Good morning everyone, welcome to the AN2 Conference Call. This call is being recorded. At the end of the company's prepared remarks, we'll open the call for questions. For our audience members that have joined via the public webcast, you can click the Ask a Question tab in the top right of the live stream player. Type in your question and click Submit. You can submit questions at any time during the presentation, and the management team will try and answer as many questions as they can during the Q&A portion of the call. I would now like to turn the call over to Mr. Eric Easom, Co-founder, President, CEO, and Chairman of AN2 Therapeutics. Good morning, thank you for joining us. You've all seen the press release we issued yesterday announcing our decision to expand the development of epetraborole into polycythemia vera or PV. Today, we wanted to provide you with a deeper dive into our rationale and plans. I wanted to take a minute to remind you that various remarks we make on this call contain forward-looking statements as detailed on this slide regarding our product candidates, future plans, strategy, and other statements. Please refer to our forward-looking statements from the press release, as well as the risk factors in our most recent SEC filings for more details. Let's get started with slide three. Joining me on the call is Dr. George H. Talbot, Co-Founder of AN2 and Senior Medical Advisor. He will walk you through the key clinical data supporting our decision to advance oral epetraborole in PV. We are also pleased to have Dr. Aaron Gerds from the Cleveland Clinic join us today. Dr. Gerds is a leading clinical researcher in the study of PV and has overseen and been involved in numerous clinical trials in the area. We look forward to hearing his perspective on the treatment landscape and the real-world challenges physicians and patients face in managing PV. After our prepared remarks, we will open up the call to Q&A. Okay, let's move to slide four. Let me start by outlining the strategic rationale for advancing epetraborole in PV. We're moving into PV with compelling enabling data from our non-PV patients that, if replicated in this patient population, could represent an important step toward bringing patients a novel oral treatment option. The clinical data are highly supportive. Multiple studies conducted at AN2 have shown consistent dose-dependent hematocrit control without clinically relevant effects on other cells, including white blood cells and platelets. Second, we believe that epetraborole's unique profile, novel mechanism of action, and oral administration would fill a gap. For PV patients, durable hematocrit control is key to reducing the risk of clots, but it remains difficult to achieve. Data from published studies show that a significant proportion of patients have poor hematocrit control using phlebotomies and medications. An oral therapy designed specifically to target red cell production and control hematocrit could expand treatment options for patients and provide physicians with greater flexibility to individualize care. There are currently no oral therapies approved or in clinical development specifically targeted at erythrocytosis. With over 150,000 PV patients in just the U.S., we see a significant market opportunity for epetraborole, and we expect this to add meaningful near-term catalyst within our runway. We plan to initiate a phase II study in the third quarter of this year and anticipate our first data readout in the fourth quarter with additional clinical updates throughout 2027. We're excited about this opportunity to advance epetraborole into PV and the potential impact it could have for patients. Let me turn the call over to Dr. Talbot, who will walk you through the clinical data that informed this decision and our development plans in more detail. George? Thanks, Eric, and thanks everyone for joining us today. By way of introduction to our clinical discussion, let me note that we have comprehensively evaluated existing epetraborole data to address whether this molecule could serve a major therapeutic need for patients with PV. I will review these data and provide an overview of our phase II trial design for PV. Next slide, please. The epetraborole clinical data package includes 10 phase I studies, two phase II studies, and a phase II/III study in NTM lung disease. I will focus first on the phase II/III NTM study, which enrolled 177 patients. 105 of these patients were treated with 500 mg of epetraborole dosed orally once per day. Both epetraborole and placebo were administered on top of an optimized background NTM regimen. In this graphic from the phase II/III study in NTM lung disease, the dark blue line represents the hematocrit levels for patients receiving epetraborole. Also shown is the 95% confidence interval for each data point. Epetraborole hematocrit values are consistently reduced as compared to those in the placebo group shown in red. Epetraborole's effect on hematocrit occurred early and remained stable over a six-month period. Once epetraborole dosing stopped, hematocrits returned towards normal. Let's go to the next slide. The hematocrit effects observed in NTM patients replicated the effects demonstrated in healthy volunteers in long-term non-human primate studies. The graphic on the left shows placebo-controlled hematocrit data obtained in healthy subjects administered epetraborole for 28 days at three oral daily dose levels, 250 mg, 500 mg, and 750 mg. In addition to a dose response effect of epetraborole on hematocrit, the treatment effect at day 28 of the 500 mg dose was a hematocrit decrease of more than 4 percentage points, similar to what was seen at month one in the NTM study. We have documented similar effects in long-term NHP toxicology studies, as you can see in the graphic on the right. These observations demonstrate that epetraborole typically produced a reproducible, targeted hematocrit-lowering effect across studies in NHPs, healthy subjects, and NTM patients. Let's go to the next slide. Data from the phase II/III study also addressed epetraborole's effect on white blood cells and platelets during six months of treatment in these ill patients with NTM lung disease. The dark blue epetraborole line in each graph confirms that there was no clinically relevant change in white blood cell counts and little change in platelet count. A variety of lines of evidence support the premise that epetraborole produces its primary effect on erythropoiesis by decreasing globin synthesis, thereby indicating that it has a novel target compared to other PV therapies. Let's go to the next slide. This schematic of the planned phase II trial design of epetraborole in adults with phlebotomy-dependent PV shows our four treatment cohorts. First is the open label sentinel PK safety efficacy cohort, as you can see in the gray box on the left. This cohort of 10 PV patients will evaluate PK, efficacy, safety, and laboratory effects of an initial starting epetraborole dose regimen. Next, to the right in blue, is part one, the open label dose cohort, during which epetraborole dose titration will be performed to identify the optimal dose regimen for each patient. An important objective of this part is to evaluate the magnitude and response time for dose titrations. In green is part two, the double-blind placebo-controlled epetraborole withdrawal cohort, which will substantiate the hematocrit effect of epetraborole and additionally provide important data on the potential alleviation of patients' symptoms. Finally, which is not shown in this schematic, part three is an open label extension cohort to evaluate the durability of the epetraborole effect. This graphic aligns with the phase II injectable rusfertide study that was published in the New England Journal of Medicine in 2024. The outcome measures to be assessed in our study also align with those utilized in the study of injectable rusfertide. These endpoints include comparison of phlebotomy event rates during epetraborole therapy versus a patient's own historical control, as well as achievement of hematocrit control less than 45%. As mentioned, the first two parts are open label, we will be getting real-time readouts on the effects of therapy, including hematocrit control, pharmacokinetics, phlebotomy requirements, and other key hematologic parameters. Among these will be erythropoietin levels, blood viscosity, iron metabolism analytes, and JAK variant allele frequency. We will also, of course, be evaluating tolerability and safety. We expect the sentinel group to begin reading out in the fourth quarter of this year, with the dose optimization portion reporting throughout the first three quarters of 2027. We expect to enroll approximately 40 to 50 patients across three to five or more sites in India. We've already seen strong interest from sites that could participate in the study. Let's go to the next slide, please. We are in the final stages of our study startup activities with a regulatory filing plan for the first quarter of this year and enrollment of the first patient in the third quarter of this year, subject, of course, to regulatory clearance to proceed. This study will be run in India with PV-experienced investigators who have participated in recent global PV trials. We believe this path forward will be the most efficient and one that will allow us to best collect essential phase III enabling data. Let's go to my final slide. My last slide summarizes the major PV program components shown in red at the top. The potential differentiating aspects of epetraborole's profile, shown to the left, and the possibility of relatively near-term data availability. In conclusion, we are initiating a clinical stage study in a patient population with high unmet therapeutic needs. Our robust enabling data indicate epetraborole's potential utility as an oral red cell targeting molecule. The phase II clinical study design comprises multiple parts to enable rigorous dose selection, assess key parameters of hematologic efficacy, and evaluate via standard PRO instruments the potential treatment effects as reflected in the patient voice. The data accrued will inform our decisions about the path forward, including the possible registrational pathways as well as later epetraborole PV studies. Thank you again for joining our discussion. Back to you, Eric. Thanks, George. I want to emphasize George's last comment because I think it really frames the opportunity here in terms of the data and rationale to support the phase II trial. Also, importantly, there are clear clinical inflection points over the next several quarters. We anticipate initial data from the Sentinel cohort in the fourth quarter with additional updates from the dose optimization phase throughout 2027. We expect that these readouts will speak directly to epetraborole's therapeutic potential. This is not just a new program for us, but one where we will have a near-term answer on whether we have something potentially quite impactful from a therapeutic and commercial point of view. Let's go to the next slide. Today, we're privileged to have Dr. Aaron Gerds, a leading expert in PV from Cleveland Clinic, join us to discuss his research and clinical experience treating PV patients. Dr. Gerds, thank you for participating in the call. We're looking forward to hearing your thoughts on a few questions we know are top of mind with investors and analysts. Thanks, Eric, so much. It's a pleasure to be with all of you today. Great. Okay. Well, let's get started with the first question. When you are treating a patient with PV, what are your primary therapeutic goals? Yeah, you know, I try to keep things simple, right? I'm not an overly intelligent person, the simpler you can keep things, I think the better. Really, in my mind, there are two kind of fundamental truths about treating polycythemia vera. These stem from two pivotal studies that were done, one the ECLAP study, the other the CYTO-PV trial. In the ECLAP study, we found that aspirin reduced risk of blood clots. Not a big surprise there. Aspirin's been used to do that, to reduce clots for quite some time in the medical world. The ECLAP study pitted aspirin versus placebo and showed that, yeah, aspirin can really reduce the risk of blood clots in patients with polycythemia vera. That's kind of one pillar we stand on. The other pillar is keep the hematocrit under 45%. That again is from the CYTO-PV trial, a trial where patients weren't randomized necessarily to a treatment, but rather a target or a goal or treatment strategy somewhat, where you would either be randomized to keep the hematocrit under 45% or keep the hematocrit between 45% and 50%. Tight control versus loose control. Tight control improved the clot-free survival of patients, with polycythemia vera. Again, kind of setting the mark at keep the hematocrit under 45%. A question the CYTO-PV trial could not answer is what's the best way to get there? It was an underpowered study in the fact that it only enrolled half the numbers of patients. A lot of the ad hoc questions we normally have with a clinical trial, we couldn't really dig into too many of the details just because the numbers weren't there. It just said that, hey, yeah, keep that hematocrit under 45%. Everything else I think in the world of PV is up to some debate. There's some art there to the science of medicine beyond those two kind of fundamental pieces of how we take care of patients with polycythemia vera. All right. Thank you. As a follow-up, data from the REVEAL study, which I believe is the largest prospective real-world study of patients with PV conducted to date, suggests that a meaningful proportion of patients' hematocrit remain uncontrolled, or they continue to require frequent phlebotomies despite available therapies. From your experience and perspective, what are the most common reasons patients struggle to achieve consistent hematocrit control, and what are the risks? Yeah, I think REVEAL is such an important study because, again, as you mentioned, it's the largest prospective observational study of PV ever done, or any MPN for that matter. We've learned so much from it so far, we're only scratching the surface of that database. You know, we learn simple things like, yeah, a lot of PV patients don't get their JAK2 tested, right? That's pretty remarkable this day and age. You know, other things that come out that, yeah, patients spend a lot of time under inadequate control, meaning that their hematocrit is not under 45%. We also found that not everybody's on aspirin either, which probably should be emphasized some more. Those two pillars or those two fundamental truths of treating polycythemia vera that I talked about earlier, we're not achieving those goals. Why not? Well, for at least for the hematocrit under 45%, there are a couple of reasons. One is if you think about just phlebotomy alone as a treatment there, it is a treatment, right? A patient undergoes phlebotomy. You take all that iron out of their body. There's a period of time where they will consume iron. The iron will be replete, and eventually their hematocrit will be again over 45. By design, phlebotomies lend patients to being over hematocrit of 45 periodically. It makes sense that, yeah, that's gonna not be perfect in controlling the counts. Then when you flip to a cytoreductive agent, these are, you know, treatments and therapies that are designed to kind of continuously keep the hematocrit under 45. We run into inadequate control, whether the disease is just proliferating through the cytoreductive therapy, or maybe they can't tolerate higher doses because of side effects, because there are very few agents that we have available in our toolbox to cytoreduce patients outside of phlebotomies alone. There, there's a clear unmet need, as identified by the REVEAL study and many other studies that have come along since, saying that, yeah, even though we know as a fundamental truth of treating polycythemia vera, we need to keep the hematocrit under 45%, we don't do that great of a job getting there. Thank you. In terms of treatments that are used, hydroxyurea being very common, you know, there also was data that suggests that control of hematocrit, even with medication and phlebotomy, is quite low. Can you speak to the control of current drugs out there and the unmet need around that? I think we just start with kind of the basics again. You know, if we look at the approved drugs to treat polycythemia vera as of today, there are two here in the United States. There is ruxolitinib, which is approved after hydroxyurea. So a patient has to be on hydroxyurea. They may have a side effect or it doesn't work, and they have to go on to another therapy or ropeginterferon. Really two drugs, right? That's not a lot. You know, we look at other diseases in hematologic malignancies, and they'll have, like, eight or 10 or 12 drugs that are FDA approved. You know, and then one of the more fundamental drugs we use, hydroxyurea, is in fact does not have a U.S. FDA label for polycythemia vera. We're really limited in the therapies that we can use. You know, again, a lot of these drugs have shortcomings. Hydroxyurea, we run into lots of side effects. You know, patients may have intolerance due to, you know, changes in their hair and nails, GI side effects, increased risk of non-melanoma skin cancers, all those types of things that, you know, we may want that leave things short. With hydroxyurea, sometimes we dial up the dose to get the hematocrit under the mark, and we run into cytopenias like thrombocytopenia or a lowering of the white blood cell count or even neutropenia in those cases. Hydroxyurea is not a perfect medication in any stretch of the imagination. Similar with interferons, there are some shortcomings to interferons. It's an injectable. It's expensive, and it's hard to sometimes get it past insurance approvals. For those who are in practice, we all feel that pain every day fighting with insurance companies, which I think limits its use, quite frankly. It can make liver enzymes go up. It can cause autoimmune disorders to flare. It can maybe even lead to depressive or at least depression symptoms or mood disturbances. There are a lot of limitations to interferons as well. Neither of these are perfect agents certainly when thinking about the frontline setting. In the second line setting, we think about ruxolitinib again, and there are limitations there. It can also cause cytopenias like hydroxyurea. It can also increase the risk of non-melanoma skin cancers and precancerous skin lesions like hydroxyurea. It can also make the liver enzymes go up like interferons. You know, it works, but maybe not work as well as some other therapies that we know of to control the blood counts. Neither of these, three kind of typical drugs we use to control the blood counts outside of phlebotomy, neither of them are perfect by any stretch of the imagination, again, leaving things open to an unmet need. Great. Looking at a drug with the potential profile of oral epetraborole and assuming data is positive and supportive of its use in PV, where might epetraborole fit into the treatment paradigm for PV patients? I think there's a couple of ways you could foresee this happening. You know, a drug like epetraborole controlling the blood counts without phlebotomy can be a useful tool, especially in the early period. Say someone is recently diagnosed, and you wanna get their hematocrit under control quickly. You know, normally, we would do a bunch of phlebotomies. You know, in my practice, maybe go once a week or every other week at the most. I've heard of others even twice a week phlebotomies, which is a big burden on patients, right? Imagine doing a blood donation that often. That would certainly wear patients down. Quick control of hematocrit, I think, is an important advantage for an agent that focuses on hematocrit control like epetraborole. I think also too in the setting of a therapy, a cytoreductive therapy that might not be quite hitting the mark. Say a patient is newly diagnosed. There's an indication or a good reason to start them on, say, interferons, you may need help controlling hematocrit early on. Interferons slowly can whittle away at disease, but it takes time. The hematocrit control is not instant with that drug and often requires dose escalation, which again runs you into the realm of side effects or at least increased risk of side effects from that agent. A drug that can control the hematocrit, giving the other cytoreductive agent time to work and time to get to its main end while eliminating the toxicity and playing well with others makes a lot of sense. I think there would be a valuable role for a drug like epetraborole or any agent that can precisely hone in on hematocrit control without causing a lot of cross-toxicity with other agents. The fact that epetraborole is oral, and it's red cell specific, it's fast acting, and it's durable control over time sounds like it could meet an unmet need. Yeah, I think so. You know, oral agent always has its advantages over injectables, you know, easier storage, easier giving the prescriptions to patients. Lots of patients prefer oral administration over a subcutaneous injection. I think there's some distinct advantages there. Now, something that focuses solely on erythropoiesis and erythroid control relative to the other blood counts is important. I mentioned earlier the major downside to hydroxyurea or ruxolitinib, or I would say even to some degree interferon, is the lowering of other blood counts. Thrombocytopenia, low platelets, lowering of the neutrophil count, or neutropenia can be an issue with these drugs. Lymphopenia for interferon also can be an issue. We would be able to back off the dose of the other cytoreductive therapy if a red cell-specific agent was also on board. Excellent. Thank you, Dr. Gerds, for joining us on this call and providing your thoughts. We believe we have a compelling opportunity in front of us, and that epetraborole has the potential to make a meaningful difference in PV. This creates a solid path towards important milestones over the next two years, as outlined on this slide. We expect to have an early and clear read on key clinical data from the PV program as soon as the fourth quarter, with additional updates coming throughout 2027. It's important to highlight that PV represents just the first of three proof-of-concept catalysts we believe we're well-positioned to achieve in the next two years and within our cash runway. The second clinical readout is for NTM lung disease caused by Mycobacterium abscessus. This is a disease with no FDA-approved drugs and high mortality. Treatment relies on off-label and burdensome IV regimens. It's a large market with approximately 15,000 U.S. patients and 50,000 across major markets. We expect to report top-line results next year. The third program is for Chagas disease, caused by the parasite Trypanosoma cruzi that infects muscle tissue, the most important of which is the heart, leading to serious complications and death. Once again, there is no FDA-approved drug for adults with chronic Chagas disease, which is by far the majority of patients carrying this silent killer. Very soon, we will announce top-line data for the ongoing phase I study, along with non-human primate data, which is shown to be highly predictive of human efficacy. We're on track to initiate our phase II program for AN2998 later this year and expect to report top-line data next year. We're also pursuing a number of oncology targets where we believe our boron chemistry offers a competitive advantage in terms of binding site differentiation, PK, drug-like properties, and IP. We plan to advance two oncology compounds targeting PI3K-alpha and ENPP1 into development this year, the first coming in just a few months. We look forward to updating you on our progress as we advance these programs. With that, I'll turn it over to the operator to open up the call for Q&A. Thank you. As a reminder, if you would like to ask a question, you can click the Ask a Question tab in the top right of the live stream player. Then just type in your question and click Submit. You can submit questions at any time during the presentation. If you have joined via the webinar and you'd like to ask a question, please click the Raise Hand button, which can be found on the black bar at the bottom of your screen. When it is your turn, you will receive a message on your screen from the host allowing you to talk, and then you will hear your name called. Please accept, unmute your audio, and ask your question. For our first question, Joe Schwartz from Leerink has submitted three written questions on epetraborole in PV treatment. Can you discuss why epetraborole's mechanism of action is well-suited to polycythemia and how this mechanism is differentiated from approved and likely soon to be approved therapies? Thank you, Joe. I'm gonna turn that over to Dr. Talbot to answer, please. Thank you. Okay, Eric, thank you very much. I hope everybody can hear me. I have to say that question drives to the heart of epetraborole's potential clinical utility. Gets right to it. For context, I would first underline what was discussed in the overview section a few moments ago. The mechanism of action of epetraborole is hypothesized, but that hypothesis is founded on a well-considered assessment by our biology expert and co-founder, Dr. Dickon Alley. Specifically, the mechanism of action is thought to be an indirect inhibition of globin synthesis, as opposed to an inhibition of heme synthesis. Obviously, production of both components is required for creation of hemoglobin. The best way to answer your question is to discuss what we know about the observed effects of epetraborole. First of all, based on the non-human primate data, specifically looking at bone marrow smears from those non-human primates, we know that epetraborole causes a pause in red blood cell production in the marrow, a block. The site of the likely interruption has been identified as between the proerythroblast and the erythrocyte stages, and that is specifically in the erythroid cell lineage, not in another one, not in the myeloid as in white cell lineage. The effect is reversible and affects only RBC production, not production of white blood cells or platelets. Meaning that dose titration is feasible and other cytopenias are not expected. As Dr. Gerds highlighted a few minutes ago, a number of the other available agents for treatment of PV can create important cytopenias such as leukopenia and thrombocytopenia, which disrupt patient therapy and prevent achievement of the therapeutic control. Now finally, other favorable effects might include a reduction in JAK variant allele frequency. That is, it might address molecular response as well as hematologic response. This potential, underlined potential effect will be evaluated in the upcoming phase II study. The hypothesis seems reasonable because of the specific block in RBC production, which would still occur in the rapidly dividing JAK mutation-driven lineage. With that in mind, and knowing that we don't have the specific answer to the exact MOA, but a very good idea of what probably is going on, we can see by these effects and potential effects, that this could really address clinical utility both for control of hematocrit and reduction of phlebotomy requirements, as well as, favorable impact on other important outcome measures. Thank you for your question. Eric? Thank you, George. Okay, I think we're ready for the next question. Your second question from Joe Schwartz. Where do you expect epetraborole could fit in within the PV treatment paradigm? Can you share more about the inclusion, exclusion criteria for phase II study and how this relates to the target population? Sure. Thank you. Maybe I'll start. Dr. Gerds earlier in the Q&A or in his discussion kind of talked about where it could fit in. I think, you know, early in the treatment when patients don't wanna undergo phlebotomies or they're difficult on patients, I think, you know, is a big opportunity. There's a lot of need for hematocrit control because the current therapies don't necessarily do that. Or as an add-on when you need more control of hematocrit because there's, you know, significant gaps, I think, with current therapies. Maybe I'll turn it over to Dr. Gerds. If you could maybe add to what I've said here about this question. Thanks. Yeah, absolutely. I'm happy to chime in. I think there are two. You know, for developing therapeutics that control hematocrit, I think there is two opportunities, as you mentioned. One major opportunity is initial time after diagnosis. You'll rapidly get that hematocrit under control without the use of phlebotomies, I think would be a huge boom for patients. It frees up time in the infusion room. It's really could be a, quite a positive there, to get that rapid control without phlebotomies. You know, two, after the diagnosis and after treatment's gonna been going on for a while, particularly with phlebotomies. I think two things there. One is in patients who have significant symptoms related to their iron deficiency. You know, there are a lot of patients who are quite symptomatic from their iron deficiency. You know, symptoms range from fatigue, muscle aches, restless leg syndrome, changes in hair and nails, the list, you know, the infamous pica. The list goes on and on. Patients really don't feel great with phlebotomy. There are certainly a quality of life angle here as well. Lastly, just a sheer fact of the matter that phlebotomies are pretty inadequate at controlling counts. You know, we presented at the ASH annual meeting this year a market scan survey, looking at over 1,200 patients with polycythemia vera. In the 969 patients that were receiving phlebotomies alone, hematocrit was under 45% all the time in only 9.4% of patients, indicating a huge area of need. When you look at the patients who were treated with hydroxyurea, that was about 140 patients, the hematocrit was under control the entire time in 44.7% of patients. When we switched to patients who were receiving both phlebotomies and hydroxyurea, which was about 130 patients, it was only under control 16% of the time. really kinda each of these phases or each of these bins of care in this population we looked at, really falling short of that major tenet of keeping the hematocrit under 45%. indicating a huge unmet clinical need and a large space for therapeutics that control the hematocrit. Yeah. Thank you, Dr. Gerds. I think, you know, this just indicates that there's a lot of room, or unmet need for another drug that could offer red cell specific, you know, be oral and not have the off-target effect. I think there's a, you know, a large, unmet need that epetraborole could address. Okay, the second part of that question was for inclusion, exclusion, criteria in the trial. Let me turn it over to Dr. Talbot to answer that question. Thanks, Eric. Hello again, everybody. We've looked very carefully at the inclusion, exclusion criteria that would be reasonable for this phase II study, but also inform clinical utility, and therefore labeling and addressing important unmet medical needs. First of all, of course, is to make sure that the patients actually have confirmed PV, that is primary polycythemia as opposed to secondary polycythemia. Secondary polycythemia is not a JAK2 mutation driven. It can be created by environmental or even inherited characteristics. It's a different pathogenesis, and we're not gonna start at least by looking at that. There might be a potential clinical utility in some patients with secondary polycythemia. The second major criterion is that the patients will be phlebotomy dependent. There's a specific definition of that that will be provided in the protocol. They need phlebotomies, and that fact is best seen when you look at what has been called a swimmer plot, which is a pre-therapy and then on therapy plot of each individual patient's phlebotomy events. Those are very informative and will highlight hopefully the fact that with the eperaborole, the number of phlebotomies will be reduced substantially. We will also be enrolling patients who are high risk or low risk. High risk are those older patients who've had a thrombotic event. Low risk are those who are younger and have not. We're gonna take both of those groups so that we understand the potential effect of the eperaborole in both of those risk categories. We'll also be allowing patients who are receiving or not receiving cytoreductive therapy for PV. We'll not want a recent significant arterial or venous thrombotic event or a major bleeding effect, and we'll exclude patients who have very high platelets or white cell counts or any evidence of peripheral blasts, because we don't want the patients who are in an AML transformation stage or are moving to myelofibrosis. Finally, we will exclude patients who have severe hepatic impairment, I would emphasize that in our past clinical experience, as well as our preclinical experience with epetraborole, hepatic injury has not been observed. We've had a couple of patients with sporadic elevation in ALT or AST, the same percentage, in fact, perhaps somewhat more in comparator or placebo groups. We've certainly not had anything approaching overt hepatic toxicity as exemplified, for example, by meeting Hy's Law. Overall, it's a pretty comprehensive eligibility package, but also one that is liberal enough to give us great information on potential clinical use in the future. Eric, back to you. Thank you, Dr. Talbot. Okay, I think we're ready for the next question. What data from the Sentinel cohort will inform a go, no-go decision? Is there a specific threshold you have set to move forward with the study? All right, Dr. Talbot, you wanna take that one? I briefly reviewed the study design, and just to refresh everyone's mind, we're going to have a Sentinel cohort that will evaluate efficacy, safety tolerability, PK, and key hematologic values. We do that because we're going into a new patient population, and we wanna make sure that we proceed with patient safety in mind, but also obtain some key confirmatory information before we move into part one of the study, which is a dose optimization cohort, which will, first of all, allow dose titration during the first 20 weeks of the part one phase and then a dose evaluation phase. I'd emphasize that each patient's dose will be individualized. That's an important component to identify the best regimen of epetraborole for each patient, regardless of the eligibility criteria that they've met. Finally, for the shorter term, you move to a placebo-controlled cohort, which is a withdrawal period, and that allows us to evaluate not only hematologic variables, but also to confirm the effect of the epetraborole on phlebotomy rate and hematocrit, but also to allow an assessment of patient symptoms because we'll be looking at two PROs, the PROMIS Fatigue PRO, and then the MPN-SAF PRO. With that in mind, let me go back then to the Sentinel group. This is designed to carefully collect data with a period of confinement during the first four days for frequent assessments of key hematologic variables, and then an outpatient follow-up, all this on a stable dose. We can understand pharmacokinetics, we can understand initial efficacy data, and we can confirm safety and tolerability. We're gonna start at a lower dose, but that's for patient safety. We think it will also show evidence of efficacy, but if there is not a major impact on efficacy in this group, that's not gonna be a problem for us. It will be very informative and allow us to choose what will be an efficacious dose as we start part one. Hopefully that's helped me to explain, helped you to understand the Sentinel PK goals. Eric, back to you. Yeah. Thank you, Dr. Talbot. I think it's important maybe to add that, you know, we're gonna start getting this data we expect by the fourth quarter of this year, so this is gonna be pretty rapid. Because it's open label, we'll also be able to have data throughout 2027. Very exciting time to for us here. Okay, time for a couple more questions, I think. Your next question will come from the line of Stephen Willey with Stifel. Your line is now open. Please unmute and ask your question. Yeah. Can you guys hear me okay? Yes. Okay, great. Thanks for hosting this. Can you maybe just speak to some of the preclinical work that you're currently doing to maybe better understand this potential mechanism of action on globin synthesis? I know you're speaking to a selective effect on red blood cells, but it also looks like there's a modest elevation in platelets. Just wondering if you think that this is occurring orthogonally to the mechanism on globin synthesis. I just have a couple follow-ups. I mean, we have, you know, an extensive, preclinical package, as Dr. Talbot reviewed in the slides, you know, both from, you know, NHP models and chronic, you know, tox. We see this kind of same effect being very targeted at red blood cells. Maybe I'll turn it over to Dr. Talbot, who can walk through a little bit more detail on that. Dr. Talbot? Thanks, Eric. Again, thanks for the question. To specifically answer your question, we're not currently conducting any animal data, animal models, for several reasons. First of all, the existing animal models rely on stimulation of red cell production by erythropoietin. We know that dapetaboral creates a situation where there is some erythropoietin response. At least that was what was seen in phase I, phase II, and phase II-III patients. That situation presents a conundrum for us and also the potential for confounding of the dapetaboral effect versus the erythropoietin effect. We're not undertaking anything now, but certainly. We have a robust preclinical dataset, as we described. Certainly that's something that we're going to be evaluating as we move forward. We sort of wanted to get started on this and understand the market and potential medical needs, understanding the MOA is important and will be important for an NDA certainly to be able to address that point. The other thing is that we have this extensive clinical database. It's extremely robust, and it's highly consistent across all patient populations. One of the things we've done, of course, is to vet this concept and these data with our external experts, including those in India, very knowledgeable investigators in India, who have conducted previous PV studies. They also concur that the robust nature of the clinical database suggests that it's both reasonable and safe for patients to move into this proof of concept study as opposed to doing more preclinical work. There was a follow-up question? Thank you. Yeah. I just have a couple more. It looks like you're achieving the majority of your efficacy within the first 28 days, per the non-human primate data, if you look at the reductions in hematocrit. It then looks like it takes an extended period of time to kind of get to a nadir effect on hematocrit. Just curious if you think this is just a function of the drug achieving some level of steady-state exposure, or do you think that this is also a function of red blood cell kinetics and turnover? I just have one more. Well, the way I'd start is that the data in human, in the human studies does not entirely replicate the NHP data. In humans, as we showed in that first slide on hematocrit effect, what we see actually is a drop over the first month. The nadir is variably met at month three and four. It tends not to be too much lower than what you see at month one. There is not a prolonged period of time to the hopefully optimal hematocrit level, and the effect is what we would characterize as early. It's different. It appears to be different in humans than in animals. This, of course, is one of the things we'll be looking at in the phase II study. That's, you know, a key question. There might be dose response and exposure response considerations. There's another important point to those graphics, and that is that it does appear that even with the variability that was shown in the hematocrit slide and was found in other studies that there might be a floor effect. The magnitude of the drop is likely to be very useful clinically, but there might be a floor such that patients don't develop some of the adverse events that are seen with other agents. If you look at some of the other recently reported data, you actually get overshoot in hematocrit decreases. If we could avoid that and get to a stable dose, relatively quickly, and then maintain that, with durability, that could be advantageous, to patients and make life easier for clinicians. It could, in my view, potentially avoid the seesaw effect, as I've termed it, that Aaron Gerds mentioned, where, you know, you phlebotomize, the hematocrit goes down, the patient consumes iron, the red cell production revs up, you know. You bounce back and forth, and you do that even if you're on cytoreductive therapies, as well, because they can be more difficult to titrate, as well. There are a variety of potential pluses to the profile as we see it. Okay. That's helpful. Then maybe just lastly, just kind of a bigger picture question. I know that there's precedent for chronic antimicrobial use in non-infectious indications, but just wondering how the company and Aaron Gerds thinks this might represent a headwind, if at all, from either a regulatory or a prescribing perspective. Thank you. Dr. Talbot? Should I start with that, Eric? Yeah. Can you start, I think. We're ID people to begin with. I'm ID trained, of course, that question comes to mind relatively quickly. We've considered that carefully. We think of it in two different strata, if you will. The first is the patient perspective, and the second is the societal perspective. From the patient perspective, the patient who's taking epetraborole, the primary consideration we would think about is whether there's a risk of Clostridioides difficile-associated diarrhea, which can be seen, as you well know, with a variety of anti-infective drugs, but some a lot more than others. Two things. Thus far in our development program, we have not seen a case of Clostridioides difficile-associated diarrhea. Second of all, the effects on the GI tract in our... all our studies show that GI adverse events are for the most part mild and self-limited. They, most importantly perhaps, have not led to premature treatment discontinuation. I'd mention that specifically in the phase II/III NTM study. These are not leading to premature discontinuation of epetraborole therapy. Both symptomatically and in terms of the risk of C-Clostridioides difficile, we think that we're on good footing. Obviously, we'll be watching for that, but we're very reassured so far. The second, you know, bucket is really the societal perspective. A major concern would be if epetraborole, the class that epetraborole belongs to, is used frequently as an antibacterial for routine bacterial therapies such as UTI. If you had a lot of epetraborole out there for these other routine bacterial infections, you would worry about the potential for emergence of cross-resistance. That is not the case. There is no epetraborole class drug out there for treatment of routine bacterial infections. We think that that societal risk and cross-resistance issue is not an issue of, you know, as we move forward into PV. All right. Thank you, George. Okay, I think we have time maybe for another question. Your next question was submitted in writing from Yuanyuan He with Evercore ISI. Hi, thank you for taking my question. I would like to double-click on the platelet effect. Do you have insights on whether the minor fluctuation on platelet count is dose-dependent from other data sets? Dr. Talbot, I'll hand that one over to you. I apologize for not addressing that orthogonal question that was asked a moment ago, in terms of platelets. We think we understand that well. The effect we see with epetraborole in our non-PV patients is that there is a modest elevation of erythropoietin. The mean erythropoietin level increases somewhat. It's not statistically significantly different from patients receiving placebo, but erythropoietin does increase in a reactive fashion. This is presumably what happened also in early animal models, where some increase in megakaryocyte production was observed. We believe that to be a reactive increase to the mildly elevated erythropoietin. What we do see is that the mean platelet counts do go up, but they remain, as shown in our graphic, within the normal range, at least the mean is. There's some patients who have a somewhat higher platelet level. We're not getting to levels of over $1 million or $1.5 million, where we would really worry about the effect of thrombocytosis on creating a prothrombotic effect. As I should have mentioned earlier, in addition to allowing continued cytoreductive therapies, we'll also allow and require continuation of aspirin therapy, which, as Dr. Gerds has so clearly outlined, is one of the pillars of anti-PV therapy. That's something we'll watch, of course, in the different patient population. So far it has not been a cause for concern. All right. Thank you, Dr. Talbot. I think, you know, there's obviously a lot of excitement here on our end. There's a lot of questions. I do wanna thank Dr. Gerds for his participation in this, and also Dr. Talbot. I think we are gonna conclude at this point, but we're happy to take additional questions, and there'll be more exciting updates as we go along. Thank you everyone for participating in this call. This concludes the call. Thank you for joining. You may now disconnect.