20 Oct 2021

Part 2 of a two-part story.

While three other Alzheimer’s immunotherapies are barreling down the approval pike (see Part 1 of this story), the first one to have nabbed a marketing license continues to tread an uncertain path. Several hospital systems have chosen not to provide the drug, and some insurers refuse to cover its cost. Thus far, only a smattering of patients are getting aducanumab infusions.

Aducanumab uptake remains slow, held back by high cost and low reimbursement.
Most Medicare beneficiaries would not qualify for treatment, based on their ARIA risk factors.
Prescription and treatment best managed by dementia specialists.

Importantly, many clinicians remain unsure about which patients can safely take aducanumab without undue risk of the brain edema known as ARIA. It may be that few of them can. In the September 9 JAMA, researchers led by Timothy Anderson at Boston's Beth Israel Deaconess Medical Center estimated that 92 percent of Medicare patients with cognitive decline would not have been eligible for the aducanumab Phase 3 trials, with most excluded due to medical issues. Clinician-researchers in the field told Alzforum that, at the moment, aducanumab treatment should be limited to the relatively small number of people with good cardiovascular health who would have qualified for the trials.

“We should be conservative. This is not a time to broaden the inclusion criteria,” said Stephen Salloway at Butler Hospital in Providence, Rhode Island. Salloway was a site leader for the ENGAGE aducanumab trial. “The letter by Anderson and colleagues is very insightful,” agreed Wiesje van der Flier of Amsterdam University Medical Center (full comment below).

Marwan Sabbagh at the Barrow Neurological Institute in Phoenix saw a silver lining, noting that the limited patient population may give clinics time to ramp up their capabilities. “If the trial inclusion/exclusion criteria are applied, then the number of people eligible and appropriate for aducanumab are far fewer than the pundits have hyped,” he wrote (full comment below).

Beset With Doubt, Aduhelm Isn't Getting Much Use
In September, Mass General Brigham, the largest hospital system in Massachusetts, became the latest healthcare provider to decide against administering aducanumab to its patients for the time being (Boston Globe). The state’s Blue Cross Blue Shield health insurance branch nixed coverage of the treatment, likewise joining several other insurers who had previously given it the thumbs-down (Boston Globe). In another sign of pushback from medical providers, a Washington, D.C., clinic even banned Biogen representatives from its premises in protest of the FDA’s decision (Fierce Pharma).

Given these stumbling blocks, only a trickle of patients have been infused so far. As of September 11, they reportedly numbered about 100 nationwide, and a company update on October 20 indicated no significant pickup since September (Stat news). “We continue to see a high level of patient interest and we are making steady progress, including new site activations,” a Biogen spokesperson wrote to Alzforum in response to a request for updated numbers.

With hospitals reluctant, freestanding commercial infusion centers have stepped in to offer the treatment, some adding incentives such as massage chairs, movies, and snacks (Axios news). Several local newspapers ran articles featuring a member of the Alzheimer’s Association’s patient advisory board receiving the treatment (AZ Central story; Des Moines Register).

Among physicians, adoption is being held back by both skepticism and skimpy insurance coverage. In a recent survey of 74 neurologists by the market research firm Spherix Global Insight, 84 percent said they had lost confidence in the FDA over the last year, partly due to the agency's aducanumab decision. Still, two-thirds of them expected to treat some patients with the antibody by next year, suggesting usage will pick up (McKnights news). Analysts at Morgan Stanley forecast that about 14,000 patients will receive the drug by the end of 2022, provided insurance covers it (Endpoints news). Some international administration may begin, as well. The United Arab Emirates recently became the second country to approve the therapy (Khaleej Times), and the European EMA is expected to issue a decision this fall.

What about insurance coverage? At the moment, most regional Medicare offices are paying for infusions. Reimbursement remains sporadic and slow while Medicare administrators are awaiting a national coverage determination (Aug 2021 news). On a technical note, Biogen reported in October that it has obtained a J-code effective January 2022; J-codes streamline billing for injectable Medicare Plan B drugs.

Medicaid’s pharmacy director has said the drug is currently covered by this program as well (Pink Sheet). Medicaid costs are borne by the states. Matt Salo, who leads the National Association of Medicaid Directors, on October 12 published a plea to CMS to have Medicare cover aducanumab at the national level, or to allow Medicaid to exempt the drug from its rolls, too (Stat news). Meanwhile, Biogen is providing some antibody infusions free of charge for patients awaiting Medicare approval; these types of pharma-run patient-access programs are not uncommon for new drugs (Reuters).

Will ARIA Limit Treatment to Only the Healthiest?
While payment issues are being sorted out, some researchers remain nervous about the treatment’s safety. A Freedom of Information Act (FOIA) request from analysts at the financial services company Baird uncovered data from the FDA’s Adverse Event Reporting System (FAERS). The data included three recent cases of ARIA due to aducanumab treatment that were severe enough to lead to hospitalization. Biogen reportedly said these cases came from its open-label extension study (Endpoints news). Most ARIA is believed to occur early in treatment; it is unclear how long the OLE participants might have been on the drug. Additional FOIA requests on aducanumab are on record with FAERS; the data are not public.

Anderson’s study underscores concerns about whether risk may be higher in the general population than in these trials. The researchers examined 2018 claims from nearly 28 million Medicare beneficiaries, narrowing the group down to the 4.3 million participants who had been diagnosed with AD, related disorders, or mild cognitive impairment. Among them, about 92 percent would have been excluded from the aducanumab trials due to either medical issues or being older than 85. Cardiovascular disease was the most common condition, present in 60 percent of people with AD or related disorders, and in 50 percent with MCI. Blood-clotting problems and chronic kidney disease were nearly as frequent. Thus, most Medicare recipients have contraindications for aducanumab use. This is concerning because the FDA label for aducanumab does not list these exclusions, the authors noted.

Philip Scheltens at VU University, Amsterdam, was “baffled” by the absence of contraindications in the FDA’s label for aducanumab, he wrote to Alzforum (full comment below). For her part, van der Flier noted that Anderson's study might have generated a higher percentage of appropriate treatment candidates had it analyzed only people with aMCI or mild AD. This group may be a bit younger and healthier than those at more advanced disease stages, and they are the population currently eligible based on the way the FDA narrowed its initial June 7 label.

Many Alzheimer’s researchers agree the absence of contraindications on the aducanumab label is a problem. “Clinicians should follow the clinical trial guidelines,” Salloway said. He noted that severe white-matter disease should disqualify people from treatment. On the other hand, he considers mild white-matter hyperintensities (WMH) on MRI scans, which are common in older adults, to be compatible with treatment. Between these extremes lies a large gray area that requires nuanced clinical judgment. Salloway said his clinic has a multidisciplinary treatment team review each case. If they believe aducanumab treatment is safe, he goes over the data with the patient and family to make sure they understand the risks. Most patients so advised are highly motivated and choose to proceed, he added.

To reduce the risk of ARIA, Salloway believes all patients should be genotyped for APOE. APOE4 carriers, especially homozygotes, need closer monitoring than noncarriers. It is crucial to catch ARIA quickly so that clinicians do not administer another dose of the antibody and worsen the ARIA, Salloway said. Because none of this is spelled out in the FDA label, he worries that ARIA may be poorly managed in practice. Salloway co-authored the recently published Appropriate Use Recommendations for aducanumab. These criteria address some of these issues, but stop short of recommending APOE genotyping for everyone (Aug 2021 conference news).

In addition, prescribing physicians encounter questions the clinical trials were unable to address. For example, do people on immunosuppressants, or those with an inflammatory disorder, have a higher risk of side effects? Do the risks differ by ethnic group? A recent study found that WMH were more associated with Alzheimer’s-like degeneration in black than white participants (Rizvi et al., 2021). Black people were underrepresented in the aducanumab Phase 3 trials, with only six in the aducanumab high-dose group, out of a trial that enrolled nearly 3,000 people (Manly and Glymour, 2021).

Other groups may be prone to WMH, as well. A recent study links WMH to sleep apnea, a common disorder in older adults (Zacharias et al., 2021). The AMDA currently recommends against prescribing aducanumab to people with early AD who live in long-term care facilities. Such residents were not included in the clinical trials; many are very old or have other exclusions (McKnights news).

Some answers will be forthcoming as aducanumab is more widely prescribed. “We’ll learn in clinical practice what predisposes to more severe ARIA,” Salloway said. In the meantime, difficult decisions will be left to physicians and patients. “Individual clinicians must make the final decision regarding whether the trial outcomes are applicable to each patient,” William Hu at Rutgers Biomedical Health and Sciences, Newark, New Jersey, wrote to Alzforum (full comment below).

One thing is certain: Across the country, physicians soon may see more people with early stage symptoms seeking treatment. Now that a drug is approved, patients are more likely to act on their cognitive concerns. “Availability of a medication like Aduhelm might change the whole diagnostic landscape, with a far larger number of people seeking a diagnosis in an early stage,” van der Flier wrote.

Many primary care physicians, internists, and even geriatricians lack the specialized expertise to decide whether aducanumab is right for the patient sitting in front of them. “With Aduhelm and others to follow later, we have entered a new era in which treating AD patients becomes more of a precision-medicine approach, in the hands of specialists only,” Scheltens noted.—Madolyn Bowman Rogers

Comments

- Wiesje van der Flier
  Vrije Universiteit Amsterdam
- Posted: 20 Oct 2021
Following approval of Aduhelm by the FDA, there have been fierce discussions in the field. In my view, one important topic is who would be eligible/who might benefit from Aduhelm. This is clearly only a small subset of all patients with AD, namely those with MCI or mild-stage dementia, with only little comorbidity, and who are willing and able to undergo the treatment regimen.

In this respect, the letter by Anderson and colleagues is very insightful, as they illustrate that only a small percentage of all AD patients would be eligible for treatment. It would be even more informative if the authors had taken the population of MCI or mild dementia due to AD as a starting point (in the paper, all AD were included). A large proportion of AD patients in the Medicare database have moderate-to-severe AD dementia. It is clear that they will not benefit, and with the narrowed labeling, they are no longer eligible to be treated with Aduhelm. I suspect that the percentage of eligible patients would be somewhat higher if MCI or mild dementia was taken as starting point.

Of note, there could also be a proportion of patients with early stage AD, particularly the MCI stage that is not known at Medicare. Many individuals with MCI due to AD go undiagnosed, and as such we do not know the true prevalence of AD. Availability of a medication like Aduhelm may change the whole diagnostic landscape, with a far larger number of people seeking a diagnosis in an early stage.

Given the potential side effects, it is indeed relevant that any factors increasing the risk of side effects be limited. I could imagine that clinicians are reluctant to prescribe Aduhelm to patients with cardiovascular disease or anti-coagulation, particularly in the coming years, while we need to get more insight into the clinical efficacy and occurrence of side effects of the treatment.

View all comments by Wiesje van der Flier

- Marwan Sabbagh
  Barrow Neurological Institute
- Posted: 20 Oct 2021
I reviewed the Anderson et al. JAMA article, and I am not surprised. One of our junior faculty at the Cleveland Clinic did his own analysis using the inclusion/exclusion criteria and came to the same conclusion.

In fact, when inclusion/exclusion criteria are applied, most patients do not qualify for aducanumab, or any monoclonal antibody for that matter. This is never reflected in the data of randomized controlled trials, because they are excluded before enrollment. RCTs include a very selected population that excludes people with pacemakers, stroke, and a variety of health conditions. Further, the aducanumab study did not assess age >85, which could be many potential patients. Thus, the effects of aducanumab in age >85 are largely unknown.

If the inclusion/exclusion criteria are actually applied, then the number of people eligible and appropriate for aducanumab are far fewer than the pundits have hyped (“Medicare will be bankrupt!”). The takeaway is that the findings from Anderson et al. are not surprising and should be considered when selecting patients for monoclonal antibody treatments in the future.

View all comments by Marwan Sabbagh

- Philip Scheltens
  Alzheimer Center Amsterdam; Head EQT Life Sciences Dementia Fund
- Posted: 20 Oct 2021
Indeed, ARIA is a concern. Although asymptomatic in most cases, it may have an aggressive course. I was extremely surprised to see the first label that was proposed and welcomed the narrowing of the population, in line with the appropriate-use criteria suggested by Cummings et al.

But the total lack of contraindications completely baffled me. Cardiovascular risk factors, such as arterial hypertension, increase the risk of ARIA, as does the use of oral anticoagulants. If I were to prescribe Aduhelm, I would aim for a patient who is relatively “clean” with regard to CV disease and MRI scan, to mitigate the risk of ARIA. Managing ARIA is only possible by repeated MRI scanning and should be done as in the trial.

Let me just add here that with Aduhelm and other therapeutic antibodies to follow later, we have entered a new era in which treating AD patients becomes more of a precision-medicine approach, in the hands of specialists only.

View all comments by Philip Scheltens

- William Hu
  Rutgers Biomedical & Health Sciences
- Posted: 20 Oct 2021
I am not a trialist, but there must be a balance between sufficient representativeness and adequate homogeneity. Practitioners of evidence-based medicine know that clinical trials provide critically important information, but individual clinicians must make the final decision regarding whether the trial outcomes are applicable to each patient considering the treatment.

I doubt there will ever a clinical trial that is completely representative of everyone eligible for the drug. For example, people who are deaf or blind can develop Alzheimer’s disease, but are not part of even the most inclusive trials. Inclusion for the sake of representativeness, i.e., enrolling a small number of participants with some of the comorbidities outlined in the article, won’t have sufficient power to address whether a drug is effective in these conditions, and risks not addressing if the drug works in an extremely artificial construct.

Many who have commented on the artificial nature of these explanatory clinical trials are essentially reinforcing the call for more pragmatic trials in drug development, that is, trials in the “real world,” which NIH has been advocating over the past years (NIH blog, 2017). Alas, until more centers have the infrastructure to implement pragmatic trials, writing off explanatory trials may be throwing out the baby with the bath water.

The COVID-19 pandemic has also reminded us that motivated physicians and scientists can design and execute elegant trials to repurpose an FDA-approved drug, or test a drug’s efficacy against another therapy when they don’t agree with the approved treatment paradigms. Given the concerns related to anti-amyloid therapy, I imagine many would prefer such studies over idle chatter.

In the meantime, patients are faced with real decisions of trying an FDA-approved drug with known limitations and known side effects versus entering other clinical trials of unknown risks and unknown outcomes. The decision to try aducanumab—or not—should eventually rest with each patient and his or her physician.

View all comments by William Hu

- Sam Gandy
  Icahn School of Medicine
- Posted: 25 Oct 2021
The FDA's Accelerated Approval for Aduhelm relies on the assertion that current amyloid fibril burden status, as determined by PET, is a useful surrogate for a meaningful and beneficial clinical response to amyloid-reducing interventions. Writing in The BMJ Open earlier this year, Ackley and colleagues performed an unbiased computational meta-analysis of all available amyloid fibril burden PET data, together with the corresponding contemporaneous cognitive status. They concluded that no important relationship links the PET data to cognitive status. The Ackley report would appear to undermine the FDA's Accelerated Approval language so directly and so effectively that the validity of the accelerated approval must be considered suspect at the very minimum.

References:

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.

View all comments by Sam Gandy