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?

  • FDA label does not specify which patients qualify for aducanumab treatment.
  • Insurers may end up making this call by limiting coverage.
  • Most U.S. clinics are unprepared to meet demand for the antibody.

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 newsAug 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 to18-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

Comments

  1. Regardless of one’s opinion on the drug, the Aduhelm approval is likely to have a huge impact on research and clinical practice.

    Regarding clinical practice, I was very surprised by the broad indication from the FDA. It seems to fly in the face of all existing data. The assumption is that CMS and insurers will limit reimbursement to patients with mild AD dementia (likely CDR 0.5) with positive AD biomarkers. We are awaiting these criteria, as they will be the key element in understanding how much impact the approval will have.

    If that occurs, then participating clinics will need to find ways to quickly screen existing and new patients for these clinical criteria, then refer appropriate and interested patients on for biomarkers and eventually infusion. This is a substantial undertaking that will require great increases in capacity for most memory clinics, and will tax nonspecialists. I have already heard from some internists and geriatricians that they cannot do this and will plan to refer to memory clinics, which will already be overwhelmed.

    Additional staff will also be needed to work on prior authorizations and insurance issues. Once infusions begin, someone will need to see these patients regularly and follow up their MRIs for safety monitoring (i.e., ARIA), which will further tax the system.

    On a higher level, practices and individual practitioners will need to decide if they want to offer this drug and how aggressively they want to pursue it. Considering the lack of guidance from the FDA, individual practices may have to set their own guidelines for prescribing. As of now, my practice group, the Memory Diagnostic Center at Washington University, is planning to offer Aduhelm to appropriate patients, although we are currently discussing these very issues.

    The reality is that probably no one is entirely ready for this approval. It was generally not financially possible to hire extra staff and physicians just in case it occurred, so everyone must now scramble. Our center has been planning for months, but there are still many unanswered questions and we don’t yet completely understand the demand.

    I am less concerned about imaging availability (MRI, amyloid PET) and infusion capacity than I am about clinical evaluation of patients. 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, and the clinical evaluation is time-consuming and not very lucrative. Unfortunately, proper clinical evaluation is really important, as the drug is guaranteed not to work if given to the wrong patients. I think it will take quite some time to work out an ideal clinical flow and to deal with the initial bolus of interested patients.

    I would imagine that the impact on traditional observational studies of AD will also be immense. Many participants in longitudinal studies will likely end up on Aduhelm once they become symptomatic, and preclinical participants may feel increased pressure to find out their biomarker status and potentially start Aduhelm as early as possible.

    This approval will also create many new research opportunities, such as developing methods for identifying responsive patients, determining optimal duration/timing of therapy, and examining Aduhelm in combination with other therapies. Patients may be reticent about foregoing Aduhelm in order to join a clinical trial, unless they are convinced that the trial drug is more effective than Aduhelm. There is no shortage of important research questions, but researchers will need to pivot.

    On the positive side, I hope that this approval, in combination with the advent of blood-based AD biomarkers, will quickly usher in the era of preclinical testing and therapy, which is where Aduhelm ultimately may be most effective. It may also accelerate the development and approval of the next generation of drugs targeting non-amyloid mechanisms that might synergize with Aduhelm (or other anti-amyloid therapies).

  2. The key questions for everyone—physicians, patients, and their families—is whether they “believe” that clearing amyloid from the brain will be beneficial and, if so, by what degree.

    The central problem is that, unfortunately and for now, answers to these questions remain in the realm of “belief.” There are those who believe that extracellular amyloid represents the disease’s pathogenic “fire”; those who believe that extracellular amyloid is the “smoke not the fire,” but that clearing smoke can be mildly beneficial; and those who believe that extracellular amyloid is completely benign smoke.

    For those in the first and third groups, the decisions are relatively straightforward, as long as everyone is honest that for now it’s just a belief.

    I am in the middle group (Small and Petsko, 2020), which is a growing camp. For us, the decision-making is the hardest, because we need to weigh potential mild benefit vs. actual side effects, cost, and burden.

    References:

    . Endosomal recycling reconciles the Alzheimer's disease paradox. Sci Transl Med. 2020 Dec 2;12(572) PubMed.

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References

News Citations

  1. Aducanumab Approval Sparks Backlash
  2. A New Era of Alzheimer’s Treatment
  3. With Little Data to Go On, Clinicians Are Left To Figure Out Way Forward
  4. $100M IDEAS: CMS Blesses Study to Evaluate Amyloid Scans in Clinical Practice
  5. In Clinical Use, Amyloid Scans Change Two-Thirds of Treatment Plans
  6. IDEAS Finds Small Drop in Hospitalizations, Missing Goal

Paper Citations

  1. . 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

  1. prescribing label
  2. coverage with evidence development
  3. Health Affairs blog
  4. press release
  5. Fierce Pharma news
  6. Liu et al., 2017
  7. statement 

Further Reading