Alzheimer’s disease research: The future of BACE inhibitors
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β-secretase inhibitors such as lanabecestat, verubecestat, and atabecestat target Bace-1 to decrease synthesis of amyloid beta.
“In order to decrease the synthesis of amyloid beta, β-secretase inhibitors (BACE inhibitors) such lanabecestat (labeled as 8, Figure 5) [157,161,162], verubecestat (labeled as 9, Figure 5) [157,163,164], and atabecestat (labeled as 10, Figure 5) target the enzyme Bace-1 [157,165].”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [162]
Clinical trials with the BACE inhibitors lanabecestat, verubecestat, and atabecestat have been recently discontinued due to unexpected difficulties.
“However, the clinical trials with the BACE inhibitors lanabecestat,32 verubecestat,33 and atabecestat34 have been recently discontinued due to unexpected difficulties.”
From Current and Future Treatments in Alzheimer Disease: An Update (2020) · cites this paper as [32]
The phase 3 lanabecestat trial was discontinued due to lack of efficacy, whereas verubecestat and atabecestat trials were ceased due to ineffectiveness and safety reasons (rash, falls, liver toxicity, and neuropsychiatric symptoms).
“The phase 3 lanabecestat trial was discontinued due to lack of efficacy, whereas verubecestat and atabecestat trials were ceased due to ineffectiveness, as well as safety reasons (rash, falls, liver toxicity, and neuropsychiatric symptoms).10,32-34”
From Current and Future Treatments in Alzheimer Disease: An Update (2020) · cites this paper as [32]
Cited by
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Current and Future Treatments in Alzheimer Disease: An Update
Yiannopoulou, K. G., & Papageorgiou, S. G. (2020) · Journal of Central Nervous System Disease · doi:10.1177/1179573520907397 · Cited by 966 · see citing works
Yiannopoulou, K. G., Anastasiou, A. I., Zachariou, V., & Pelidou, S.-H. (2019) · Biomedicines · doi:10.3390/biomedicines7040097 · Cited by 330 · see citing works
“Further examples of agents targeting Aβ that failed due to lack of efficacy include the β-Secretase (BACE) inhibitors lanabecestat [16], verubecestat [17] and atabecestat [18].”
BackgroundRecent advances on drug development and emerging therapeutic agents for Alzheimer’s disease
Athar, T., Balushi, K. A. A., & Khan, S. A. (2021) · Molecular Biology Reports · doi:10.1007/s11033-021-06512-9 · Cited by 261 · see citing works
Therapeutic Approach to Alzheimer’s Disease: Current Treatments and New Perspectives
Pardo-Moreno, T., González-Acedo, A., Rivas-Domínguez, A., García-Morales, V., García-Cozar, F. J., Ramos-Rodríguez, J. J., & Melguizo-Rodríguez, L. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14061117 · Cited by 239 · see citing works
Drug development for alzheimer’s disease: Microglia induced neuroinflammation as a target
Dong, Y., Li, X., Cheng, J., & Hou, L. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20030558 · Cited by 136 · see citing works
“Multiple phase II and III clinical trials have been conducted for early to mild AD treatment, however they were later terminated because of a lack of effect (NCT02245737, NCT02972658, and NCT02783573) [133].”
BackgroundHabtemariam, S. (2019) · Molecules · doi:10.3390/molecules24081519 · Cited by 107 · see citing works
“This is also the area of frustration for the failed clinical trials of drugs such as Lanabecestat [12] and is the basis for the current pessimism in this therapeutic approach.”
BackgroundIliyasu, M. O., Musa, S. A., Oladele, S. B., & Iliya, A. I. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1081938 · Cited by 101 · see citing works
“The β-secretase (BACE) inhibitors, lanabecestat (Burki, 2018), verubecestat (Egan et al., 2019), and atabecestat (Henley et al., 2019), as well as the anti-amyloid agents such as semagacestat (Doody et al., 2013), bapineuzumab (Vandenberghe et al., 2016), and solanezumab (Neurology, 2016), failed…”
BackgroundOno, K., & Tsuji, M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21030952 · Cited by 92 · see citing works
“A recent failure in phase 3 involved the investigation of a β secretase in patients with mild-to-moderate AD [17].”
BackgroundTherapeutic potential of quinazoline derivatives for Alzheimer's disease: A comprehensive review
Haghighijoo, Z., Zamani, L., Moosavi, F., & Emami, S. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.113949 · Cited by 75 · see citing works
Amyloid Cascade Hypothesis for the Treatment of Alzheimer’s Disease: Progress and Challenges
Wu, T., Ding, L., Cheng, Y., Jiang, S., Riaz, M. W., Fu, N., Mou, C., Ye, M., & Zheng, Y. (2022) · Aging and Disease · doi:10.14336/ad.2022.0412 · Cited by 75 · see citing works
“Yet most of the evidence so far suggests the amyloid cascade hypothesis still makes sense, especially in the condition of a presymptomatic phase of AD or in the very mild cognitive impairment stage [53].”
BackgroundSiddappaji, K. K., & Gopal, S. (2021) · AIMS neuroscience · doi:10.3934/neuroscience.2021020 · Cited by 57 · see citing works
“Upon oral administration of small-molecule BACE1 inhibitors like lanabecestat, atabecestat in AD patients displayed reduced Aβ, total tau, and phosphorylated tau levels in the CSF, but the usage of these drugs is terminated due to side effects of skin rashes, liver toxicity, and neuropsychiatric symptoms [183,184].”
BackgroundRecent Advances in Therapeutics for the Treatment of Alzheimer’s Disease
Thawabteh, A. M., Ghanem, A. W., AbuMadi, S., Thaher, D., Jaghama, W., Karaman, D., & Karaman, R. (2024) · Molecules · doi:10.3390/molecules29215131 · Cited by 56 · see citing works
“In order to decrease the synthesis of amyloid beta, β - secretase inhibitors (BACE inhibitors) such lanabecestat (labeled as 8 , Figure 5) [157,161,162], verubecestat (labeled as 9 , Figure 5) [157,163,164], and atabecestat (labeled as 10 , Figure 5) target the enzyme Bace-1 [157,165].”
BackgroundStatus and future directions of clinical trials in Alzheimer's disease
Plascencia‐Villa, G., & Perry, G. L. (2020) · International review of neurobiology · doi:10.1016/bs.irn.2020.03.022 · Cited by 48 · see citing works
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Liu, J., Ting, J. P., Al-Azzam, S., Ding, Y., & Afshar, S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22062805 · Cited by 35 · see citing works
Brendel, M., Jaworska, A. M., Overhoff, F., Blume, T., Probst, F., Gildehaus, F., Bartenstein, P., Haass, C., Bohrmann, B., Herms, J. W., et al. (2018) · Theranostics · doi:10.7150/thno.27868 · Cited by 34 · see citing works
“Very recently, two phase III trials with Lanabecestat were discontinued early as they would probably not have met their primary endpoints [29].”
BackgroundMarciani, D. J. (2019) · Research · doi:10.34133/2019/5341375 · Cited by 31 · see citing works
Chen, G., Yang, K. Y., Du, W., Hu, X., & Han, Y. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-190501 · Cited by 29 · see citing works
“Therefore, the best time to treat AD would be in the ultra-early phase, namely, in the preclinical stage of AD, when the damage is reparable [8].”
Kabir, M. T., Uddin, M. S., Mathew, B., Das, P. K., Perveen, A., & Ashraf, G. M. (2020) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026620666200422105156 · Cited by 31 · see citing works
Mosaic Somatic Gene Recombination as a Potentially Unifying Hypothesis for Alzheimer’s Disease
Kaeser, G. E., & Chun, J. J. M. (2020) · Frontiers in Genetics · doi:10.3389/fgene.2020.00390 · Cited by 22 · see citing works
“Another major criticism of the amyloid hypothesis has been its failure to yield any diseasemodifying therapies despite the many clinical trials targeting Aβ components (Carlsson, 2008; Cummings et al., 2014; Anderson et al., 2017; Mehta et al., 2017; Burki, 2018; Egan et al., 2018).”
BackgroundMishra, K. A., & Sethi, K. K. (2024) · Archiv der Pharmazie · doi:10.1002/ardp.202400748 · Cited by 21 · see citing works
Abosharaf, H. A., Elsonbaty, Y., Tousson, E., & Mohamed, T. M. (2023) · Journal of Neuroendocrinology · doi:10.1111/jne.13356 · Cited by 19 · see citing works
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Bhatti, J. S., Khullar, N., Mishra, J., Kaur, S., Sehrawat, A., Sharma, E., Bhatti, G. K., Selman, A., & Reddy, P. H. (2023) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2023.166712 · Cited by 17 · see citing works
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“However, recent publications relate the possible fail of BACE inhibitors in Alzheimer’s trials [14, 15].”
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The endocrine pancreas of old obesehyperglycemic mice.
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“To date attempts at therapeutic intervention in AD have largely focused on limiting Aβ production, an approach that has met with limited success, perhaps due in part to the key role of Aβ in regulating several vital neural functions (Drachman, 2014; Herrup, 2015; Burki, 2018).”
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Natarajan., P., Mumthaj., P., Vijay., J., & Gokul., V. (2021) · International Journal of Pharmaceutical Sciences Review and Research · doi:10.47583/ijpsrr.2021.v68i01.017 · Cited by 2 · see citing works
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“Studies show that the β-site amyloid precursor protein cleaving enzyme 1 (BACE1) initiates the production of Aβ and is a prime target for AD [10].”
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“terms of inhibiting the progression of dementia [18,14,58,56,7,16,27].”
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- Authors
- Burki, T.
- Corresponding author
- Burki, Talha
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2018-06
- Volume
- 391
- Issue
- 10139
- Pages
- 2486
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- OpenAlex
- W2809592476
- Cited by
- 40
- References
- 0
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 3 · 2023: 5 · 2022: 4 · 2021: 7 · 2020: 6 · 2019: 10 · 2018: 1
- FWCI
- 4.14
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Lancet (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, BACE inhibitors, beta-secretase, clinical trial failure, drug development, amyloid-beta
- MeSH terms
- Drug Development, Alzheimer Disease, Humans, Aspartic Acid Endopeptidases, Treatment Failure, Clinical Trials, Phase III as Topic, Biomedical Research, Amyloid Precursor Protein Secretases
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