Third Amyloid plaque clearing drug against AD in two years is reason for hope

On May 3rd, 2023 Ely Lily  announced positive results from their phase 3 clinical trial (TRAILBLAZER-ALZ2) for the drug, Donanemab, a monoclonal antibody (Lilly’s Donanemab Significantly Slowed Cognitive and Functional Decline in Phase 3 Study of Early Alzheimer’s Disease, n.d.). This is the third Amyloid plaque clearing drug after Biogen’s Aducanumab and Eisai’s Lecanemab in two years! Alzheimer’s Disease (AD) is characterized by accumulation of Amyloid plaques and neuronal Tau (protein) deposits. Donanemab was developed to reduce the Amyloid plaques in the brain. The drug significantly reduced cognitive loss by 35% in some individuals in a clinical trial of 1736 participants. In addition, Amyloid plaques were cleared from the brain of participants as assessed by positron emission tomography (PET) scans. However, 31.4% of the participants given the drug showed typical side effects of brain swelling and bleeding including 2 deaths. The details of the study are still to be published.

Late last year results from TRAILBLAZER-ALZ, a Phase 2 trial were published (Shcherbinin et al., 2022). For the phase 2, the company recruited 272 participants with early signs of Alzheimer’s Disease with mild cognitive impairment. Participants were randomly split to two groups; one received a placebo, and the other group was given the drug. Primary endpoint of the trial was reduction in Amyloid plaques and Tau deposits. Representative figure (below) shows dramatic reduction in Amyloid plaques some participants. In fact, 68% of those who received the drug showed clearance of amyloid plaques by 76 weeks.

Figure1: Reproduced from supplementary figure (Shcherbinin et al., 2022); CL refers to centiloids, a unit used to quantify the levels of Amyloid plaque. In these images, the red/orange/yellow tones represent a higher level of Amyloid plaque whereas the blue/green tones represent lower levels. Donanemab reduced the Amyloid plaques dramatically!

Post hoc analyses (analyzed after primary data was seen) recorded change from baseline of cognition scored by a cognitive assessment called the integrated Alzheimer’s Disease Rating Scale (iADRS). These analyses showed a high correlation of better iADRS scores (no loss of cognition) in those who had significant reduction in Amyloid plaques. Positive results from phase 2 led to the phase 3 (TRAILBLAZER-ALZ2) that appeared to have confirmed the results as per Ely Lily’s May 3rd announcement.

These results are highly impressive and are very exciting for the research community in the field of AD. This might be the first time that a reduction in Amyloid plaques has led to tangible clinical outcomes. However, the side effects that included 2 deaths in the phase 3 trial remain an area of concern. These side effects, known as Amyloid Related Imaging Abnormalities (ARIA) have been reported for most antibodies developed to target Amyloid plaques.

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Lilly’s Donanemab Significantly Slowed Cognitive and Functional Decline in Phase 3 Study of Early Alzheimer’s Disease. (n.d.).

Shcherbinin, S., Evans, C. D., Lu, M., Andersen, S. W., Pontecorvo, M. J., Willis, B. A., Gueorguieva, I., Hauck, P. M., Brooks, D. A., Mintun, M. A., & Sims, J. R. (2022). Association of Amyloid Reduction After Donanemab Treatment With Tau Pathology and Clinical Outcomes: The TRAILBLAZER-ALZ Randomized Clinical Trial. JAMA Neurology, 79(10), 1015–1024.