Background

Ar1001 is a selective inhibitor of phosphodiesterase 5. This new pyrrolo-pyrimidinone was first developed for treatment of erectile dysfunction in South Korea, and is now being tested for Alzheimer’s disease. Its maker claims AR1001 to be 10-fold more potent at inhibiting PDE5, and better at entering the brain, than approved PDE5 inhibitors, including sildenafil.

The rationale for using PDE5 inhibitors in AD stems from animal studies, where these compounds enhance memory and learning by increasing the intracellular messenger cGMP, and also possibly by improving blood supply to the brain. Several PDE5 inhibitors have been reported to curtail amyloid production, and to lessen neuroinflammation and learning and memory deficits in mouse models of AD (see review by Zuccarello et al., 2020).

Three studies have reported PDE5 effects in people. Men being treated for erectile dysfunction with low doses of the PDE5 inhibitors tadalafil or udenafil daily for eight weeks improved performance on tests of cognition and cerebral blood flow, while a single dose of sildenafil improved brain blood supply in people with AD (Choi et al., 2019; Shim et al., 2014; Sheng et al., 2017). A study of potential AD targets for drug repurposing has identified sildenafil, and a medical records analysis reported that men who used it lowered their risk of AD by 69 percent (Fang et al. 2021). Other analyses found no such evidence (Desai et al., 2022)

The only public preclinical data on AR1001 was presented by Aribio at AAIC 2020, where the company reported reduced Aβ plaque deposition in 5XFAD mice, and improved memory in NSE/APP-C105 mice after treatment (Kang et al., 2020). The company later published similar results using the approved PDE5 inhibitor mirodenafil (Kang et al., 2022).

Findings

In April 2019, Aribio began a Phase 2 study of efficacy in clinically diagnosed people with mild to moderate AD. The trial recruited 210 subjects at 21 sites in the U.S. A 26-week course of 10 or 30 mg daily AR1001 or placebo was followed by an optional 26-week extension, where the 10 and 30 mg groups continued at that dose, and placebo takers were randomized to 10 or 30 mg. Primary endpoints were change from baseline in ADAS-Cog13 and ADCS-CGIC; secondary endpoints included various measures of cognition, behavior and function, and exploratory plasma biomarkers. The study ended in June 2021, and results were presented at the CTAD conference in November. There was no significant change from baseline in either the ADAS-Cog13 or ADCS-CGIC at 26 or 52 weeks, and no difference from placebo at 26 weeks.

More than half of participants were taking other, unspecified AD medications, and a post hoc subgroup analysis hinted those taking 30 mg AR1001 alone, but not those with concomitant treatment, might have improved on the ADAS-Cog13. The mild, but not the moderate, subgroup also showed improvement on the same endpoint. There was no placebo group for comparison at 52 weeks. The treatment was well-tolerated, with a similar incidence of side effects and discontinuation in all groups. There was one death from COVID, and one person on the high dose had a serious adverse event of fainting, possibly related to drug. According to additional data presented at the October 2023 CTAD conference, both doses led to a decrease in plasma pTau181, compared to an increase in the placebo group. A post hoc analysis suggested that in people with the highest pTau181 levels at the start, and thus most likely to be amyloid positive, the 30 mg dose may have slowed decline on the ADAS-Cog13.

In December 2022, the company began a Phase 3 study in people with MCI or mild dementia due to AD. Called Polaris-AD, it is enrolling, at approximately 65 research sites, 1,150 people with MMSE scores above 20, CDR global ratings of 0.5 or 1, and RBANS of 85 or less, and confirmation of amyloid pathology by CSF test or PET. Participants will take one 30 mg tablet or placebo daily for one year. The primary outcome is change in the CDR-SB after one year; secondary outcomes include ADAS-Cog 13, the Amsterdam Instrumental Activities of Daily Living, Geriatric Depression Scale, MMSE, and RBANS. The study will also track safety, as well as plasma and CSF biomarkers, and offers a two-year open label extension. Completion is anticipated in December 2025.

Aribio has FDA approval for a Phase 2 trial in vascular dementia (Korea Biomedical Review news). On its pipeline, it also lists Phase 2 development for dementia with Lewy bodies and dementia with depression/PTSD, but no trials appear in common registries for these indications.

For details on AR1001 trials, see clinicaltrials.gov.