The Price of Accuracy
By Claudia Stahl
Vol. 24 No. 7 P. 22
Revisions to CMS reimbursement policies could improve PET access for Alzheimer’s disease therapies.
Another five months, possibly more, of remembering to walk the dog, pay the electric bill, get to a dental appointment, buy a birthday card. That’s what people in the early stages of Alzheimer’s disease (AD) might expect while on Leqembi (lecanemab), the latest FDA-approved member of a family of drugs that target amyloid plaque in the brain. Leqembi won’t cure AD or improve cognition, but it slows the rate of cognitive decline from the disease by as much as 27%. For some patients, that’s enough justification to move ahead with the therapy, despite potential side effects such as brain bleeding and swelling, known as amyloid-related imaging abnormalities.
Like many novel, specialized therapies, Leqembi comes with a high price tag. The infusions alone, delivered twice a month, have an annual cost of $26,500. Most of the patients who meet the early-stage criteria for the drug (roughly 1.5 million of the 6 million people in the United States who have AD), fall under the umbrella of Medicare or Medicaid, which picks up 80% of the bill. That’s good news, except for patients who lack the financial means or supplemental insurance to pick up the $6,600 difference.
But Lequembi’s associated expenses— office visits, genetic tests, and brain scans—rocket the therapy beyond the financial reach of many more patients. With those factors considered, Leqembi could burden patients with $18,000 in out-of-pocket costs and taxpayers with $82,500 annually per patient, according to estimates from the Institute for Clinical and Economic Review. In a CBS news report, UCLA professor and researcher John Mafi, MD, estimated the drug would cost Medicare $2 billion to $5 billion a year, making it one of the most expensive taxpayer-funded treatments to date.
Medicare subscribers are already feeling the economic impact of drugs in this class. CMS increased Medicare Part B premiums by 15% in 2021 to manage costs for Aduhelm, another antiamyloid drug approved the same year by the FDA. Consumers can expect a second jump in premiums in 2024, in part to offset the costs of Leqembi and, possibly, donanemab, another AD drug in the same class that is currently under review by the FDA.
One and Done
Following a battery of cognitive assessments, a diagnosis of AD is confirmed by the presence of amyloid proteins in the brain, which form sticky plaques that inhibit neurological activity.
Typically, clinicians identify these biomarkers with amyloid PET scans, which can cost upwards of $5,000, and through cerebrospinal fluid (CSF) tests, which are less expensive but require invasive, sometimes painful, lumbar puncture.
Amyloid PET is the most common method of qualifying patients for trials of AD therapies and for treatment with FDA-approved antiamyloid drugs. While patients are on these therapies, clinicians use PET scans to track amyloid depletion and MRI to monitor for adverse events.
The trouble is CMS covers the cost of only one amyloid-detecting PET scan in a patient’s lifetime and only for patients enrolled in approved clinical trials per its coverage with evidence development policy.
But that could change in the coming months. After months of persistent lobbying from industry groups and professional organizations such as SNMMI and Medical Imaging & Technology Alliance, CMS has issued a proposed decision memo to eliminate its single-scan limitation for patients with AD, as well as the national coverage determination for beta-amyloid PET scans. The 30-day public comment period for the memo began this year on July 17.
The Imaging Landscape for AD
AD is a complex disease with symptoms that can be shared by other types of dementia as well as non-AD conditions such as tumors, past strokes, hydrocephalus, and head trauma. Following cognitive analysis, clinicians and researchers rely on imaging to confirm the diagnosis, assess the stage of the disease, and, if applicable, follow the progress of treatment.
Typically, neuroimaging in AD falls into the following categories:
• Structural: MRI and CT to rule out factors and diseases that mimic AD, assess brain tissue, and confirm atrophy in regions associated with AD, such as the hippocampus and amygdala.
• Functional: PET and functional MRI to assess glucose activity in the memory, learning, and problem-solving centers of the brain. CMS supports FDG-PET to distinguish between frontotemporal dementia and AD in people with cognitive decline of six months or more, as the diseases have similar symptoms.
• Molecular: PET with highly targeted radiotracers to track disease-related changes in the brain. Some of the leading AD diagnostics and research involve tracers that target beta-amyloid and tau, the proteins that form the characteristic tangles in the brains of people with AD.
Amyloid PET imaging has played a central role in AD research and clinical evaluation for more than 15 years. According to an article in Seminars in Nuclear Medicine, amyloid PET improves the accuracy and efficiency of AD diagnosis and informs therapeutic decisions throughout the course of the disease—for example, ensuring that antiamyloid therapies are prescribed only for the most appropriate (ie, early-stage) AD patients and continued only for as long as they’re effective.
“Knowing when to stop these therapies is just as important as knowing who should get them,” says Richard L. Wahl, MD, past president of SNMMI and a professor of radiology at the Mallinckrodt Institute of Radiology at Washington University School of Medicine in St. Louis. “Once the amyloid is gone, you can potentially suspend the therapy, and PET scans can help in that regard.”
Researchers made the connection between tau protein and the neurofibrillary tangles (NFTs) in AD-affected brains more than three decades ago, but it took until 2020 for the first tau tracer, Tauvid (flortaucipir), to receive FDA approval.
Flortaucipir makes tau NFTs—once visible only in autopsies—appear bright red on PET scans, allowing clinicians to evaluate their distribution and density in living patients. Val J. Lowe, MD, director of nuclear medicine research at the Mayo Clinic, is the lead investigator of a study comparing tau in the brain and blood over time in people with AD and cognitive impairment with a control group of healthy patients.
Using a variety of tau radiotracers, “we’re looking at the brain for pathology for AD and other dementias and correlating that with PET imaging,” Lowe says, a process that involves evaluating around 5,000 PET scans per year. In part, the research aims to leverage tau PET to identify NFTs sooner, establish a correlation between tau levels and findings from cognitive tests for AD, and predict patients at high risk of developing AD sooner than what’s possible with amyloid markers alone.
Multimodal imaging continues to play an important role in identifying AD. A poster presented at the SNMMI 2023 conference, “Early diagnosis of Alzheimer’s disease using multiparametric hippocampal signatures with 18F-FDG PET/ MR radiomics,” used a hybrid PET/MRI model to correlate predictive radiomic features such as glucose metabolism, decreased cerebral blood flow, and hippocampal atrophy in patients with AD, mild cognitive impairment, and normal cognition (NC). The model demonstrated a 100% sensitivity rate for differentiating between AD and NC and an 81% sensitivity rate for differentiating mild cognitive impairment from NC.
At the same meeting, Roger Lecomte, PhD, a professor of nuclear medicine and radiology at the University of Sherbrooke in Quebec, Canada, discussed how an ultrahigh resolution brain PET scanner has enabled his research team to detect radiotracers in small areas of the brain, such as the subfields of the hippocampus, that are affected by AD. The technology, which he describes as “a quantum leap in terms of spatial resolution,” has implications for earlier diagnosis, as well as tracking disease progression and the effects of AD therapies in regions of the brain that are not visible with whole-body PET.
CSF and Blood Tests
Imaging is only one type of modality that scientists and clinicians use to identify AD biomarkers in the body. Amyloid and tau are found in CSF, which is extracted through a lumbar puncture (spinal tap). The procedure can be unappealing to some patients, but it’s an effective method of screening for AD and tracking therapeutic outcomes, especially in clinical trials.
The blood also carries proteins that signal changes in the brain resulting from AD and other dementias. Until recently, blood tests, while more convenient, were not as accurate at detecting AD biomarkers as CSF. But research presented at the Alzheimer’s Association International Conference in July 2023 showed that a finger-prick blood test measuring beta-amyloid and phosphorylated tau was more than 80% accurate in identifying AD-related changes. By comparison, primary care physicians in the study correctly diagnosed AD, or AD-related behavioral changes, in approximately 55% of the cases.
In comments at the conference, Maria C. Carrillo, PhD, the chief science officer of the Alzheimer’s Association, said, “While further standardization and validation are needed, blood tests may soon be an important piece of the diagnostic workup in everyday practice for detecting and monitoring treatment of Alzheimer’s disease.” Once approved, they would be “a quick, noninvasive and costeffective option to ‘gold standard’ tests like CSF and imaging.”
Accessibility to care, especially when that care is part of research in academic medical centers, is a significant factor in patients receiving timely diagnosis and treatment of AD, regardless of the screening method. An at-home blood test would remove many of the obstacles that discourage people from seeking care, such as high treatment costs and the challenges of getting to and from appointments.
“Currently, use of Alzheimer’s blood tests is limited by the need to visit a clinic, administration by trained personnel, and strict time-limited and temperature-dependent delivery and storage procedures,” notes Hanna Huber, PhD, who oversees a study of the finger-prick test at University of Gothenburg in Sweden. “A method that allows blood collection at home and that is simple enough to be performed independently, or by caregivers, would … result in improved early diagnosis and better monitoring of patients considered at risk, or those who are receiving approved therapies.”
Time will reveal how recent screening innovations such as at-home blood tests and, potentially, eye exams (currently in clinical trials) translate to earlier and more accurate recognition of AD. Even as new options evolve, nuclear medicine remains the primary tool for evaluating the presence of and treatment-induced changes in the brain. However, even if CMS decides to pay for additional PET scans, “it doesn’t mean the scans will be widely available,” Wahl cautions.
The problem relates to how Medicare bundles its payments to hospitals. “The Medicare payments for these PET scans right now are substantially less than they should be because they only cover one-third of the cost of the newer, specialized radiopharmaceuticals, such as the ones that find amyloid,” Wahl explains.
The Facilitating Innovative Nuclear Diagnostics Act of 2023, a bipartisan congressional bill currently in committee, would require CMS to pay separately for radiopharmaceuticals, potentially expanding access to PET scans for AD, cancer, and neurological diseases. The bill has more than 90 industry and professional society cosponsors, including SNMMI.
“In nuclear medicine, diagnostic studies are the GPS that will tell you where you’re going and how to get there,” Wahl says. “Without it, you may be on a very expensive journey, giving therapies to patients who don’t need them, and you need a reimbursement structure in place to support those who do. We don’t want these wonderful diagnostic tests and encouraging therapies to be unavailable because of reimbursement approaches that have not worked very well.”— Claudia Stahl is a freelance writer based in Ambler, Pennsylvania. She specializes in writing about the health of people and the planet.