New treatment for Alzheimer’s disease comes with risks that clinicians need to be ready for, researchers said.
The association of amyloid-related imaging abnormalities (ARIA) with monoclonal antibody therapy for early Alzheimer’s highlights the importance of clinician and institutional preparedness, observed Vijay Ramanan, MD, PhD, of the Mayo Clinic in Rochester, Minnesota, co-author of the American Academy of Neurology (AAN) Quality Committee’s new guidance about the drug class.
“ARIA is typically a manageable side effect of treatment,” Ramanan said. “Most findings of ARIA are detected incidentally on scheduled safety monitoring scans, and in many cases may not require stopping treatment or other major course changes.”
“However, the fact that ARIA can develop and worsen in the background — only later to cause potentially significant complications and in rare cases, even death — is all the more reason for neurology clinicians and patients to take it very seriously,” he added.
ARIA can be associated with edema (ARIA-E) or with hemorrhagic changes (ARIA-H). Serious intracerebral hemorrhages were seen in patients treated with this class of medications.
ARIA-H and ARIA-E can co-occur as well. Although ARIA is not limited to people treated with anti-amyloid monoclonal antibodies, its incidence is increased in this population, which drives requirements for risk assessment, monitoring, and response.
Anti-amyloid agents with phase III trial data include lecanemab (Leqembi), which received full FDA approval in 2023, and donanemab, for which an FDA decision is expected in 2024. Another anti-amyloid treatment, aducanumab (Aduhelm) received accelerated FDA approval in 2021 but is being discontinued by the drugmaker.
All three drugs reported the presence of ARIA in clinical trials. In some cases, ARIA was associated with serious outcomes, including death.
“Nearly all catastrophes associated with ARIA can be avoided through proper vigilance and management,” noted Jeffrey Cummings, MD, ScD, of the University of Nevada in Las Vegas, who led the independent Alzheimer’s Disease and Related Disorders Therapeutics Work Group that produced lecanemab appropriate use recommendations in 2023.
“Adherence to the MRI screening recommendations and getting an additional MRI for any symptoms suggestive of ARIA will allow prompt, appropriate modification of therapy and reduction of the risk for severe consequences,” Cummings said.
In the phase III CLARITY-AD trial, ARIA-E occurred in 12.6% of participants treated with lecanemab. Most cases were asymptomatic, and ARIA-E tended to occur during the first 3 months of the study. Concurrent ARIA-E and ARIA-H occurred in 8.2% of participants and isolated ARIA-H occurred in 8.9%. Fatalities were reported in the CLARITY-AD open-label extension study.
In the phase III TRAILBLAZER-ALZ2 trial, ARIA-E occurred in 24% of participants treated with donanemab; most were asymptomatic cases. The incidence of ARIA-H in the absence of ARIA-E was 12.7%. In the donanemab group, three participants with serious ARIA subsequently died.
The lecanemab label carries a boxed warning for ARIA, noting that APOE4 homozygotes have a higher incidence of ARIA, including symptomatic and serious ARIA, compared with noncarriers and heterozygotes.
Prescribing information calls for monitoring MRIs after lecanemab infusions 5, 7, and 14. “We recommend an additional week 52 (i.e., before the 26th infusion) MRI scan, especially for APOE4 carriers and those with evidence of ARIA on earlier MRIs,” the Alzheimer’s Disease and Related Disorders Therapeutics Work Group said in its recommendations. “This safety monitoring should be supplemented by unscheduled safety MRIs, obtained in response to the occurrence of symptoms potentially caused by ARIA.”
After 12 months of treatment, MRIs should be guided by symptoms and prior MRI findings, they added.
ARIA symptoms can include headache, confusion, visual change, dizziness, nausea, and gait difficulty. Status epilepticus, encephalopathy, stupor, and focal deficits may be seen in severe cases.
“Responding to patient-reported symptoms suggestive of ARIA by obtaining an MRI is critical to good management,” Cummings emphasized.
If ARIA is detected, decisions about additional work-up, acute treatment, whether to continue the drug, and follow-up plans need to be made. The patient’s treatment context must include provisions for hospital and critical care, if needed, with personnel experienced in managing cerebral edema.
Recommendations for acute ARIA management include an established written protocol before patients are treated. Early high-dose glucocorticoids, brain MRI to exclude stroke, seizure monitoring, and planned treatment should be considered.
The lecanemab appropriate use recommendations call for both the radiographic severity (mild, moderate, or severe) and symptom severity (absent, mild, moderate, or severe) of ARIA to guide management decisions. The drug can be continued with asymptomatic ARIA of either type so long as it is also radiographically mild, and in some cases, stopped lecanemab may be restarted. In severe cases, discontinuation is recommended.
The AAN Quality Committee’s guidance highlights the need for close attention to factors that could influence the likelihood of developing ARIA, such as APOE allele status, the baseline presence of microbleeds, and the possible effects of medications and medical comorbidities, Ramanan noted.
Practices need “to develop rigorous plans for safety monitoring with MRI scans and clinical touch points, and prepare contingencies in advance so that resources can be efficiently deployed when needed,” he said. “Patient and caregiver education on potential symptoms of ARIA and the importance of timely detection and management also will be critical.”
Ramanan reported he is a site clinician in the Eisai-supported AHEAD 3-45 trial, the co-principal investigator for a trial sponsored by the Alzheimer’s Association, and a site clinician for trials supported by the Alzheimer’s Treatment and Research Institute at USC and Transposon Therapeutics. He reported research funding from the NIH and the Mangurian Foundation.
Cummings has provided consultation to Acadia, Actinogen, Acumen, Alpha Cognition, Aprinoia, AriBio, Artery, Biogen, BioVie, Cassava, Cerecin, Diadem, EIP Pharma, Eisai, GemVax, Genentech, GAP Innovations, Janssen, Jocasta, Karuna, Lilly, Lundbeck, LSP, Merck, NervGen, Novo Nordisk, Oligomerix, OptoCeutics, Ono, Otsuka, PRODEO, Prothena, ReMYND, Roche, Sage Therapeutics, Signant Health, Simcere, Sunbird Bio, Suven, SynapseBio, TrueBinding, Vaxxinity, and Wren Pharmaceutical. He reported grant support from the NIH and others.
Source link : https://www.medpagetoday.com/spotlight/alzheimers-disease/108667
Publish date : 2024-02-09 11:51:56
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