Phenserine on the Alzheimer's Treatment Horizon, Study 1

NCT06774261 | Completed Phase 1 DMC

• 1 other identifier: EuCT: 2023-510282-10-00
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Alzheimer Disease; Mild Cognitive Impairment

Keywords

Alzheimer's Disease; Phenserine; Donepezil; Randomized Controlled Trial; Cognitive Decline

Outcome Measures

Primary Outcomes (5)

• Panel 1: Concentration of Biomarkers Associated with Preprogrammed Cell Death (PNCDD)

  Quantification of exosome-derived BAX and Bcl-2 markers. This outcome measure will assess changes in biomarkers related to preprogrammed cell death, specifically BAX and Bcl-2. These biomarkers provide insights into apoptotic processes and any alterations observed following treatment with phenserine or donepezil.

  From enrollment to the end of treatment at 8 weeks.

• Panel 2: Concentration of Synaptic Integrity Biomarkers

  Measurement of exosome-derived synaptic markers. This outcome measure will evaluate changes in synaptic markers, including synaptotagmin, to provide insights into synaptic integrity and function.

  From enrollment to the end of treatment at 8 weeks.

• Panel 3: Concentration of TNF-α (Inflammatory Biomarker)

  Quantification of exosome-derived TNF-α. This outcome measure will assess changes in TNF-α levels (ng/mL), a key inflammatory biomarker.

  From enrollment to the end of treatment at 8 weeks.

• Panel 3: Concentration of interleukins, IL-1β, IL-6, and IL-10. (Inflammatory Biomarker)

  Quantification of exosome-derived IL-1β, IL-6, and IL-10.IL-1β (pg/mL). This outcome measure will assess changes in interleukin levels, a key inflammatory biomarker.

  From enrollment to the end of treatment at 8 weeks.

• Panel 4: Concentration of Exosome-Derived Alzheimer's Disease-Specific Biomarkers

  Quantification of exosome-derived Aβ1-42. This outcome measure will assess changes in exosome-derived Alzheimer's Disease-specific biomarkers, including Aβ1-42, to elucidate molecular signatures associated with AD pathology.

  From enrollment to the end of treatment at 8 weeks.

Secondary Outcomes (19)

• Adverse Events (AEs) and Tolerability Profile

  From enrollment to the end of treatment at 8 weeks.

• Cholinesterase Inhibition Target Achievement

  From enrollment to the end of treatment at 8 weeks.

• Blood Pressure (Safety Assessment)

  From enrollment to the end of treatment at 8 weeks

• Pulse (Safety Assessment)

  From enrollment to the end of treatment at 8 weeks.

• Urine Testing (Safety Assessment)

  From enrollment to the end of treatment at 8 weeks.

Other Outcomes (6)

• FLAME computer-based domain composites

  At baseline and end of treatment at 8 weeks

• Montreal Cognitive Assessment (MoCA)

  At baseline and end of treatment at 8 weeks.

• Cerebrospinal Fluid (CSF) Levels of Aβ1-40 and Aβ1-42

  Baseline and end of treatment at 8 weeks.

Study Arms (2)

Phenserine

ACTIVE COMPARATOR

Phenserine will be formulated as a capsule, with dosages of 5mg and 10mg. Participants randomized to the phenserine arm will start at 5 mg twice daily (bd) with escalations every two weeks, as tolerated to 10 mg bd and to a maximum dose of 10 mg three times daily (tds).

Drug: Phenserine

Donepezil

ACTIVE COMPARATOR

Participants randomized to the donepezil arm will start at 5 mg tablet once daily (od) with escalation, to 10 mg od from Week 5, as tolerated.

Drug: Donepezil (Aricept®)

Interventions

Phenserine DRUG

Phenserine is a next generation AChE inhibitor being developed for the treatment of AD. Unlike currently marketed AChE inhibitors, it has additional mechanisms of action that also include a mediating effect on cell death pathways and anti-amyloid activity, which may confer disease-modifying effects in people with AD. Phenserine was originally identified and developed by the United States (U.S.) National Institute of Aging (NIA), part of the U.S National Institute of Health (NIH). The study intervention will be open label. No blinding will be performed. Participants and site staff will, however, will be blinded to the results of the exosome and blood/CSF biomarker evaluations until the study is completed.

Phenserine

Donepezil (Aricept®) DRUG

The substance donepezil (under the brand name Aricept®) is a resale product. No additional manufacturing or labeling measures is necessary for this study. The NIMP, donepezil will be available in 5 mg and 10 mg strengths (table 3) and will be dispensed by the local pharmacy at the hospital where the participant in the donepezil arm is included. We have based the use of donepezil as a treatment in the study on the original product from Pfizer, but it is also possible to use generic products of donepezil if this is what the local pharmacy has for dispensing. Participants randomized to treatment with donepezil will follow the treatment plan according to the patient information leaflet. . These tablets are approved for clinical use and comply with all relevant safety and efficacy standards.

Donepezil

Eligibility Criteria

• Age: 50 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• A diagnosis of AD based on the most recent NIA-AA diagnostic criteria for AD.
• A significant change on a validated AD amyloid or tau biomarker (as determined either by visual reading of amyloid PET scans \[using any of the approved ligands\], or CSF Aβ 1-42 or blood p-tau 217 levels \[cut-off as determined by the individual laboratory.
• A CDR Global rating of 0.5 or 1.0.
• An MRI scan within the past two years that has no findings inconsistent with AD.
• Participants who have recently participated in other clinical trials or have been under treatment with memantine or acetylcholinesterase inhibitors (e.g., Donepezil, Rivastigmine, Galantamine) must undergo a washout period of at least 4 weeks prior to the start of the study.
• Capacity to give informed consent based on the clinical judgement of an experienced clinician.
• The participant has an individual who is in regular, daily contact via phone or in-person visits and who can act as a reliable study partner and provide meaningful input into rating scales.
• Age ≥50 years.
• Fluency in Norwegian and evidence of adequate premorbid intellectual functioning.
• Capable of participating in all scheduled evaluations and complete all required tests.
• Female participants must be of non-childbearing potential or have a negative serum pregnancy test up to 24 hours prior to the baseline assessments and agree to use effective birth control throughout their participation in the study from signing informed consent form until at least 30 days after last administration of phenserine or donepezil..

You may not qualify if:

• Significant cerebrovascular disease, as indicated by clinical history, neurological examination, or on MRI (including cortical infarction or deep white matter or periventricular white matter hyperintensities with a Fazekas scale score of 3 (25).
• Current treatment with a cholinesterase inhibitor or memantine.
• Hypersensitivity to AChE inhibitors or related compounds: Known hypersensitivity to donepezil, piperidine derivatives, or any formulation components.
• Participants undergoing or planning procedures requiring anesthesia with depolarizing neuromuscular blockers (e.g., succinylcholine) due to the risk of prolonged paralysis or apnea when combined with AChE inhibitors.
• Active peptic ulcer disease or gastrointestinal bleeding, or a history of gastrointestinal ulcers or bleeding.
• Severe cardiac conditions: Significant arrhythmias, sick sinus syndrome, supraventricular conduction abnormalities, or other cardiac rhythm disorders that could pose a risk with cholinesterase inhibitors.
• Severe respiratory disease: Chronic obstructive pulmonary disease (COPD) or poorly controlled asthma.
• History of urinary obstruction or bladder issues, particularly those requiring catheterization.
• Current clinically significant depression or other mental disorders likely to affect cognition or interfere with study participation.
• Participants using sedating drugs, if unavoidable, will be excluded from the study. However, short-acting sleep medications can be used if taken as recommended and if the participant has maintained a stable regimen for at least 3 months prior to the start of the study.
• Current participation in any other drug trial(s).
• Currently ongoing life-threatening disease, such as metastatic cancer, advanced cardiovascular disease, advanced respiratory disease, terminal kidney disease, or advanced stages of an infectious disease.
• Any current or past neurological disease unrelated to AD and with cognitive sequelae.

Sponsors & Collaborators

• Helse Stavanger HF: lead
• Helse Fonna: collaborator
• St. Olavs Hospital: collaborator
• University Hospital of North Norway: collaborator
• University of Exeter: collaborator
• National Institutes of Health (NIH): collaborator

Study Sites (1)

Stavanger University Hospital

Stavanger, Norway

Location

Related Publications (12)

• 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.

  PMID: 26528237 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.

  PMID: 27254111 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.

  PMID: 11261809 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.

  PMID: 28963051 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.

  PMID: 24362362 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.

  PMID: 11830755 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.

  PMID: 11336614 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.

  PMID: 15132713 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.

  PMID: 26401704 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.

  PMID: 18300284 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.

  PMID: 29318971 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.

  PMID: 16248851 BACKGROUND

MeSH Terms

Conditions

Alzheimer Disease; Cognitive Dysfunction

Interventions

phenserine; Donepezil

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; Cognition Disorders

Intervention Hierarchy (Ancestors)

Indans; Indenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Polycyclic Compounds

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 18, 2024
• First Posted: January 14, 2025
• Study Start: February 1, 2025
• Primary Completion: December 1, 2025
• Study Completion: December 8, 2025
• Last Updated: May 4, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

NO (1)