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

David Greeley, MD

The 2023 Clinical Trials on Alzheimer’s Disease (CTAD) conference, held October 24-27, in Boston, Massachusetts, was filled with numerous presentations on promising agents in the Alzheimer disease (AD) pipeline. One such agent, AriBio’s AR1001, an oral phosphodiesterase (PDE5) inhibitor, was assessed in a phase 2 trial (NCT03461276) of 210 patients diagnosed with mild to moderate AD. In the study, patients were randomized to receive either 10 or 30 mg of AR1001, or placebo, daily for a 26 weeks, with an additional 26-week extension following that.

Patients in the study were diagnosed clinically based on the 2011 National Institutes of Aging and Alzheimer’s Association criteria, with plasma phosphorylated tau (ptau) 181 levels measured at baseline, 26 weeks, and 52 weeks after starting treatment. With linear mixed models performed using time, findings showed that the AR1001 30 mg group had a relative decrease in ptau181 level compared with placebo (ß = –0.03 [SE, 0.01]; P = .042). The effect of time for AR1001 on the longitudinal Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) was not significant (P = .644).

In a subgroup analysis, higher baseline ptau181 was associated with worse longitudinal outcomes on ADAS-Cog13 in the placebo group (ß = 0.03 [SE, 0.01]; P = .002) and AR1001 10 mg group (ß = 0.02 [SE, 0.01]; P = .029) but not in the AR1001 30 mg group (ß = 0.0002 [SE, 0.01]; P = .985). Following these results, NeurologyLive^® sat down with David Greeley, MD, chief medical officer at AriBio and study author, to discuss the findings in detail. Greeley provided commentary on the mechanism of action of AR1001, its promising effect on ptau181, and the next steps in development. Additionally, he spoke on the possibility of this agent being used in combination with other approved therapies and whether that would cause issue.

NeurologyLive®: Can you provide an overview of the study and how it was conducted?

David Greeley, MD: It was a phase two trial that actually started back in 2017. We presented the initial phase two results two years ago here in Boston. What we're presenting now is a more detailed look at the data and why we used it as a rationalization for moving to phase three. The phase two data itself, obviously, covers the phase two trial. We're an oral agent, a repurposed drug that's actually a PDE5 inhibitor, similar to the class that Viagra and Cialis belong to. We're using it at a dose that is subtherapeutic for its original indication, and it is indicated and approved in South Korea for erectile dysfunction. But at the dose we're using on a daily basis, we found it to be helpful and has a good polymechanistic action as to why we think it would be good for Alzheimer's disease. The population was similar to many other studies for Alzheimer's disease. We looked at mild to moderate AD. A Mini-Mental Status Exam, capped at 26, showed that the mild population did better. When we looked at the data more closely, the moderate group had basically a higher level of p-tau to start with. So we were able to see a reduction in phosphorylated p-tau 181 in plasma, which was not a primary endpoint of the study but was what we analyzed after the study completion.

What is the significance of this drug’s impact on p-tau 181? What does that mean clinically?

I think what we've seen, especially over the years and especially at this meeting, is that phosphorylated tau, even in plasma, is a great indicator of amyloid in the brain and of the disease itself. We've seen that now a plasma marker can be used. It's not yet FDA approved, but it can be used to correlate very well with amyloid in the brain. We were able to see a reduction in p-tau 181, again, at a level and a degree that was greater than what is seen with the monoclonal antibodies. Again, a reduction of picogram per milliliter that, in a year-long study, is quite dramatic and correlated in our minds with our clinical benefit. So we're very proud to be able to show that, and again, with very little risk and very little need for monitoring for an oral drug that performed as well as some much more potent agents that are given intravenously or with a need for extensive monitoring and care.

Can you provide insight on the origins of this drug and how it came to clinical studies?

The CEO and founder of the company saw a signal that indicated increased cerebral blood flow, potentially having mechanistic action with stroke or vascular dementia, but an even greater signal and significance for Alzheimer's disease. This has been reiterated at this meeting by the Cleveland Clinic, who looked at Viagra and sildenafil. They found that it had a possibility. They conducted a database search of basically all available medications and found sildenafil to have the most likely ability to improve patients with dementia. So, through its polymechanistic approach, it's not just an amyloid drug. It actually increases cerebral blood flow, decreases neuroinflammation, stabilizes the mitochondrial membrane of vascular membranes, works throughout the Wnt pathway, and other pathways to decrease apoptosis or cell death, increase neurogenesis and synaptogenesis. Again, through all of these mechanisms of action, we believe it has great potential.

Is there potential for this drug to be used in combination with other approved agents?

This drug has already been on the market in this country and in Korea for 10 plus years, and it's very safe. It has been used with other drugs, although we need to be cautious when used with nitrates or similar drugs. There's no reason to suggest that it would have any problems with a monoclonal antibody. Because we're not primarily working on amyloid, even though it did have an anti-amyloid effect, we think it could be used as concomitant therapy. We are conducting research to explore how it could be additive, both for prevention and concomitant use, or even not sequentially with other drugs. We believe that Alzheimer's disease has multiple mechanisms for causing injury, so it will likely require multiple medications to treat effectively.

I think safety is something that people don't discuss enough. We look at results and try to extrapolate their clinical significance, but it's important to consider the drug's risks, the time it would take to make a difference, the cost, and individual variation. Our drug, because it works through various mechanisms, could potentially help most individuals and is very safe. There is very little cost compared to a monoclonal antibody. We have initiated our phase three trial, recruiting participants across the country, and expanding to Europe, Korea, and China. We are looking for people who are interested. This drug could be safe and effective for those who do not qualify for a monoclonal antibody. We do not require MRIs, so individuals with pacemakers or cardiovascular risk factors can participate without concerns about bleeding. Our trial is much less complicated and more inclusive than monoclonal trials.

Can you provide details on the design of a potential phase 3 trial?

It's very similar to trials that are ongoing. Just like the monoclonal trials, we need to confirm that people have amyloid beta pathology. We are doing that with lumbar puncture or cerebral spinal fluid testing. If individuals have had an amyloid PET scan or have historical data to prove amyloid positivity, we can accept that. However, we still need to prove that they have Alzheimer's disease, meeting the criteria for the disease, with no better explanation for their cognitive or functional impairment. We are inclusive, reaching out to marginalized communities and those who have been previously excluded from research. We accept people with risk factors for heart disease and stroke, including those with obesity, pacemakers, and heart disease. Our goal is to reach the average community member in America. When we show results, we can roll it out to everyone in America. Monoclonal studies are limited to a small part of the population, making it challenging to extrapolate the results to a broader community.

Click here for more coverage of CTAD 2023.

REFERENCE
1. Ye BS, Greeley D, Kim F, Choung JJ. Evaluating the efficacy of AR1001 on plasma ptau181 levels and ADAS-Cog13 in mild to moderate Alzheimer’s disease: results from the phase 2 trial. Presented at: Clinical Trials on Alzheimer’s Disease conference; October 24-27, 2023; Boston, MA. POSTER LB21