Donanemab: A Promising Anti-Amyloid Therapy

     Due to inconsistent effects of anti-amyloid therapies, such as aducanamab, a recent shift from the “amyloid hypothesis” to the “tau hypothesis”, has occurred. The primary issue with most anti-amyloid therapies, is that the successful removal of amyloid-β (Aβ) plaques doesn’t significantly reduce the clinical symptoms, suggesting that significant damage to the underlying brain structures has already occurred. However, donanemab, another anti-amyloid therapy, promises to be different, and here’s how.

        Firstly, donanemab, unlike most of the previous anti-Aβ therapies, is designed for early use in Alzheimer’s disease (AD), when Aβ levels are notable yet phosphorylated tau (pTau) making up neurofibrillary tangles (NFTs) are not widely deposited. The presence of amyloid is believed to form pTau misfolding and aggregation into NFTs. Not including individuals with widely dispersed NFTs helped provide a clearer picture of what Aβ removal can improve, without significant NFT presence contributing to continued dysfunction and cell death. Secondly, in a Phase-II trial donanemab met its primary outcome measure, producing a significant improvement in 2 cognitive/functional rating scales compared to controls. The secondary outcomes did not reach significance in this trial, but likely could have in a trial with more participants (such as the stage 3 trial with donanemab that our site is participating in). Finally, it targets a specific type of Aβ known as N3 truncated, pyroglutamylated Aβ (pE-Aβ) which is present in relatively low quantities compared to other types of Aβ but is especially prone to “seeding” or propagation of Aβ pathology by interacting with and misfolding other proteins.

      This pE-Aβ has been researched previously and is strongly implicated in the pathogenesis of AD. Its role in neurodegeneration was confirmed in AD mouse when its inhibition improved memory and decreased Aβ deposition. This is because pE-Aβ works synergistically with conventional Aβ when co-incubated, forming resilient hybrid oligomers that have stronger cytotoxic effects than oligomers formed by non-pE-Aβ alone. Therefore, a drug such as donanemab that targets pE-Aβ before they initiate the cascade of plaque formation could, in theory, prevent significant plaque-induced neurodegeneration.

         Even more exciting, in the Phase-II trial also improved Aβ clearance with spectacular results such that within 24 weeks of starting treatment, 25% of the subjects on active drug reached Aβ negativity as reflected in Amyloid-PET scans. By week 76, 68% were Aβ negative. Furthermore, as expected, these results were strongest in those with lower pTau burden at baseline. On the other hand, there were also unexpected outcomes such as the lack of significant hippocampal volume change and an overall decrease in brain volume and increase in ventricular size for those in the treatment group compared to controls. Researchers hypothesized this was due to the rapid removal of plaque volume. Despite these promising outcomes, donanemab is not expected to be a sole treatment for AD in the future. Alzheimer’s is a multi-factorial disease and therefore researchers expect to someday utilize a multi-factorial combination of therapies to specifically target each phase of the disease spectrum and the new Phase-III TRAILBLAZER-ALZ2 trial for donanemab may emerge as one of these future treatments!

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Sources:
Talan, J. A New Monoclonal Antibody Shows Promise Early in Alzheimer’s Disease [Article]. Neurology. 2021.
Nussbaum, J., et al. Prion-like behavior and tau-dependent cytotoxicity of pyroglutamylated amyloid-β [Online]. Nature. 2012. Available from:  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3367389/