Monoclonal antibodies (mAbs) constitute the newest and most rapidly developing group of drugs in the current medical market. Three have been approved by the FDA thus far for the management of Alzheimer’s disease (AD): lecanemab (Leqembi), aducanumab (Aduhelm), and most recently, donanemab (Kisunla). Lecanemab and donanemab were approved by the standard process by the FDA in July of 2023 and July of 2024. Aducanumab was approved accelerated approval mechanism in 2021, however it was discontinued from use in November 2024.
These drugs are indicated in early AD patients with MCI or mild dementia who have evidence of brain Aß from amyloid PET or CSF studies. The target dose for lecanemab is 10 mg/kg biweekly. Donanemab is approved for 700mg every four weeks for the first three doses and 1400mg every four weeks thereafter. These drugs are a major breakthrough in AD management, representing the first potential disease-modifying therapies for this disease.
The amyloid hypothesis states that amyloid, particularly amyloid-beta (Aß) protein, accumulation in the brain is the main trigger for the inflammatory processes that involve the development of AD. This is believed to be due to irregularities in microtubule-associated proteins, called tau proteins, causing them to aggregate into neurofibrillary tangles that make up the aforementioned Aß. The mAbs are hypothesized to work by triggering microglia to phagocytose fibrillar amyloid-beta. However, there are subtle differences in the mechanisms of the approved medications. Lecanemab targets both the amyloid monomer and its protofibril precursor, whereas donanemab targets pyroglutamate Aß present only in plaques.
Trials for the above drugs have been promising. In the phase III trials for aducanumab, there were two identically designed 18-month randomized, double-blind, placebo-controlled, parallel-group studies, ENGAGE and EMERGE, that enrolled 1,653 and 1,638 participants with MCI due to AD or AD that received either low-dose aducanumab (3 mg/kg for APOE €4 carriers, 6 mg/kg for non-carriers), high-dose aducanumab (10 mg/kg for APOE €4 non-carriers, 6 mg for carriers), or placebo every 4 weeks for this time period. inclusion criteria were a baseline MMSE score of 24–30; a CDR-SB global score of 0.5; and positive amyloid positive electron tomography (PET). ENGAGE was halted after a futility analysis while the other met its primary and secondary endpoints for the high-dose group, showing a dose- and time-dependent decrease in amyloid as seen on imaging. In both groups they also found a decrease in CSF p-tau and serum p-tau levels. The most common side effects in the high-dose groups were amyloid-related image abnormalities (ARIA) due to cerebral edema (35%) intracerebral hemorrhage (19%).
The Phase 3 trial for lecanemab, CLARITY AD, enrolled 1,795 patients who, via randomization, received either 10 mg/kg biweekly lecanemab (n = 898) or placebo (n = 897). Inclusion criteria were age (50–90 years), an MCI or mild AD diagnosis (National Institute on Aging-Alzheimer’s Association [NIA-AA] criteria), a 1 standard deviation (SD) decrease in objective episodic memory below the age-adjusted mean (WMS-IV LMII), and Aß positivity by PET. The primary endpoint was the clinical Dementia Rating-Sum of Boxes (CDR-SB). Participants in the lecanemab group has a slower decline of CDR-SB by 0.45 points (+ 1.21 point change) as compared with the placebo group (+ 1.66 point change), which was statistically significant.
In the TRAILBLAZER-ALZ 2 18-month study with 1,800 participants, donanemab slowed the rate of cognitive decline by 35% in CDR-SB and led to 40% less decline in activities of daily living measured by iADRS (integrated Alzheimer’s Disease Rating Scale). Inclusion criteria were MMSE score of 20-28 and demonstration of Aßpathology by PET.
The major concern for these mAbs are ARIA (amyloid-related imaging abnormalities) related events, comprising ARIA-H (hemorrhage) and ARIA-E (cerebral edema). It is thought to occur due to leakiness in cerebral blood vessels from inflammation. These abnormalities can manifest as headaches, dizziness, nausea, difficulty walking, confusion, vision changes, seizures and in rare cases, death. Risks factors for developing ARIA-E are a positive carrier status for apolipoprotein E €4 gene and prior multiple cerebral microhemorrhages. An exclusion criteria for the aducanumab and lecanemab trials were having more than four microhemorrhages due to increased ARIA-E and ARIA-H risk. Risk factors for developing ARIA-H are age, antithrombotic use, a history of prior strokes and a history of cerebral microhemorrhages.
It is worth noting that participants with prior ischemic and hemorrhagic strokes involving the basal ganglia, the presence of two or more lacunar strokes, or large areas of vascular territory were excluded in the lecanemab study. Furthermore, caution is recommended in patients with uncontrolled hypertension, anticoagulation use or other vascular comorbidities such as diabetes mellitus and smoking given the connection of ARIA to vascular injury and leakiness.
Studies have shown that apo€4 allele carriers and homozygous individuals have increased risk for ARIA. In the lecanemab studies, 39% of homozygous individuals developed ARIA-H, as opposed to 19.7% of heterozygotes and 11.9% of noncarriers. In donanemab studies, there has been a report of 44% incidence of ARIA in homozygous individuals, 30% in heterozygous and 11.1% in noncarriers.
Looking forward, the mAb remternetug has shown promise in its Phase 3 clinical trials thus far, pending further results. Although another mAb, gantenerumab, was terminated in its Phase 3, it has been combined with a ‘brain shuttle’ using the transferrin transporter to enhance BBB penetration, which is in its Phase 2 trial currently, called trotinemab.
The future of AD management is bright with these multiple contenders and currently established pharmaceutical therapies, and there is still more to come.
Mr. Dos Santos is a rising fourth-year medical student at the Medical College of Georgia. He completed a Bachelor of Science in Chemistry at Davidson College. He is interested in plastic and reconstructive surgery.
Dr. Stuart is Chairman of the Board for the Atlanta Neuroscience Institute. He is a graduate of Princeton University and Emory University School of Medicine. Dr. Stuart completed his medical internship at Emory University Hospital, his residency in neurology at the University of Chicago and a fellowship in Clinical Neurophysiology at Emory University. Dr. Stuart has participated as an investigator in a number of research trials for MS treatments and is currently Medical Director for concussion and memory loss.
References
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Cummings J. Anti-Amyloid Monoclonal Antibodies are Transformative Treatments that Redefine Alzheimer’s Disease Therapeutics. Drugs. 2023 May;83(7):569-576. doi: 10.1007/s40265-023-01858-9. Epub 2023 Apr 15. PMID: 37060386; PMCID: PMC10195708.
Prins ND, Scheltens P. Treating Alzheimer’s disease with monoclonal antibodies: current status and outlook for the future. Alzheimers Res Ther. 2013 Nov 11;5(6):56. doi: 10.1186/alzrt220. PMID: 24216217; PMCID: PMC3978826.
Doran SJ, Sawyer RP. Risk factors in developing amyloid related imaging abnormalities (ARIA) and clinical implications. Front Neurosci. 2024 Jan 19;18:1326784. doi: 10.3389/fnins.2024.1326784. PMID: 38312931; PMCID: PMC10834650.
Withington CG, Turner RS. Amyloid-Related Imaging Abnormalities With Anti-amyloid Antibodies for the Treatment of Dementia Due to Alzheimer’s Disease. Front Neurol. 2022 Mar 23;13:862369. doi: 10.3389/fneur.2022.862369. PMID: 35401412; PMCID: PMC8985815.
Other links:
https://investor.lilly.com/news-releases/news-release-details/lillys-kisunlatm-donanemab-azbt-approved-fda-treatment-early
https://www.aan.com/tools-resources/monoclonal-antibodies-alzheimers?form=MG0AV3
