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AD/PD 2023 | Phase II trial of AR1001 as a potential treatment for Alzheimer’s disease
AR1001 is a novel, oral, brain-penetrant PD5 inhibitor that increases cerebral blood flow and has recently been investigated as a treatment of Alzheimer’s disease (AD). In this video, David R. Greeley, MD, FAAN, AriBio Co., Ltd, & Northwest Neurological, Spokane, WA, explains the results of the Phase II trial of AR1001 in patients with mild to moderate AD, as well as the upcoming Phase III trial plans. In the Phase II study, plasma p-tau was measured over time, with patients in both the 10mg and 30mg treatment groups showing statistically significant reductions in p-tau181 from baseline to week 52. Overall, there was no significant change from baseline in either the ADAS-Cog13 or ADCS-CGIC, although a post-hoc analysis indicated that the mild disease subgroup showed improvements in ADAS-Cog13. The Phase III trial (NCT05531526) will look at those at an earlier stage of AD compared to the Phase II trial, enrolling 800 patients with mild cognitive impairment and mild AD (MMSE below 20) to receive 30mg AR1001 or placebo for 12 months. This interview took place at the AD/PD™ 2023 congress in Gothenburg, Sweden.
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Transcript (edited for clarity)
So AR1001, it is a novel PD5 inhibitor, so similar drugs in that class people know about in the world are sildenafil or Viagra and Cialis, drugs of that class. And so the difference of this drug though is that it does cross the blood-brain-barrier and has an effect of increasing cerebral blood flow and in that sense we feel it’s got a superiority and ability to do things that others in its class have not been able to do...
So AR1001, it is a novel PD5 inhibitor, so similar drugs in that class people know about in the world are sildenafil or Viagra and Cialis, drugs of that class. And so the difference of this drug though is that it does cross the blood-brain-barrier and has an effect of increasing cerebral blood flow and in that sense we feel it’s got a superiority and ability to do things that others in its class have not been able to do. It’s an oral agent, so it’s a small molecule. It doesn’t need to be injected or infused and it doesn’t require MRI monitoring. It would be able to be given therefore to people who have pacemakers, people who have tendencies towards bleeding, or on antiplatelet agents which are contraindicated for a lot of the studies of the monoclonals, if you will. So, it’s the first in its class to reach Phase III and that’s why we are excited about it.
There are certainly many agents in the oral class for Alzheimer’s disease being studied, but we think this one is unique simply because of its multiple mechanisms of action and it’s the potential of a PDE5 inhibitor helping in Alzheimer’s disease. It’s a drug that has a different mechanism of action in contrast to others in the class. So to be technical, it works through both the Krebs pathway and the Wnt signal process. But basically in the end again, it increases cerebral blood flow, protecting the mitochondrial membrane, decreasing oxidative stress, reduces neuroinflammation, and in the end then stimulates neurogenesis. So this is a pathway that’s different than many other drugs out now for Alzheimer’s disease. And in the end, though, it reduces the Aβ42 and also the tau phosphorylation that many other drugs have been seeking to do. In that sense, we think it’s again got benefits across the board.
Plasma p-tau181 was studied both at baseline, week 26, and week 52 during our Phase II trial and the average tau level in pg/mL started at somewhere between 4.2 and 4.6 in total. But we were able to see at week 52 more than 1pg/mL drop in that value, which is very significant. This is bigger than even some of the monoclonals that I had mentioned that have already been given accelerated approval through the FDA. So we’re excited to show that not only is this drug able to improve cognition in a post-hoc subgroup, but also to be able to show the reduction in p-tau181 to make it consistent that again there is some correlation.
So the Phase III study has already started in the US and we’re looking for sites right now to be participants in that. But the Phase III study is looking at a little bit earlier stage of Alzheimer’s disease illness. So in the first study in our Phase II trial, we studied mild and moderate Alzheimer’s disease and in this study we’re looking more at MCI or mild cognitive impairment and mild patients. So a little bit earlier, MMSE over 20 with a CDR® global of 0.5 -1.0 for inclusion. Top line results we wouldn’t expect until maybe 2026 because this is a plan to be initially 800 patients versus placebo and we were thinking about doing two Phase III trials to start with but now we’re talking about doing one global trial including Europe and Asia, as well as North America. So now we might be going towards more 1200 people in one study. So it’s just started in, so we just have just a handful of sites and just a few patients already enrolled, but we’re looking for, again, 800 to 1200 patients in total.