AdventHealth Physicians Examine the New Alzheimer’s Infusion Therapies

In the past year, the U.S. Food and Drug Administration (FDA) has approved two new monoclonal antibody intravenous (IV) infusion therapies for the treatment of mild Alzheimer’s disease: lecanemab (Leqembi®) and donanemab (Kisunla™). Both drugs

have demonstrated promise, clearing amyloid plaque to help slow progression of the disease. However, they also come with risks and limitations.

AdventHealth’s Valeria Baldivieso Hurtado, MD, medical director of memory care at AdventHealth Central Florida, and Daniel Ebele Okobi, Jr., MD, PhD, medical director of behavioral neurology at AdventHealth Neuroscience Institute, recently sat down to discuss these two new Alzheimer’s treatments, including the benefits, risks, challenges and limitations.

Progress on Treating a Challenging Diagnosis

Nearly 7 million Americans age 65 and older are living with Alzheimer’s, and without development of effective treatments or a cure for the disease, that number is expected to grow to 12.7 million by 2050. An irreversible, progressive brain disorder, Alzheimer’s was the fifth-leading cause of death among people age 65 and older in 2021. Although the specific cause is not clear, the formation of amyloid beta plaques and tau protein tangles are the pathological hallmarks of the disease and one of the primary targets of Alzheimer’s research and drug development.

Dr. Baldivieso: For many years, researchers have been focusing on the amyloid plaque as a key to slowing progression of Alzheimer’s. This resulted in the development of these two new monoclonal antibody infusions now approved by the FDA. It is a significant advancement in that they are the first traditionally approved treatments to address the underlying biology of the disease in the early stages.

Dr. Okobi: While lecanemab and donanemab are not cures, they are certainly a step in the right direction, demonstrating the ability to delay disease progression. Up until this point, we have had limited treatment options for Alzheimer’s, and the drugs available only addressed some of the symptoms of Alzheimer’s, not the underlying disease.

Understanding Lecanemab (Leqembi®) and its Effectiveness

Dr. Baldivieso: In July 2023, lecanemab was the first Alzheimer’s infusion to receive full approval by the FDA after a prior accelerated approval in January 2023. It is a humanized immunoglobulin G1 (IgG1) monoclonal antibody that binds to soluble amyloid-beta (Aβ) protofibrils. It is administered every 2 weeks for 18 months and is appropriate for use in patients who have a biomarker-confirmed diagnosis of mild cognitive impairment or mild dementia due to Alzheimer’s disease.

Dr. Okobi: FDA approval was granted following completion of the 18-month Clarity AD clinical trial, a Phase III, multi center, randomized, double-blind, placebo-controlled, parallel-group study that involved participants 50 to 90 years of age who had early Alzheimer’s disease and evidence of amyloid on positron-emission tomography (PET) scan or by cerebrospinal fluid (CSF) testing. The study concluded that lecanemab reduced markers of amyloid plaque in the brain of early Alzheimer’s patients and resulted in moderately less decline on measures of cognition and function than placebo at 18 months. However, the drug was also associated with adverse events. In all, we’ve found that lecanemab slows the progression of Alzheimer’s disease by about 5 months.

Understanding Donanemab (Kisunla™) and its Effectiveness

Dr. Okobi: Also an IgG1 monoclonal antibody, donanemab was designed to bind with the N-terminal truncated form of beta amyloid present only in brain amyloid plaques. It aids in plaque removal through microglial-mediated phagocytosis. Donanemab was approved by the FDA in July 2024, and is administered via IV infusion every 4 weeks for up to 18 months.

Dr. Baldivieso: Donanemab was studied in the TRAILBLAZER-ALZ 2 randomized clinical trial, a global Phase III, double-blind, placebo-controlled, parallel-group study. The trial assessed the drug’s efficacy in people with early symptomatic Alzheimer’s disease along with amyloid and tau pathology. The trial showed statistically significant reduction of amyloid plaque and a slowdown in clinical progression. The overall benefit of the drug is that it slows disease progression by about 6-7 months. However, it was also associated with adverse events, which occurred at a higher rate than lecanemab.

Risks and Safety Warnings for Lecanemab and Donanemab

Dr. Baldivieso: While both new infusion drugs have demonstrated promising amyloid plaque clearance, they also carry a boxed warning for amyloid-related imaging abnormalities (ARIA). These most commonly present as brain edema, temporary inflammation and swelling that usually resolves over time. However, the edema can also result in seizures or be accompanied by intracerebral hemorrhages, which can be fatal.

Dr. Okobi: Patients who are ApoE ε4 (APOE4) homozygotes have a higher incidence of ARIA compared to heterozygotes and noncarriers. As a result, testing for APOE4 status should be performed prior to beginning treatment with either drug. In addition, use of anticoagulant medication was associated with an increased number of intracerebral hemorrhages in patients taking Leqembi compared to placebo. Both lecanemab and donanemab also carry risk of infusion-related reactions, and headaches were another reported side effect.

The Importance of Diagnostic Testing Before and During Treatment

Dr. Baldivieso: Prior to starting lecanemab or donanemab, patients must obtain a recent baseline MRI to evaluate for any pre-existing ARIA. They must also have confirmation of the presence of beta-amyloid plaques through either an amyloid positron emission tomography (PET) scan or lumbar puncture (CSF test). If cleared to begin one of the new Alzheimer’s infusions, patients must have additional MRIs throughout the course of their treatment to monitor for ARIA side effects.

Dr. Okobi: For patients on lecanemab, they must have MRI scans prior to their 5th, 7th and 14th infusions. An MRI scan is also recommended prior to the 26th infusion at week 52, especially for patients who are APOE4 carriers or who had evidence of ARIA, with or without symptoms, on prior scans. Patients taking donanemab must obtain an MRI prior to their 2nd, 3rd, 4th, and 7th infusions. If radiographically observed ARIA occurs, treatment recommendations are based on the type, severity and presence of symptoms.

Costs and Insurance Coverage

Dr. Okobi: Like any newly approved treatment, there are some hurdles when it comes to cost and coverage of both new Alzheimer’s infusion treatments. Our teams work with each patient to help them navigate their specific coverage and cost. Without insurance coverage, lecanemab costs around $26,500 per year. Treatment costs for donanemab are higher, at about $32,00 per year, though many patients should be able to stop between month 12 and 18. Both drugs are now covered by Medicare. Most insurance companies require pre-authorization, and due to its recent approval, donanemab is not yet on many insurance formularies. With both drugs, there are additional costs for the required pre-treatment testing and monitoring MRIs.

Challenges and Limitations of the New Alzheimer’s Infusion Therapies

Dr. Baldivieso: While both lecanemab and donanemab offer the benefit of providing those with mild Alzheimer’s more time to participate in daily life and live independently, they still aren’t a cure, and they are not for those with moderate or severe Alzheimer’s. We encourage each patient considering one of these drugs to carefully weigh this benefit against both the risks and treatment burden. An extension study is currently evaluating weekly subcutaneous administration of lecanemab, which would help enhance patient convenience, eliminating the need to travel to an infusion center every two weeks for treatment. We look forward to reviewing the results of that study.

Dr. Okobi: We know there can be a real stigma about memory loss, and it can be overwhelming for both the patient and their family members. Too often, by the time they seek help, the disease is already in a moderate or advanced state. These two new treatments are yet another reason why early medical evaluation by a primary care physician, geriatrician, neurologist or psychiatrist is critical when someone first begins to experience cognitive challenges. Doing so allows for these treatments to be an option.