On July 6, 2023, the U.S. Food and Drug Administration granted traditional approval for lecanemab, currently sold under the name Leqembi, a drug proven to slow the progression of early Alzheimer’s disease dementia. According to B. Joy Snider, MD, PhD, the drug represents just the beginning of new treatments that target an underlying cause of the disease.
“Up to this point, the drugs approved to treat Alzheimer’s were developed to help with the symptoms of the disease, and they were not very beneficial to patients,” said Snider, professor of neurology at WashU Medicine and director of clinical trials at the Knight Alzheimer Disease Research Center. “Lecanemab actually changes the biology of the disease by targeting the amyloid-beta protein, a primary component of the amyloid plaques that form in the brains of patients with Alzheimer’s disease. Lecanemab and other anti-amyloid immunotherapies in development are not a cure, but they have been shown to slow the progression of the disease in its early stages.”
The identification of patients who can undergo treatment with the drug requires a complex screening and monitoring process. MIR, the Department of Neurology and BJC HealthCare have ensured patients receiving the medication in St. Louis — and in some instances around the world — are properly screened and monitored throughout the course of their treatment.
First Step: Identifying AD
The first step toward patients being approved for treatment is determining whether they have Alzheimer’s disease and if so, how advanced it is. A critical component of this early assessment is a brain MRI, which is used to help rule out other causes of dementia. To confirm Alzheimer’s disease, a specific test for amyloid pathology is needed.
“Patients being considered for treatment with lecanemab need evidence of amyloid-beta deposition in the brain through biomarker tests such as PET scans or cerebrospinal fluid analysis,” said Maria Rosana Ponisio, MD, associate professor of radiology at MIR. “Negative results reduce the likelihood that patients’ cognitive impairment is due to Alzheimer’s disease. If there is no evidence of brain amyloid deposition, patients are not eligible for the treatment.”
“Patients being considered for treatment need evidence of amyloid-beta deposition in the brain.”
A positive PET scan shows increased radiotracer uptake in affected areas of the brain, an indication of moderate to frequent amyloid plaques. “It is important to note that amyloid plaque may also be present in patients with other types of neurologic conditions, as well as in older people with normal cognition,” Ponisio said. “Therefore, the PET results are used in conjunction with a clinical evaluation.”
In addition to patients’ initial testing, follow-up PET scans may be used to monitor treatment by assessing changes in amyloid plaque levels associated with the disease over time, especially when compared to baseline amyloid levels before the onset of treatment.
Anti-amyloid immunotherapies work by delivering a monoclonal antibody — a laboratory-produced molecule engineered to trigger an immune response — that binds with amyloid-beta plaques and helps clear them from the brain. During the normal course of Alzheimer’s disease the body has the ability to clear these plaques as well.
Monitoring the Patient
In some patients, either or both of these actions can result in amyloid-related imaging abnormality, which can cause brain edema (ARIA-E) and hemorrhage (ARIA-H). ARIA is usually asymptomatic but in more serious cases can cause headache, confusion, vomiting, nausea, tremor and gait disturbances. The possibility of patients developing ARIA prompted the FDA to include a boxed warning for anti-amyloid immunotherapies to caution about safety risks.
“The MRI scan required as a baseline for patients beginning their treatment, and those repeated at predetermined intervals during treatment, have a specific protocol to detect ARIA,” said Tammie L.S. Benzinger, MD, PhD, professor of radiology and a principal investigator in MIR’s Neuroimaging Labs Research Center.
“ARIA hemorrhages can be as small as 1 millimeter, and these cannot easily be seen on a standard brain MRI. For instance, a standard scan may show three ARIA hemorrhages when in fact there are five. That is a significant difference in determining whether a patient can begin taking the drug, or if they need to pause or stop treatment.”
Benzinger co-chaired an American Society of Neuroradiology study group created to facilitate the exchange of information in the field of Alzheimer’s disease and dementia, with a specific interest in sharing information about the diagnosis, treatment and research of ARIA. During the yearlong project, the group partnered with equipment manufacturers to present optimized Alzheimer’s disease therapeutic imaging protocols.”
“During this process, BJC HealthCare became the main partner with Siemens to calibrate the ARIA MRI protocols for scanners throughout the health system,” said Benzinger, also a professor of neurological surgery, biology and biological sciences.
Optimizing Protocols
Within the BJC system there are 10 Siemens MRI scanners of varying ages and six software levels. Since follow-up MRI scans are required throughout a patient’s treatment, the challenge was to ensure each scanner was calibrated to produce comparable ARIA MRI scans whether they were done at, for instance, main-campus Barnes-Jewish Hospital or Missouri Baptist Sullivan Hospital. Amanda Woelfel and Tim Street, clinical applications specialists for BJC, were responsible for collecting and disseminating data for the system’s hospitals.
“Lecanemab actually changes the biology of the disease by targeting the amyloid-beta protein.”
“There was an ongoing dialogue between Dr. Trevor Andrews (associate professor of radiology and MRI physicist) and the engineers at Siemens to analyze the parameters of each sequence within the ARIA protocol for each scanner,” Woelfel said. “Test images were obtained on patients with known pathology, such as a hemorrhagic tumor. These images were shared at virtual meetings; any modifications were again trialed to further refine each sequence. By mid-November 2023, a version was developed for each of our software platforms.”
The software versions were distributed throughout BJC and shared at the 2023 conference of the Radiological Society of North America. Siemens posted them on its MAGNETOMWorld website for use by Siemens MRI scanner users worldwide.
In addition, the BJC group working on the ARIA project developed a specific risk vs. benefit grading template for radiologists to use when reading MRI exams for the presence of ARIA. BJC’s electronic medical record, EPIC, was programmed to flag patients receiving lecanemab to alert clinicians to the possibility of ARIA symptoms.
Eliminating Delays in Treatment
Because patients prescribed lecanemab are required to have multiple follow-up MRIs during the first few months of treatment, or when they become symptomatic, they benefit from the availability of AIRA MRI at hospitals throughout the BJC system. Receiving the drug is just as convenient.
“Patients receive the medication through intravenous infusion over 60 minutes every two weeks,” said Michelle Onder, director of diagnostic services at Missouri Baptist Medical Center. “In addition to Missouri Baptist, patients may receive their medication at any of the BJC infusion sites throughout the system. It is a straightforward procedure, with vitals taken before and after infusion and no need for an observation period once completed. To date, we haven’t had any patients experience a hypersensitivity reaction.”
“Patients may receive their medication at any of the BJC infusion sites throughout the system.”
According to Benzinger, WashU was one of the earliest sites to begin clinical therapy with lecanemab and remains one of the top five medical centers in the U.S. prescribing this treatment. She credits the collaborative effort of MIR, the School of Medicine and BJC support staff for streamlining the process by which patients are screened and then monitored throughout their treatment.
“We made a strong commitment at the outset to eliminate any potential bottlenecks or hurdles that would cause delays in patients receiving this new treatment for Alzheimer’s disease,” she says. “Although not a cure, this drug helps patients maintain their independence and enjoyment of their daily lives. It is important that they experience the benefits as quickly and easily as possible.”
Published in Focal Spot Fall 2024 Issue