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
- Lecanemab Follows Aduhelm’s Path to Accelerated Approval
- Will Insurance Cover Aducanumab? Jury Is Out
- Aducanumab: Will Appropriate-Use Recommendations Speed Uptake?
- Rizvi B, Lao PJ, Chesebro AG, Dworkin JD, Amarante E, Beato JM, Gutierrez J, Zahodne LB, Schupf N, Manly JJ, Mayeux R, Brickman AM. Association of Regional White Matter Hyperintensities With Longitudinal Alzheimer-Like Pattern of Neurodegeneration in Older Adults. JAMA Netw Open. 2021 Oct 1;4(10):e2125166. PubMed.
- Manly JJ, Glymour MM. What the Aducanumab Approval Reveals About Alzheimer Disease Research. JAMA Neurol. 2021 Nov 1;78(11):1305-1306. PubMed.
- Zacharias HU, Weihs A, Habes M, Wittfeld K, Frenzel S, Rashid T, Stubbe B, Obst A, Szentkirályi A, Bülow R, Berger K, Fietze I, Penzel T, Hosten N, Ewert R, Völzke H, Grabe HJ. Association Between Obstructive Sleep Apnea and Brain White Matter Hyperintensities in a Population-Based Cohort in Germany. JAMA Netw Open. 2021 Oct 1;4(10):e2128225. PubMed.
- Anderson TS, Ayanian JZ, Souza J, Landon BE. Representativeness of Participants Eligible to Be Enrolled in Clinical Trials of Aducanumab for Alzheimer Disease Compared With Medicare Beneficiaries With Alzheimer Disease and Mild Cognitive Impairment. JAMA. 2021 Oct 26;326(16):1627-1629. PubMed.