ONO-2020 is a new type of drug targeting epigenetic pathways in Alzheimer’s Disease (AD) and preventing the inactivation of a molecule that boosts memory and cognition. The idea is that with increased levels of this, often inhibited, molecule in the brain, there might be beneficial effects on AD related symptoms.
ONO-2020 has been found to improve hippocampal long term potentiation deficits in aged mice, and co-treatment with Donepezil has shown higher efficacy than either treatment alone. It has also been found, in mice, to decrease amyloid beta (Aβ) accumulation, inhibit cell death from neurofibrillary tangles (NFTs), and suppress inflammatory microglial activation.
Epigenetics explores how the environment and our behavior modifies the expression of genes without changing DNA. Epigenetics could describe the behavioral differences in our offspring. Epigenetics is impacted by environmental factors; diet, stress, toxins, and lifestyle choices and is targeted by drug developers to change how cells function in progressive diseases, i.e. diabetes, cancer, and AD treatments.
ONO-2020 is an oral Lysine demethylase 5 inhibitor that inhibits the KDM5 family of Histone demethylases. These enzymes are responsible for inactivating H3K4me3 which starts gene activation. Inhibiting KDM5 may increase the number of H3K4me3 at transcription start sites and potentially reverse destructive gene alterations in AD, delay cognitive decline, and reduce agitation in moderate AD patients.
The clinical trial is a phase II, double-blind, parallel-group, placebo-controlled study to assess safety, tolerability, pharmacokinetics, and efficacy of ONO-2020 in patients with mild to moderate AD. There is still a lot of research to be done to determine if ONO-2020 will be an important emerging drug to combat AD progression. This clinical trial is one step in a long process to prove the safety and efficacy of one of many evolving epigenetic modifiers in AD therapy.
Sources:
Shivraj Sohur U, O’Neill S, et al. (2025). A Study of ONO-2020 in Participants with Mild to Moderate Alzheimer’s Disease. Gov, Ono Pharmaceutical Co. Ltd. clinicaltrials.gov/study/NCT06881836?cond=Alzheimer%27s+Disease.
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Jianbing Men, Xinyue Wang, Yunnuo Zhou, Yumeng Huang, Yue Zheng, Yingze Wang, Shuang Yang, Nan Chen, Nan Yan, Xiaoxu Duan. (2025). Neurodegenerative diseases: Epigenetic regulatory mechanisms and therapeutic potential. Cellular Signalling. 131(1).
Howe FS, Fischl H, Murray SC, Mellor J. (2017). Is H3K4me3 instructive for transcription activation? Bioessays. 39(1), 1-12.