AR1001 (mirodenafil) is an orally administered phosphodiesterase-5 (PDE5) inhibitor being developed by AriBio Co. Ltd. as a potential disease-modifying therapy for Alzheimer’s disease (AD). Originally created for erectile dysfunction, AR1001 is now in Phase 3 clinical testing for early-stage AD due to its neuroprotective and synaptic-enhancing mechanisms.[1][2][3]

Mechanism of Action

AR1001 selectively inhibits PDE5, the enzyme that degrades cyclic guanosine monophosphate (cGMP). Inhibiting PDE5 increases intracellular cGMP levels, which enhances CREB (cAMP-response element-binding protein) and BDNF (brain-derived neurotrophic factor) signaling—pathways essential for learning, synaptic plasticity, and neurogenesis. This mechanism distinguishes it from amyloid- or tau-targeting biologics by boosting neuronal function rather than clearing aggregates.[4][1]

Preclinical studies show AR1001:

  • Increases hippocampal cGMP and BDNF.
  • Improves learning and memory in transgenic AD mouse models.
  • Reduces amyloid-β and phosphorylated tau accumulation without neuroinflammatory side effects.[5][1][4]

Clinical Trial Findings

Phase 2 (NCT03625622)

In a 26-week, placebo-controlled trial of 210 mild-to-moderate AD patients:

  • Safe and well tolerated at 10 mg and 30 mg daily doses.
  • 30 mg dose led to improved plasma biomarkers:
    • Reduced pTau-181 and pTau-217.
    • Lower GFAP (glial fibrillary acidic protein), indicating reduced astrocytic activation.
  • Cognitive benefits were more pronounced in participants not receiving other AD drugs.[2][6][5]

Phase 3 (POLARIS-AD, NCT05531526)

The ongoing global Phase 3 trial is testing 30 mg AR1001 once daily for 52 weeks in early Alzheimer’s disease. The study’s primary endpoint is change in Clinical Dementia Rating – Sum of Boxes (CDR-SB), with secondary measures including ADAS-Cog13, Mini-Mental State Examination (MMSE), and blood/CSF biomarkers (pTau, Aβ42/40, GFAP, NfL). No amyloid-related imaging abnormalities (ARIA) have been observed. Topline results are expected in mid-2026.[3][7][8]

Therapeutic Potential

AR1001 represents a non-amyloid, synaptic-rescuing approach to AD, potentially beneficial as both a monotherapy and adjunct to other treatments. Its oral dosing convenience, favorable blood-brain barrier penetration, and impact on tau and glial biomarkers make it a leading small-molecule candidate among next-generation neurotherapeutics.[9][10][3]

Summary Table

FeatureDescriptionSource
CompoundAR1001 (mirodenafil)[1][2]
MechanismPDE5 inhibition → ↑cGMP → ↑CREB/BDNF[1][4]
Target IndicationEarly Alzheimer’s disease[3][8]
DeveloperAriBio Co. Ltd.[3][9]
Phase 2 ResultReduced pTau-181, pTau-217, improved cognition in monotherapy[2][5][6]
Phase 3 TrialPOLARIS-AD (NCT05531526), 52-week design[3][7][8]
Key AdvantageOral, BBB-penetrant, non-amyloid mechanism[9][10]

Overall, AR1001 is an advanced-stage, oral PDE5 inhibitor showing biomarker improvements and synaptic restoration potential, with pivotal Phase 3 results expected in 2026 that will determine its clinical viability as a disease-modifying therapy for Alzheimer’s disease.

  1. https://pmc.ncbi.nlm.nih.gov/articles/PMC11713056/    
  2. https://www.neurologylive.com/view/phase-2-trial-data-support-ar1001-potential-alzheimer-disease-monotherapy   
  3. https://www.clinicaltrialsarena.com/features/trials-to-watch-three-major-catalysts-in-alzheimers-disease/     
  4. https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.082892  
  5. https://pmc.ncbi.nlm.nih.gov/articles/PMC12501329/  
  6. https://pubmed.ncbi.nlm.nih.gov/40912996/ 
  7. https://clinicaltrials.gov/study/NCT05531526?term=AREA[BasicSearch](AR1001)&rank=2 
  8. https://www.scripps.org/clinical_trials/843-aribio-ar1001-polaris-clinical-trial-of-investigational-drug-for-alzheimer  
  9. https://www.clinicaltrialsarena.com/news/aribio-mhra-alzheimers-trial/  
  10. https://pmc.ncbi.nlm.nih.gov/articles/PMC12131090/ 
  11. https://www.alzdiscovery.org/uploads/cognitive_vitality_media/AR1001.pdf
  12. https://clinicaltrials.gov/study/NCT03625622
  13. https://www.clinicaltrialsarena.com/marketdata/phase-ii-trial-of-anti-amyloid-ar1001-signals-little-promise-for-patients-with-alzheimers-disease/
  14. https://alz-journals.onlinelibrary.wiley.com/doi/abs/10.1002/alz.047266
  15. https://www.neurologylive.com/view/neurovoices-david-greeley-ar1001-oral-pde5-inhibitor-alzheimers
  16. https://www.sciencedirect.com/science/article/pii/S2274580725002791
  17. https://www.hra.nhs.uk/planning-and-improving-research/application-summaries/research-summaries/phase-3-double-blind-randomized-trial-efficacy-and-safety-of-ar1001-in-early-alzheimers-disease/
  18. https://www.bcm.edu/healthcare/clinical-trials/h-53973
  19. https://euclinicaltrials.eu/ctis-public/view/2023-508306-15-00
  20. https://ctv.veeva.com/study/phase-3-double-blind-randomized-placebo-controlled-trial-to-evaluate-the-efficacy-and-safety-of-a