Traws Pharma Q4 2024 & Study Update Earnings Call Transcript

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March 31, 2025

There are 6 speakers on the call.

Operator

Good morning, and welcome to the TROS Pharma investor call on bird flu and COVID and TROS Innovative Small Molecule Product Candidates. At this time, all attendees are in a listen only mode. A question and answer session will follow the discussion. If you'd like to submit a question, you may do so by using the Q and A text box at the bottom of the webcast player. As a reminder, this call is being recorded and a replay will be made available on the TRAS website following the conclusion of the event.

Operator

Before we begin, on this slide, you will see TRAS standard disclaimer language. Statements in this presentation and on this call may be forward looking, including our plans, objectives and expectations for our antiviral pipeline programs. These matters involve risks and uncertainties, and the company's actual results may differ significantly due to a variety of factors that are discussed in detail in the company's SEC filings. And with that, I'd like to turn the call over to Doctor. Werner Kautrials, Chief Executive Officer of Charles Pharma.

Operator

Please go ahead, Werner.

Speaker 1

Thank you, Tara, and good morning, everyone. I am Wenner Kautrios, and I'm CEO of Charles Pharma. Welcome everyone to Charles Investor event and thank you for joining us today. Today's event is an important event for Charles. We will discuss the unmet needs and the public health risk in bird flu and COVID or two antiviral product candidates.

Speaker 1

Our two main speakers today are Doctor. Robert Redfield and Doctor. David Bausa. Doctor. Redfield is our Chief Medical Officer and previously was Director of the CDC.

Speaker 1

Doctor. Faussa is our Chief Science Officer and will be presenting the data of the compounds. Today also, our Executive Chairman, Doctor. Ian Dukes will be part of today's call and some other members of the management team will be available also to take your questions and answer those questions. We believe that our antiviral compounds have the potential to be best in class compounds as you will hear today.

Speaker 1

Our lead program is tivoxavir marboxyl in development for bird flu. We will also introduce ratutrelvir in development for COVID. I'm now turning it over to Robert Redfield who will start on the bird flu and medical need and public health. Bob?

Speaker 2

Bird flu is a growing pandemic, as many of you know, particularly in the agricultural space. But it does have enormous pandemic potential if it learns how to eventually go human to human. Right now, we've had from 2019 to now, we've had over 150,000,000 chickens and jerkies infected. It's now infecting over 40 mammalian species in The United States. Although it hasn't learned how to go mammal to mammal, it only seems to know how to go bird to bird.

Speaker 2

There's a small species barrier for it to eventually flip over to be able to affect humans. So far, we've had approximately seventy humans infected in The United States, all of them from bird to human with no evidence of human to human transmission. But the pandemic risk when this virus learns how to go human to human can be catastrophic. The human cases that have occurred, particularly in Southeast Asia, have had greater than a forty percent mortality. So this does pose an enormous potential pandemic risk.

Speaker 2

And if you look at what we're seeing right now, we're seeing a huge epidemic in the agricultural space, particularly in chickens and turkeys. It's also moved into dairy cattle. More recently, it's moved into pigs. And very recently, it's moved into sheep. With this virus moving among those agricultural animals, fairly efficiently, although it doesn't appear to be going mammal to mammal, it's going bird to mammal, bird to mammal, bird to mammal.

Speaker 2

Eventually, what one can see is there's occasionally cases of bird or dairy cow to human. And when that occurs so far, the human has not transmitted among other humans. But that's the real pandemic concern that eventually through changes in its amino acid sequences that it will learn how to go human to human and when that occurs will cause a catastrophic bird flu pandemic. So when you look at right now the issue with bird flu, clearly one of the important things about the product that we're developing, it has a broad resistance profile against AV and flu strains, including the strain of the Texas dairy worker, which is currently a prototype strain and the strain of the individual that eventually died of bird flu in The United States. It's a very good pharmacokinetic profile and that one dose will provide production for probably up to three weeks.

Speaker 2

And it's also been shown to reduce disease and mortality in three accepted preclinical animal models. It is able to cause a massive reduction in virus replication in vivo in all three of these animal models. One dose is able to maintain a plasma level above the EC90 for, as I mentioned, at least three weeks in our Phase one studies. And overall, it has an excellent tolerability profile, which will enable even higher concentrations to potentially be used to treat or prevent bird flu.

Speaker 3

So, good morning, everyone. I'm Dave Pasa. As Werner said, I'm the CSO. And I'll walk you through some of the current data that we've obtained to really pursue the application of this compound in the bird flu space. So, several years ago, as we were beginning to worry about this problem, Doctor.

Speaker 3

Redfield and I had spent a lot of time talking about the future pandemic potential of influenza. And we had been watching this for a long time. This compound, at that point in time, was then introduced into the Centers for Disease Control, who assayed the compound against a number of H5N1 type viruses that were circulating in nature in 2022, '20 '20 '3. And on the right side, you see the EC50 or effective concentration 50% in nanomolar for, tavoxavir. And you see it's all subnanomolar concentrations against these H five N ones.

Speaker 3

So we knew we had a compound that was potent and it was going to be at least in the game for preventing a future H five N one outbreak. Now, Doctor. Redfield also mentioned the transmission of this virus from a cow to a dairy worker in Texas. We think that we were very fortunate in that instance that that person did not subsequently transmit that virus to other humans. And the reason is because that the virus in the dairy worker evolved nine unique mutations that were not present in the cow, who who infected him in the first place.

Speaker 3

Those mutations are all associated with increased efficiency of virus replication and increased transmissibility. And, so I show you the map there to show you the distribution of these. Those are the unique ones that separated the virus in man from cow. So as soon as that virus got into the Texas dairy worker, it started to adapt quickly. And that's the problem that will fuel any future pandemic outbreak.

Speaker 3

When we look at commonly used antiviral agents against, that are used against seasonal flu, These were tested against the same Texas isolate, the eight thirty Texas thirty seven isolate. So if we look at oseltamivir on the right, which is Tamiflu, against the an H1N1, which represents seasonal influenza, you see that the EC 50 there is subnanomolar. If we look at that same compound against one of these H5N1s that I showed you on the previous slide, it would be a collection of those kind of wild viruses, it's already significantly less potent with a higher EC 50 of 2.7. And then you go into this atexus strain and you get this remarkable problem of that atexus strain now as five thirty EC 50. Now we have to be careful because that Texas dairy worker was treated with Tamiflu.

Speaker 3

And this may be a resistant variant that emerged in him. But if you were to transmit that, you're transmitting a completely Tamiflu resistant virus. Veloxavir is another compound, that has is available for seasonal flu. You could see it has a little bit about one and a half nanomolar EC 50 against a h one n one seasonal flu. It's fairly potent against a representative H five n ones in the wild collection, but it's extremely higher EC 50 against the atexus strain.

Speaker 3

So while these antivirals will be used right now as the primary therapeutics for these viruses, you can see that they're unlikely to be highly effective in controlling this, especially after this virus begins to adapt in people. So we, we began, the more serious investigation, the deeper investigation of the h five n one by taking this virus, this atexas virus, and putting it into a mouse model. And we were one of the first groups that was able to do this because we had early access to the virus strain and vendors with the capability to do this at biosafety level three. So we infected mice through the intranasal route and treated them one time with our compound, taboxavir marboxyl, by oral route. So we're preserving the as much as we can, a mimic of the clinical experience.

Speaker 3

On the right side in the top panel, you see that the vehicle control animals shown in black are all deceased by day six. That's a very rapid killing in terms of most influenza strains. Commonly, when you work with an influenza strain in the mouse, you adapt it to the mouse first and then you study it. This is the human virus, just grown once to expand the virus and then put directly into mice. So there's no adaptation here.

Speaker 3

The treatment with tamoxifir marvoxel called TRX one hundred on this slide provided one hundred percent protection and where all animals were surviving. On the lower on the lower part of that slide, you see a very typical marker for influenza, which is a rapid body weight loss shown for in black for the untreated animals. And in red, no body weight loss for our treated animal group. So in that initial animal study, tavoxirir marboxyl was an outstanding antiviral. To go a little bit more into this, the two main things we will be looking at to evaluate any antiviral efficacy would be number one, body weight, as I mentioned, and number two, how much virus is growing in the lung.

Speaker 3

Virus growing deep in the lung is the real challenge here and and will be the real, lethal mechanism of viruses like this. As you can see on the left, in the vehicle controlled animals, virus titers in the lung are very, very high, sometimes approaching 10 to the ninth. If you did this with a typical seasonal influenza virus, maybe the highest you would have in this experiment is about 10 to the sixth virus titer. So you can already see quite easily that this virus is much more aggressive than a normal influenza. On the right side, we did the virus titration from animals that had been treated with tavoxavir and marvoxel, and you could see that all animals had virus levels below the lower limit of quantitation.

Speaker 3

So that's a stunning effect on the viremia. That means that we're close to six logs of virus reduction at minimum in this experiment and, and clearly demonstrated why these animals were surviving. Our next effort was to move this into ferrets. Ferrets are a commonly used strain of animals for looking at influenza outcomes, doing therapy and vaccine development. So we took ferrets.

Speaker 3

We inoculated them with a lethal dose of, this atexas virus. In this case, it was a thousand infectious doses. And we treated them with two different dose levels. One dose level was equivalent by scaling to a 20 given in humans, and the second dose was equivalent to a two hundred and forty milligrams in humans. The previous mouse experiment was done with two forty milligrams in humans equivalent.

Speaker 3

I put these numbers on here very importantly to make a contrast with baloxavir, which baloxavir is an approved drug. And the label says that if you're sixty kilograms or less, you can treat with forty milligrams. And if you're above sixty milligrams, you can treat with eighty. And you can see that those two approved dose levels are not very close to what we're looking at here. So we had two groups of animals.

Speaker 3

We treated them. We looked at our three, our three indications, survival, our body weight, and virus burden. And we saw a pretty dramatic effect of the antiviral on these three endpoints. So in survival terms, all the ferrets, untreated ferrets were dead by day four. Again, a highly, highly lethal infection.

Speaker 3

The animals treated with the equivalent to two hundred and forty doses had fifty percent survival by day 14. And, and we saw a what appears to be a dose effect, dose response effect by a little bit lower survival in the hundred and twenty milligram equivalent group. So and in terms of body weight, you see the same thing. And, so when we looked at these data carefully and said, we got the first two criteria that we were looking at correct. We had an increase in survival and we had a decrease in body weight loss.

Speaker 3

What about the viremia? And, the viremia data, from this ferret model are essentially stunning. You can see extremely high virus loads now clearly in the 10 to the nine range in some animals with with a very large suppression of virus in animals treated with either of the doses of taroxvir and marvoxel. And the lower descriptors there, cranial caudal, these these describe portions of the lung that were sampled individually in this study. These animals were euthanized and, and tissues were removed to perform these analyses.

Speaker 3

So by three days after infection with a single treatment of tamoxifir marvoxel, we got this result again showing the extraordinary antiviral efficacy. And I wanted to just show that in a different way. And, so if we color code the regions of the lung to represent how much virus was measured in there, then we have the red and orange colors, meaning the highest viral load, and we get down to the blue, purple, and pink are the lower viral loads. So in the controls, you can see the lungs are massively attacked by this virus. Extraordinary high virus loads and, and predictive of extreme lung damage, which is what we've seen on histology studies.

Speaker 3

In the, dose equivalent to one hundred and twenty milligrams in humans, we see a substantial reduction in the virus burden. And, but that lower right lung still has some appreciable viremia in it. And that's telling us that this is the real site of attack of this virus. And a virus that grows like this in the lower lung is very dangerous. And on the far right side, you can see the animals treated with the equivalent to two hundred and forty milligrams, mostly pink lungs, which is what we're looking for, and a little bit of virus still growing.

Speaker 3

So, again, we've met all the criteria that we established before, and we will repeat this experiment by going to the next higher dose level, which we think will be have a much bigger effect and was still within our safety range. The final study that we've done is we've completed a study in nonhuman primates. These were in rhesus macaques. And, they were they were infected and treated 12 later with, again, an oral dose of tavoxavir marboxyl. We used the dose that was equivalent to four hundred and eighty milligrams in a human, and we have five animals per group.

Speaker 3

Now this this experiment turned out to be a nonlethal infection. And as I said, this was very early time, with little experience of this virus in nonhuman primates. So the virus dose was probably a little low. We got a nonlethal infection. But it allowed us to explore the parameters again that were important to us.

Speaker 3

So we don't see the survival parameter, but we see the change in body weight and the change in lung viremia as, again, registering the substantial antiviral effect of this compound. So in terms of body weight, you can see it's a highly significant difference between animals that were, treated and animals that were untreated. And this the with a very extraordinarily good p value for especially for an animal study of this type. So there was a clear differentiation in terms of body weight. There was a clearer even more clear differentiation in terms of lung viremia.

Speaker 3

So we've color coded again the same way. And because of the virus dose, we didn't get up into the orange and reds, zone for virus burden in lung, but we got substantial virus replication in lung in the control animals compared to the treated animals where we get all pink lungs, which remember was what we wanted. So we've demonstrated the substantial impact of viremia and a highly significant impact on body weight loss, again, confirming the activity. So now we have three species with very similar, very significant data telling us this antiviral is working. And, maybe, Bob, you wanna tell us the the well, I'll I'll continue.

Speaker 3

So we've asked we asked ourselves, what would we do, then to go through and begin to characterize this in humans? And we've completed a phase one study in humans, which was healthy volunteers looking at safety and tolerability. And the details of the study are outlined on this slide. We looked at participants that were 18 to 64 years of age, males and females. This is the pharmacokinetics result from that study.

Speaker 3

And I think we see a nice dose response in the pharmacokinetics of a single dose. And I wanna keep emphasizing this, that this antiviral is given one time when as soon as symptoms are apparent. And here in healthy volunteers, again, we gave only one time. And differently than than the other products, I want to really emphasize the range of doses that were evaluated in this study. So the range of doses went up to four hundred and eighty milligrams.

Speaker 3

Why? Because we believe these are the kind of doses that are going to be required to contain a highly aggressive, human adapted h five n one virus. And, and here I've shown you, in dotted lines, what it would take to control a seasonal influenza with this compound. And you can see that a single dose is gonna give you good viral control out to about three weeks. And we haven't really done any more, development to try to extend that.

Speaker 3

And there there may be ways to even make that go farther. So three weeks would control against the seasonal influenza. It may also control dairy workers and poultry workers from that initial transmission event of the bird flu into them. However, we know that high that we will require the high doses, that will be necessary once this adapts to humans. So I think this this is also very encouraging data.

Speaker 3

And, so the primary path for us to go forward is we want to apply this to bird flu. And, and we believe that bird flu represents an exceptional situation for two very important reasons. Doctor Redfield told you of the extraordinarily high lethality of this virus once it begins to spread among humans. We have about thirty years experience with this virus. And when outbreaks have occurred, the lethality has been tremendous.

Speaker 3

Second, right now, there are very few cases of this in The US. So So it'd be impossible to do a clinical trial of human adapted bird flu at the present time. But we believe that the risk is there. The threat is coming. And I would remind everybody that we're in the beginning of the south to north bird migration, and there's a wave of bird flu coming with these wild birds as they travel north.

Speaker 3

So we, we have not seen the end of this. This is not like a seasonal flu, which will just be here for a few months. And veterinary epidemiologists have predicted that this influenza will circulate in domestic animals for at least five to seven more years. So so this is an exceptional situation, and we think that the FDA so called animal rule is appropriate here because the animal rule is intended to allow studies where you demonstrate the efficacy of a compound in animal studies because it would be unethical or impractical to do these in humans. And so as I said, exceptional pathogenicity, the fact that we can demonstrate this efficacy in animals that we believe these are directly translatable to human beings.

Speaker 3

And that we've already begun to accumulate the safety of pharmacokinetics in human beings. And we, we are prepared to respond to the FDA guidance, concerning going forward. And so now, I'm going to stop there. And now we're going to transition to COVID. And I'd like to turn it back to Doctor.

Speaker 3

Redfield.

Speaker 2

I just want to emphasize that COVID continues to be a very significant cause of human disease in The United States today. It's going to be responsible for anywhere from probably thirty thousand to eighty thousand deaths per year. And this virus, unfortunately, is going to probably stay with us until the end of time. The vaccines that we have right now, they do not prevent infection. They do have an impact on hospitalization and death in individuals that are highly vulnerable.

Speaker 2

But again, they don't really have an impact on whether someone gets infected or not. And therefore, there's an enormous need to develop effective antiviral. The virus does continue to mutate. And that means, again, makes the vaccines persistently less and less effective. When we look at why we really need better therapies for COVID, clearly, I talked about the decrease in the acceptance of the vaccine among the American public.

Speaker 2

Also the fact that the vaccine itself does not prevent against infection. It just modifies disease course. And again, the virus continues to evolve. And so there's a poor match between the vaccine and the circulating strains. It's an enormous clinical burden, as I mentioned, cause significant cause of premature death.

Speaker 2

And again, the economic burden is also substantial, particularly when you look at one of the consequences of COVID is that a significant percentage of people, and it's been estimated between five and maybe as high as twenty percent of individuals who develop COVID, develop a prolonged syndrome post COVID that we call long COVID, which has significant impact on those individuals' ability to work, etcetera. There's really limitations of the current antiviral that we have, Paxlovid. It works. It's an excellent drug. But the challenge with Paxlovid is that it requires a PK enhancer, Ritonavir, in order for it to get the levels needed to be efficacious.

Speaker 2

And that PK enhancer then makes it ineligible for people that are on blood thinners like Eliquis and many of the elderly that are on other drugs where there are drug drug interactions so that they really can't take Paxlovid. Again, I will argue that Paxlovid is now really pretty much established as a long term public health challenge in need of improved antiviral therapeutic products to help address this challenge. When you look at it, the threat to human health, as we've estimated, this is CDC's estimates, anywhere up to seven million to thirteen million infections, two million to three million people seeking outpatient visits for two hundred thousand to four hundred thousand basically being hospitalized. And CDC currently estimates twenty six thousand to forty three thousand deaths to be attributed to COVID. When you look at the proposition that we currently have with our lead candidate, it has a broad, broad, broad resistant profile, which allows it to be active against a variety of the emergence variance and treatment against resistant strains that are currently resistant to the current Paxlovid related products.

Speaker 2

That the dose has a very favorable PK profile. It's estimated that it's about 13 times EC50 of the current, faclobin. The data basically on drug metabolism is extremely, I think exciting and distinguishes this product and that this drug can maintain the appropriate blood levels required independent of Ritonavir and therefore makes it available to the high risk patient population that Paxlovid currently is contraindicated in. It's got a very good safety profile in the Phase one studies that we've done up to ten days, and will allow one to design this drug as a ten day therapeutic. Right now Ritonavir Paxlovid is used as a short course five days.

Speaker 2

And some of us see that that is maybe one of the reasons why current COVID is associated with rebound in many of the patients that are treated. And also, as I mentioned, associated with a high penetration of long COVID. So we think that this product gives the potential for longer therapy, which we think will decrease rebound and potentially have an impact on the development of long COVID.

Speaker 3

Okay. Thank you, Bob. So I'm going to take you now through the data package on the COVID-nineteen drug, ritutrovir. It's a main protease inhibitor, as Doctor. Efil said, for a ritonavir independent ten day regimen.

Speaker 3

And we'll explain the reasoning for these things as we go through. So ritutravir, was compared using laboratory testing against a couple of other compounds. So nirmatrelvir is the Proteus inhibitor component of PAXLOVID. And so when, when you test nirmatrelvir in the lab against a large number of SARS CoV two variants, you can see the EC 50 values there on that left panel. And in every case, ritutravil is more potent against the same virus tested at the same time.

Speaker 3

So these panels were commissioned by Truss Pharma and did the head to head testing. The Ibusatrelvir numbers are, taken from the literature from a publication that's cited there. Ibusatrelvir is the current ritonavir independent coronavir mPRO inhibitor that Pfizer is developing and has in late stage clinical trials. But it's important to note the potency differences here. More than 50 times difference against the original COVID strain and, and really, not a very potent drug against the viruses that we see there.

Speaker 3

So on the right hand panel, then I've taken again those three compounds, plus I've added incitriovir, which is the compound that is licensed in Japan and currently in clinical studies in The United States. And I've shown you the average EC 50 across a number of strains. So nirmatrelvir, we looked at nine strains that were tested. 23, EC 50. And sitrovir, sixty nine.

Speaker 3

For the three strains that I could find published, a 23 for the Ibusetrovir. And for our compound, 8.4, and that's tested against 18 different COVID strains. And so when we take an EC 50 value and then we wanna know what's the real threshold value we wanna reach in the blood of individuals, what's our predicted window, then we usually multiply that value by three, get a predicted EC 90 value. And that's really what's important for dosing considerations and safety considerations. So you can see the EC nineties there are quite substantial.

Speaker 3

So especially in sitralvir, two hundred and seven, and this ipuzatrelvir now 369, nanomolar in blood in order to reach efficacy levels compared to our compound, which is only 25 in order to reach the therapeutic level. So there's a substantial differentiation in terms of potency and efficacy. Now a very important issue in antiviral treatment is always the evolution of drug resistance. And so here, I'm showing a little bit of information taking from the published literature, which now is beginning to reveal the frequency of nirmatrelvir resistance mutations in populations treated with Paxlovid. And you can see that, that in the that we got up to ten percent of participants in this one study had a Paxlovid resistance mutation already.

Speaker 3

So that's relatively high and may indicate that the virus was incompletely suppressed in those individuals. In terms of encitrovir, which is shown in the middle panel, the main resistance mutation is this M49L. And you can see the one country in the world which is licensed encitrovir has a massive number of these mutations appearing. And in The US, where it's been used mostly in clinical trials, we're also seeing mutations appearing as well against EncitroVir. In the right side, I give you a table which lists one by one all these amino acid changes in the protease gene, which are associated with resistance.

Speaker 3

And I've checked off which ones are found in Nirmatrelvir clinical study and which ones are found in in Sitralvir clinical study. And then I've added the ones that we found in a laboratory study where we intentionally evolved the virus to be resistant to the drug. And you can see that there's very minimal overlap between our resistance pattern and the others. There's a little overlap between our compound and Nirmatrelvir, zero overlap with the resistance pattern to Incytrovir. So our unique pattern of drug resistance indicates that we may be effective against some of the variants that are appearing already.

Speaker 3

And these variants are continuing to spread in the population. To return to Ritutrovir, we want to show you some information, direct information about the pharmacokinetics in our healthy volunteer study. And this I'm showing you the data for a once daily dose of six hundred milligrams of Ritutravir. And again, importantly, once daily dose taken for ten days. And as you can see, if you plot the pharmacokinetics over a short number of hours, if you plot it for the dose on day one and the dose on day ten, the first and last dose, you could see that there's not very much difference between the PK profile.

Speaker 3

That tells you we're not inducing the metabolism of the drug, which is the problem with with others where they've had to introduce ritonavir, and we're not really accumulating the drug either. So in terms of antiviral, this is extraordinarily well behaved drug. On the right side, I showed you the the drug levels at twenty four hours after each daily dose. And it's also important that these drug levels are very stable and very reproducible against the across the whole profile of ten days of treatment. And, and then, we can summarize it all here.

Speaker 3

And I wanna come back to this picture in just a moment because I wanna put this into context of something that doctor Redfield mentioned about long COVID. And we internally have long believed that you have to very effectively suppress this virus and suppress it for long enough to prevent viral rebound. And we had the concept for a long time that if people rebound, this is an indication they're gonna have a susceptibility to long COVID. And now we're starting to see the first amounts of real data being released from other groups proving this point. So this group, presented a poster at the CROI meeting in 2025 demonstrating directly that there was if you have more symptoms of COVID or if you have slower decrease in viremia, you have a much higher risk of having long COVID.

Speaker 3

This risk is amplified in women. So it's true for everyone, but it's exacerbated in women. And and it is it is the direct common sense view of this. Right? If you don't get rid of the virus early and you let it linger, then bad things are going to happen.

Speaker 3

And so we're seeing the real data of the bad things. And, doctor Redfield, has a lot of experience treating people with long COVID and tells us stories which are sometimes quite horrified. Here's the additional look at the data provided by this group and identifying exactly the symptoms that are most associated with the risk of long COVID. And they are, again, what you might imagine, this brain fog, shortness of breath, GI symptom. And so these are all the things that tell you you had a more intense infection and it lasted longer than it should have.

Speaker 3

And, if you could reduce this viremia, accelerate the clearance of the virus, you're going to impact these factors which are making you at risk for long COVID. So finally, just to conclude, I wanted to return back to the PK curve. And this needs just a little explanation because you see the the peak on day zero to one and another peak on nine to 10. That's because those are the only two days where we take these samples over a short period of time. But you could see that, again, they look dissimilar.

Speaker 3

The first and last dose look similar. The, trough levels are very consistent, and we get a kind of free two days after the treatment of days eleven, twelve still being in the zone of therapeutics. So remember, I told you that the EC ninety was 25 nanomolar. You can see that, where that positions on the curve. You can also see that our trough levels are 13 times the EC 50, which means we have plenty of room in there for viruses of with unanticipated behavior.

Speaker 3

And we think it's a very important feature to to put into this. The compounds that are using pachytenavir are barely getting over the EC 90 line with the metabolism inhibitor. We're comfortably above that by a very wide margin without any metabolism inhibitor. And we have extraordinary multiples up to our safety limit, our limit of exposure. So this is a safe, well behaved drug doing everything we wanted it to do in terms of profile in volunteers.

Speaker 3

Okay. And, and so just to conclude, we've shown for the coronavirus drug that we can have very high safety and tolerability in human clinical trials. And we've also shown you data supporting its potency against a broad variety of coronavirus strains, including the uniqueness of the drug resistance profile, which is another differentiator from the existing molecules. We are right now preparing to, go into a pre IND meeting with the FDA to align on what are the next steps. And we are pursuing the application and importance of this compound in the long COVID space.

Speaker 3

And now I'd like to turn this back to Werner. Go ahead. For, to, sorry, to Ian for some final remarks.

Speaker 4

Thank you, David. And thank you, both Dave and Bob. To conclude, we presented what I believe to be a compelling story for two best in class antiviral drugs that address critical threats to human health. First, the bird flu with TAVOXO and naboxel. I think we've shown convincingly that we have a potent and broad resistance profile that includes strange resistant to other agents.

Speaker 4

We've shown very good data in three well accepted bird flu models that confirm the efficacy potential. In terms of human exposures, we have very favorable PK with plasma levels that are sustained for at least three weeks with good safety with the potential to go even longer with optimization of the formulation. Single dose therapy provides the opportunity for bird flu treatment as well as prophylaxis. And we are progressing with discussions with the FDA along the animal rule for rapid approval of this drug. For COVID, for racetralovir, again, we've shown a very potent broad resistance profile for our drug compared to gold standard drugs currently available or in development.

Speaker 4

We have a ritonovir independent regimen, which mitigates drug drug limitations and opens the door to patients who cannot take Paxlovid. We are a single dose once a day, which shows favorable PK, but again with good safety, allowing a ten day dosing regimen. And that ten day will allow for the prevention of both COVID rebound and long COVID. Next slide. So now I just want to give you a quick overview of our financials, the market potential and some milestones for the company.

Speaker 4

First, on the financials, our cash and cash equivalents and short term investments as of December 31 were $21,300,000 and our cash position is sufficient to support the planned operations into Q1 twenty twenty six. As far as market potential is concerned, Doctor. Redfield has described quite clearly the potential for both bird flu and for COVID. But if we just start with bird flu, if we were using the stockpile estimates, we would think between 900,000 doses would ultimately need to be stockpiled to prevent pandemic threats. For COVID, we have a potential best in class agent to replace existing therapies and prevent clinical rebound.

Speaker 4

And so guidance along the current sales of Paxlovid are reasonable as we think about this agent. With respect to anticipated upcoming milestones, all the major milestones are in bird flu and have been summarized by Dave and Bob. But essentially, the first major update will be discussions with the FDA regarding the animal rule and we expect to get feedback from the FDA in Q2 twenty twenty five. We will also in parallel be finalizing formulations and CMC scale up and finalizing also the development for bird flu and moving forward on a path to approval. For COVID, we'll be submitting a pre IND meeting request to engage with the FDA to understand the milestones and endpoints for long COVID in this quarter.

Speaker 4

So at this point, I think I'll hand it over to Tara for Q and A. Tara?

Operator

Yes. Thank you, Ian. So at this time, we will be conducting a question and answer session with our speakers. As a reminder, if you'd like to submit a question, you may do so by using the Q and A text box at the bottom of the webcast player. I'll now turn the call over to Bruce Mackle at LifeSci Advisors to moderate the session.

Speaker 5

Thank you, Tara. So it looks like we have a few questions have come in. First one, can you further clarify the process with FDA regarding the animal rule?

Speaker 1

That's a question for David.

Speaker 3

Yes. Thank you, Bruce. So the animal rule to reiterate the important aspects, it is a mechanism to allow approval of drugs that cannot be effectively tested in human beings. And, they can be tested for safety, but they can't be tested for efficacy because either the potential for risk is so high that you would never use a control group or the frequency of the disease is so low that you can't practically do the experiment. So we fit into both of those criteria and we believe the animal rule is an appropriate path for us to address the FDA.

Speaker 1

Thank you, David.

Speaker 5

All right. Next question regarding the next steps for bird flu development. Can you just summarize and clarify those again in terms of the timing?

Speaker 3

So this is Dave Pazza again. So, we have submitted the pre IND meeting request. And let me just clarify that. FDA accepts requests for a meeting under the pre IND category, which may include just the discussion of the animal rule. So we will have that pre IND meeting, and the important outcome will be their view about the applicability of animal rule for this program.

Speaker 3

And we are expecting that they have thirty days from the March 21 in order to schedule this meeting, and then probably something like thirty days after that to get to the meeting. And then we should we should have feedback during that time from FDA about our status and what their concept of where we should go next. Thank you, David.

Speaker 5

Next one is for Doctor. Redfield. I understand that you are still in active clinical practice. From your experience, what are the most important challenges with COVID patients?

Speaker 2

Yeah. I think it's really important to realize that this issue, what we call long COVID, is really a very significant clinical illness that some patients get post COVID. And again, the estimates are as low as five percent and what is as high as twenty percent. And in my own view, poses one of the largest economic burdens on The United States of the COVID pandemic. This long COVID can be quite significant and severe that I have a number of patients that as a consequence of long COVID have no longer been able to carry on their jobs.

Speaker 2

Many of them are quite successful leaders of companies where they've just not been able to maintain their jobs either because of significant cognitive dysfunction or because of extreme fatigability or in some cases, a very unusual severe autonomic dysnomia, which they lose their ability to control their pulse and blood pressure. So they can only really maintain themselves if they're in the lying down position. It's a quite significant disease. And hopefully, the NIH and others will invest heavily in trying to develop therapies that will improve this condition. I do agree with what Dave proposed that one of the approaches is that this condition is exacerbated by prolonged viral replication.

Speaker 2

That is probably not addressed by short term treatment that is currently being done with Paxlovid, which is only five days. So we're hopeful that, the approach that we're taking with a longer therapy for ten days and even potential doing studies with our products that may even go out longer where we may treat for, you know, four, six, eight, twelve weeks to see if we can impact the occurrence of long COVID.

Speaker 1

Thank you very much, Bob.

Speaker 5

Next question here is, can you describe the market outlook for bird flu and the market opportunity?

Speaker 1

Doctor. Redfield can come back to this in terms of like the stock market.

Speaker 2

Yes, I think the most I ran CDC and of course, really important to the national defense for is our stockpile, which Secretary Kennedy has just reprogrammed to go back to CDC to manage it. But my own view is there will be a high interest in trying to stockpile an effective antiviral for bird flu. And so that's why I give the estimates of anywhere between 900,000,000, I think is probably what would be appropriate to anticipate for the stockpile of the cure of an efficacious antiviral agent for bird flu.

Speaker 5

Next question. How significant is the fact that Ritutrivilir does not need the co administration of Ritonavir?

Speaker 2

Yes. I think it's critically important. If you look at the people that will benefit from Paxlovid currently, to prevent serious illness, hospitalization and deaths, those are individuals that we consider vulnerable. Now probably the greatest vulnerability is this thing called age. Once you're greater than, say, 65, you're at high risk for bad outcome.

Speaker 2

And as I mentioned, unfortunately, COVID continues to have significant mortality in The United States with, I think, conservative estimates of at least forty thousand people planned to die this year. And the problem is that because of drug drug interactions, Paxlovid is contraindicated in a significant number of the elderly that are at high risk for bad outcome. So a number of those individuals are not able to be treated with Paxlovid. The other issue that I would comment is that Paxlovid is a drug, that Ritonavir is a drug that has significant tolerability issues in patients. And also is probably one of the reasons why Pfizer has limited the therapeutic course to five days.

Speaker 2

So I think it's quite significant the limitations that Paxlovid has. And I probably think that's one of the reasons Pfizer is developing an alternative candidate themselves.

Speaker 1

David, you have some additional comments? Yes.

Speaker 3

I just wanted to comment on information released by Pfizer showed strong growth in request for per treatment prescriptions both in 'twenty three and in 'twenty four. And, and a market for PAXLOVID well north of 5,000,000,000. And so, if we're leaving on the table, so to speak, about between ten percent and twenty percent of people seeking prescriptions who have become ineligible, that's a substantial market that exists for a drug with properties of Ritutrovia.

Speaker 1

Thank you, Dave.

Speaker 5

Next question is, why do you think Ritutravir is useful in addressing viral rebound and long COVID?

Speaker 2

I think as Dave alluded to in one of the slides is really looking at the slope and decrease in viral replication in vivo. And it really is probably been underappreciated, the degree in which this virus replicates post infection. And I think the new thinking that many of us have that are in this clinical space is this is a virus that's going to require much longer therapy to get down to viral clearance. And that may be, you know, initially we were going to do ten days. But as I said, I can see that you might even design some long COVID studies where that's the outcome that you may go longer.

Speaker 2

It looks like if you don't treat somebody with anything, that the risk for a rebound is relatively low. If you do treat people with PAXLOVID, the risk for rebound is much higher. And it's, I suggest, it's, again, that there's just incomplete viral suppression and viral persistence that's leading to this problem and the requirement for therapy to be repeated.

Speaker 1

Thank you, Bob.

Speaker 5

The next question, can you comment on the development of the compound in bird flu versus seasonal flu? And is there a certain link between these two developments? Dave?

Speaker 1

So,

Speaker 3

as throughout the presentation, we included data against season showing efficacy against seasonal flu. We have a lot more of that information which we didn't include today for time. For example, we've tested our compound against viruses that are resistant to baloxavir. And for the main resistance mutations to baloxavir, our compound is more effective. Baloxavir has a problem in the clinic in which it generates a high level of resistance mutations.

Speaker 3

So we're able to do address that. We also have high potency against viruses that are resistant to Temaflu, oseltamivir, and very high potency against all seasonal flu strains that we've tested. And Bob's going

Speaker 2

to add

Speaker 3

something here.

Speaker 2

I think it's important to look at just from the clinical perspective when patients present with influenza. It's complicated because the clinical availability of timely real time antiviral testing isn't really there. So having an antiviral against influenza that if you will is really efficacious independent of beloxavir or Tamiflu resistance, which are becoming much more common now among circulating flus, I think will have a potential advantage in the marketplace. The second thing I want to just say, and it is speculative, but I want to put it out there. When you have a drug that has a pharmacokinetic profile where it can last, say, three weeks and its current data that we have, it does raise the possibility that this drug may also have efficacy as Dave alluded to among dairy workers and chicken workers and agricultural workers.

Speaker 2

It may be have efficacy as a chemoprophylactic agent. I will remark as CDC director, one of the things that, I wanted to emphasize is that the current influenza vaccines, at best, are 50% efficacious. And frequently, they can be as low as 25% efficacious. They're also not efficacious among the patients frequently that you really want efficacy. That is the old elderly, pregnancy, immunosuppression.

Speaker 2

So the potential, I think, for a safe, prolonged pharmacokinetic chemoprophylactic agent, that actually could eventually maybe even replace the influenza vaccine marketplace, I think is very real.

Speaker 1

Thank you, Bob.

Speaker 5

Next question. Can you talk about potential prophylactic settings for TXM?

Speaker 2

Walt? Well, I think the question really will come down as we're already beginning to see more and more of the agricultural space is starting to screen agricultural workers for bird flu. And they are finding a number of individuals that have been infected. I think, and Dave may correct me, I think one of the studies that we reviewed was around seven percent or eight percent showed evidence of previous bird flu infection. So I do think that it's potentially very probable that the agricultural space may evolve from an occupational health perspective in looking at the use of chemoprophylaxis in agricultural workers, dairy farmers, chicken farm workers, turkey workers.

Speaker 2

But as I mentioned, unfortunately, this virus now has spread into pigs and it's spread into sheep.

Speaker 1

Thank you, Bob.

Speaker 5

Next question. Can you comment on how the data from misferon nonhuman primate studies are predictive of human studies?

Speaker 3

Dave? Thank you. Yes, we're always careful about the translational Gives us a little information about dose, gives us a little information about how the antiviral is working. But then we really look to species like ferrets and nonhuman primates for, really the final data that's, that's going to stand up and really be proof of principle for this drug. And, so we've been through one round of those animal studies already.

Speaker 3

We'll probably come back to them and refine the parameters and repeat that again. But, as I said, I think that the mouse was the introduction. The ferrets and the nonhuman primates really carry the weight of evidence, and we're very glad that the activity of the drug has held up well in all of those tests.

Speaker 1

Thank you, Dave.

Speaker 5

Great. Well, we're pushing up against an hour or so. We're going to wrap here. I'm going to turn the call back over to Werner for closing comments.

Speaker 1

Thanks, Bruce, and thanks to speakers and answering those questions. It's my privilege to thank on behalf of the Charles team all of you that have participated in this call today and having shown your interest in our company and the future of these very important new compounds. I believe this concludes the Charles investor call. And then back to Tara.

Operator

Great. Thank you, Werner. So this concludes today's event. You may now disconnect.

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