and how payers may restrict access to it, possibly exacerbating inequities in healthcare. Many clinicians are conflicted about aducanumab, believing the efficacy data did not warrant approval just yet. Most of those decline to be quoted. Despite their misgivings, they told Alzforum they will offer it to their patients, in the context of an honest discussion of the treatment’s risks and limitations. Ready or not, Alzheimer’s treatment has entered a new era.
Broad Label Confounds Clinicians
Alzheimer’s physicians expressed consternation over the lack of guidance on what type of patient should receive the treatment. Biogen’s Phase 3 trials enrolled people with amnestic mild cognitive impairment or mild dementia due to AD, all of whom had biomarker confirmation of amyloid buildup in the brain. Researchers assumed that if the agency approved aducanumab, it would restrict the drug to this group. However, the FDA prescribing label specifies only “Alzheimer’s disease.” The label requires two MRI scans to monitor for the most serious side effect of the antibody but does not require confirmation of amyloid plaques.
This could open up aducanumab to misuse, researchers said. “I found the label profoundly inadequate—way too broad—and potentially harmful to patients, the field, and the drug as well,” Philip Scheltens at VU University, Amsterdam, wrote to Alzforum. Johannes Levin, of Ludwig-Maximilians-Universität München, called the label “almost careless” (see full comment below Part 4).
For one, the label lists no contraindications. This point urgently requires guidance, clinicians agree, as patients with numerous prior microhemorrhages, or people who take blood thinners, may face a higher risk of ARIA-related complications. Prescribing physicians need to know what to do with patients whose Alzheimer's is accompanied by cerebral amyloid angiopathy or cerebrovascular disease.
For another, the label does not require that the prescribing physician confirm the presence of brain amyloid. Researchers broadly agree that doing so will be crucial, as it would be unethical to give the antibody to someone without the pathology it targets.
Thirdly, clinical stage is important. People with more advanced disease, where progression is believed to have become independent of amyloid, are likely to be both most desperate for aducanumab and least likely to benefit from plaque removal. There are no data on the safety and effectiveness of aducanumab in moderate or severe Alzheimer’s. A majority of the Alzheimer's patients who are currently in the care of primary care physicians, geriatricians, and neurologists across the country are at stages more advanced than aMCI/mild AD. On the flip side, most researchers suspect that people in the preclinical phase may reap the greatest benefit from aducanumab, though this has not yet been proven in randomized controlled trials, either.
“I was very surprised by the broad indication from the FDA, which seems to fly in the face of all existing data,” is how Erik Musiek at Washington University in St. Louis summed it up (full comment below).
Gatekeeping Left to Insurers
The open-ended label leaves it up to individual physicians and insurers to control access to aducanumab. Because of the antibody’s price tag of $56,00 per year, payers will wield tremendous authority over who can receive the treatment outside of boutique medicine for the wealthiest. The Centers for Medicare and Medicaid Services are required to provide Medicare enrollees access to approved drugs, but CMS can set eligibility requirements. CMS will likely be guided by the clinical trial data available thus far. Or it may invoke a coverage with evidence development pathway whereby large studies whose participants need not pay for the medication gather real-world evidence that becomes the basis for a nationwide coverage decision by the CMS. This is being done for amyloid imaging (Apr 2015 news; Aug 2017 news; Aug 2020 news). One editorial has already called for CMS to follow the same path for aducanumab (Health Affairs blog).
In a June 8 call with investors, Biogen CEO Michel Vounatsos said the company has been in talks with CMS, and expects the insurer to cover 80 percent of the cost of the treatment. This would leave about $11,000 per year in out-of-pocket costs, although many Medicare participants have secondary insurance that could bring that down, or annual spending caps that limit liability. Biogen estimates that the population eligible for treatment under CMS restrictions will amount to 1 to 2 million people in the U.S.
Emily Largent, who teaches health policy and ethics at the University of Pennsylvania, Philadelphia, noted that CMS coverage may not suffice to ensure equal access to treatment. “Even if insurers do cover aducanumab, there will be disparities in access due to out-of-pocket costs that are burdensome or even prohibitive for some individuals. Here, we have to think about the co-payments and co-insurance associated with the infusions, but also with the scans and office visits that will be needed,” she wrote to Alzforum.
Scott Small at Columbia University, New York, agreed that the associated costs of amyloid screening, office visits, and MRI scans are not trivial. “We’ve done the math. It’s over $100,000 a year if you factor that in,” he told Alzforum. It will be incumbent upon physicians to talk fully and honestly about cost, risk, and the efficacy data with patients and their families. “We have to engage our patients in tough decision-making. Cancer doctors do that all the time,” Small said (additional written comment below). In multiple sclerosis, too, disease-modifying treatment started, some 25 years ago, with exorbitant costs and small effects.
To promote use of aducanumab and cut costs, Biogen is developing a program of cerebrospinal fluid testing with the Mayo Clinic Labs and LabCorp, a testing supply company based in Burlington, North Carolina. In the investor call, Vounatsos promised a financial assistance program for patients, focusing on underserved communities, but offered no details. A press release discusses some organizations Biogen is working with, such as CVS Health and the National Association of Free and Charitable Clinics.
Production: Ready. Clinics: Not So Much.
Another question is whether there will be enough antibody to meet demand. Here, Biogen appears on top of things. The company recently opened a new factory in Solothurn, Switzerland (Fierce Pharma news). The site complements Biogen’s existing facility in Research Triangle Park, North Carolina. Together the factories can produce enough antibody to treat about 3 million patients per year, according to Nicole Murphy, who leads global manufacturing at Biogen. She said the company will begin shipping the antibody in late June.
Where will these doses go? Vounatsos said Biogen has identified 900 clinical sites in the U.S. that have the capacity for amyloid testing, MRI monitoring, and neurological diagnosis. It is unclear what type of clinics these are, although Vounatsos said they are not primary-care centers. Biogen representatives did not respond to multiple requests for more information, and several Alzheimer's disease clinics at academic medical centers contacted by Alzforum said they are not among the 900.
These clinics might not be enough to meet demand if aducanumab use becomes widespread. A 2017 Rand Corp. study commissioned by Biogen modelled what might happen after approval of an Alzheimer’s therapy. The researchers assumed that most people over 55 would undergo cognitive screening in primary care, followed by a visit to a dementia specialist and amyloid screening. If implemented, this process could result in 2.4 million Americans eligible for aducanumab treatment. In this scenario, the scarcity of dementia specialists in the U.S. would become the primary holdup, leading to 18-month wait times for office visits, the researchers predicted. Lack of PET scanning facilities and infusion centers could also be limiting factors (Liu et al., 2017).
Musiek agrees that dementia specialists represent the bottleneck. “Imaging studies are generally well-reimbursed, and infusion centers can be quickly expanded. But physicians with expertise in dementia cannot be created suddenly out of thin air,” he wrote to Alzforum. Musiek and WashU's John Morris articulated anticipated shortages in the Alzheimer's health care system in a recent perspective article (Musiek and Morris, 2021).
The day of the approval, many clinics started fielding calls from interested patients, with some receiving hundreds a day. They are counseling patience, noting that they are still awaiting guidance from insurers to set up screening procedures. This could take months, as spelled out in a statement from the Knight ADRC at Washington University in St. Louis. “We will push on, finding the best way to get this new treatment to our patients who might benefit,” Joy Snider at WashU wrote to Alzforum. Across the board, clinicians agreed the rollout of aducanumab treatment will be difficult and slow.
For more on the conundrums facing physicians, see Part 4 of this series.—Madolyn Bowman Rogers
References
News Citations
- Aducanumab Approval Sparks Backlash
- A New Era of Alzheimer’s Treatment
- With Little Data to Go On, Clinicians Are Left To Figure Out Way Forward
- $100M IDEAS: CMS Blesses Study to Evaluate Amyloid Scans in Clinical Practice
- In Clinical Use, Amyloid Scans Change Two-Thirds of Treatment Plans
- IDEAS Finds Small Drop in Hospitalizations, Missing Goal
Paper Citations
- Musiek ES, Morris JC. Possible Consequences of the Approval of a Disease-Modifying Therapy for Alzheimer Disease. JAMA Neurol. 2021 Feb 1;78(2):141-142. PubMed.
External Citations
Further Reading
With Little Data to Go On, Clinicians Are Left To Figure Out Way Forward
The FDA’s approval of aducanumab has given Alzheimer’s physicians a new treatment option, but little guidance on how to put it into practice. Clinicians are debating issues such as when to prescribe, who qualifies, and how to ramp up capacity (see Part 3 of this story). They also have to figure out how to communicate the potential risks and benefits to patients and their families, and how long to keep patients on drug. Biogen’s post-market study may answer these questions, but the nine-year timeframe means this is no help for clinicians now. Around the world, physicians are preparing to enter a challenging new phase of Alzheimer’s care.
To Prescribe or Not to Prescribe?
Beyond the logistical challenges of bringing monthly infusions into clinical practice lie ethical ones. Some clinicians doubt the value of aducanumab for their patients. Nonetheless, all clinicians Alzforum contacted said they would offer their patients the option to take it. “I believe that patients and families have a right to this treatment now that it is approved, and also that they should receive accurate information from knowledgeable providers about the risks and benefits to help their decision-making,” Suzanne Craft at Wake Forest School of Medicine in Winston Salem, North Carolina, wrote to Alzforum (full comment below).
Even outspoken critics of the FDA approval are taking this approach. David Knopman at the Mayo Clinic in Rochester, Minnesota, who had urged the FDA to demand a confirmatory trial before approving, told Alzforum, “If my patients and their families express interest, I will discuss the pros and cons with them.” Ditto for the National Institute on Aging’s Madhav Thambisetty, who as a fellow AdComs member had advised against approval but more recently wrote about his first physician consult discussing aducanumab with a son and his dad, whose disease was likely too advanced to benefit from the treatment.
Jason Karlawish at the University of Pennsylvania, Philadelphia, described his reluctance to prescribe aducanumab in an editorial prior to June 7. The approval is now forcing his hand because he also believes in respecting an Alzheimer’s patients’ autonomy. “After discussion with a patient and family about this drug, if they want to take it, I’ll prescribe it,” Karlawish told Alzforum. He noted that the clinical conversation would be quite unusual. “In clinical practice we don’t routinely begin with the point that the drug may not have a benefit,” Karlawish said.
How Long Should You Take It?
Biogen has not specified a maximum length of treatment. In the investor call, Al Sandrock, who leads R&D at Biogen, said that participants in extension studies continued to benefit from treatment for as long as five years, and anecdotally reported feeling worse after the infusions stopped.
At conferences, Biogen researchers have reported that two years of treatment at 10 mg/kg drove people's brain amyloid loads below threshold, but even after that, those on this highest dose continued to decline more slowly on cognitive tests than those in lower-dose groups (see Nov 2018 conference news). It is unclear if this beneficial effect required continued dosing, or was due to complete clearance of amyloid. In biochemical and mouse studies, aducanumab stops the formation of toxic Aβ oligomers, hinting that it could have benefits beyond plaque removal (Sep 2020 news; Nov 2020 news).
In trials of Lilly's investigational antibody donanemab, patients switch to placebo once their brain amyloid has dropped below a set threshold, and continue to take cognitive tests to track their rate of decline. No such data exist for aducanumab. The specter of indefinite dosing distinguishes aducanumab from expensive hepatitis or cancer drugs, which are curative or given for a limited, one-time course, and it has intensified the outcry over its list price.
What if people progress from mild to moderate dementia while getting these infusions? After all, aducanumab is claimed to slow progression by 23 percent over 18 months, not halt or reverse it. Should the doctor stop treatment when a patient worsens? This, too, remains unanswered, and the decision again may be left to insurers.
And how will physicians know for certain if a given patient is responding with a clinical benefit? With cholinesterase inhibitors, AD researchers attempted for some time to establish guidelines for stopping treatment, but the drugs’ small effects on “soft” AD clinical endpoints rendered the effort unsuccessful. “We essentially said we will treat as long as we can,” said Philip Scheltens of Vrije University, Amsterdam. For a treatment of monthly infusions, stopping criteria will be more important, because continued treatment at late stages could prolong suffering, said Liana Apostolova of Indiana University School of Medicine in Indianapolis. Apostolova and Scheltens spoke on June 21 in a four-hour webinar hosted by the Alzheimer's Association, playable here.
No Answers For Nine Years?
Many researchers are hoping Biogen’s post-market study will provide clarity. So far, Biogen has been tight-lipped on its design, noting only that it is in talks with the FDA. Some worry the study may not be rigorous enough to provide good data. “If the field leaves the execution of the Phase 4 trial as requested by the FDA to the free market alone, we will see mostly results from a complex patient population, resulting again in blurred and controversial signals,” Bart De Strooper at the U.K. Dementia Research Institute at University College London wrote to Alzforum.
In the cancer field, numerous drugs were approved based on surrogate markers, but post-marketing studies were slow in coming and FDA enforcement was lax. The drugs continued to be prescribed in a knowledge vacuum for years. In April 2021, the FDA reviewed post-market oncology data and concluded two drugs did not work for specific cancers: Keytruda for gastric cancer and Opdivo for hepatocellular carcinoma. The drugmakers stopped marketing their products for those diseases. Only 6 percent of accelerated approvals for oncology therapies have ever been withdrawn (Healio news).
Maria Glymour at the University of California, San Francisco, believes the nine-year timeframe for a confirmatory Phase 4 trial will delay certainty about whether aducanumab helps AD patients. “This feels like we have failed patients and families,” she wrote to Alzforum.
Will the World Follow Suit?
While aducanumab so far is approved for use in the U.S., Biogen has applied in Japan, Australia, Switzerland, the European Union, Canada, and Brazil. Some believe the FDA decision is likely to influence other regulatory authorities. After the FDA ruling, Japanese health minister Norihisa Tamura told the media, “This is a big step forward and a breakthrough method; we’ll make a final decision after a careful review on its safety and efficacy.”
Takeshi Iwatsubo at Tokyo University noted that media coverage of aducanumab approval in Japan has been positive, but said the country is not ready for clinical rollout. “We may have to formulate a guideline for the appropriate use of anti-Aβ antibody drugs,” he wrote to Alzforum. “We do feel much is left to be done prior to the implementation of these drugs.”
Like in Japan, German neurologists and psychiatrists have founded a network to help standardize clinical care. And like Iwatsubo, Jörg Schulz at RWTH Medical School, Aachen, and Johannes Levin of Ludwig-Maximilians-Universität München, hope that if the European Medicines Agency approves aducanumab, it will stratify patient eligibility by disease stage and risk factors, and define stringently how to prescribe aducanumab and monitor patients. For example, APOE4 carriers are known to be at higher risk of ARIA but also had the greatest benefit, according to Biogen’s FDA briefing materials. Clinicians are hoping for guidance on how to deal with this conundrum. “In Europe, we are anxiously waiting for the decision of the EMA,” Schulz wrote to Alzforum. “I hope Biogen will support the learning curve by rigorously controlling access to the drug,” Levin concurred (full comment below).
In post-Brexit U.K., approval will come through that country's own regulatory agency, the MHRA. “So far in the U.K. the professional community is divided, with views ranging across the spectrum from condemnation of FDA to optimism for this being the gateway to a new research era,” Catherine Mummery at the National Health Service told Alzforum. She, too, hopes that any approval will require biomarker confirmation and disease staging (comment below). Other clinicians in European countries, who withheld their names, expressed hope that the EMA will be free to deliberate based on the data before them, without the stakeholder pressure that bore down on the FDA.
Despite the many open questions now, many researchers take the long view. They think approval of the first amyloid-lowering drug could spur the field forward. “I hope this approval, in combination with the advent of blood-based AD biomarkers, will quickly usher in the era of preclinical testing and therapy,” Erik Musiek at Washington University in St. Louis wrote to Alzforum.
Gil Rabinovici at the University of California, San Francisco, called on the field to work together to overcome the many challenges this new therapy will bring. “While the debate on aducanumab over the past few months has been very contentious, I hope that now that the FDA decision is made, we can move forward together to define the critical next steps in AD care and research,” he wrote to Alzforum. This was the overall tenor at the January 21 Alzheimer's Association webinar as well. —Madolyn Bowman Rogers
References
News Citations
- How Will Aducanumab Approval Change Clinical Practice?
- Second Look at BAN2401 Data Still Positive, Despite Snafu
- Of Four Aβ Antibodies, Only Aducanumab Stems Tide of Toxic Oligomers
- In Mice, Aducanumab Neutralizes Aβ Seeds