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Welcome to BIOTECH NATION !!! With understandable interviews requiring no background in science, BTN attracts a wide global audience. From everyday people looking for hope in treatments in development, to bioentrepreneurs interested in the experience of their fellow travelers, to venture capitalists looking for possibilities in cutting-edge breakthroughs, to scientists simply interested in the work of others, BioTech Nation is the voice of human endeavor, driving science to new realities for everyone. These interviews are drawn directly from the public radio program, "Tech Nation", which also can be heard in numerous global radio and podcasting venues.
The world we know is changing. I'm Moira Gunn, and welcome to Biotech Nation. New science is offering new approaches for innovative treatments for Alzheimer's, Parkinson's dementia, and other neurodegenerative diseases. Today, one such approach has entered late stage human clinical trials. Doctor Mark Litton is the president and CEO of Athira Pharma.
Dr. Moira Gunn:Well, Mark, welcome back to Bio Tech Nation.
Dr. Mark Litton:Thanks. Pleasure to be here.
Dr. Moira Gunn:Athira already has, a drug in phase 2 and phase 3 human drug trials. That's in the phase 1, 2, 3 drug approval trifecta as I call it. And so now this is becoming very real. How is what you are doing, what Athira Pharma is doing, different from the other approaches to treating or arresting the progression of Alzheimer's?
Dr. Mark Litton:Our approach is all focused on essentially using a naturally occurring repair mechanism that the body uses every day to restore one's nerve cells. And we like to talk of ourselves as we're focused on the cells. And Alzheimer's is a is a really good example where it really is a breakdown in the communication of these nerve cells. It's all about the connections, what we call synapses. And in Alzheimer's, right, this is a disease that slowly they lose all their connections over time and these synapses go away and the nerve cells go away.
Dr. Mark Litton:And by using this naturally occurring repair mechanism or what we call the HGF system, we're able to hopefully restore and repair these connections. And we believe sort of our small molecules that our small molecules enhance this HGF biology.
Dr. Moira Gunn:Now I did some homework and I read that there's a 100,000,000 neurons in our brains and a 1,000,000,000,000,000 synapses connecting them. Now how much do they have to degrade before you get Alzheimer's?
Dr. Mark Litton:Well, it's it's a fair question. So if you look at the the disease state of Alzheimer's, it's just essentially you you lose about 20% of these synapses. Now I I would also like people to know is that your your brain really is plastic and that it it can repair. For example, people have strokes. They get better over time in some cases.
Dr. Mark Litton:And we really believe that you have this injury, which is going on in Alzheimer's, and you're losing these synapses, and we're hopeful that we can repair them.
Dr. Moira Gunn:Now as I understand it, there's HGF all over your body. If you read about any condition of an organ, it could be the liver, it could be cardiovascular. Frequently, you'll find this h g f. So it's all over the place. And you need the HGF, you know, going into the cell to just to kick start, if you will, the natural repair mechanism that's inside a cell.
Dr. Moira Gunn:No different than in the brain. And in the case of Alzheimer's, I understand that both HGF can be measured, that it's an it's been reduced, but also the receptor in the brain cell which takes it up is reduced.
Dr. Mark Litton:Yes. We do know that the HGF and its receptor have been been reduced in in Alzheimer's patients.
Dr. Moira Gunn:So one theory is is that you've gotta get that repair mechanism in place again, both not just giving HGF, but also somehow repairing or or enabling that receptor to work.
Dr. Mark Litton:Yeah. And and one could almost think of it as wound healing. Right? As we know, wound healing, over time as we get older, it gets slower and slower. One could also see that that's the same thing that happens in Alzheimer's.
Dr. Mark Litton:And one of the key, aspects of our platform and our technology is identifying and discovering these small molecules that cross the blood bank barrier. Because in your body, of course, HGF is floating around and it lasts seconds, if not minutes. So first and foremost is it it doesn't last very long in your body. And one of the things that people have tried for many years is to find a molecule that enhances this and it crosses the blood bank barrier. And that's exactly what our lead molecule and our platform does with fosconium intent.
Dr. Moira Gunn:Now fosco
Dr. Mark Litton:We call fosco.
Dr. Moira Gunn:I was gonna say, I call it Fosco. I looked at that, and that's never gonna fly on the radio. But you got to say it was, but it's Fosco. And now, I know you're in in the phase 2, phase 3 trials, but I'm very interested in how you even begin to test this. And let's talk about, Fosco.
Dr. Moira Gunn:What was the first test? You know, we always start in phase 1. How did that work? What did you measure?
Dr. Mark Litton:Yes. So we you start with phase 1. And so let's go back to the concept that the brain is a network of cells all interacting together. And one way that we look at the brain is to measure the electrical current of the brain because all of these cells connecting create a current. And the other thing that we can do if we combine measuring the electrical current and we combine that with an auditory signal, we can actually measure the speed of how well the brain is working or processing information.
Dr. Mark Litton:And so we've utilized a test. It's not our test. This is a test that's been around for for many years and it's called the event related potential p 300 test.
Dr. Moira Gunn:Needs a new name. New name. But what does it do?
Dr. Mark Litton:So this is a test that the subject has a skull cap that's measuring the electrical current, and they're wearing headphones so they can listen to a series of tones. And there's a series of tones in a space with an odd tone, and then they're asked to count the odd tone. And so the computer can actually measure how fast it takes them to 1 recall the odd tone and begin counting. And and normal healthy people, it's about 300 milliseconds and that's why it's called p 300. Interestingly enough, as we get demented and as we progress in Alzheimer's, the time it takes to actually count and listen to that odd tone gets longer and longer.
Dr. Mark Litton:And so when we did a small study, it was 11 subjects, mild to moderate Alzheimer's patients, they on average with their p 300 test was 390 milliseconds. So almost a 100 milliseconds longer than a normal individual. And what we found after 8 only 8 days of treatment with Fosco is there was a dramatic improvement in their brain processing speed, and they went down to essentially 300 and 17 milliseconds. So on average, a 73 millisecond improvement on their brain processing speed.
Dr. Moira Gunn:Were there also people, who were taking placebo? Healthy volunteers?
Dr. Mark Litton:Absolutely. This was a placebo blinded controlled trial. There were 7 people on the VASCO and 4 people on placebo. And in the placebo arm, they did not show an improvement in their p 300.
Dr. Moira Gunn:Okay. So we know we're getting it in there, and we know we're seeing some improvement. Now you said earlier, small molecule. We just have you know, working on this drug small molecule. Usually, we leap to, oh, we'll make it a pill.
Dr. Moira Gunn:Everybody loves pills. But you have it as an injection. Why is that?
Dr. Mark Litton:Yes. So this is, an injection that can be, it's got done daily, and it's really, done for mostly compliance sake In the fact that when you get an injection, you know the person has been given the the potential therapy As opposed to sometimes in this population, they have hard time remembering if they took their pills or maybe they take many pills and it's never quite easy. And, of course, this is mild to moderate. So most of these patients have caregivers. So really up this strategy is more for compliance so that we can ensure that the patients get Vosco.
Dr. Moira Gunn:Okay. So you you're like, oh, this is great news. You know, we're seeing this increase. We know it's being taken up and now you're moving into, phase 2 and phase 3. In fact, those are happening at the same time.
Dr. Moira Gunn:Tell us about the smaller phase 2 study. What's that about, and what are you checking there?
Dr. Mark Litton:Yes. So the the phase 2 study is ACT AD. It has 77 subjects in it. Again, mild to moderate Alzheimer's patients, very similar to our phase one b. And we're also looking at so in the smaller study, we only looked at it for 8 days, but we're now looking at it for 6 months and we wanna see if we can repeat what we saw with the p 300 test over 6 months.
Dr. Mark Litton:But in addition to that, we'd like to look at what's really important is these psychometric measurements. Now the trial the smaller trial is not statistically powered to see a difference of these psychometric measurements, but we're we're hopeful to see some trends. And and trends looking at whether it's cognition or the way the physicians are seeing the improvement or how the caregiver is assessing how the these subjects, are doing with their independence.
Dr. Moira Gunn:Now there are 3 kinds of tests that I know you're looking at in this phase 2 study. The first is cognition. How what is cognition and how do you measure it?
Dr. Mark Litton:Yes. So cognition is, has to do with memory and language and there this test we use is called the ADIS Cog 11 or just to be clear, these are a lot of, you know, no nomenclature, but it's the Alzheimer's disease assessment scale. And it was developed in the eighties, and it was really developed to understand the level of decline in cognition for these Alzheimer's patients. It it has become the gold standard. The FDA uses this test.
Dr. Mark Litton:Many, many of the Alzheimer's trials have used this test. And then it essentially is testing word recall, naming objects, following commands. I mean, it's a score of 0 to 70, 70 being the most severe impaired.
Dr. Moira Gunn:And so you're trying to see like, you're giving them 3 words, and then you're trying to see if they can repeat the 3 words?
Dr. Mark Litton:Correct.
Dr. Moira Gunn:And perhaps later and, you know, so a delay of time and that type of thing. I see. So I I understand a test like that. The next one are are activities of daily living and independence. What what are those?
Dr. Mark Litton:Yes. So this is another this is another test that is done by the caregiver to assess how well the subject is doing with this with his or her independence. And this is a series of questions that are asking about eating, dressing, bathing, cooking, how maybe shopping, right, really is just to better understand the independence of the subject.
Dr. Moira Gunn:Yeah. If you're brushing your teeth or you're not brushing your teeth.
Dr. Mark Litton:That's correct.
Dr. Moira Gunn:It's really these seem very simple, but they all aim toward independence. Can you live independently without someone overseeing you? And then the final one is behavioral testing. What does that mean in terms of Alzheimer's?
Dr. Mark Litton:Yeah. So the the final one is a is an assessment done by the clinician, and it's, it's called the clinical impression of change or CGIC as we call it. And it's essentially the clinician understanding how well the patient is doing. And it's a measurement of 1 to 7. 1 would indicate there's an improvement, 7 would indicate there's worsening, and 4 is no change.
Dr. Mark Litton:And each of these 3 are all used to better understand how our our molecule might be clinically beneficial for for these subjects. In fact, this assessment by the physician covers many different aspects, and it's really looking at how well are they having a conversation, how well are they anxious. And it's just assess at at each time point of, you know, where where the patient is at that point. And let me just remind everybody that it's really scary. Alzheimer's is a scary disease.
Dr. Mark Litton:And and, you know, your orientation, where you are, who you were talking to, it can be scary for the individual.
Dr. Moira Gunn:This phase 2 with the 77 patients, are they also getting the hearing test?
Dr. Mark Litton:The 77 patients are getting the hearing test. Yes. The p 300 test so that we're looking to see how that does over 6 months. And they're also getting these psychometric measurements so that we while not powered to show statistical difference, we can begin to understand what this new approach is doing to to help these folks with als mild to moderate Alzheimer's.
Dr. Moira Gunn:Now I don't think you have to be a rocket scientist to figure out. Normally, we do phase 2 and after that, we do a phase 3. With Vosco, you started phase 3 already with many more patients. Now now tell us how it's different and tell us how phase 2 relates to phase 3.
Dr. Mark Litton:So we're taking a little unique strategy. So there's been many, many examples when people look at interim data of phase 3, and it's sort of unclear.
Dr. Moira Gunn:Like, early data, like, a quarter of the way in, something like that.
Dr. Mark Litton:Correct. And and sometimes it looks good, sometimes it doesn't look good. You lose statistical power. And so we took a strategy as let's do a separate complete study. They all have the same criteria.
Dr. Mark Litton:They all have mild to moderate, Alzheimer's. And that we would use this smaller study to help us with the large phase 3 study because the readout, which is coming, in q 2 this year for for the smaller study will help us. It can teach us so that we can ensure a better successful outcome for the larger phase 3 study. So the trials are the exact same in terms of their layout. The ACT AD, which is the small phase 2, has 2 doses of fosco 7040 milligram and a placebo.
Dr. Mark Litton:And in addition, the LIFT Act d, which is our phase 3 study, has exactly the same three groups.
Dr. Moira Gunn:Now in the phase 3 study, the big study, you're not doing hearing test?
Dr. Mark Litton:We're not doing hearing test. We are dealing with the most important aspect is hopefully looking at cognition or the activities of daily living or the clinicians scale. And the FDA when we met with the FDA, there was we need to choose 2 of those 3. We will choose ADAS cog 11, which is the the gold standard of cognition, And then we need to choose whether it's the clinician score, which it probably will be, or the activities of daily living. And that's those 2 different ones and that choice is what we're gonna learn in ACT, the phase 2 study.
Dr. Moira Gunn:Ah, so that's see, that was the first time I understood. They're not like, They don't wanna see all your data. You gotta choose a subset of the data you're collecting. That's very interesting. Why would they do that?
Dr. Mark Litton:Well, all so here's the thing. As we know, Alzheimer's is very complicated. This is a totally new approach repairing these connections, and we don't really know how well this is gonna have have a benefit. And so we gotta look at each of these different domains and understand, okay. Well, where where is this potentially being beneficial?
Dr. Mark Litton:So today, we don't know, and that's why we're asking all these different things.
Dr. Moira Gunn:So let's say let's hope this works. Would this replace other Alzheimer's treatments?
Dr. Mark Litton:So right now, the way we're running our trials is it's an add on therapy and that means that participants can have standard of care and we just add our Fosco to that.
Dr. Moira Gunn:You know, I do wanna say one thing, which may have occurred to people who were listening earlier and is this question of for the hearing test, which I think is fascinating. It's like, oh, wait a minute. What do you mean you have this cap on and you're measuring brain currents? If you've had any kind of brain injury, if you've had they're trying to measure epilepsy or This is very it's been comp for decades. They're able to do that and they're trying to see are there anomalies in the brain current.
Dr. Moira Gunn:So that portion of it, that measurement portion of it is actually very settled. You aren't doing anything on tour there or new there in that sense.
Dr. Mark Litton:Yeah. And we're really not. I mean, people have described it like what you do with EKG to measure your heart. It's very similar. P 300 is another test that just assesses the health or the connections and how fast your brain is processing.
Dr. Mark Litton:And it's something that cannot be faked. It's everybody has it, and, it's just an interesting measurement.
Dr. Moira Gunn:It is what it is. Now if you give Fosco to healthy volunteers who start out with this 300 millisecond, can they get faster?
Dr. Mark Litton:The answer is no. Unfortunately, not. We we we
Dr. Moira Gunn:Darn.
Dr. Mark Litton:We're not making superhumans. Yes. No. So it it does not have any effect. Really, most of the time, this mechanism is recurring from an injury.
Dr. Mark Litton:Right? So there's a healing of it. It's not making it better.
Dr. Moira Gunn:Now I understand that you're also working on dementia in Parkinson's Parkinson's dementia. What are you doing there?
Dr. Mark Litton:So we're we're again, we've started a phase two trial, which is called SHAPE. And we're looking at, again, testing and and looking at FOSCO in this patient population because roughly about 50% of Parkinson's patients suffer from, impairment in cognition.
Dr. Moira Gunn:Where else can, Fosco or I know you have some other compounds, I can see it. Where else might it help in terms of medical conditions?
Dr. Mark Litton:So we're we're looking at a broad range of neurological diseases using the concept of just repairing or restoring nerve cells. One of the places where we've we we just showed preclinically, that it might have a benefit is in schizophrenia. And another place that we are looking at and it might have a benefit, is in depression. And these are this is we have another molecule, which is ATH 10/20 that just entered phase 1 this week. And so we're looking at that.
Dr. Mark Litton:That's oral, so it's not with an injectable. And we continue to explore various areas where if there's been an injury to the nerve cell that, repairing it might be beneficial.
Dr. Moira Gunn:Well, it's it's fascinating because there's no doubt that if you've had an injury or genetically or however it worked, your cell isn't working properly. Just returning it to working properly could be the solution to the entire problem.
Dr. Mark Litton:Well, we'll see. We're very hopeful. And, again, it's it's all about the science and just taking another step forward in in understanding what's going on in a in a very complex place. I mean, neurological diseases are have not been given all the insight that, say, oncology has been given. So we're hopeful that we're gonna take a little bit step, And and once we learn from that, then we make some improvements and and we create another improvement.
Dr. Moira Gunn:Well, Mark, this has been terrific. I hope you come back and, see us again. Keep us filled in.
Dr. Mark Litton:Moyer, the pleasure is mine. Always always fun to talk to you.
Dr. Moira Gunn:Doctor Mark Litton is the president and CEO of Athira Pharma. More information is available on the web atathera.com. That's athiraathera.com. Listen to more biotech podcasts at biotechnation.com or subscribe on your favorite podcast provider. Bio Tech Nation is a regular feature of the weekly public radio program, Tech Nation.
Dr. Moira Gunn:Listen to the full show via podcast or on your local public radio station. For Bio Tech Nation, I'm Moira Gunn.