Phase 2 Trial Data Support AR1001 as Potential Alzheimer Disease Monotherapy

James Rock, senior vice president of clinical operations at AriBio

New phase 2 data (NCT03625622) presented at the 2025 Alzheimer’s Association International Conference (AAIC), held July 27-31, in Toronto, Canada, suggest that AR1001 (mirodenafil; AriBio), a second-generation PDE5 inhibitor, may offer cognitive and biomarker benefits as monotherapy in patients with mild to moderate Alzheimer disease (AD). The findings demonstrate its potential as a disease-modifying agent targeting multiple AD pathways.

The phase 2 AR1001-ADP2-US01 trial evaluated the safety and efficacy of 30 mg AR1001 in 210 patients with mild to moderate AD. 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 suggest that AR1001 may exert therapeutic effects through multiple mechanisms beyond traditional symptomatic treatment.¹

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. Plasma concentrations of phosphorylated tau (ptau) biomarkers were also significantly reduced: ptau-181 by 1.361 pg/mL (P = .023) and ptau-217 by 0.426 pg/mL vs placebo at Week 26.¹

“Advancing safe, effective and meaningful therapies for this devastating disease is our top priority at AriBio,” James Rock, senior vice president of clinical operations at AriBio, said in a statement at the time of enrollment completion back in 2020.²

The trial, a double-blind, randomized, placebo-controlled, parallel-group study, enrolled participants clinically diagnosed with mild to moderate AD using the 2011 National Institute on Aging–Alzheimer’s Association criteria. 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. Of the 69 participants assigned to the 30 mg AR1001 group, 46 (65.7%) were on concomitant AD therapy.¹

Originally approved in South Korea for erectile dysfunction, mirodenafil has shown brain penetrance and higher selectivity for PDE5 than earlier drugs in its class. Preclinical research suggests potential neuroprotective mechanisms, including improved mitochondrial function, reduced tau phosphorylation, and increased neurotrophic signaling, such as BDNF and NGF.³

In the phase 2 trial, 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 (NCT05531526), a 52-week study evaluating AR1001 in early AD.³

Subgroup analysis show that participants who received 30 mg AR1001 without any concomitant therapy experienced the most benefits. The agent may hold potential as a standalone disease-modifying therapy, particularly in patients who are newly diagnosed or not currently receiving standard treatment.¹

Preclinical research has shown that mirodenafil may exert neuroprotective effects across several AD pathways. In transgenic mouse models of AD, mirodenafil not only reduced amyloid-β and phosphorylated tau burdens, but also reversed memory dysfunction. Its mechanisms of action include activating the cGMP/PKG/CREB signaling pathway to support neuronal survival, enhancing autophagy-lysosome clearance of toxic proteins, and modulating transcription factors like glucocorticoid receptor (GR) and Dkk1 to restore Wnt/β-catenin signaling.⁴

Importantly, unlike many single-target agents, mirodenafil’s polypharmacological profile may help overcome the complexity of AD pathophysiology while also maintaining tolerability. According to those who’ve studied the therapy, its blood-brain barrier penetrance, potential to improve cerebral blood flow via pericyte relaxation, and impact on neuroinflammation and mitochondrial health make it a great candidate for disease modification; critical rationale for its continued clinical development as a therapeutic approach that simultaneously addresses multiple aspects of AD.⁴

No major safety concerns were observed with either 10 mg or 30 mg dosing, confirming a favorable safety profile across treatments. The trial also met some key biomarker endpoints, showing statistically significant reductions in plasma ptau species among patients treated with 30 mg AR1001.

Unlike first-generation PDE5 inhibitors, AR1001 is being investigated for its neuroprotective properties, which may be linked to enhanced cerebral blood flow and reduced tau pathology. The findings support for AR1001’s use as a monotherapy and warrant additional evaluation in larger, phase 3 trials to further determine its disease-modifying potential.

REFERENCES:
1. 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.
2. AriBio Announces Completion of Enrollment in Phase 2 Alzheimer’s Study with AR1001. BioSpace. Published June 18, 2020. Accessed July 28, 2025. https://www.biospace.com/aribio-announces-completion-of-enrollment-in-phase-2-alzheimer-s-study-with-ar1001?utm_source=chatgpt.com
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
4. Kang BW, Kim F, Cho JY, Kim S, Rhee J, Choung JJ. Phosphodiesterase 5 inhibitor mirodenafil ameliorates Alzheimer-like pathology and symptoms by multimodal actions. Alzheimer’s Research & Therapy. 2022;14(1). doi:https://doi.org/10.1186/s13195-022-01034-3