My name's Nicole Martucci. I'm an associate here at TD Cowen. Thank you all for joining us this afternoon. Here with us today, we have Eric, who's CEO of AN2 Therapeutics, and he'll be providing a corporate update. Following their presentation, we'll have a question-and-answer session. Please take it away.
Great. Thank you, Nicole. Thanks for TD Cowen for having us. All right, just forward-looking statements we'll be talking about today. To start off, I just wanted to introduce again the company. We're a boron chemistry platform company. We use the power of boron essentially to hit undruggable targets. I've got a couple of examples I'll show you here in a bit. It's also very tunable to drug-like properties like oral PK and selectivity and things like that. We have demonstrated this in our prior experience at Anacor, previous to AN2. We had two FDA drugs approved through this mechanism or through boron chemistry platform. We also have another drug before the EMA, and my team discovered probably 15 more drugs that are in development somewhere along the way. It's quite a productive platform.
Our pipeline coming out of that is we have two good examples of this. Epetraborole is our lead asset that hits a novel target that's never been precedented in human drugs before: LeuRS, leucyl-tRNA synthetase. We have AN2-502998 , which is an antiparasitic against Chagas disease that hits a novel target too, never precedented by human. We have a number of research programs underway as well. Epetraborole is being studied in the lead indication for nontuberculous mycobacteria lung disease, or NTM, caused by MAC, or Mycobacterium avium complex. I will talk about that a lot in this presentation, but we just announced last week that we're going to unblind the phase III study, big difference, in the second quarter of this year.
We have a number of indications there around the NTM that I won't speak to, but there's a number of opportunities there that we're pursuing. We also have a second indication in melioidosis, which I'll speak briefly about today. Again, this is a high unmet need with 50% mortality of those unfortunate enough to have this infection. Our second molecule, as I mentioned, is Chagas disease. This is a chronic infection primarily of the heart muscle that causes serious cardiac issues. There's 7 million people on the planet that have Chagas, somewhere between 300,000 plus are in the United States with no treatment really that's effective against chronic Chagas. On our boron platform, the boron chemistry is applicable, and our experience so far has been primarily around infectious diseases.
Last year, we announced that we had a couple of programs that we had expanded in oncology following the biology and chemistry. There are a couple of really exciting projects where we think we could be best in class or first in class on a couple of very interesting targets that we'll be talking about more later. In the near term, our key inflection points are going to be NTM. As I mentioned, we're going to have phase III data unblinding in the second quarter of this year. Melioidosis, we expect to start a phase II study. In Chagas, we plan to complete a phase I study this year, plan for phase II, and begin that phase II study next year. Longer term, we have oncology, which we expect to put in at least one compound into development later this year.
Our cash runway that we've guided to is we have enough cash in the bank right now to cover this development pipeline, as we talked about, through 2027. Okay, I'm going to dig deeper into NTM lung disease. This is our phase II, III program. NTM is a chronic, progressive, serious disease of the lung caused by the bacteria Mycobacterium. It leads to very high five-year mortality rates and is really serious. There's a lot of coughing, coughing with sputum, coughing up blood, and it just progressively damages the lungs that is irreversible. There's only one FDA-approved drug for this, which is an inhaled antibiotic that was approved by the company Insmed, and it is Arikayce. You may have heard of that. That was Insmed's first commercial drug there.
Our whole value proposition is we have an oral drug that's a lot less irritating upon inhaled. Insmed's drug has a very high discontinuation rate. It's hard to take, especially for elderly patients. We have a drug that's oral that we believe, so far in our data, is well tolerated. We've got some interesting efficacy data I'll talk about. In terms of market size, the refractory in the U.S. is 20,000 patients. It's a $1 billion plus just in the refractory setting alone. This is a big chronic marketplace. The phase II/ III, we ran a phase II/ III seamless design study. Basically, we put 80 patients in the phase II where we studied EBO, or epetraborole, our drug on top of an optimized background regimen, and then placebo on top of that. It's a superiority design.
We had one-to-one randomization, 40 v 40 in that trial. The 81st patient came in immediately before we reached the primary endpoint, which was month six in the study. We have right now 97 patients that have completed the phase III portion. We have locked the database, and we will announce that phase III data in the coming quarter. In terms of the data around this, we announced in August of last year the top line data from the phase II. Overall, the clinical, we were able to, what we believe, have a good package to validate the PRO tool, which is essential to have that be your primary endpoint. You do that on blinded data. We were able to make a statement at that time. We also saw a nice clinical signal in terms of what you would expect to see.
We developed our own PRO called MACRO-2. We had a discrete responder. There were seven symptoms. They had to improve on the worst one and be no worse on the rest. We see a signal that was statistically meaningful, and it was generally well tolerated at that time. The sputum culture conversion, which was slightly in favor of EBO, five to four, was very low. I think afterwards, at that time, we halted the trial. We had very difficult-to-treat patients, and we knew that. We wanted to slow this kind of seamless, rapid design down and see kind of what we have and where we go. Also to note, it was a secondary pre-specified clinical endpoint of QOL-B respiratory domain.
We had a stat sig, or nominally stat sig signal with that PRO instrument, which will be important to the remaining story I'm about ready to tell you here. In terms of patients that we enrolled, here we have a side-by-side comparison of the EBO, or epetraborole patients we enrolled in our trial. Then we show the convert patients. This was Insmed, Arikayce's pivotal trial. Here you can see a couple of really important factors. One is that we had four times as much cavitary disease. This is the most severe, worst form of the disease that are very difficult to treat compared to what Arikayce had studied in their pivotal trial. We had three times as long of disease duration in patients, so nine years versus three to four years.
We had 20% almost of patients who were refractory to Arikayce, meaning they were on Arikayce as part of their optimized background regimen. We had two-thirds of patients that were at baseline resistance to amikacin, which is the root drug of Arikayce. A third of them were macrolide resistance, which is the workhorse of NTM drugs like azithromycin. We had a lot of multi-drug resistance, refractory to Arikayce. These were the most difficult of patients to treat with that. When we spoke to KOLs, they're like, "There's no way you're going to convert these patients in six months." That explained a lot of the culture conversion that we saw, is that these are just difficult patients that you're trying to maintain or improve their health, but it's going to be difficult with all that lung damage and cavitary disease and so forth to do that.
This is important context, I think, to try to help us understand the data that we had. What we do know at this point is that the FDA guidance for NTM drug development has as its sole endpoint for approval a primary endpoint. The sole efficacy endpoint is a PRO or clinical endpoint. They want feels function survives. This is why Insmed now is doing a confirmatory study, by the way. We will come back to that. They recently, Insmed, in their confirmatory study, agreed with FDA or announced that they had agreement on QOL-B respiratory domain as their primary endpoint in this confirmatory study in treatment naive patients. This kind of sent the light bulbs off for us, obviously, because this is the secondary pre-specified endpoint from our phase II that we hit nominally statistically significant results in a very small 80-patient trial.
That was the first big kind of announcement that we had this past fall. The second one was, we took that MACRO-2, the second PRO that we developed internally, that we had announced responder level kind of binary yes/no data. We converted that to an evenly distributed 100-point scale, just like QOL-B, so more of a continuous monitor versus discrete. It too also showed a statistical post hoc, a statistical, nominally, statistically significant result. Now we have two PROs, both of which could serve as the sole primary efficacy endpoint for a pivotal study. We're sitting on 97 patients of phase III data, which is a very unusual position to be in. At this point, I think the plan forward probably makes a lot more sense. Just to show you some data on this.
Here's QOL-B kind of at baseline, month three, and month six, showing the change here with nominal statistical significance in this trial. Just for reference, I'll just mention it. In Insmed's phase II, or their treatment-naive study called ARISE, they show a 4.5 difference between background and their drug on top of background and a P of 0.1 in a 100-patient trial in treatment-naive. These are more sick patients. We're showing a nice clinical response using this tool. In our MACRO-2, we also see an anomaly statistically significant change separation at month six from placebo. What we have agreed, or what we announced last week, was that we have updated our statistical analysis plan, or SAP, and submitted that to the FDA for any comments for unblinding the 97 patients.
We plan to unblind that in the second quarter of this year. Afterwards, depending on the results, we would take both studies and the weight of that evidence to the FDA and discuss future paths forward for registration of this drug in treatment refractory patients. We're excited about that. The other thing I should mention is that all along, we've been getting ready for NDA filing. We've done registration batches on manufacturing. We've done all the long-term tox studies, the two-year carcinogenicity study, etc. We really have prepared for NDA preparation and could move very quickly, depending on the output here of the FDA meeting and the top line data. Shifting to Chagas disease. This is another molecule that we're very excited about. This is a parasitic disease.
Just to mention briefly, it's transmitted by, I'll give you the common name, but the kissing bug up on the top. It bites people usually while they're sleeping, takes a blood meal, defecates on your skin, and then you scratch, and the parasites go in the puncture wound. It's quite nasty, but you really don't know. There's mild flu-like symptoms. Then it's silent in your body for decades. What happens is about 30% of the patients develop very serious cardiac issues where they're having aortic aneurysms. They're having cardiac failure. It also goes into GI muscle. It goes into muscles all over the body, but those are the two that are really problematic. You don't want this. The vector, the bug, infected bugs mostly are in Latin America, but they're all over the southern U.S., Florida, Texas.
Probably half of the dogs in those states have Chagas because they eat the bugs, for example. It is north and coming north. There is an estimate, so there are six or seven million globally, mostly in Latin America. There are 300, some people will say there are even upwards of a million persons in the United States with Chagas currently. It is serious. There is no drug to treat chronic Chagas that is used. It is a serious unmet need. This is an area where perhaps it is being overlooked, but this is an area that is close to our space. In terms of distribution, it is all over the United States. You can see kind of a heat map here of where it is. It is here, it is in Canada, it is all over Europe, etc., and spreading.
We also believe that there's local transmission of this because the vector being involved in the southern U.S., we just don't have good data on that. We have a compound, has the nice boron atom in there as part of our technology that we're really proud of. It hits a target called CPSF3. There's no drug on the market that hits that. This is a novel undruggable target here to now. It comes from the same class of benzoxaboroles that are the other two FDA-approved drugs we got at Anacor. It also, importantly, has completed phase III for African sleeping sickness, which is another trypanosome bug like Chagas. There are three of them in the world. That's the second one. It had a 95% cure rate, and phase III is a single oral dose cure of that 100% fatal disease that's horrible caused by the tsetse fly.
We have high confidence in the mechanism. There's definitely proof of concept against trypanosomes and human disease in phase III data. Our data internally, both in vitro and preclinical models, looks outstanding, as I'll show you real quickly here. This is parasite load on the Y axis and then weeks studying this. There are two drugs that are approved for acute Chagas in the United States. One of them is benznidazole. It's the one that's mostly only used, really. It has mediocre efficacy. This was from a chronic monkey study. These are monkeys that were at a cancer center in Texas and ate the bugs and have long-term chronic infection. They're natural hosts, so it presents and does a lot of things that it does in human, which gives us a lot of confidence. This isn't a furry test tube kind of animal model.
This is a real model. So benznidazole works mediocre in that model in terms of curing parasites. If you don't kill them all, they're going to come back. It also happens to be extremely toxic. So less than 1% of patients would use this today as a treatment. There were two other compounds. They were these conazoles, ravuconazole and posaconazole, that were developed by Eisai and Merck. Both of those failed in the clinic. Had they run this monkey model, they would have seen why before they got into significant human trials for that. Our drug, we've got data now, I think, out to five years, but this shows one-year data, is 100% curative in these naturally acquired, genetically diverse, chronic monkey infections. You can see why we're excited. That compound will be these are ones.
Novartis also has a program they're working on in this space. We do not know a lot about that. They have not published a ton about it. We know we have the only one that has been shown in these chronic monkey models to cure them. We are going to have phase I this year. phase II will start next year. We will have phase II data, proof of concept within our cash runway as current. All right. Last, or not last, but at least, melioidosis. This is a second indication for epetraborole, our drug for NTM. Melioidosis also is a very serious disease. There are only a couple of hundred thousand cases per year. You can see the mortality rate is 90,000 patients. We just completed a phase II study that has not quite read out.
Our early data shows us that the 90-day mortality in these patients with the best of care treatment, meaning they've got an antibiotic that works so-so against that, meropenem and ceftazidime. Under care in a hospital, they have 50% mortality in 90 days. The U.S. government, governments around the world are very concerned about this because it's easy to get your hands on because it's ubiquitous in soil and water in South Asia and even in the southern U.S., there's cases in kind of the tropical, like Mississippi, Gulf Coast states, where it's endemic. Given the high mortality, there's not a very effective cure. We believe we can reduce the mortality in those patients.
We're finishing that observational trial, which is helping us design a phase II, which we plan to start later this year and then have phase II data towards the end of next year and initiate a phase III, all within cash. This would be something that we would be eligible for a priority review voucher, also stockpiling and other government things. It's not a billion-dollar blockbuster, but it's certainly a very important disease and something that we think we can make a difference on. Okay, and then research pipeline. As I mentioned, we primarily have been an infectious disease company, but we also follow the chemistry and biology and had revealed a number of targets that hit oncology that are quite unique and we think could be extremely important. We've got a couple of projects there.
We plan to put at least one of those into development this year and hope to have early clinical data on that. That in itself could be a very valuable set of assets for us going forward as a very productive research pipeline. In conclusion, all the focus right now is on the phase III data and unblinding in the second quarter of this year for treatment refractory MAC, NTM. In the midterm, it is going to be Chagas and the rest of our pipeline, melioidosis, that we have from our boron chemistry platform. We have cash runway through 2027. We are quite confident that we have a number of pathways to success here. I think that is all I had prepared. I am happy to take any questions you might have.
Okay. Thank you so much. I think to kind of kick off the discussion a little bit, your phase II, we'll start off with the NTM program. Your phase II data was in really difficult-to-treat refractory patients. If you decide to kind of pursue the front-line treatment space, can you maybe talk about how you see that switch happening and what is it that you think FDA really wants to see maybe differently in front-line patients versus the refractory patients?
Yeah, I mean, I think it's similar. We want to play the story out on refractory and see what happens. In treatment naive, it's basically patients that don't have all the cavities and fibrocavitary and serious disease conditions. From an NTM development guidance from the FDA, they want to see exactly the same thing. They want to see a clinical primary endpoint, so QOL-B or MACRO-2. We're choosing QOL-B, by the way. I didn't mention this earlier because it's not proprietary that we developed. It's something that Insmed is using in their trial and lots of trials have used before. They want to see that. They want to see safety. Also, it would be, I think at that point, good to show microbiology tied to why we're seeing this clinical improvement. It's much easier.
There's a much higher success rate than you see in refractory patients.
What is the biology behind why patients become refractory to treatment? Is it just progression of NTM disease, or is there something else that's different about refractory patients in the way that they're presenting or in the biology of their disease?
Yeah, it's a tough question to answer, I think. In fact, we had an interview last week with one of the key KOLs who treats tuberculosis, which is Mycobacterium tuberculosis in the same bacteria family. It's much different, much easier. NTM is something that is just really challenging. I think as patients progress, they get all this lung involvement in cavities, and it really messes up, for lack of a better word, the plumbing inside of the lung. It is poorly vascularized. It's hard to get inhaled drugs. You've got to get them to these spaces, but yet the plumbing in the lung is messed up. Once you're in that situation, it is really challenging to treat. You also have the fact that the drugs that are used are mostly off-label. They're, in many cases, very challenging for patients to take.
They don't want to take them. Maybe there's compliance issues. There's lots of multi-drug resistance issues because of that over time. I think it's just a very complex situation. Yeah.
Is culture conversion easier to achieve in front-line NTM patients compared to refractory patients?
100% easier. I mean, you see that in the data. For example, the standard of care regimen that's in the treatment guidelines, there's not been a lot because they're all off-label. There's not been a lot of really high-quality studies. You look at meta-analysis, and it's around 60%. That's what Insmed showed in their study versus 9% in refractory in the Insmed trial. We showed 10%. It's a night-and-day difference in terms of easier. Yeah. That's, we think, because, A, these bugs are not resistant. They haven't seen every drug under the sun for nine years or ten years. The plumbing, back to that analogy, are intact at that point. It's just much easier to treat. It's not easy, by the way. I mean, everybody would say it's much more challenging, even the TB.
TB, you get 80%, 90%, 95% even cure rates in early-stage non-MDR TB. The best we're getting here is 60%. Yeah.
Two unrelated questions. The first is, how do you demonstrate proof of concept in Chagas? I'm curious how to tie the parasitic infection to clinical pathology and then where an anti-infective gets involved and how you show that downstream. Completely unrelatedly, I guess, with all the infrastructure you have in ID, can you talk about how you can compete in oncology for what you have and what areas acknowledging where your infrastructure is? Where can you leverage what you have and how does target selection fit into that?
Yeah. Okay. I think with Chagas, taking the first question, I think clearance of parasites is going to be, if you don't clear the parasite, that's what's causing the inflammation or whatever, nobody's ever going to do a, these patients don't have a lot of clinical signs until they end up in a cardiologist's office or they die or what have you. I think we're going to have to work with the regulatory agencies to demonstrate. I think there's a lot of evidence showing that correlation between those two, but you've got to get rid of the parasite 100%. That's why a cure is so important. There are a number of ways that we plan to show that in a phase II study. We've already shown proof of concept in this monkey model. Nobody is going to do a 10-year mortality study.
It just will never happen. We're going to have to come up with more creative ways to do that. On your second question on oncology, how do we pick these targets? It's interesting. We follow the science. We were working on certain targets for infectious disease, and we learned some things about oncology. We're very good at discovering drugs. You give us a target, and we don't even have to have a crystal. We could use phenotypic screening and so forth as many of our programs that didn't even know the target. In these cases, we have targets. We can use rational design, crystallography, biochemistry. We can design a drug. We know the targets are valuable in oncology. Ultimately, we're going to have to partner, I think, once we get beyond phase I are pretty straightforward.
Once you get beyond that to really expand, I think we'll need to partner to be effective.
Just that cancers that where you've been following the science are ones that emanated from a virological origin and then integrated with DNA or something else like that and caused cancer as opposed to a more, I don't know, something caused by cancer suppressor genes or something.
Yeah, these have nothing to do with the cause of it because the targets we're going after are broad solid tumor targets that affect breast, lung, all the big suspects, not liquid cancers. I mean, I think the other thing I'd say is infectious diseases and oncology are similar. You're trying to treat and kill something in the human body without harming the host or as little as you can. There is a lot of rationale to what we're doing. We're very good at discovering drugs. At Anacor, the drug that Pfizer ended up buying us was for atopic dermatitis and was an anti-inflammatory. The boron chemistry can go against anything. We internally have hired cancer expertise and have some very, I think, good insights into what we're going after here. Thank you.
Okay. With that, we are slightly over time. Thank you so much for the presentation. I hope everyone enjoys the rest of the conference. Thank you.
Super great. Thank you. Yeah, if you all have any other questions, I'll stick around and we can chat.