The chief executive officer of Aruna Bio provided context on a newly accepted phase 1/2 trial assessing the company’s neural-derived exosome agent AB126 in patients with acute ischemic stroke.
Stroke is the second most common cause of global death following coronary artery disease, and estimates show an annual incidence of 12.2 million. Reports also showed that stroke is the third most common contributor to disability and increased morbidities in approximately half of the stroke survivors over 65 years of age. While thrombolytic agents have been effective in helping restore blood flow through an occluded vessel, the field is still in search for neuroprotective agents that focus on maintaining the function of neurons surrounding brain tissue and, hence, limit poststroke deficits.
Recently, the FDA cleared an investigational new drug application to pave the way for a phase 1b/2a trial assessing Aruna Bio’s investigational agent AB126 in patients with acute ischemic stroke. AB126 is an unmodified neural-derived exosome with an innate ability to traverse the blood brain barrier and has shown evidence of anti-inflammatory and neuroprotective properties. The dose-ascending trial will include those with a poor prognosis post-thrombectomy who will receive 3 intravenous treatments of AB126 at low, medium, and high doses.
As part of new iteration of NeuroVoices, Stephen From, chief executive officer of Aruna Bio, sat down to discuss the phase 1b/2a trial and some of the major goals investigators are looking to achieve. In the first half of the conversation, From spoke about the complexities with conducting stroke trials, how the field has changed over the years, and what goes into study inclusion. In addition, he described the advantages of AB126, the design behind an exosome therapy, and why it may be beneficial for those following acute ischemic stroke.
Stephen From: If you know much about stroke, it's really been a difficult area for clinical development, especially for neuroprotective or anything that's not a thrombolytic. Even the thrombolytics, I mean, TPA, which got approved back in '96, is the only drug that's ever been approved for the treatment of acute ischemic stroke. Even it had difficulty even getting through the clinical because of that, STAIR (Stroke Treatment Academic Industry Roundtable) came together in 1998, they had their first meeting in '99, just to help the whole community try to figure out how to get through the clinical development stage. Even myself, my background was in CNS, most of my time as a CEO has been in the ophthalmology space, I'm new to the CNS space, I've been CEO of this company for just under two years. I had a huge steep learning curve to really understand not just stroke but the whole CNS because we're also examining neurodegeneration with AB126 products, but stroke is the lead indication.
Trying to get my head wrapped around, why have all these products failed, there are a lot of reasons, but a lot of times it starts with the clinical design. Part of the problem with clinical design is you got to work with the tools you have. The tools have really evolved in stroke over the last five years, things have really evolved since thrombectomy, has really improved since 2015, but things have really changed. There's a lot more information because of the thrombectomy procedure and how successful it's been. There's a lot more data out there. The first thing was really trying to put together an appropriate protocol for our very first study of patients. It is a safety study, and it's designed as a safety study. It's your traditional dose ascending trial. We're going to start with a low dose and go to a medium dose and do a high dose. We have four cohorts, each comprised of four patients, three in the treated regimen, one placebo. We start with the first cohort of four, make sure it's safe, then we'll go up to the next one. When we get to the high dose, assuming everything works, we’ll repeat it. That's why there are four cohorts. Alright, if everything's perfect, we have 16 subjects. It's not meant to be a large study; it's meant to prove we're the first axes on a company using therapeutic exosomes going into the clinic for a CNS (central nervous system) condition.
The FDA doesn't have a lot of experience around exosomes; there aren't many exosomes that have been in the clinic. It's a safety study, but I also have to think about it from an investor point of view because regardless of whether the FDA cares about it as a safety study, the patients and all investors are going to care about whether we showed efficacy. Safety becomes one line item on the deck on the corporate deck. But from an FDA point of view, it is the whole deck. I have to think about safety and efficacy. But from a safety perspective, we wanted to see if we could get the most homogenous patient population, we could and get rid of a lot of the noise or the background noise from a safety perspective. Exosomes are new, and going in there is a new modality. We're under the Cell and Gene Therapy portion of the FDA. They want us to go slow, they want everything to go slow. Anytime there's going to be a very severe adverse reaction, whether there's going to be a death, which happens in stroke, they want us to stop and make sure it wasn't treatment emergent. You want to make sure there's you're getting rid of a lot of those very severe or the background noise, as I call it, so that we don't have to take two years to do a small study. That's what led us to thrombectomy patients. Thrombectomy patients have to have a certain profile in order to have a thrombectomy, which can be traumatic in its own right.
Although the thrombectomy patient population probably isn't the right population to show the true benefit of our product, it is the right population, probably for a safety study. We're doing dose ascending in thrombectomy. This is where I'm really pushing our ad board and our PI. We now know that these guys are great at doing thrombectomy; they don’t even worry about their TICI (thrombolysis in cerebral infarction scale) scores anymore. Their reperfusion rates are there; they're absolute. But even with that, only about 50% resolution is happening. 50% of the population is resolving, you know, to a modified rank and scale of less than two. What about the other 50%? That's where our protocol is, really, and I think this comes with all of the literature that's come out in the last five years; we're really trying to understand is there something that could help us identify that 50% of the population that will have a poor prognosis that day 90, which is the endpoint. If we could do that, it'll help us show the true efficacy of our product. That's where a lot of our brainstorming is going on is, how do we do that? Because there's no perfect prognosticator out there, but there are things that we can do to help us try to find and identify those that could have a poor prognosis. And there aren't any; I haven't seen any protocols of any clinical studies that have really tried to do that, really try to understand and identify those with a low or poor prognosis. I think that's what will help us in this smaller first study, show what our capabilities are.
It all starts with our chief science officer, who's the founder of the company, Dr. Steven Stice. Dr. Stice has been in the cell therapy field for nearly 40 years; he's been working with neural stem cells for about 20 years. This guy has so much experience working in this field. It's one of the reasons why I became CEO of the company because of the experiences this guy has, and also because of the complexity of our product. There’s a lot of factors that go into all of this, but he's been working with neural stem cells, as I mentioned, for about 20 years; he actually published some papers as far back as 2009, showing that neural stem cells have a very positive effect in stroke models. But what we were finding is the stem cells themselves didn't get to the stroke or the infarct region but the infarct region was still having this benefit. Putting 2 and 2 together, something that's being produced by the stem cells is allowing for this therapy to actively treat the stroke. And that's where, eventually over time, we learned that extracellular vesicles were being produced and they're largely responsible for a lot of this therapeutic effect.
About six, seven years ago, they started up an exosome company. It's not all extracellular vesicles, its specifically looking at exosomes, which have a certain size. These exosomes carry a lot of the biomolecules and proteins on the exterior surface that you would see coming from a neural stem cell. All cells produce exosomes pretty well; exosomes are first and foremost used for communicating and regulating like-type cells. They're going to have a footprint of the characteristics of the parent's cell that makes them. Hence, neural stem cells are going to have characteristics that are ideal for working in the CNS space. It's also what helps facilitate crossing the blood-brain barrier; we have markers on the exterior surface that allows us to do that.
There are three interesting things that are going on. Because our route of administration is systemic, we do an IV push right now for the acute conditions. We see first and foremost facilitation across the blood-brain barrier. Because of their anti-inflammatory characteristics, we also have some proteins on the exterior surface that allow for migration to the area of injury, whether that be an acute injury or even chronic. We have some anti-inflammatory characteristics because we see it going to the area of inflammation within the brain; once it's in that area, we see tropism predominantly to the neurons, we'll see some to the other glial cells as well, but predominantly, we'll see a tropism effect to the neurons. All these things make it ideal for treating these conditions in the brain. Now getting to an acute injury like a stroke, but even some of the chronic ones, these are very complex, multifactorial conditions; there's a lot going on. To think that maybe just a neuroprotectant, especially in the hyperacute or acute stage of a stroke, is going to work on its own, is difficult.
But if you have a product that can act as not just a neuroprotectant but also an anti-inflammatory and also have some regenerative capabilities, that could be huge. And that's what this is. That's how complex an exosome is; I do not believe that, man, pharmaceutical companies, biotech has the ability to make in one product, something that has all of these factors. But biology does, obviously Mother Nature does. We're just harnessing what our body already makes. Our body makes these exosomes in the brain, though we do have stem cells, but they don't have the same regenerative capabilities. As we get older, these stem cells have less and less regenerative capabilities. We're augmenting that; that's all we're doing. We're pushing in a lot more of these exosomes that have these regenerative capabilities but also have anti-inflammatory and protective abilities.
Transcript edited for clarity.