Newly Launched Phase POLARIS-AD Trial Tests Oral Therapy AR1001 for Early Alzheimer Disease

POLARIS-AD is an ongoing phase 3 global, multicenter, double-blind, placebo-controlled, 52-week treatment parallel group trial (NCT05531526) evaluating the safety and efficacy of AR1001 (mirodenafil), a novel oral therapy targeting toxic amyloid-beta oligomers, in patients with mild cognitive impairment (MCI) or mild dementia due to Alzheimer disease (AD). The trial, a large-scale study of more than 1500 patients, is expected to have topline results readout in 2026.¹

Baseline demographics and characteristics of the trial participants were presented at the 18th Clinical Trials on Alzheimer’s Disease Conference (CTAD), held December 1-4, in San Diego, California. At baseline, patients had a Clinical Dementia Rating-Sum of Boxes (CDR-SB) mean score, the primary end point, of 3.45 (±1.70). On other secondary outcomes, such as Alzheimer’s Disease Assessment Scale – Cognitive Subscale, 13-item (ADAS-Cog13), patients had a baseline score of 27.75 (±8.02).

Continued data showed that at baseline, patients had Amsterdam Instrumental Activities of Daily Living Questionnaire (A-IADL) score of 72 (±20.72), Geriatric Depression Scale (GDS) score of 1.6 (±1.81), and an Mini-Mental State Evaluation (MMSE) score of 24.01 (±2.70).

Led by Neils Prins, MD, PhD, director of Progress Clinical Research, in The Netherlands, the study screened a total of 4025 participants and 1535 (62%) were successfully enrolled across five global regions: North America (n = 658), the Republic of Korea (n = 200), the United Kingdom (n = 49), the European Union (n = 502), and China (n = 126). The enrolled population was 55% female, with a mean age of 73 years. Racial composition was 72.3% White (including 11.7% Hispanic or Latino), 22% Asian, and 2.7% Black or African American).

“POLARIS-AD represents one of the largest global enrollments for an oral, multi-mechanistic therapeutic agent in Alzheimer disease” study authors wrote.¹ “Its biomarker-agnostic design broadened participant access and enabled the establishment of the largest CSF sample repository to date. Baseline demographics and cognitive profiles are well aligned with those of other landmark AD trials. Interim safety data reveal no new safety signals, and enrollment into the extension phase has been exceptionally strong. Top line results are anticipated in 2026.”¹

To be considered for the trial, participants had to be 55 – 90 years old with MCI or mild dementia due to AD, defined by stage 3 to 4 according to the National Institute on Aging and Alzheimer's Association (NIA- AA) 2018 criteria. Amyloid positivity is confirmed via either visual and quantitative positron emission tomography (PET), with a Centiloid value of more than 30 CL, where available, or cerebrospinal fluid (CSF) assays including the FDA cleared Lumipulse®G amyloid- ß (1-42/1-40) ratio and Roche Elecsys® assay ratios of t-tau/amyloid- ß (1-42) and pTau-181/amyloid- ß (1-42).

READ MORE: NeuroVoices: David Greeley, MD, on AR1001, an Oral PDE5 Inhibitor for Alzheimer Disease

Additionally, participants were required to have cognitive and memory decline within 5 years, a Mini-Mental State Examination (MMSE) score of more than 20, a CDR – Global Score of 0.5 or 1 and a Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) score of no more then 85.

Previous data involving AR1001 acting as a second-generation PDE5 inhibitor have demonstrated its potential as a disease-modifying agent targeting multiple AD pathways. The completed phase 2 double-blind, randomized, placebo-controlled, parallel-group trial (NCT03625622), enrolled participants clinically diagnosed with mild to moderate AD using the 2011 National Institute on Aging–Alzheimer’s Association criteria. The study evaluated the safety and efficacy of AR1001 in 210 patients and findings indicated the cognitive and biomarker benefits of AR1001 as a monotherapy.²

In the study, patients were randomized to receive placebo, 10 mg AR1001, or 30 mg AR1001. Those already on standard AD therapies such as acetylcholinesterase inhibitors or NMDA receptor antagonists were allowed to continue use if on a stable dose for at least 3 months before screening. In the subgroup of participants not receiving concomitant AD medications, 30 mg AR1001 once daily for 26 weeks was associated with a statistically significant 4.019-point improvement from baseline on the Alzheimer’s Disease Assessment Scale–Cognitive Subscale 13 (ADAS-Cog-13; P = .012), the primary end point. Of the 69 participants assigned to the 30 mg AR1001 group, 46 (65.7%) were on concomitant AD therapy.

Although AR1001 did not meet its primary endpoint across the full population, patients receiving the 30 mg dose as monotherapy demonstrated significant cognitive improvement and reductions in plasma ptau181 and ptau217. These biomarker findings add to the rationale for the ongoing phase 3 Polaris-AD trial.³

As an oral PDE5 inhibitor with known blood-brain barrier penetration, AR1001 was assessed not only for cognitive outcomes but also for changes in plasma biomarkers of neurodegeneration. Overall, the study’s findings suggested that AR1001 may exert therapeutic effects through multiple mechanisms beyond traditional symptomatic treatment.²

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REFERENCES
1. Prins N, Atri A, Melgar-Somoza F, et al. POLARIS-AD: Global Enrollment in the Largest Phase 3 Trial of an Oral Multi-Mechanistic PDE5 Inhibitor for Early AD Using Biomarker-Agnostic Modalities for Amyloid Confirmation. Presented at: Clinical Trials on Alzheimer’s Disease Conference (CTAD); December 1-4; San Diego, California
2. Kim F, Xi T, Lee HJ, Rock JA, Kim S, Choung JJ. Evaluating AR1001 as monotherapy from a phase 2 study in mild to moderate Alzheimer’s disease patients. Presented at: Alzheimer’s Association International Conference (AAIC) 2025; July 27–31, 2025; Toronto, Canada. Abstract 107781.
3. Phase 3, Double-blind, Randomized, Placebo-controlled Trial to Evaluate the Efficacy and Safety of AR1001 in Participants With Early Alzheimer’s Disease (Polaris-AD). Clinicaltrials.gov. Published 2025. Accessed July 28, 2025. https://clinicaltrials.gov/study/NCT05531526