Already, 2023 is shaping up to be an eventful year in Alzheimer’s disease (AD) drug development. After the FDA’s approval of Eisai/Biogen’s Leqembi (lecanemab) on January 6, the AD field is now looking toward the upcoming approval decision for Lilly’s donanemab expected in May. Although both donanemab and lecanemab have similar therapeutic targets, the two AD antibodies employed notably different trial designs.

Lilly is seeking accelerated approval for donanemab based on the 272-patient Phase II TRAILBLAZER-AD study (NCT03367403). TRAILBLAZER-AD met its primary endpoint of change in the Integrated Alzheimer’s Disease Rating Scale (iADRS)—a new AD scale combining two established measures of function and cognition.

Notably, donanemab also demonstrated a significant reduction in amyloid plaque in patients’ brains. The FDA considers amyloid plaque reduction to be a valid AD biomarker based on the long-held theory that amyloid reduction can slow AD cognitive decline.

Meanwhile, lecanemab’s approval was based on an 856-patient Phase II study (NCT01767311), which used a primary endpoint of Alzheimer’s Disease Composite Score (ADCOMS). Although lecanemab also demonstrated a reduction in amyloid plaque, it missed its Phase II primary outcome of ADCOMS.

Separately, a Phase III trial of lecanemab (NCT03887455) met its primary endpoint of slowing cognitive decline in November, though this study was not part of the accelerated approval package. Eisai and Biogen plan to file for a full FDA approval in AD based on these results. Meanwhile, Lilly is also running the Phase III TRAILBLAZER-ALZ 2 study (NCT04437511) of donanemab in AD, with results expected in Q2 2023.

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Meanwhile, the controversial accelerated approval of Biogen’s Aduhelm (aducanumab) remains in the shadow of donanemab and lecanemab. The FDA approved Aduhelm based on reduction amyloid plaque, despite an FDA advisory committee's overwhelming rejection. Aduhelm has not yet met a primary endpoint in a Phase III trial.

Different primary endpoints for lecanemab, donanemab

While the forthcoming accelerated approval decision will likely hinge on donanemab’s demonstrated ability to reduce amyloid plaque, the Phase III trial will likely dictate the drug’s market success. Lecanemab is the only AD drug to demonstrate a slowing of cognitive decline in a Phase III study, setting the benchmark for the field.

The Phase III TRAILBLAZER-ALZ-2 trial of donanemab uses the iADRS scale, which was developed by Lilly. iADRS combines two established scales: the cognitive scale Alzheimer’s Disease Assessment Scale (ADAS-Cog13) and functional scale Alzheimer’s Disease Cooperative Study-Instrumental Activities of Daily Living Inventory (ADCS-iADL). However, when Lilly first published results with the iADRS scale in the Phase II TRAILBLAZER-ALZ trial, many experts expressed skepticism over the scale’s interpretability.

Meanwhile, the Phase III study of lecanemab used a primary endpoint of Clinical Dementia Rating-Sum of Boxes (CDR-SB), which is a well-established endpoint of AD disease progression. CDR-SB is among the secondary endpoints of TRAILBLAZER-ALZ-2, and it was also the primary endpoint of the two failed Phase III trials of Aduhelm. A subsequent post-hoc analysis indicated that a subset of patients in one of Aduhelm’s two Phase III trials met the primary endpoint of CDR-SB.

Beyond donanemab’s efficacy, the AD field will also closely monitor the forthcoming trial results for the side effect known as ARIA-E—a type of brain swelling that, although usually reversible, can prove to be serious. In Phase III trials of Aduhelm and lecanemab, ARIA-E occurred in 35% and 12.5% of patients, respectively. While ARIA-E is common among antibodies targeting AD, some researchers believe AD vaccines could act on similar targets without this safety concern.