journal articles
A PHASE 2 RANDOMIZED, PLACEBO-CONTROLLED STUDY ON THE EFFICACY AND SAFETY OF AR1001, A PHOSPHODIESTERASE-5 INHIBITOR, IN PATIENTS WITH MILD-TO-MODERATE ALZHEIMER’S DISEASE
David Greeley, Marshall Nash, Brad Herskowitz, Fred Kim, James Rock, Neils Prins, SangYun Kim, Tianyang Xi, Jonathan A. Busam, Benoit Tete, Jai Jun Choung, Sharon J. Sha
J Prev Alz Dis 2025;9(12)
BACKGROUND: AR1001 is a phosphodiesterase-5 inhibitor that produces improved cognitive performance and reduces amyloid-β and phosphorylated tau burdens in preclinical models of Alzheimer’s disease (AD).
OBJECTIVES: To evaluate the safety and efficacy of AR1001 in participants with mild-to-moderate Alzheimer’s disease (AD).
DESIGN: Randomized, double-blind, placebo-controlled phase 2 trial conducted at 21 sites in the United States.
PARTICIPANTS: Adults aged 55–80 years with mild-to-moderate dementia as determined by National Institutes of Aging-Alzheimer’s Association (NIA-AA) stage 4 or 5 and Mini-mental State Exam (MMSE) score 16-26.
INTERVENTION: Once daily oral administration of placebo, 10 mg AR1001, or 30 mg AR1001 for 26 weeks followed by 26 weeks optional extension.
MEASUREMENTS: Co-primary efficacy endpoints were changes from baseline at Week 26 in Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog 13) and Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC). Secondary endpoints included measures of cognition, daily living, and depression. Levels of plasma biomarkers pTau-181, pTau-217, Aβ42/40 ratio, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) were also examined.
RESULTS: A total of 210 participants were enrolled and 82% completed 26 weeks of treatment. AR1001 10 mg and 30 mg were well-tolerated with a similar safety profile compared to placebo. After 26 weeks, there were no differences in ADAS-Cog13, ADCS-CGIC, or in secondary efficacy endpoints between groups. Levels of plasma biomarkers pTau-181, pTau-217, and GFAP were improved in the 30 mg AR1001 group compared to placebo.
CONCLUSION: AR1001 was safe and well tolerated. Although primary efficacy endpoints were not met after 26 weeks of treatment, participants receiving 30 mg AR1001 showed favorable changes in AD-related plasma biomarkers compared to placebo.
CITATION:
David Greeley ; Marshall Nash ; Brad Herskowitz ; Fred Kim ; James Rock ; Neils Prins ; SangYun Kim ; Tianyang Xi ; Jonathan A. Busam ; Benoit Tete ; Jai Jun Choung ; Sharon J. Sha (2025): A phase 2 randomized, placebo-controlled study on the efficacy and safety of AR1001, a phosphodiesterase-5 inhibitor, in patients with mild-to-moderate Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100337