Jackie Baxter 0:00
Hello, and welcome to this episode of the long COVID Podcast. I am delighted to welcome back Margaret Koziel from Axcella Therapeutics. So I spoke to Margaret in Episode 35, which was earlier this year, about something that they were developing to help people with long COVID. And there have been some exciting results from the trials. So that is kind of what we're going to be talking about today. So welcome back.
Margaret Koziel 0:26
Thanks for having me back.
Jackie Baxter 0:27
It's lovely to see you again. So, would you mind just very quickly introducing what you do, and a little bit about Axcella.
Margaret Koziel 0:37
So I'm the Chief Medical Officer for Axcella Therapeutics, and we are a biotechnology company that is focusing on harnessing the body's power to tackle complicated diseases. And so there are several things in that statement. So first of all, when I say harnessing the body power, what we're using is long standing knowledge about ways in which the body can generate changes in how the body behaves, and therefore improve the biology behind complicated diseases. So specifically, what we're doing here is we're using amino acids, which are the building blocks of protein. We've known for many years that those amino acids can change how the body functions. There are other molecules that are other examples of endogenous metabolic modulators as we call them. But for the purposes here, today, we're talking about amino acids. And so that has an advantage not only a long history of what we know about how they might act, we also have a long history of safety, as we all consume amino acids on a daily basis as part of our protein intake. So that's at the heart of what we do.
And the other feature that is important to us is, by design, we are tackling problems, where many pathways in the body are going wrong, so called multifactorial diseases. We work on non alcoholic steatohepatitis, which is a really good example, where there are problems across how the body handles fat and energy, how the body sets up and maintains an inflammatory response. And also what happens to lead to scar tissue within the liver.
And then about a year ago, we turned our attention to long COVID, as another example of a disease where there appear to be many processes within the body that are not functioning correctly. So we've been looking at mitochondria. And as we talked about last time, the mitochondria are the powerhouse of the cell. And they also control immune responses. We've learned a lot in the last year about how immune responses are abnormal in people with long COVID. And so that's another example of again, a disease where there's not one single thing that is going wrong, and people with long COVID, but many things. And that's how we're trying to tackle one of the major symptoms that people with long COVID have, which is the fatigue.
Jackie Baxter 3:13
Fantastic. So in the previous episode, we talked a lot about what you're trying to do. So I don't want to make you repeat yourself when we've done that bit before. But would you mind just giving us a very quick recap of what the very catchy, AXA1125 - I think is that correct? Sort of what it does?
Margaret Koziel 3:34
yes. So we, we have been busy in the last couple of months reading out our long COVID. So I'm afraid that we haven't come up with a catchy name. That's what you asked Bill last time. And I'm afraid we haven't turned our energies to that particular, we will, in time, have an easier name to say. But what AXA1125 is, it is a combination of six different amino acids that we have combined in ways that we think will address the biologies of what's going on. Again, we started with trying to tackle this in non alcoholic steatohepatitis or NASH, or fatty liver. And we had good insights into what the biology of that problem was. And then when we started looking to see how we could help in long COVID about a year ago, we realized there's actually an overlap. And a lot of the body's problems are the same between NASH and long COVID. So that's how we turned to this particular amino acid composition. And again, the good thing for us is as we started a long COVID trial, we already had a good amount of information about the safety and tolerability because we tested it in many people before we even began the long COVID study.
Jackie Baxter 4:49
Yes, of course. And that enabled you to go in at a high, it was at a higher level of the trials, wasn't it?
Margaret Koziel 4:55
That's correct. Yes.
Jackie Baxter 4:56
Yeah. We talked a little bit about that last time. You just mentioned the overlap between the NASH and long COVID being, you know, fatigue is a sort of a huge crossover symptom. And we know that quite a lot now about fatigue being a crossover symptom between Long COVID and MECFS. A lot of other long term chronic conditions. This is me spitballing, but do you think this might be something that could help those people as well?
Margaret Koziel 5:25
Now, it's certainly something that as we were thinking about how to tackle long COVID, we certainly looked at that literature between the chronic fatigue there are - to go back to the heart of it, what do patients tell us they're feeling? What patients with myalgic encephalomyelitis, or chronic fatigue syndrome and what patients with long COVID tell us who have fatigue, is a very similar story. So that is part of what we looked at when we were examining what causes fatigue in long COVID. I want to be clear, our efforts now are focused on long COVID because of the public health emergency, the sheer numbers of people who are out of work, out of school, not doing the things they really care about because of fatigue, are quite staggering. So our attention is really focused on that at the present time as a small company. We are certainly looking at ways that we could help other people. We don't know if chronic fatigue or myalgic encephalomyelitis, we don't know if that's the same problem or not. I think we need to do some more work in that area. But it's certainly those parallels have intrigued us. And it's something we're thinking about.
Jackie Baxter 6:45
Yeah, absolutely. Yeah, that's absolutely fair. I think last time we left off just as you were heading into trials, and you're working with Oxford University, won't you on these trials?
Margaret Koziel 6:59
That's correct.
Jackie Baxter 7:00
So what happened? I guess.
Margaret Koziel 7:03
So we're very excited to release the results. So just to refresh your memory about what the trial was looking at; when we went into it, we were interested in two things. One is to better understand the biology of long COVID. This was a year ago. And to see whether or not AXA1125 could influence that biology, and in particular, if it could result in an improvement in fatigue.
So like many early phase studies, we centered the trial around biomarkers, which are things that we can measure that reflect whether or not disease is improving or not. We also included as part of the trial, a tool to measure fatigue, and a six minute walk test. Literally, that's what it is, how far can somebody walk in six minute walk. And those are both tools that reflect at the end of the day, how people feel and how they function. So we used those, and our expectation going into the trial was that we would see some improvement. But it was a small trial. And it was only a month. And so our expectations were modest.
And what we learned far exceeded those expectations. So after a month of dosing, and I'll say that this was a placebo controlled trial. So half the people in the trial got AXA1125, half got something that was identical in appearance and weight and taste, and so on. After just 28 days, we saw significant improvements in fatigue using this tool. And what was particularly exciting, when we look at the numbers, about 70% of the people who got X 1125 had improvements in physical fatigue, compared to basically no one in the placebo group. And a few people even went back to their baseline. So this tool asks, when you last felt well, so it's imagining, okay, I got COVID 15 months ago, how do I feel before I got COVID? And the people in this trial told us that they were back to their healthy state. And that's as a clinician, that's incredibly exciting to see people - in 28 days, we had really no expectation that we would see this degree of improvement. And it's in both the physical aspects of fatigue as well as the mental aspects of fatigue. And so, we are, I use the word astounded, amazed and thrilled to have this opportunity to move something for that could potentially help people suffering from fatigue feel better?
Jackie Baxter 10:06
Yeah, that's incredible. I mean, that's the I mean, you say it's a small study. But even so those numbers are impressive.
Margaret Koziel 10:14
We've shown it to a number of people, the doctors who take care of people with long COVID. We have shown it to some patients as well, some other people who are suffering from long COVID. And that is the reaction that most people have, which is when they look at these numbers, you just want to pinch yourself and say, you know, is this real? And it is real, as I said, that was one of the advantages we had going in is that this is placebo controlled. So that represents the highest scientific standard for saying, is something that you're observing real? Or is it a matter of chance, or how people may be perceiving the benefits? But this was very clearly related to having taken AXA1125 during the trial.
Jackie Baxter 11:04
Yeah, that's huge. And you said that a lot of people had massively improved, you know, back to their pre COVID feeling, if that's a word. The people that didn't - did they still improve?
Margaret Koziel 11:18
Yeah, so let me correct that. So it wasn't the majority of people who went back to their baseline, there were a handful, three out of the 21, in the AXA1125 arm, basically went back to the what they said was their baseline during the 28 days of the dosing. Most of the people improved. So they went from again, this tool says it's moderate to severe physical fatigue. And then most individuals, when they improve, they went to what is called mild physical fatigue. And you can use the scoring instrument. That still, in the context of 28 days, it was a short dosing period. And so we would anticipate that had we continued it for longer, and in future studies, when we look at it, if you go through longer dosing periods, that you would see more and more improvement over time,
Jackie Baxter 12:13
Right, sorry. Yeah, I obviously completely - those numbers went over my head, and I made something up there.
Margaret Koziel 12:18
It's hard, I have the graph in my head. So it's easier. So thank you for allowing me to clarify that.
Jackie Baxter 12:23
So yeah, that is huge. So yeah, even the fact that, you know, even if they didn't all magically become cured, which going into it, you weren't expecting that, were you? You know, that some of them did significantly. And you know, they did even just sort of level up a bit. That is a massive improvement, you know, you would take any improvement, wouldn't you?
Margaret Koziel 12:43
Well, we'd obviously we'd like to get everybody back to their normal state. And so that's what as we move this forward, and we talked a little bit about the process of drug development last time we spoke, as we move this forward, that will be one of the questions that we will take a look at is, as we go longer into dosing, what proportion of people really get back to their baseline. And as you say, what we want to measure is improvement, we want people to feel better.
The other thing that's important is that we looked at what happens as the fatigue improves, can people say walk farther? And that's in fact, what happened that as physical fatigue, improved or mental fatigue, people are able to go farther in the six minute walk test, because you want to see those move together? You want to say as people feel better, and that, again, is an early scientists - can they start to get up and go do their daily activities, and in general, feel better. So that's one of the things that we can use, again, in early drug development to say, yes, those two are moving together. And that's a very positive sign.
Jackie Baxter 13:52
So we know that sort of post exertional malaise or post exertional symptom exacerbation, I think are the two that we call them. And you know, this idea where you might be able to do a short walk, but it then hits you sort of 24 hours later. And again, that's probably quite difficult to measure. Because it's often for me, certainly, it's quite hard to tell what it is that set that off. But the people that were able to do physically slightly more, were they unaffected by the post exertional malaise side of it as well?
Margaret Koziel 14:23
So that's a great question. And going forward, we would look to a different instrument to measure that. So that I think is certainly - we use the six minute walk as in an early phase, it is easy to do. It's very standardized. We know, for example, what people with long COVID, on average do, but I think you get to the heart of the question, which is what is meaningful to people living with long COVID? Which is, for example, the ability to get back to work. Overall, do people feel like their quality of life has improved? And so going forward in time now that we have this data from this trial, what it'll help us do is design the next trial to address those questions, right? Because you want to look at the total physical activity over time, not just what you can do in six minutes. But what can you do over the course of say, a month? So we're currently in the process of running through some of the tools that we have at our disposal to measure that, and gathering those together
Jackie Baxter 15:29
Of course, because it is, it's a really difficult thing to measure. I try to work things out myself, and I'm one of these people that sort of, you know, when I start feeling bad, I sit down with a list and I try and work out what it was that set it off. And it's impossible, sometimes - the parameters change all the time. So I'm sure it's gonna be really, really difficult to measure in a clinical setting.
Margaret Koziel 15:48
So I think that there are tools out there, some of those are instruments that like have been used in other fields to measure, for example, what does returning to work look like? They're actually questionnaires that have been developed to ask that question. There are actually several out there and we're in the process of, again, picking which one might be best for the next study. Same thing with physical activity. There are different ways to measure that, ranging from asking people do you feel like you were able to do more, say this month, than three months ago, when you started study product? So there are a couple of ways we can do this. And that's what we're in the process of, of mapping out.
Jackie Baxter 16:30
Yeah, definitely. So you've mentioned the next phase of the trial. So again, I think we talked about this a little bit last time. But what happens next?
Margaret Koziel 16:39
So we're really looking forward to starting the next study. And that's what I alluded to before, is that we're starting to put those pieces in place. And that involves a lot of different parties, and planning for that. So if we think about the end goal, which is to try to get a drug out there to help the millions of people who have long COVID and fatigue. The health authorities, so in the United States, it's called the Food and Drug Administration. In the United Kingdom, it's called the MHRA. What they're interested in is two major things are, do people feel better? Are they functioning better? And is the drug that you're using safe enough? So what we have to do is design a trial that answers those questions. Have we proven, and the legal standard is beyond a reasonable doubt, right, proven to a high level of rigor, that we in fact, make people feel better and that they're functioning better.
And this is, again, we believe that again, by using amino acids and this long track record that there's already a considerable amount of information about the high degree of safety and tolerability people have. So when you look at the balance of that equation that health authorities are always looking - it's like a seesaw, right. And you have to be on the up part where the efficacy outweighs any safety or tolerability problems. That's where we have our advantages, again, because we believe that amino acids are intrinsically safe and well tolerated. So the onus is on us next to prove that we can improve the fatigue, and then again, that helps people function better.
Jackie Baxter 18:28
Excellent. And the fact that you've had such good results from the first stage will help, I guess, would it?
Margaret Koziel 18:35
Yeah. Because they will look at each stage of the approval process, you review your data with the health authorities and say, Are we ready to move on to the next stage? And so that's part of the discussion that you have in drug development is to say, how, how do we move this along? And we will have very specific discussions with them. Is the trial we're designing, going to answer that question? So they will go through it from all the perspectives, and they have very important roles. They have a number of people. This is true for all the health authorities, they have a lot of people who look at these proposals, and we'll say yes, that trial should answer the question now, you know, then it becomes on us to go execute it and get it done.
Jackie Baxter 19:19
Right. So you actually work quite closely together with the health authorities then?
Margaret Koziel 19:24
Yes,
Jackie Baxter 19:24
Yeah. Oh, that sounds really great. So yeah, you've been speaking about the FDA and the sort of health agencies on your end of this. How does that work sort of across the pond in the UK, for example, and working together with with us?
Margaret Koziel 19:40
So there we work with a branch of the government called the MHRA that regulates drugs and devices in the United Kingdom. And so when we started the trial, about a year ago, we had a discussion with the MHRA, who provided advice and now that we have done the trial, we are going back to them, and having a discussion about how to move on to next steps.
And I would characterize that as a very positive relationship, they're obviously keenly aware of the public health problems, there's, again, really strong data showing how many people are out of work and not recovering. In the United Kingdom, they're clearly aware of that, and are viewing this as part of the ongoing pandemic, and part of the public health emergency that is long COVID. So, again, very positive, the voice of the patient there has clearly been heard across the pond. So that's really important for this group to think about is how we can all work together.
As we talked about before, during vaccine development and treatments for acute COVID, what was powerful there was the lesson that when everybody works together, things get done really quickly. And so we're hoping that we all approach long COVID with the same degree of urgency. We certainly are. And we would like our partners to approach that with the same degree of urgency.
Jackie Baxter 21:16
Yeah, definitely. So you're obviously pulling this all together at the moment. Do you have any idea when the next phase of this is sort of going to start? And I guess, how long is it going to take?
Margaret Koziel 21:28
So we don't anticipate, and I'll go back to some of my results. Again, we were amazed to see results within 28 days. So we don't anticipate that the next trial will be long. I don't want to give a definitive timeline for when we might get to that because we do have to have the conversations with the FDA and others to make sure that we're setting up the trial in the right way.
While I can't give you a definitive answer, what I can give you is a promise that I understand that every day matters for somebody with long COVID. And so we're doing everything possible in our end, to make sure that that we move forward as quickly as we humanly can. Because I get it at the heart of this, a lot of people are suffering. And whatever we can do, if we can relieve that suffering, again, of the millions and millions of people. That's what we're trying to push forward. It is a sincere promise. Every day, we all ask ourselves, what can we do to make this go as quickly as possible?
Jackie Baxter 22:37
And I guess you want to do it fast. But you have to do it right as well, don't you?
Margaret Koziel 22:41
Yes, we have to do it fast and well. And that's where the health authorities play an important role to, if you will, look over our shoulders and make sure we're doing that. And I can at the end of the day, they have a very important role to make sure that anything that comes out as a therapeutic is both efficacious and safe. And so that's, again, those are part of the conversations that we're having is how to do that.
Jackie Baxter 23:04
So this next phase is the trial - you mentioned earlier, you know, the 28 days that you did before, and you know, the really impressive results that you had within that. Are you imagining that the next phase will run for longer than the 28 days?
Margaret Koziel 23:17
Yes. Although I don't expect, at least in our present thinking is that this is not going to take years to show an effect. So it's a little bit longer than 28 days. But it's we don't think this is going to be a five year trial, for example, we want to get to the answer as quickly as we can.
Jackie Baxter 23:35
Yeah, brilliant, I guess. People with long COVID, as you said, we we're impatient, we want answers. And you know, you guys are really are doing your best. So I don't think the blame is laid at your doors.
Margaret Koziel 23:48
Well, I understand if people are frustrated, given them 10s of billions in this country alone, 10s of millions of people with long COVID who are suffering, I don't blame people for being frustrated. Right? That's natural when you're miserable. So all I can say is that we are trying to move it along as quickly as we can. Again, we're trying to be focused and efficient and move this, but I certainly understand.
We are leading in this particular space. If you look at the clinical trials, and anyone can go on this website called clinicaltrials.gov and see what's out there for clinical trials. And we're one of the few placebo controlled trials, that's really important. And we're one of the few that has anything in fatigue. And now we have a positive readout. So this is where we're ahead. There's not been a lot of work in this area. Again, for the patient community that's very frustrating not to see a lot of trials out there. So that's where we're in a leading position on this one, to be able to get something out there as quickly as possible.
Jackie Baxter 25:05
Yeah, definitely. I mean, I think what we all want to see is something that my doctor can prescribe for me, that will make me feel better. And you know, it would be so easy, wouldn't it if that was the case. But people like yourselves really are, well not even just trying, you're succeeding.
Margaret Koziel 25:19
And there, and there is a process. And it takes time. And it takes some time to have the discussions with health authorities and have the discussions and get all the pieces in place to actually run the trial. And again, it's hard work, but it's good work at the end of the day, because we know what we're trying to do here. So we're very happy with the results.
I'd say one other thing I want to mention is that, as I described at the beginning, the purpose of the trial was also to understand about the biology of 1125. And how 1125 is affecting that biology. And one of the interesting things we saw was that some of the tests that we use to measure mitochondrial function are way way off. We started off a conversation with almost a given like, oh, well, there's mitochondrial dysfunction. Remember, that's not completely settled in the medical and scientific literature. And some of our findings, when they're published, I think, will really speak to that, to say that this is a disease with real biology, because that's the other thing you might read in the popular press, or you might see people commenting on.
And I'll say this very much in quotes, this is not my personal belief that "it's just all in your head," right? No, that's not what's happening here, we are seeing fundamental changes, and how the body processes and handles energy, that again speaks to both how we work and also the biology of this disease. So I think that's the other really important message is that we are really trying to get to the bottom of what is the problem here, and we believe that that, again, our amino acid composition, is tackling something that's really real. So I think that it's really important to demonstrate the clinical trial results. And it's also important that we've said something fundamental about the biology here.
Jackie Baxter 27:25
Yes, because one of the things one of the chief frustrations with people with long COVID is well, firstly, being told it's all in their heads. But you know, the thing that leads people to say that, I think is that, you know, everyone's tests keep coming back clear. So, you know, if your tests are coming back clear, well, there's nothing wrong with you, then? You know, but we know that there is, so actually having someone say, well, actually, you know, this is a test that proves that there is actually something wrong, you know, it sounds bizarre doesn't it, you know, being pleased to have a test come back with something abnormal, but
Margaret Koziel 27:55
But it is. So I will also say that so our results join some of the literature. Unfortunately, right now, we're not at a place where a simple blood test that would be available to say a family practice physician, we don't have that yet. We are starting to pin down the biology and then then it's just a matter of time, you know, how do people - it may be us, it may be somebody else? How do people come up with a blood test or something that's simple to do, that you could measure that. We're concentrating on? Listen, it is one of the ways that when you're tackling a symptom, and I would say, say fatigue, headache is another example. Depression, when you develop drugs for all of those things, what do you do at the heart of it, you asked how people are feeling. So we are concentrating on Can we make people feel better, and again, improve their functioning along with it. I think other people will be developing the blood tests and so on. But that is an important part of this that I don't want to get lost is that we believe that the biology here is real, we believe that we are doing something important to try to get people back. And then how we measure it is to say, Are people less fatigued? And the answer is yes,
Jackie Baxter 29:15
Definitely. No, that's that's a good point. Thankyou
Margaret Koziel 29:17
Thank you. Again, as we talked about last time, I would encourage active involvement of people who are living with long COVID. That is really important, that people in government, the people who have to make some of the decisions about this are influenced by what patients have to say, that's very clear. And I don't mean this to say that they haven't listened. But the louder the voice is, the more support we can get. Again, we're a small company. So we will take all the help we can get to move this forward as quickly as possible. So I want to encourage people who are listening to this podcast to again, work with your local governments, wherever that may be, to find an effective solution. We're certainly interested in that patient voice. We are trying to listen actively and say, what can we learn from the patient community? And so the louder and clearer that voice is, the better it is for everybody.
Jackie Baxter 30:16
Fantastic. Yes, absolutely. Sure. Well, I'll put a link to the trial results into the show notes. So anybody who is interested, can follow up on that.
Margaret Koziel 30:26
The other thing that's good that will be on our website is that when we open up the next clinical trial, we'll have an announcement. And of course, it will go on clinicaltrials.gov, the public listing site, so I'd encourage people who are interested in clinical trials to follow that space, and take a look. And that's when you'll know the next study is up and running. And we also post locations and so all that information will be publicly available.
Jackie Baxter 30:54
Well, thank you so much for joining me today. It's been so great to hear about the amazing progress that you've been making. So thank you for today and thank you for everything that you're doing.
Margaret Koziel 31:05
Thank you very much.
Transcribed by https://otter.ai