Good afternoon, everyone. Welcome back to Oppenheimer 35th Annual Healthcare Conference. This is Fanyi, [Joan Francini], and [Alex] Jeff Jones' biotech team. Now, we have AN2 Therapeutics CEO, Eric Easom, to give us a presentation of AN2. Just give you a brief introduction of the company. AN2 Therapeutics is a biotech focused on developing novel small molecules from the boron chemistry platform in infections, diseases, and oncology. I'll stop here, Eric, and turn it over to you.
Thank you, Fanyi, and thanks for having us today. I'll jump right in here. Forward-looking statements we'll be talking about, so disclosures there. AN2, we are a boron chemistry platform company. Our history has been primarily in infectious diseases, and we also now have moved into oncology. There's a lot of similarities between the two areas, and our technology is well-suited. We believe boron has the ability to interact with novel targets that have been traditionally undruggable by carbon-based chemistry. We also know that once those targets are good targets for boron, we're able to optimize drugs for drug-like characteristics that are important for target product profiles that we need to get. We have a very high level of demonstration of this.
We had two drugs approved as part of our previous life at Anacor Pharmaceuticals, where we focused on this, and one is pending before the EMA currently. We know it's a very promising and productive technology platform. Our compounds that we focus on, we're going to spend most of the time here today talking about epetraborole, and specifically our NTM lung disease trial that has been ongoing, and we have lots of data to discuss there. We also are pursuing epetraborole for melioidosis, which is a severe, deadly bacterial infection that we just recently completed an early observational study where it has 45% mortality at 90 days under the best treatment available today. It is a really serious disease, and we're excited about that potential there. We also have a drug for Chagas disease.
I'm going to talk a little bit more in depth about Chagas, which is a serious, severe parasitic disease that particularly affects the heart and GI tract. Not as much time today, but as I mentioned, we've got a very active and ongoing research work going on, and we think that we can deliver two candidates in development. We're on track to do that this year. These are novel oncology targets where we think we can be first or best in class. These are some really exciting, up-and-coming programs that we've not really applied the technology to in the past, as well as some other infectious disease projects. Overall, I think we've got quite a promising pipeline coming along here. NTM is where we're going to talk mostly today.
Just to remind the audience, NTM caused by MAC lung disease is a serious problem with very high five-year mortalities, and patients have very limited to no drug options to treat this. In the U.S., you can see that there's around 50,000 patients that have been diagnosed with treatment naïve or early-stage disease. Another 20,000 have refractory, and then there's the 15,000 that have abscesses, which is another high unmet need. These have serious consequences. There's only one drug approved by the FDA, which is ARIKAYCE, which was approved six or so years ago and sells about $400 million just for treatment refractory currently. All right, we have been over the last few years running a seamless Phase II-3 design.
It's a superiority design where we put epetraborole on top of an optimized or a background regimen, and that's compared to placebo plus an optimized background regimen. We ran this trial. We read out the top-line data for the Phase II part of this trial in August. This trial had 80 patients in it, randomized one-to-one. The Phase III enrolled the 81st patient and was continuing in the background up until we stopped the trial. We have 97 patients that are still blinded in the Phase III trial, but we decided to halt the trial in August because we wanted to really slow down and take a look at the data and make sure that we understood the path forward for the company. In the Phase II trial, as we've previously reported, on the primary endpoints, the trial overall was considered a success.
We had developed our own PRO. The FDA wants a clinical primary endpoint. We developed our own PRO called MACrO2, which we deemed at that point fit for purpose or we think is validatable to be confirmed with the agency. That was positive. We also had a numerically positive effect of 39.5% responders to the MACrO2 PRO compared to just 25% with the placebo and a statistically meaningful result. In the Phase II, this is kind of what you want to see. It was generally well tolerated. We all had very low discontinuations. I think two patients overall had discontinued. In terms of secondary endpoints, one of the ones as an antibacterial was sputum culture conversion, which was slightly in favor of epetraborole, but not statistically meaningful at all at five to four patients.
Another secondary endpoint was a second very important PRO called quality of life bronchiectasis, respiratory domain. The change from baseline to month six in that was very positive for epetraborole over placebo with a nominally statistically significant result. Based on these results, we really felt like that. Plus, I'm going to kick on to the next slide, which is a comparison of the population that we enrolled in this study in the kind of the darker blue column compared to the CONVERT study, which was the Insmed pivotal Phase III study in treatment refractory MAC patients. In this population, you can see that we had four times as much cavitary disease, three times as much duration of disease. These patients were refractory to ARIKAYCE itself, which is amikacin liposomal inhaled solution.
20% of the patients nearly were on ARIKAYCE itself, and there was a substantial amount of multi-drug resistant patients at baseline. We had a really sick population here. In hindsight, I think knowing this and knowing the culture conversion, it is going to be hard to convert these patients in six months. We have had many discussions with key opinion leaders in this space around that. We did see a promising clinical signal. We went to work looking at all these data to really understand what this meant and what our path forward was. Going to this slide, I basically want to emphasize that. The FDA recommends the primary endpoint is clinical, measured through something primarily a PRO is what we and other companies in the space are doing. This is the guidance of the FDA.
That's the primary endpoint, what you need to seek for approval. The FDA working with Insmed in their ongoing treatment naive study. They're doing a confirmatory study from the refractory in treatment naive, and they have to also show a PRO. After about a year's work with them from their Phase II or kind of their ARISE study, they determined that QOL-B respiratory domain change from baseline using least squares mean as the analysis is the primary endpoint. We had QOL-B as a secondary endpoint with a nominally stat SIG readout. We already have one of the potential primary endpoints in our Phase III. Also, on a previous slide, I mentioned that we had a 39% responder to 25% for placebo. That was a binary discrete output of the PRO. The whole point of the Phase II was to learn and make adjustments.
We converted that MACrO2 PRO to a 100-point continuous scale to really where it would not be so sensitive to minor changes or unimportant changes in the PRO to this continuous scale, exactly how QOL-B is done with a 0 to 100-point scale. It takes into account all the patient information, and that we also had in post-hoc analysis a nominally stat SIG signal. Now we have two clinical PROs that could serve as a primary endpoint to our Phase III study. Just to look at that data, here was the QOL-B response. You can see over time, three months and six months, that we see a nice response clinically with this PRO and nominally stat SIG. For the MACrO2, more negative means improvement in this scale. It too was nominally stat SIG with that.
Bottom line is we're sitting on 97 patients. It's two-to-one randomization in the Phase III. It still remains blinded. Our plan is to, over the next coming weeks and months, engage with the FDA and unblind the Phase III. If we have two studies that show the same result, we think this is really powerful in terms of what the plan would be to move forward with treatment refractory in this disease. We're quite excited about that. It's aligned with the FDA guidance, and I think we've learned a lot from this trial, and we're ready to move forward on that. That's the NTM. I also now want to turn to Chagas disease real quick just to cover what we think is a really exciting and upcoming program. This is a compound that we also discovered at Anacor.
It hits a novel target just like epetraborole does with our boron chemistry. Chagas disease is, well, let me just say this. It's going into Phase I, and we'll complete that this year, Phase II next year. This is a really unrecognized, underserved population, I think, in the United States and other developed countries. Let me just highlight some of the background. This is caused by a bite of an infected kissing bug. It usually bites patients on the face. They scratch. It defecates on your skin, and that's where the parasites are. You scratch the itchy wound, and it goes into the puncture wound, and they ultimately go into muscle tissue. The ones that cause serious clinical effects are they go into the heart and the GI tract and the esophagus, and they will live there for decades and basically have inflammation.
Ultimately, it's one of the leading causes of infectious disease death in Latin America because you have heart failure, cardiac aneurysms, and things like that that are really serious in about 30% of the patients. It's quite widespread. Now, you'd say, "I haven't heard of this before," but globally, there are six or seven million patients. It's quite prominent, primarily in Latin America, although the kissing bug, infected kissing bugs, roam the southern US quite frequently. We believe there's a fair amount of transmission going on throughout the southern US that we don't have a good handle on with that. There's about 300,000 patients in the US and another 100-plus thousand in other developing world countries that we believe would be a great market that we've done a lot of pricing research and payer research and so forth to look at the potential there.
We think this is a potential $500 million-$1 billion market per year in those territories. If you looked at the US, the patients are very geographically dispersed, as you can kind of see on this sort of heat map type of plot. The compound itself is a boron-containing compound. It hits a novel target, CPSF3. This is not precedented in any human drugs. We were part of discovering a drug that is before the EMA now for African trypanosomiasis or sleeping sickness, which is another trypanosome disease that's 95% cure with one single oral dose cure and is a complete game changer for patients who it's a 100% fatal disease. Same target. Target validation, we believe, is high from a technical success where we believe this is very well suited.
Most importantly, we have studied this in a number of preclinical models, but a naturally infected human, I mean, a monkey model in Texas at a cancer research center shows that these monkeys eat the bugs, get infected naturally. They have chronic disease, and we have been able to show 100% cure in those monkeys. This is the only drug we know that 100% cures these. We've been following them for quite some time now. The only other drug that's approved in the U.S., well, there's two, but benznidazole and another drug that's rarely ever used barely will show cure in this type of chronic model. There were a couple of conazoles by Merck and Eisai that also failed in the clinic, but in retrospect, in this model, don't cure monkeys.
We believe we have something that's really important that's going to address this high unmet need for patients who've been suffering for decades from this disease. We're excited about that. This just shows a couple of the companies that have been working. Novartis has a compound they plan to go into Phase II. There's some attention from a lot of the major players here. In terms of we're going to complete Phase I this year, Phase II will start. We believe Phase II data will be within our cash runway. We will confirm this, but we think a single pivotal Phase III will be sufficient. These can be enrolled pretty quickly and efficiently. Research pipeline, I'm not going to spend much time on this, but oncology, we have some really exciting projects.
We think at least one of those are going to development this year. These have potential major inflection points for the company, but they address targets that are not precedented by other oncology drugs on the market that could have a real impact. We're bringing boron chemistry to the table here for the first time ever, which we're excited about. We have other antibacterial, again, undruggable targets, great drug-like properties in terms of oral, PK, things like that, off-target effects, limited, very specific. We're excited about that, and we'll have more to say on that as we go through the year. Bottom line, in the near term, it's all about NTM and, excuse me, treatment refractory MAC and then Chagas. We have cash to last through 2027 as our guidance, and we have a pipeline also that we'll add to that. Excuse me.
That is where we're at, and we're really excited. That's the end of the formal presentation. I don't know if Fanyi or any of the audience members have any questions.
Great. Thanks, Eric. Thanks for the nice presentation and the clinic updates and the pipeline updates. I'm checking the questions, and then we have a few questions from our end and from the audience. First, the epetraborole. What is giving you the confidence in the path forward for this candidate? For example, time for the FDA feedback and the potential next steps in NTM.
Yeah. No, that's a very important question. I think the fact that we are seeing a robust clinical signal in a very small study, and we're seeing it across multiple clinical endpoints, as we talked about with the QOL-B respiratory domain, which is the primary endpoint of Insmed's pivotal study and frontline, and the fact that we have 97 patients in the Phase III that remain blinded that we plan to unblind here. I think the fact that we're seeing that robust clinical signal gives us a pretty decent confidence that we have a chance here to see a similar signal in the Phase III.
Gotcha. Yeah. For the potential outcomes from the FDA meetings, I think what we can expect, and we want to know your views on the likelihood for each possible scenarios.
Yeah. I think we're currently exploring the option of, do we meet with FDA first and then unblind, or do we just go ahead and accelerate the unblinding? If we have the power of both of these studies, I think it could be a more robust conversation with FDA. We're going to make that decision very soon and potentially unblind these data sooner than later is one of the options we're looking at. In terms of outcomes, I think if we have a second study that shows a powerful response on the clinical, that is the primary endpoint, the only primary endpoint the FDA requires per their guidance for approval. You could speculate that, is there in patients who in a serious life-threatening disease, they have no options essentially or very limited, why wouldn't you get that out with some sort of post-marketing commitment?
If we have to run an additional study, then we have two studies that show high confidence that we can hit a primary endpoint. I think aligning around that and the lack of need for any micro as a secondary endpoint or culture conversion as a key secondary endpoint will have a lot of confidence going forward. I think those are probably a couple of options that would be really important for us. This could be a huge win for patients and for AN2 going forward.
Great. Thanks. As you mentioned, for 97 patients, you already enrolled for the Phase III study, right? How can you leverage those Phase III patients you have already enrolled? Any thoughts on this?
Yeah. I mean, I think leveraging them would be that if we have 97 patients, it's two to one epetraborole is the randomization for that versus one to one for the Phase II. If we have two studies showing us a robust clinical signal, which we're seeing in the Phase II, and that repeats in the Phase III, then I think we've got a really strong case for taking this forward either for NDA or for reducing the risk substantially that we could do it yet again in a third trial.
Their data are still blended, right, for you and then still follow up for these patients, right?
Yeah. I mean, for these highly treatment refractory patients, I mean, treatment refractory patients have there's only one drug approved in their case. As you saw from our data, many of these drugs are multi-drug resistant and so forth. These patients have been nine years on average of disease. They have almost no options available to them. This would be having an oral well-tolerated drug that improves their situation, I think, would be a really valuable addition to the treatment options.
Yeah. I agree with that. I think, as you talked earlier, for the PRO endpoint and the micro. As for the endpoints, still wanted to know your view on the results, like PRO results generated, the selection of the PRO endpoint and the micro, which are suitable for the approval. I know we are waiting for FDA feedback, but any thoughts on that from your perspective because there was no clear path prior for this?
Yeah. I think there is a clear path. What I would say is the FDA guidance, which was formalized and finalized after we started this study, recommends a clinical endpoint as the primary endpoint, not anything else. I think the guidance is very clear that that is the case. We now have two endpoints that hit that. As I mentioned, Insmed is using QOL-B respiratory domain change room. This endpoint, Insmed is using for their pivotal treatment naive study. We and they've gone through lots of discussions with the FDA to agree to that. We think also there's precedent and there's a high likelihood that this also is going to be acceptable as a primary endpoint, even though we use MACrO2. A lot of other studies have used this kind of traditional quality of life bronchiectasis. We're indifferent.
The data look great on this. I think you can see right here. We're planning to use probably this endpoint as our primary endpoint.
Great. Thanks, Eric. Probably, I think for this candidate, I think there's another small study, right, in melioidosis. I don't know if that's still ongoing, any updates there for this trial or.
Yeah. Yeah. I'm just pulling up a slide here to help us visually. Yeah, melioidosis. We just completed an observational trial of 200 patients treated with either ceftazidime or meropenem in a hospital setting and showed that the 90-day—we don't have the final numbers yet, we're just getting them, but it's close to final—which is around 45% of patients die by day 90 on the two best available therapies. There's a huge unmet need here and a high mortality rate. It's a vicious disease. This does exist, by the way, endemic in the southern U.S. in tropical areas, essentially. We plan to start a study in the second half of this year for melioidosis. All the preclinical data for epetraborole is incredibly powerful that shows it.
We're going to add it on as an add-on to either meropenem or ceftazidime as a superiority design to reduce all-cause mortality in these patients. We think the hypothesis is that epetraborole could reduce mortality substantially in these patients and bring something really novel to bear here. This is all paid for because it's up there with anthrax and other high, because of the mortality rate and the seriousness of it as a national threat level. Anyway, we're excited about the potential of this project. We've been working for a long time. Yeah.
Funded by NIH, right? No cost to firm?
Yeah. All the work so far is under contract with the NIH. That's right.
Thanks. I think we have a couple of minutes left. As you mentioned, for the second asset AN2-502998, any updates about these candidates like Phase I study mentioned in Chagas and next year? You mentioned Phase II data in 2027 or 2026, but it seems like Phase I will be completed in this year or next year. Will you plan to publish Phase I data then?
Yeah. I mean, we're finalizing kind of the last of the Phase I enabling talks currently and are gearing up the Phase I trial. It'll run in the second half of this year. As soon as we can get the Phase II started, we're going to do that starting next year. We'll have proof of concept, we think, fairly quickly with this. We're quite confident from a technical point of view, given that we have the other drug for African sleeping sickness called acoziborole, by the way, that hits the same target. We're highly confident in this unless there's some unforeseen human PK or safety issue or something that we haven't seen.
We think this is a pretty high-profile compound that potentially has the ability to cure chronic Chagas for these patients, 7 million patients suffering that do not have a drug for that. In the U.S., we think that alone is a $500 million-$1 billion a year market. It is important for patients. Yeah.
Yeah. Sounds high on money as well. Very last question from us. As for the disclosed targets, how are you thinking about the additional target selection and the indications? Any clear you can share?
Yeah. Just due to the highly competitive nature of the oncology space in particular, we haven't yet announced that. We have very promising compounds that should meet all the aspects of an orally bioavailable, highly potent, highly specific compound. We are just working to finish off and get those compounds into development quickly. Any one of these, I think we believe could be a huge inflection point for us as a company. We are pretty excited about that potential. We haven't revealed the targets just due to competitive nature. We will, at some point in the near future, do that.
Okay. We'll stay tuned. Thanks. All right. Thanks, Eric. I think we are fine. Thank you so much for the time this afternoon. We are so glad to have you to present us AN2 stories. We are really looking forward to FDA's feedback and your first quarter earnings in the near future. Good luck with all the meetings and have a wonderful rest of the day. Thank you.
Thank you, Fanyi. Yep. Thank you. Bye-bye.