Phenserine on the Alzheimer's Treatment Horizon, Study 1

Summary

The goal of this clinical trial is to evaluate if phenserine can treat early or mild Alzheimer's Disease (AD) by comparing it to donepezil. This study will include participants with early or mild Alzheimer's Disease, and the main questions it aims to answer are: How does phenserine affect exosome biomarkers of cell death compared to donepezil? What is the safety and tolerability profile of phenserine at ascending oral doses compared to donepezil? Researchers will compare participants receiving phenserine to those receiving donepezil to see if phenserine produces better pharmacodynamic outcomes and if it is safe and well-tolerated. Participants will: Be randomized to receive either oral phenserine or oral donepezil for a treatment duration of 8 weeks. Undergo oral dose escalation based on tolerability. Complete regular follow-up visits every two weeks to assess pharmacodynamic, pharmacokinetic, and safety measures.

Timeline

Start

2025-02-01

Primary completion

2025-12-01

Completion

2025-12-08

Publications

• Background Reijs BL, Teunissen CE, Goncharenko N, Betsou F, Blennow K, Baldeiras I, Brosseron F, Cavedo E, Fladby T, Froelich L, Gabryelewicz T, Gurvit H, Kapaki E, Koson P, Kulic L, Lehmann S, Lewczuk P, Lleo A, Maetzler W, de Mendonca A, Miller AM, Molinuevo JL, Mollenhauer B, Parnetti L, Rot U, Schneider A, Simonsen AH, Tagliavini F, Tsolaki M, Verbeek MM, Verhey FR, Zboch M, Winblad B, Scheltens P, Zetterberg H, Visser PJ. The Central Biobank and Virtual Biobank of BIOMARKAPD: A Resource for Studies on Neurodegenerative Diseases. Front Neurol. 2015 Oct 15;6:216. doi: 10.3389/fneur.2015.00216. eCollection 2015.
• Background Tweedie D, Fukui K, Li Y, Yu QS, Barak S, Tamargo IA, Rubovitch V, Holloway HW, Lehrmann E, Wood WH 3rd, Zhang Y, Becker KG, Perez E, Van Praag H, Luo Y, Hoffer BJ, Becker RE, Pick CG, Greig NH. Cognitive Impairments Induced by Concussive Mild Traumatic Brain Injury in Mouse Are Ameliorated by Treatment with Phenserine via Multiple Non-Cholinergic and Cholinergic Mechanisms. PLoS One. 2016 Jun 2;11(6):e0156493. doi: 10.1371/journal.pone.0156493. eCollection 2016.
• Background Greig NH, De Micheli E, Holloway HW, Yu QS, Utsuki T, Perry TA, Brossi A, Ingram DK, Deutsch J, Lahiri DK, Soncrant TT. The experimental Alzheimer drug phenserine: preclinical pharmacokinetics and pharmacodynamics. Acta Neurol Scand Suppl. 2000;176:74-84. doi: 10.1034/j.1600-0404.2000.00311.x.
• Background Chang CF, Lai JH, Wu JC, Greig NH, Becker RE, Luo Y, Chen YH, Kang SJ, Chiang YH, Chen KY. (-)-Phenserine inhibits neuronal apoptosis following ischemia/reperfusion injury. Brain Res. 2017 Dec 15;1677:118-128. doi: 10.1016/j.brainres.2017.09.015. Epub 2017 Sep 27.
• Background Becker RE, Greig NH, Giacobini E, Schneider LS, Ferrucci L. A new roadmap for drug development for Alzheimer's disease. Nat Rev Drug Discov. 2014 Feb;13(2):156. doi: 10.1038/nrd3842-c2. Epub 2013 Dec 20. No abstract available.
• Background Braida D, Sala M. Eptastigmine: ten years of pharmacology, toxicology, pharmacokinetic, and clinical studies. CNS Drug Rev. 2001 Winter;7(4):369-86. doi: 10.1111/j.1527-3458.2001.tb00205.x.
• Background Desai A, Grossberg G. Review of rivastigmine and its clinical applications in Alzheimer's disease and related disorders. Expert Opin Pharmacother. 2001 Apr;2(4):653-66. doi: 10.1517/14656566.2.4.653.
• Background Wilkinson DG, Francis PT, Schwam E, Payne-Parrish J. Cholinesterase inhibitors used in the treatment of Alzheimer's disease: the relationship between pharmacological effects and clinical efficacy. Drugs Aging. 2004;21(7):453-78. doi: 10.2165/00002512-200421070-00004.
• Background Nordberg A, Kadir A, Andreasen N, Almkvist O, Wall A, Langstrom B, Zetterberg H. Correlations between Alzheimer's Disease Cerebrospinal Fluid Biomarkers and Cerebral Glucose Metabolism after 12 Months of Phenserine Treatment. J Alzheimers Dis. 2015;47(3):691-704. doi: 10.3233/JAD-132474.
• Background Kadir A, Andreasen N, Almkvist O, Wall A, Forsberg A, Engler H, Hagman G, Larksater M, Winblad B, Zetterberg H, Blennow K, Langstrom B, Nordberg A. Effect of phenserine treatment on brain functional activity and amyloid in Alzheimer's disease. Ann Neurol. 2008 May;63(5):621-31. doi: 10.1002/ana.21345.
• Background Becker RE, Greig NH, Lahiri DK, Bledsoe J, Majercik S, Ballard C, Aarsland D, Schneider LS, Flanagan D, Govindarajan R, Sano M, Ferrucci L, Kapogiannis D. (-)-Phenserine and Inhibiting Pre-Programmed Cell Death: In Pursuit of a Novel Intervention for Alzheimer's Disease. Curr Alzheimer Res. 2018;15(9):883-891. doi: 10.2174/1567205015666180110120026.
• Background Greig NH, Ruckle J, Comer P, Brownell L, Holloway HW, Flanagan DR Jr, Canfield CJ, Burford RG. Anticholinesterase and pharmacokinetic profile of phenserine in healthy elderly human subjects. Curr Alzheimer Res. 2005 Oct;2(4):483-92. doi: 10.2174/156720505774330564.

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Indications