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
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