Welcome, everyone. I'm Trevor Allred, part of the Life Sciences team here at OpCo. Today I have with me the INmune Bio team, RJ, David, and Mark. As always, feel free to submit any questions you have, and we'll try to answer them later on in the presentation. With that, RJ and David, take it away.
Appreciate it, Trevor, and thank you, Oppenheimer, for having us for your healthcare conference. I'm David Moss, and you have the three co-founders on the webinar. As many of you know, we're a company that's focused around innate immune dysfunction, and we have two platforms. One is XPro, which is geared towards CNS disease and is in the middle of a phase 2 trial currently. It'll be fully enrolled by the middle of this year, and about six months later, we'll have top-line data. The second platform, which has been invented by Professor Mark Lowdell, is around natural killer cells, and that program is related towards oncology. We're very proud of our history and our capital structure. To date, the company has 18 million shares outstanding. Our last reported financial statement showed $41 million in cash.
I think that it's important to note that the three of us on the phone are very large shareholders of the business. We've been purchasers of stock. We own a lot of stock. And the reason why is because we really believe in what we're doing. I think it's a little unusual for most biotech companies to have management own that much, but we've worked very hard to build this company in a special way because we really believe in our science. I think a simple way to look at our business is between the two platforms, XPro and INKmune. It's an attractive value of parts. I really look at it almost as two companies in one. Each of them have large potential. We all know that the Alzheimer's dementia market worldwide is very large.
Even with the approved drugs, there are not drugs that adequately deal with the disease. In the case, as Mark will tell you, with regards to INKmune and prostate cancer, it's an area where immunotherapies have failed in the past, and we think we have a good understanding of the reasons why. INKmune is designed to really overcome some of the obstacles related to prostate cancer, which Mark will share with you later. So with that being said, I want to emphasize that our flagship program is XPro for Alzheimer's disease. RJ will go through some of our phase 1 results, and we'll share with you our phase 2 program. I want to emphasize that we call this our flagship program because it's the one that clearly is most advanced. It's right in the middle of a phase 2 study.
And it will fully enroll towards the middle of this year. And again, I want to emphasize the top-line data, which will tell us if you get rid of neuroinflammation and do it properly, and I emphasize the word properly, does it make a difference in cognition? It will answer that seminal question. Then we expect to start a treatment-resistant depression program towards the second half of this year. It's a phase 2 program. And as Mark will tell you about our prostate cancer program with INKmune, which is currently in a phase 1 program, that can roll over to a phase 2 program. So with that being said, I will hand this over to RJ, who will talk about our Alzheimer's program.
Thank you, David. I think this slide, in a very clear way, really differentiates our approach to treating Alzheimer's disease compared to virtually everyone else. We treat Alzheimer's disease as an immunologic disease, not a neurologic disease. That means we are targeting neuroinflammation. Why are we so convinced that, one, neuroinflammation is important, and two, TNF, which is the target of XPro, our drug, is important? These data show really why it is so important. The bottom figure here is what's important. In women that have rheumatoid arthritis, they have chronic inflammation, they have elevated TNF levels, they have an eightfold increased risk of Alzheimer's disease compared to you and me, unless they get treated with a TNF inhibitor. If they are treated with a TNF inhibitor, their risk plummets to less than 60% of the risk that you and I have.
So clearly, neuroinflammation is a key point, and TNF is a key player. Your question, though, is, well, there have been TNF inhibitors on the market for a long time, so why don't we just use them? And that's because they are destructive of the brain. They are different than our second-generation TNF inhibitor because they promote demyelination. You see this area that's white? It should be blue. That's lack of myelin, and they cause neurodegeneration. It should be black here because of axonal degeneration. You can see when you treat these animals with XPro that, in fact, you get regeneration of myelin and protection of the axons. And this is also shown in humans. When you treat patients with the current drugs, they can develop MS. So you don't want to treat them with a drug that gives them a neurologic disease.
We completed a phase 1 study that, quite frankly, was wildly successful. We had four questions. The first question was, is XPro our drug safe in patients with neuroinflammation? It is. Second, does XPro get rid of neuroinflammation? In fact, it did, and I'll show you more of that in a minute. The third thing is, were there downstream benefits of getting rid of neuroinflammation? The answer is yes. Did we identify a dose to take into the phase 2, which is ongoing? The answer is yes. I would just point out one of the important differences of how we treat the disease is that we use biomarkers to select patients. We're looking for patients that have neuroinflammation, and we effectively find them by testing for simple blood tests, and you need one of these to be enrolled.
You get treated with XPro, and you have neuroinflammation. All of your biomarkers of neuroinflammation go down. This is an Olink panel. Lots of cytokines. You don't need to know what the cytokines are specifically, but you know that they all go down. And that's consistent with the inflammatory, shall we say, environment of the brain improving. But so what? The so what is, what are the benefits of decreasing neuroinflammation? And there are two major benefits. The first is you decrease nerve cell death. And whether you measure pTau, phospho-tau, excuse me, neurofilament light chain, or visinin-like protein, you, in fact, have a decrease in nerve cell death. And then you also see an improvement in synaptic function. Remember, the synapses - the nerve cells have to talk to each other - and the synapses are what allow them to communicate.
One of the first things that gets destroyed in the setting of neuroinflammation is that ability to communicate. Now, we've become quite interested in the use of non-invasive biomarkers with neuroimaging, something called MRI DTI. What we have shown is that these biomarkers are very valuable for looking at inflammation, axonal disruption and loss, and myelin degradation and repair. What we're looking at is in the white matter tracts, a normal white matter tract has the axons in green, the myelin in purple, and this space in between, which is the free water, in blue. When you get neuroinflammation, you get edema, you get swelling. You see you get lots of blue, you get axonal degeneration, they get balloon, and then they die, and you get the myelin gets dysregulated, and as you can see, it is disorganized. All those changes we can see.
This is an example of looking at white matter free water. As you treat the patients over time, that white matter free water decreases when you treat them with XPro, and that means neuroinflammation is going away. Likewise, you get improvements in apparent fiber density, which is the neurons, and you get improvements in remyelination. In the purple here, the remyelination is actually going down, means the myelin's getting better. So that's interesting. That's lots of biology, but where the rubber meets the road is when you're talking about what happens with the patients. A great example is one of our patients who was a teacher. He had to retire because he had Alzheimer's disease. What you're seeing in the purple here are the white matter tracts associated with Alzheimer's disease.
The white matter tracks are the superhighways in your brain that connect the parts to the brain that work together. In fact, he couldn't remember his patients, his students' names, and he couldn't remember his lesson plan. He was put on XPro, and you see these sproutings, green and yellow fibrils. He went back to work at 6 months, continued to improve, and he improved, continues on XPro 2 years later, and he's back to normal. In fact, I challenge you to find any treatment which actually improves patients with XPro. So all of that data was used to construct a very novel phase 2 trial that's ongoing. This phase 2 trial is enrolling in 9 countries, as you can see in the green, both in North America, Europe, and the Pacific Rim. There are a couple of very important points.
The first is it is short, 6 months. It is small, 201 patients. It uses enrichment criteria. In other words, we use biomarkers to select those patients who have neuroinflammation because we want to match the drug with the patients that have the disease. And that's about half of the patients with Alzheimer's disease. And then finally, we use a very special cognitive endpoint called EMACC. EMACC is a built-for-purpose, fit-for-purpose cognitive endpoint that is ideal for patients with early Alzheimer's disease. Early Alzheimer's disease are patients who have either MCI, mild cognitive impairment, or mild AD. So this trial is ongoing. It's a 2-to-1 randomization, and we expect to read out mid-year, excuse me, we expect to complete enrollment by mid-year with a readout 6 months later. So what are patients looking for?
What they get today with lecanemab, the patients get worse on placebo, and they don't get worse as fast, their cognitive dysfunction doesn't get as bad quickly with lecanemab. But the fact is, they're still getting worse. What our patients showed us in a small trial is, in fact, that they stopped declining once they put on XPro. So that is our promise to patients, that in fact, the moment they get put on XPro, their cognitive decline stops. And this is what patients want. They don't want to get better. They'll take it. But they want to stop getting worse, and we think we can safely and effectively deliver that.
Great. Mark, I'm going to stop sharing, and I'm going to pass it over to you to talk about our second platform of INmune.
Thank you very much, David, and thanks once again for this opportunity to share our data with you. I'm going to talk about, change tack entirely now, and talk about INKmune in our cancer therapy program, currently in myelodysplastic syndrome, acute myeloid leukemia, and prostate cancer. But I hope the next few slides will show you that it won't advance. Okay, hang on. What's gone wrong?
If you click on the slide and hit the arrow, it might work.
No, it's just not responding to.
I just talked to it, Mark.
Okay. I think it's better if you've got to talk to it, David, without the slides. That's just too much. It was working earlier on. So what's gone wrong? Can you see me? Can you hear me?
You are.
I've got nothing here.
You're sharing the wrong screen, Mark.
No, I can only apologize for this. We've got a meltdown with my laptop.
It was working. It was moving. Slides aren't, Mark. We're going to.
Why are we interested in NK cells? Well, they are an incredibly well-preserved immune response against cancer. What you can see here is that even healthy individuals that have poorer NK cell function have a significantly increased lifetime risk of cancer. If you look here at all of these different cancers, patients with a high NK cell infiltrate have a significantly improved prognosis. In the two diseases we're targeting, prostate cancer and acute myeloid leukemia, or MDS, patients who have a good NK function have improved overall survival running to many months and years. NK cells have been studied for many years, and this is the first study from Steve Rosenberg's group. The take-home message here is, if you get the doses right, you can actually have significant benefit.
Here in all comers with metastatic cancer, you've got complete remission in some and partial remission in others. These doses that they had to use are two logs higher than current trials of adoptive immunotherapy in cancer. We've been looking at this for many years, and here you can see that using INKmune, even if you have patients with ovarian cancer (here are six of those) or breast cancer, they have very poor NK cell function in response to killing their own tumors. And yet, after priming, we get very, very enhanced killing in both ovarian cancer, breast cancer, and as we've seen now in prostate cancer and many others.
I won't go through the mechanism here, but this is just suffice to say that we know a lot about the biology of these cells and how they function, and this allows us to develop this drug very efficiently. So what is INKmune? Well, it's a tumor cell that's replication incompetent, and this tumor cell interacts with resting NK cells, as you can see here. And in the interaction, the resting NK cell actually takes part of the membrane of the tumor cell and carries it away with it. And this turns the resting NK cell into a memory NK cell that has much enhanced function. You can see here, these are resting NK cells from a patient with ovarian cancer, and the ovarian cancer cells here, the NK cells in blue, the ovarian cancer cells are recognized by the NK cells.
They bind very poorly, and they don't kill the tumor cell. If you take the same NK cells and prime them with INKmune, you can see here, come on. You can see here that the NK cells bind much more efficiently. They form a very, very tight immune synapse, and ultimately, you'll see that cell being killed. What we know from our studies in patients is that once the patient's been treated with INKmune, the NK cells in their peripheral blood increase their expression of CD2. This is a molecule that NK cells use as a co-stimulatory molecule. And even after the first dose by day eight, you can see this increasing. But probably more impressively, we know that NK cell dysfunction in patients is often due to the lack of this molecule, granzyme B, that NK cells use to kill tumor cells.
This is the normal level in healthy individuals, the bottom end of that. You can see here that even after just a single dose of INKmune, this patient's Granzyme B levels in their NK cells have fallen up in the normal range. It's also associated with metabolic changes, and we see here changes in mitochondrial survival proteins. We know that NK cells in tumors are impaired because of a lack of mitochondrial function. Yet, when we prime them with INKmune, we resolve that back to normal levels. We've got a lot of data on the science behind this, the genomics, the proteomics, and the metabolomics. In all cases, they identify unique changes associated with INKmune-treated NK cells compared to other immunotherapies. These are associated with, as I said, increased metabolic function. Here you can see maximal mitochondrial respiration by these mitochondria.
And more importantly, after they functioned, the NK cells activated with INKmune retain additional respiratory function. So none of this works if you can't make the drug. And one of the great challenges of cellular immunotherapy is getting the doses to the patients. And we've thought about that from the get-go. So we have a bioprocessor already in a very small scale and gives us the 23 patient doses per manufacturing run. But this is entirely scalable to a 15-liter one. You can see the size of these bioreactors relative to one of us and very easily scaled up to 80 liters, where we're talking about hundreds or thousands of patients treated with a single manufacturing run over three days. And obviously, these can be run in parallel in multiple sites.
So the downstream process is also sorted out, and we're able to produce these doses for patients at a very cost-effective manner. So we have a clinical trial running at the moment in myelodysplastic syndrome and AML. And you can see here for a publication from our group from some years ago that patients who present with this disease and have low NK function have a median survival of 18 months, and they're all dead within 2 years. Whereas those with high NK function do better, median overall survival is 54 months, but some long-term survivors. And so the aim of this trial is to move patients who are here onto this line here. And in line with our manufacturing process, we also have a very, very efficient supply chain from the manufacturer to the patient that doesn't require vapor phase nitrogen like CAR T cells and other immunotherapies.
Uniquely, our therapy is given as an outpatient. This is some data from a patient treated on the U.K. arm of the MDS trial. Four of the five patients treated so far at the lowest dose have shown clinical responses and biomarker responses. But this patient, number one, who's the longest patient out since treatment, came into the trial with severe clinical—it was a really poor clinical outcome—ECOG status of two, three doses of INKmune. You can see that in contrast to this conventional chemotherapy, where the disease worsened over time and was under control, after treatment with INKmune, the disease markers improved somewhat. Now, these are far less impressive than actually the clinical improvement, where his ECOG status improved to an ECOG status of zero. He became fully active and was able to leave hospital and engage in regular exercise with his friends.
The in vivo biomarkers, we can see NK cell activation very rapidly, two different types of NK cells, two populations of NK cells, increases in the cytokines in the peripheral blood with time that we would expect to see post-treatment, presence of increasing numbers of mature, highly functional NK cells after treatment, and most importantly, this poor NK function where he fell into the short-term survivor group from our previous study. Within two treatment levels, he came above that threshold, and by day 43, he exceeded that and became normal NK function. And most importantly and remarkably, those NK cells were not any normal, but they were more active than NK cells in URI because they were also capable of killing an NK-resistant tumor. So I've rattled through quite a lot of data, but I hope it shows you that we really understand this drug. We understand how it works.
We understand its potential. It's not restricted to prostate cancer and AML and MDS. It can actually work in a number of solid tumors. It generates memory-like NK cells, which are the most potent form of NK cells. These have characteristics that suggest they will have enhanced function in the immunosuppressive tumor microenvironment. We can generate these functionally active NK cells in patients. The requirement for adoptive immunotherapy with tens of billions of cells is actually not required with this drug. These patient-owned autologous NK cells may be defective, as you've seen, but once they're appropriately primed with INKmune, they're no longer ineffective, and actually, they have the capacity to resolve disease. Thanks very much. Sorry for the delay earlier.
Thanks, Mark. So from there, I guess we always have the availability for questions. If you want to ask any questions, feel free to submit to the portal. We do have a few questions coming in. Now that the FDA has lifted the hold, can you guys talk about when you think this study for depression might begin?
Yeah, thank you. David mentioned in his talk that we expect it to begin by the end of the year. I will say that it was put on, shall we say, on the shelf while we were working through the FDA hold, and we have begun to execute against that. And so the expectation is by the end of the year.
Okay, thanks. And then I guess can you touch on how XPro is infused? How much blood-brain barrier penetration is there? Is this something where you see it needs a certain amount, or is it kind of systemically active?
Yeah, those are great questions and very important. This is a drug that is given by the patient, self-administers, once a week as a subcutaneous injection. So think about how the GLP-1 inhibitors for obesity are given. This is exactly how they're given as a once-a-week subcutaneous injection. They don't need to come into a physician's office for an infusion. The dosing of the drug is such that it, well, first of all, the structure of the drug and biology of the drug is it does cross the blood-brain barrier. There's about a 10:1 gradient. The pharmacology of the drug is that we can give, it is safe, so we give robust doses to allow us to get therapeutic doses in the brain to treat neuroinflammation despite that 10:1 involvement.
The important point is that a very large amount of central inflammation in the brain is driven by peripheral inflammation, things like autoimmune disease, cardiovascular disease, diabetes. In fact, the fact that we're giving it a drug systemically, we not only cool the fire peripherally, but we extinguish the fire in the brain. This is the reason why this drug will really make a difference in patients with Alzheimer's disease.
Okay, great. Yeah, that's super helpful. I guess also then, can you touch on some of the limitations that other TNF-alpha inhibitors have that are currently approved?
Yes. So the main limitations is they actually have an FDA warning on their label that they should not be given to patients who have neurologic diseases. And this is because in the past, when this was seen, when this was done, the patients developed neurologic symptoms. That is, they caused demyelination, and they had neuroinflammatory results. Early on, I showed a slide of that in animal models. And we know that the most commonly one of the causes of MS in the U.S. is patients who have been on long-term TNF inhibitors of the first-generation type, current ones that are approved. XPro is a second-generation program. Works completely different. And most importantly, it does not have these side effects because it doesn't block transmembrane TNF. And I would suggest if those that are interested go to our website.
We have a very nice video on the mechanism that'll explain the difference between the current TNF inhibitors and how XPro works.
Great. Also, another question on the side effects of both XPro and INKmune. What things have you guys seen?
So I'll comment on XPro, and I'll let Mark comment on INKmune. XPro is extremely well tolerated. The only thing is we get some injection site reactions, kind of like a little mosquito bite, and that's because the drug is PEGylated. That's a half-life extender. And it is well known that patients can have a little bit of an immune reaction against the PEG. Mark, you want to comment on INKmune?
Yes. So we've had a lot of experience, obviously, with animal models and had no toxicity whatsoever. And in the patients treated to date, of which there are seven, no one has shown any adverse side effects whatsoever, even at the time of infusion. So it's an extremely well-tolerated drug at present.
Yeah, I would emphasize we have a solid tumor trial going on with INKmune prostate cancer. That is an outpatient trial. Those patients are never in the hospital. They come in. INKmune is given by an infusion that takes about 20 minutes. They get no premedication. They sit there for 4 hours, drink coffee, watch CNN, and off they go. So it is an extraordinarily well-tolerated drug to date.
It is indeed the very first cellular drug that the FDA is allowed to be given as an outpatient in a phase 1 trial. Yeah, we're very, very pleased with that.
Great. All right. Well, that is all the time we have today. Thank you all for joining us, and we'll see you in the next presentation.
Thank you, guys.
Thank you very much.