This fireside chat I'm very pleased to host with Eric Easom, CEO of AN2 Therapeutics at a very exciting time for the company. Thank you for keeping us on our toes with the recent announcement that you're taking epetraborole into development for polycythemia vera. Yes, very excited about that. Yeah. Maybe to start us off, just give us some context for this decision, and then we'll dive into specific questions. Sure. Well, I think, you know, we have epetraborole's a compound that we've been working on for a number of years in NTM and have a lot of clinical observations that there was a very specific red cell block that doesn't affect white cells or bone marrow progenitors or things like that. It's an oral compound, and so we had a lot of preclinical and clinical experience that showed that it could be a very useful drug for PV. We decided to get a lot of input from experts in the field, both you know academics and folks who've been involved in a number of trials, and they were very excited about the data as we were. We quickly ramped up a plan to how do we get this drug tested in patients as quickly as possible and that's where we are today. We're planning to start our Phase 2 trial in this. We're gonna dose the first patient in August of this year is the plan, and we'll have data as soon as early fourth quarter, and then throughout 2027. We're very excited about it. Okay. Great. Well, let's talk a little bit about the trial. I think the first part involves a 20-week dose titration. Can you give us some context for that design aspect? Sure. We're running a trial. We're gonna have a small sentinel patient group of 10 patients, where we'll start out at a low dose just to confirm biology, make sure all of our PK assumptions aren't different in PV patients. You know, any safety issues which, of course, we don't expect. We'll start off slow with a 10-patient sentinel group. That's the part we'll read out in the fourth quarter, and then that will roll right into around a 40-50 patient dose ranging study, where we'll individualize doses for 250, for example, once a day oral, 500, you know, as high as probably 750, depending on how much hematocrit reduction we need to control the dose. The epetraborole is very. What we have learned over time is it's very exposure. There's a dose-exposure relationship to the hematocrit reduction. We'll be able to learn that and then that'll fix it for a double blind placebo-controlled trial that will run at the tail end of that. It's a multi-part study then with a long-term even follow-up beyond that that we'll have. We'll have data in next, you know, this year and next year. The, you know, our plan is that we'll set up a Phase 3 trial that we would then run in the future. Given phlebotomy works pretty quickly, do you foresee the ability to like have a dose that or doses that could be used to, you know, go straight to those doses as opposed to doing a dose titration? We'll learn a lot, but I think once we know of a dose. You know, the way epetraborole works is that you get a downregulation over the first two to four weeks, and then it kinda nadirs at eight weeks and really holds flat in non-PV patients. As soon as you take the block off, it goes back. We'll know and if we can find, I think, a common dose, like 500 milligrams oral once a day would be, you know, ideally suited for this. That's exactly what we'll plan to do in that dose titration. That's, you know, that would be the plan. Now, in terms of how it'll be used, you know, the feedback we're getting from KOLs, we just recently held a call with an interview with Dr. Aaron T. Gerds that we have on our website, which is great, and he talks about the potential of using epetraborole in lieu of phlebotomies because patients don't like to come in and schedule them, they make them tired. It's not their favorite activity, as you know, they call it bloodletting for a reason, I think. You could. He sees a use case of epetraborole for instead of phlebotomies or in addition, 'cause when you phlebotomize somebody, then they eventually eat their way back with iron up through and start getting higher than 45, and you gotta just keep, you know, the seesaw effect of phlebotomies. If you could. Once you get them down, smooth that out and hold them. You can combine it with other drugs where you're not getting the control, which is greater than 50% of patients are not controlled. I think the aha moment for us is that this is not a second line drug that you use after you use all these other options. You know, it's oral and it could be used early in the life cycle, as soon as before phlebotomies or with phlebotomies up front or with HU or with other, you know, ropeg, interferon, all the other drugs, it would combine nicely. That and another, not to go on and on, but, you know, in terms of DDIs, this drug is very clean. We, you know, we just ran an NTM trial on top of rifampicin in almost all the patients and azithromycin, ethambutol, a lot of somewhat nasty drugs from that point of view. You know, we didn't have any issues. We don't see any elevations in liver enzymes to speak of, whereas some of the other drugs in this category do. It makes it a nice combinable drug profile. You know, all those make this, I think, super exciting. The key question's gonna be, you know, how does all that evidence translate to PV patients? That's a good segue to my next question. How did the degree of hematocrit reduction in the non-PV patients look? And is there any way to project whether patients with PV will get to below 45% when you know they usually start much higher? Like how do you anticipate the potential efficacy might translate on that key biomarker? Yeah, we saw in 105 pretty old, you know, pretty advanced NTM patients. These are, you know, we see a 5-6 percentage point drop in hematocrit. That's about a 15%. This is, you know, at 500. You know, we can model that out and show that, you know, 250 gives, you know, half of that, and 750 gives more than that, and so forth. But that's a pretty, you know, good number compared to other data I've seen from other therapeutics in terms of an absolute drop. I think that gets us, you know, to where we need. Now, in PV patients, I think some of them, you know, will start pretty high. whether or not drug alone or you need to phlebotomize to get them at least down to a level, and then you apply, epetraborole or a drug to hold them below 45, as that key, you know, clinical indicator to reduce the risk of clots. Mm-hmm. Interesting. Okay. Do you think that epetraborole could be a disease modifier, or is it likely to be a symptomatic agent like hepcidin mimetic? Any thoughts on that? Yeah, I mean, we do a lot of, you know, hypothesis generation in the company. You know, we think, you know, we have a couple of targets. We don't know exactly the mechanism of action for the red cell block. We have two or so hypotheses that we're pretty sure are right. We need to, you know, this is moving so fast, the biology hasn't quite caught up to it. We will be sorting that out, I think, but over time. I'm trying to get back to your question here. Well, I guess. Yeah. No, you were answering it well. I guess, you know, you're doing this, you're evaluating the JAK2V617F. Oh, the allele frequency. Yeah allele burden. I guess, is that to answer? Yeah that question? It is. I think we also believe that there is a possibility that we also could affect that and reduce the allele, you know, the frequency of that and have a disease modifying effect. That's, you know, it would be a lot of arm waving to get to that. We don't wanna speculate, but that's why we're measuring it is there is a real possibility that could happen with what the targets we think and have hypothesized are. That would be. You know, to me, the biggest takeaway in all the discussions with the KOL is that, you know, the question is: Do we need more hematocrit lowering drugs? The answer is yes, 'cause, A, there's not very many of them. There's not many options. The ones we have are not all that great. The key goal is you need, you know, less than 50% of patients or hematocrit is well controlled under 45. We need that. Ultimately, if you could change the disease, modify the disease through these JAK mutations, that would be beneficial, but it's not, you know, critical. Okay. Interesting. I think unlike rusfertide, which sequesters iron, epetraborole modulates erythropoiesis differently. How do you think baseline ferritin and iron stores might impact the response? We don't know. I mean, that's something we do have data on from our past trials. You know, there is not much change in those parameters. You know, everything stays within normal limits. I think, you know, we're not gonna know if there's something different in PV patients. Theoretically, you know, based on what we know, it shouldn't have a change. There's no change in white blood cells, which you do see in other therapies, which can be really problematic, as well. I think, you know, there's more to learn, obviously. That's why we're doing the Phase 2. All the observational data we have now would suggest that that's not gonna be an issue. Okay. Interesting. Are you gonna prioritize enrollment of any particular kinds of patients, like HU-resistant or intolerant patients, or just take all comers? Yeah, I mean, we're doing the trial in India, primarily. I know a lot of people have questions about that. This drug has been studied extensively in patients and volunteers in many different geographies, you know, U.S., Japan, et cetera. You know, with India, we can go very fast and it's cost-effective for a small biotech like us. I think, you know, we're doing it there. Now, in India, you know, we have inclusion, exclusion criteria. We're, of course, getting lots of input from U.S. KOLs who've been intimately involved with a number of the current trials that have gone on over the past several years. We're getting input from investigators in India who also happen to be PV KOLs and heavily involved and were involved in a lot of these current trials. I think we're getting all that. Inclusion, exclusion criteria, most of these patients are in India primarily for cost or they use phlebotomy and HU 'cause it's cheap, so they don't use a lot of the newer, more expensive agents. There's a lot of patients with that who aren't particularly well controlled. Our trial design will look a lot like the rusfertide trial that published in The New England Journal, the Phase 2 trial is the plan using experienced investigators, making sure the other critical thing in India, you see more secondary PV instead of primary. You see things where they have infections or other reasons that might cause them to have excess red blood cells. You know, we just need to make sure that the patient selection is uniform and the ones we want to study the drug, and I think we'll manage all that. Okay. Yeah. Interesting. Let's talk about the phase II that you've laid out for us. What threshold of hematocrit reduction in the four-week open-label sentinel cohort would justify advancement into the part one titration phase? Yeah. That sentinel cohort, we don't know, you know, we're being, how would I say, cautious about. You know, we're treating it like any trial you would. We're going in with a low dose 'cause we don't know if PV patients will be more sensitive to the drug or not. We're going in at 250 every other day in the sentinel first 10, and then in the dose range, depending on what we find, we can change, but then we'll go in, the dose ranging at 250 once a day, 500, you know, the ability to escalate. 250 every other day, you know, we don't necessarily have to see a strong signal. From our modeling, we should see, you know, somewhere between a 5%-10% percentage change in hematocrit. All the biology should start moving in the right direction, and we'll confirm that quickly with that. Then if we need to go to a higher dose, which we expect, we would go to 250 daily and then so forth, we'll do that. Okay. Interesting. Yeah. All right. We talked about the part one titration. Yes You're going to part two, the randomization part, where there's an endpoint after four weeks, which is defined as hematocrit control without phlebotomy. Why was four weeks chosen as the cutoff? Are you having a washout period? Well, these patients won't be on cytoreductive therapies, right? No, I mean, we're basically gonna, I think it's 12 weeks, not four. Oh, 12, sorry. All this is, like, moving very quickly, so I'm trying to keep up with the team. I mean, the reason we're doing that piece is it's a placebo-controlled double-blind study, basically to show that patients who aren't, you know, on the epetraborole are well controlled, and those who are not, you're gonna see breakthrough phlebotomies and so forth. The other, you know, critical point of that study is one of the endpoints that we need to be able to show is kind of, you know, feel and function. Function-wise, you can show lack of phlebotomies, but feels, we have to implement PROs and, you know, are they, those who are getting phlebotomies feel worse. They feel tired and it has an effect, you know, on them, on their health. Others have been able to show that, and we'll show that. That's how that part will work. We have that kind of, you know, double-blind, placebo-controlled, part of this trial. Okay. Yeah. All right. Great. I guess it's obviously an oral agent, which is pretty attractive. Then again, rusfertide has like a 77% responder rate, I think. What is the push and pull with, you know, that oral route that, you know, where would these agents ultimately like fit into the treatment paradigm if you didn't give up on efficacy versus could you give up on a little efficacy just because it's an oral agent and, you know, an injectable is obviously not probably ideal? Yeah. I think, I mean, oral is a big deal, but also having meaningful control. In the Phase 3 non-PV patients with that 105, you know, we have a very tight confidence intervals around that. There clearly is a block. There's a distribution around that, but we're getting pretty significant and stable over long periods of time and have proven data. I think there's a lot of ways we can win, but oral will be a big one, particularly in the earlier frontline therapy where there's a, you know, a big, much bigger opportunity. Was there anemia seen for epetraborole in the NTM patient population? Yes. Yeah, I mean, that's how we have been tracking. We picked up this signal in NHPs in tox studies. We ran a lot of studies. Even our phase one, we ran a one-month confinement study looking at various doses and modeled out hemoglobin reduction. So hemoglobin, if you could almost superimpose the graph on hemoglobin on hematocrit, I mean, you get a nice lowering, same shape. It flattens out, and as soon as you take the block off, it goes back up. So that was one of the, you know, the most obvious. Now, patients didn't report it because they it was so, you know, in NTM, it goes down slowly over four weeks, and in the PV world, that's early and fast. Most of the drop in some cancers, you know, it can go plummet immediately. We did see that, yes, and we've been monitoring that as, you know, and it would drop a point or two on a hemoglobin scale. If you started at a 14, you might end up at a 12 and be perfectly in the normal range, and it would just hold there until you take the block off, and the patients didn't realize it. We also, interesting, I think, for this is that we measured PROs in the NTM trial thinking that, well, if they have slight anemia or mild anemia, would they feel fatigued or whatever? But they, you know, the patients didn't even know this was happening because it was so slow, and there was a compensatory effect over time. We didn't see any changes in, you know, fatigue scores or things like that. That was, yeah, reassuring, I think. Right. Yeah. Especially because NTM patients, and you had really advanced ones. Yeah You know, can be afflicted with a lot of fatigue and, interesting. Yeah. The PV population that can be elderly and have cardiovascular comorbidities. How do you think of these two patient populations and their potentially overlap? All- potential overlap there and susceptibility to anemia? Well, first of all, in PV patients, they're gonna start very high, and so you're not gonna. It's not like they're starting at 10, and you could take them to 9.5 or something, or, you know, you're not gonna see grade 3 anemia, I don't think, with any dose type that we're using even in NTM. I think that you're not worried about that. I would say that we had a very sick population in that NTM trial, which is part of the reason why it failed. They were, you know, years of disease and multidrug-resistant and lots of cavities and so forth. We can talk about that maybe in a minute, but we have a very exciting Mycobacterium abscessus trial that's starting imminently. We'll dose the first patient in this quarter, so soon, and that's exciting. Anyway, those patients, we have a lot of data on them with epetraborole. We've done lots, all the long-term tox, all the CMC. We were basically ready to file an NDA. We've done two-year carcinogenicity studies. We've done hERG study. We've done renal insufficiency studies. I mean, this drug is ready to go for PV, and we can move quickly, and it won't cost us a fortune going forward. Super interesting. Yeah. Last question on this program. What kind of regulatory clearance do you need in order to start the PV work with the- We'll file this month with the Indian regulatory authorities, and we expect to get their clearance in 4-5 months timeframe. You know, they have a committee there that works on this, and will approve that, and then as soon as we get that, we'll start. We've got all the drug product. You know, we're submitting the protocol, everything, in a matter of the next 2 weeks or so. It's moving very fast and exciting. Cool. Very interesting. Yes. Well, stay tuned. Now, M. abscessus, what's the status of that program? Obviously, you saw some interesting signals in MAC and NTM, but abscessus is a pretty tough target. What did you learn from your experience in MAC, and how are you designing the abscessus program now? Yeah, I mean, you know, we went after MAC first because it's the bigger market of the two and more patients there. I would say it's not the biggest unmet need, though. Abscessus has 15,000 patients in the U.S., probably 25,000 in Japan, quite a few in Europe, and it's a. In patients, when they go on therapy for abscessus, there's no drugs approved for this disease, which causes really high five-year mortality. You know, basically, it's the patients are subjected to daily IV therapy, multiple IV antibiotics, which you can only imagine imipenem, amikacin, taking that daily would be like cancer or worse. An oral therapy here would be huge. What we learned from that trial is the patients were very sick. We had planned to try to run one like Insmed's trial that they got approval on MAC in refractory patients. We had 9 patients with an average of 9 years up to 20-some years of disease. They had an average of 3 years. We had 60% amikacin resistance. They had zero because that's their drug, so they prescreened and selected out patients. Our patients had a lot of cavities. We don't know exactly, but, you know, we thought that a lot of NTM was intracellular in macrophages where our drug gets in 5x. But in these type of patients, you get more extracellular where we have 0.5 exposure compared to plasma. We had lower drug. Our MIC90 shifted up in these patients that had been treated with antibiotics. Even though they weren't resistant, they were just tough, kind of hardy bugs, let's say, that had MICs of 16 and 32. You get higher MICs, and you get lower exposure in the ELF, and that's bad news for an antibiotic. I think that's why we struggle to see a strong micro signal. In M. abscessus, we're 250x more potent, so the MIC90 is 0.06. The animal model data looks as good as imipenem. You know, the investigators that did these were blown away that it could be as good as their core IV drug. We're going into treatment-naive patients, and Paratek just ran a trial just like what we're doing as a monotherapy 3-month treatment trial. Assuming all that works, like we think, we've got a really good shot here of taking those learnings and posting a good win for a drug where they need it desperately to have oral antibiotics. We're super excited. This is a multi-billion dollar opportunity, and, you know, we'll be working on it. We'll have data next year. We've got the top investigators in the field that are gonna participate. 84-patient trial, two dose groups, you know, 10-15 sites across the top centers in the U.S. Only. Okay. Interesting. What level of culture conversion, or are you looking at the PRO, the QOL-B or something that? All the above. What would get you excited? I think if we posted data similar to what Paratek did last year for omadacycline. They had, you know, 40-some% culture conversions versus 20%, I think, for placebo. When you looked at if you had two consecutive months or three consecutive months in a row, even though it's a 3-month study, it had an early effect. You start getting, like, 30% versus 10%. It takes out some of the noise. I think if we got a similar effect to that, then that shows us a clear sign and then PRO benefits as well. Paratek's omadacycline data would be our benchmark, I think. Okay. Very helpful. Yeah. Chagas, we haven't even talked about that. You're gonna have We've got a lot. Phase 1 data very soon, right? Yes. In the next couple weeks. Cool. It's done. We need to get the final. Yeah data analysis and then report it. Okay. What would you like to see there? Well, I mean, Chagas disease is one that, you know, PV, there's lots of molecules and competition and whatever. Chagas is just a huge unmet need that has been mostly neglected, I would say. There's 10 million patients in the world that have parasites in their heart muscle that is a silent killer. About 30% of patients have heart failure and aortic aneurysms, and it's a really nasty disease that probably none of us have ever heard of. There are 10 million, mostly in, they're in the Americas, but there's 300,000 in the United States. We've got a drug that we've shown cures non-human primates, monkeys, that get naturally infected in the state of Texas. We have these parasites all throughout the United States as well in the vector. We have a drug that's proven to kill monkeys, which is about as close to proof of concept in human as you can possibly get in an area that's already close. We've had three monkey trials where we have 100% efficacy, cure rates. If you don't kill all the parasites, then they come back, they recrudesce. We've got the PK. We'll dose for a month daily, and we have high confidence in cure because of this monkey data. The second thing I would say about that is we also were part of a team that discovered acoziborole. There's a lot of boroles now coming on. It just got EMA recommendation for approval two weeks ago for African sleeping sickness, which is a Trypanosome disease. It's the same molecular target as this, which is CPSF3. Never been in a human drug, but showed 96% cure rate in a fatal Phase 2 in stage two sleeping sickness. That compound, you know, to me shows the mechanism works in a related disease. We cure monkeys, so technically I would give this one a very high, about as high a mark as I can give for success. The question is the 300,000 patients in the U.S., you know, we think there's a good opportunity, and, you know, this is a terrible disease. It's killed hundreds of thousands of people with not very effective treatment, so we're super excited about this. Hmm. Our boron platform, just to put a plug is, you know, we have two exciting cancer projects that are going into development, and we got a bunch of things behind that. We have, you know, we've got a lot under the hood, I would say. Yeah, I think so. The boroles are on a roll. Yes. Boron has got a lot to show the world, I think. We've done it in global health and infectious diseases, but it can apply to any therapeutic area, and it's really exciting. Thank you, Eric. Keep up the good work. Thank you. Thanks for all your coverage. Thank you, Larry.