Fatal bleeding events in clinical trial participants with Alzheimer’s disease may be associated with the investigational anti-amyloid drug lecanemab, a case report suggests.
But the fate of lecanemab, in particular, hinges on a possible FDA approval for early-stage Alzheimer’s disease later this week, so the investigational drug still doesn’t want to blame.
Information about this case first surfaced just days before the November report of the randomized CLARITY AD trial. It occurred during the open-label phase of the trial.
In another letter published in New England Journal of Medicinea team in the Northwest who treated stroke patients shed light on the large number of abnormal acute intracerebral hemorrhages observed, but researchers in the CLARITY study suspected a potential role for the patient’s underlying disease, not lecanemab. emphasized.
Study participants APOE4 allele and received the last lecanemab infusion 4 days before the onset of stroke. A head MRI performed 81 days before his stroke showed mild small vessel disease and no microhemorrhages, edema, or amyloid-related imaging abnormalities (ARIA). According to Sherry Chow, M.D., Ph.D., a neurocritical care specialist at Northwestern University Feinberg School of Medicine in Chicago, and colleagues, a CT done just before the tPA administration showed no bleeding.
Patients received IV tPA as there were no contraindications to thrombolytic therapy. After 50 minutes of the infusion, she had a problem with a sudden onset of hypertension and was forced to stop the tPA infusion. CT showed extensive multifocal intraparenchymal hemorrhage without systemic hemorrhage.
Chou et al. administered cryoprecipitate and tranexamic acid. They also administered multiple antiepileptic drugs for frequent nonconvulsive seizures seen on electroencephalography. Three days later, the patient underwent endotracheal intubation and imaging showed acute right thalamic sac infarction and numerous multiple cortical and subcortical hemorrhages with surrounding edema.
At the family’s request, the patient received comfortable treatment before death. Autopsy showed diffuse histiocytic vasculitis with extensive multifocal intraparenchymal hemorrhage, cerebral amyloid angiopathy, neuropathologic changes in Alzheimer’s disease, and necrotizing angiopathy with amyloid deposits within the vessel wall. rice field.
“The wide variation in the number and size of cerebral hemorrhages in this patient is unusual for a complication of tPA associated with cerebrovascular amyloid alone. Increases the likelihood of vascular disease.Who was given lecanemab,” wrote Chou’s group.
CLARITY AD investigators Marwan Sabbagh, M.D., Ph.D., of the Barrow Neurological Institute in Phoenix, Arizona, and Christopher van Dyck, M.D., Ph.D. revealed that it may have been affected by of patient bleeding.
The duo also highlighted the known risk of intracerebral hemorrhage in CAA patients not receiving anti-amyloid therapy, and rare cases of vasculitis.
“We agree that this case raises important management issues for patients with Alzheimer’s disease, especially those who are homozygous for Alzheimer’s disease. APOE4 Alleles,” said Saba and van Dijk.
It occurred in the extended phase of CLARITY AD and was not included in the 13 deaths (6 in the lecanemab group and 7 in the placebo group) in approximately 1,800 trial reports.
Also not included was the death of a 79-year-old woman in prolongation of CLARITY AD. This occurred recently after the patient experienced extensive brain swelling and bleeding and seizures. Previously, a man in his late 80s died of a brain hemorrhage after using lecanemab and apixaban (Eliquis) for atrial fibrillation, but lecanemab developer Eisai said the death was unrelated to the drug. claimed.
During the CLARITY randomization phase, no deaths were determined to be related to lecanemab or occurred in ARIA. ARIA with edema or exudate occurred in 12.6% of her who received lecanemab. A combination of cerebral microhemorrhage, cerebral macrohemorrhage, and superficial siderosis occurred in 17.3% of her, the study authors report.
CLARITY’s main finding was that lecanemab was associated with a small but statistically significant reduction in clinical decline after 18 months in patients with early Alzheimer’s disease.
The FDA will soon announce whether it will grant accelerated approval of lecanemab for early Alzheimer’s disease. Some have suggested that the FDA needs a risk assessment and mitigation strategy in the face of concerns about ARIA risks in drugs.
Chou consults for CSL Behring, serves on the Board of the Neurocritical Care Society, and has received institutional grants from the National Institute of Neurological Disorders and Stroke and the Neurocritical Care Society.
Sabbagh has previously disclosed personal relationships with Alzheon, Athira, EIP Pharma, Eisai, Eli Lilly, Genentech, NeuroTau, NeuroTherapia, Novo Nordisk, Quince, Signant, Synaptogenix, T3D, and uMETHOD Health.
van Dyck previously reported relationships with Biogen, Biohaven Pharmaceuticals, Cerevel Therapeutics, Eisai, Eli Lilly, Genentech, Janssen, Novartis, Ono Pharmaceuticals, Roche, and UCB.
New England Journal of Medicine
Reference source: Reish NJ, et al. “Multiple cerebral hemorrhages in patients treated with lecanemab and treated with t-PA for stroke.” New Engl J Med 2023; DOI: 10.1056/NEJMc2215148.
New England Journal of Medicine
Reference source: Sabbagh M, van Dyck CH “Response: Multiple cerebral hemorrhages in patients receiving lecanemab and treated with t-PA for stroke.” New Engl J Med 2023; DOI: 10.1056/NEJMc2215907.