Promising candidates from drug clinical trials: Implications for clinical treatment of Alzheimer's disease in China

Abstract

Alzheimer's disease is the most common neurodegenerative disease. Prior to 2017, National Medical Products Administration approved only four drugs to treat Alzheimer's disease, including three cholinesterase inhibitors and one N-methyl-D-aspartate receptor antagonist. We queried ClinicalTrials.gov to better understand Alzheimer's drug development over the past 5 years and found 16 promising candidates that have entered late-stage trials and analyzed their impact on clinical treatment of Alzheimer's disease in China. The 16 compounds selected include disease-modifying therapies and symptomatic therapies. The research and development pipeline now focuses on disease-modifying therapies such as gantenerumab, aducanumab, ALZ-801, ALZT-OP1, donanemab, lecanemab, simufilam, NE3107, semaglutide, and GV-971, which could put an end to the situation where Alzheimer's patients in China have no effective treatment alternatives. The reuse of drugs or combinations currently under investigation for the psychiatric treatment of Alzheimer's disease, including AXS-05, AVP-786, nabilone, brexpiprazole, methylphenidate, and pimavanserin, could provide physicians with additional treatment options. Although most of these drugs have not been explored in China yet, due to the current development trend in this field in China, it is expected that China will be involved in research on these drugs in the future.

Alzheimer’s Disease: The Past, Present, and Future of a Globally Progressive Disease

“…Interestingly, the GLP-1 agonist semaglutide demonstrated promise in preclinical studies and successfully lowered the risk of acquiring dementia by 53% compared to a placebo in people with early AD during a phase-3a trial. Thus, presently, two phase-3 trials, EVOKE (NCT04777396) and EVOKE Plus (NCT04777409), are investigating the safety and efficacy of semaglutide in early AD [ 31 ].…”

Unlocking the Potential: Semaglutide’s Impact on Alzheimer’s and Parkinson’s Disease in Animal Models

“…This localized distribution in the hypothalamus is significant as it aligns with the proposed effects of SEM in the brain, such as neuroprotection. These effects are believed to be associated with the interaction of SEM with GLP-1 receptors in the brain [ 64 , 65 , 66 , 67 , 68 ]. This paradoxical finding underscores the complexity of SEM’s interaction with the brain and challenges the conventional understanding of its BBB permeability.…”

“…SEM has shown protective effects against the detrimental effects of Aβ25-35 on SH-SY5Y cells [ 35 ] and has also been found to activate the SIRT1/GLUT4 pathway [ 33 , 36 , 64 , 65 , 66 , 67 , 68 , 79 , 80 ].…”

“…Autophagy is a cellular process involving the degradation and recycling of cellular components. The reversal is confirmed by alterations in the expression of key autophagy-related proteins: LC3II (a marker of autophagosome formation) increases; ATG7 (an essential autophagy-related protein) exhibits enhanced expression; P62 (a protein degraded during autophagy) decreases; Beclin1 (a regulator of autophagy initiation) shows increased expression [ 35 , 68 , 80 ].…”

“…GLUT4 holds particular significance in glucose metabolism [ 33 , 36 ]. The interplay between SIRT1 and GLUT4, known as the SIRT1/GLUT4 pathway, appears to be crucial [ 33 , 36 , 68 ]. This pathway likely contributes to the regulation of glucose metabolism, potentially augmenting glucose uptake by cells, particularly in regions like the hippocampal CA3 region [ 33 , 36 , 68 ].…”