Differences Between Antiamyloid Therapies Lecanemab and Donanemab: Martin Sadowski, MD, PhD

WATCH TIME: 5 minutes

"Instead of targeting the whole range of beta-amyloid species state, [donanemab's design] went after the specific antigen that was uniquely present on beta-amyloid plaques. [The developer] wanted to get a drug that is very potent in clearing beta-amyloid plaques, but they also wanted to avoid ARIA, amyloid-related imaging abnormalities."

The traditional approval of lecanemab (Leqembi; Eisai) earlier this year marked another major step in bridging access to treatments for patients with Alzheimer disease (AD), a patient population that’s expected to grow over the coming decades. Lecanemab, a monoclonal antibody designed to target amyloid plaques, is the first in its class to receive traditional approval and has opened the door for other similarly acting agents. Many in the field are awaiting the approval of donanemab (Eli Lilly), another antiamyloid therapy that has shown an ability to reduce amyloid plaques across phase 2 and 3 studies.

At the start of 2023, Eli Lilly received a complete response letter from the FDA for the submitted application of donanemab, citing the need for more longterm data on the drug’s efficacy and safety.¹ The phase 2 TRAILBLAZER-ALZ study (NCT03367403), which served as the basis for the biologics license application of donanemab, included more than 100 patients; however, it was designed so that patients would complete the treatment course once they reached a predefined level of amyloid plaque clearance. While similar to lecanemab, donanemab has different properties and may elicit a lower risk for amyloid-related imaging abnormalities (ARIA), says Martin Sadowski, MD. In the phase 3 TRAILBLAZER-ALZ 2 study (NCT04437511), donanemab was associated with a rate of ARIA-E of 24% (n = 205) and a rate of ARIA-H of 31.4% (n = 268).² In phase 3 data on lecanemab (NCT03887455), its treatment was associated with rates of ARIA-E and ARIA-H of 12.6% (n = 113) and 17.3% (n = 155), respectively.³

Sadowski, a professor of neurology, psychiatry, and pharmacology at the NYU Grossman School of Medicine, has served as a trial investigator for some of donanemab’s clinical development. At the 2023 Clinical Trials on Alzheimer’s Disease (CTAD) conference, held October 24-27, in Boston, Massachusetts, NeurologyLive^® sat down with Sadowski to discuss some of the major differences and similarities between lecanemab and donanemab. He spoke specifically about their mechanisms of action, the clinical development of donanemab, and some of its supporting data.

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REFERENCE
1. US Food and Drug Administration Issues Complete Response Letter for Acceleterated APproval of Donanemab. News release. Eli Lilly. January 19, 2022. Accessed November 13, 2023 prnewswire.com/news-releases/us-food-and-drug-administration-issues-complete-response-letter-for-accelerated-approval-of-donanemab-301726325.html
2. Sims JR, Zimmer JA, Evans CD, et al. Donanemab in Early Symptomatic Alzheimer Disease The TRAILBLAZER-ALZ 2 Randomized Clinical Trial. JAMA. 2023;330(6):512-527. doi:10.1001/jama.2023.13239
3. van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in Early Alzheimer's Disease. N Engl J Med. 2023;388:9-21. doi: 10.1056/NEJMoa2212948