AN2 Therapeutics, Inc. (ANTX) Earnings Call Transcript

This fireside chat. I'm very pleased to host with Eric Easom, CEO of AN2 Therapeutics at a very exciting time for the company. And thank you for keeping us on our toes with the recent announcement that you're taking epetraborole into development for polycythemia vera.

Very excited about that. Yes.

So 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 we have -- epetraborole is 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. And so we decided to get a lot of input from experts in the field, both academics and folks who've been involved in a number of trials, and they were very excited about the data as we were. So 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. So we're planning to start our Phase II trial in this. We're going to 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. So 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 28-week dose titration. Can you give us some context for that design aspect?

Sure. So we're running a trial. We're going to have a small sentinel patient group of 10 patients where we'll start out at a low dose to confirm biology, make sure all of our PK assumptions aren't different in PV patients and any safety issues, which, of course, we don't expect. So 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 a around a 40 to 50-patient dose-ranging study where we'll individualize doses for 250, for example, once-a-day oral, 500 as high as probably 750 depending on how much hematocrit reduction we need to control the dose. So epetraborole is very -- what we have learned over time is it's very exposure -- there's a dose exposure relationship to the hematocrit reduction. And so we'll be able to learn that and then that will fix it for a double-blind placebo-controlled trial that will run at the tail end of that. So it's a multipart study then with a long-term even follow-up beyond that, that we'll have. But we'll have data in next -- this year and next year. And then the -- our plan is that we will set up a Phase III trial that we would then run in the future.

Okay. And given phlebotomy works pretty quickly, do you foresee the ability to like have a dose that -- or doses that could be used to go straight to those doses as opposed to doing a dose titration?

Yes. So we'll learn a lot. But I think once we know of a dose, the way a epetraborole works is that you get a down regulation over the first 2 to 4 weeks and then it kind of [ nadirs ] at 8 weeks and really holds flat in non-PV patients. And then as soon as you take the block off, it goes back. So we'll know and if we can find, I think, a common dose like 500 milligrams oral once a day would be ideally suited for this. So that's exactly what we'll plan to do in that dose titration. So that would be the plan. Now in terms of how it will be used, the feedback we're getting from KOLs, we just recently held a call with an interview with Dr. Aaron Gerds that we have on our website, which is great. And he talks about the potential of using a 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 they call it blood letting for a reason, I think. So you could -- he sees a use case of a epetraborole for instead of phlebotomies or in addition because when you phlebotomize somebody, then they eventually eat their way back with iron up through and start getting higher than 45 and you got to just keep the seesaw effect of phlebotomies. So if you could smooth -- once you get them down, smooth that and hold them. So basically, the idea or you can combine it with other drugs where you're not getting the control, which is greater than 50% of patients are not controlled. So there's a lot of -- 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. It's oral and it could be used early in the life cycle as soon as before phlebotomies or with phlebotomies upfront or with HU or with other ropeginterferon, all the other drugs, it would combine nicely and another -- not to go on and on, but in terms of DDIs, this drug is very clean. So we just ran an NTM trial on top of rifampicin almost in all the patients and azithromycin, a lot of somewhat nasty drugs from that point of view. And we 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. So it makes it a nice combinable drug profile. So all those make this, I think, super exciting. So the key question is going to be how does all that evidence translate to PV patients.

That's a good segue to my next question. So 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 below 45% when they usually start much higher? Like how do you anticipate the potential efficacy might translate on that key biomarker?

Yes. So we saw in 105 pretty old, pretty advanced NTM patients. So these are -- we see a 5 to 6 percentage point drop in hematocrit that's about 15%. So this is at 500, and we can model that out and show that 250 gives half of that and 750 gives more than that and so forth. But that's a pretty good number compared to other data I've seen from therapeutics in terms of an absolute drop. So I think that gets us to where we need. Now in PV patients, I think some of them will start pretty high. So 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 a key clinical indicator to reduce the risk of clots.

Interesting. Okay. And 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?

Yes. I mean we do a lot of hypothesis generation in the company. And we think we have a couple of targets. We don't know exactly the mechanism of action for the red cell block. We have 2 or so hypothesis that we're pretty sure are right. We need to -- this is moving so fast. The biology hasn't quite caught up to it. So we will be sorting that out, I think, but over time. But I'm trying to get...

Well, I guess -- yes. No, you were answering it well. I guess you're doing this -- you're evaluating the JAK2 V617F.

The allele burden.

Yes, allele burden. And I guess, does that answer that question?

Well, so it is. So I think we also believe that there is a that we also could affect that and reduce the allele -- the frequency of that and have a disease-modifying effect. That's -- it would be a lot of arm waving to get to that. And so we don't want to speculate, but that's why we're measuring it as there is a real possibility that could happen with what the targets we think and have hypothesized are. So that would be -- to me, the biggest takeaway in all the discussions with the KOL is that the question is, do we need more hematocrit lowering drugs? And the answer is, yes, because, a, there's not very many of them. So there's not many options. The ones we have are not all that great. So the key goal is you need less than 50% of patients are hematocrit is well controlled under 45. So we need that. But ultimately, if you could change the disease, modify the disease through these JAK mutations that would be beneficial, but it's not critical.

Okay. Interesting. And I think unlike Rusfertide, which is sequesters iron, epetraborole modulates erythropoiesis differently. So 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. And there is not much change in those parameters. Everything stays within normal limits. So I think we're not going to know if there's something different in PV patients. But theoretically, based on what we know, it shouldn't have a change. And there's no change in white blood cells, which you do see in other therapies, which can be really problematic as well. So -- so I think there's more to learn, obviously, that's why we're doing the Phase II. But all the observational data we have now would suggest that, that's not going to be an issue.

Okay. Interesting. Are you going to prioritize enrollment of any particular kinds of patients like HU resistant or intolerant patients or just take all comers?

Yes. I mean we're doing the trial in India, primarily just -- I know a lot of people have questions about that, but this drug has been studied extensively in patients and volunteers in many different geographies, U.S., Japan, et cetera. But in India, we can go very fast, and it's cost effective for a small biotech like us. So I think -- and so we're doing it there. Now in India, we have inclusion/exclusion criteria. We're, of course, getting lots of input from U.S. KOLs who've been instantly involved with a number of the current trials that have gone on over the past several years. And we're getting input from investigators in India who also happen to be PV KOLs and heavily involved and we're involved in a lot of these trials that have current trials. So I think we're getting all that. But -- so inclusion/exclusion criteria, most of these patients are in India, primarily for cost or they use phlebotomy and HU because it's cheap. So they don't use a lot of the newer, more expensive agents. So there's a lot of patients with that who aren't particularly well controlled. So our trial design will look a lot like the Rusfertide trial that published in the New England Journal, the Phase II trial is the plan using experienced investigators, making sure the other critical thing in India, you see more secondary PV instead of primary. So you see things where they have infections or other reasons that might cause them to have excess red blood cells. So 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. Yes. Interesting. So then let's talk about the Phase II that you've laid out for us. What threshold of hematocrit reduction in the 4-week open-label sentinel cohort would justify into the Part 1 titration phase?

Yes. So that sentinel cohort, we don't know -- we're being, how would I say, cautious about -- we're treating like any trial you would. So we're going in with a low dose because we don't know if PV patients will be more sensitive to the drug or not. So 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, in the dose ranging at 250 once a day, 500, the ability to escalate. So 250 every other day, we don't necessarily have to see a strong signal. From our modeling, we should see somewhere between a 5% to 10% percentage change in hematocrit. So all the biology should start moving in the right direction, and we'll confirm that quickly with that. And then if we need to go to a higher dose, which we expect we would go to 250 daily and so forth, we'll do that.

Okay. Interesting. All right. And we talked about the Part 1 titration.

Yes.

And then you're going to Part 2, the randomization part, where there's an endpoint after 4 weeks, which is defined as hematocrit control without phlebotomy. Why was 4 weeks chosen as the cutoff? And are you having a washout period for -- [indiscernible], these patients won't be on cytoreductive therapies, right?

No. But we -- I mean, we're basically going to -- I was -- I think it's 12 weeks, not 4. All this is like moving very quickly. So I'm trying to keep up with the team. But 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 on EBO are well controlled and those who are not, you're going to see breakthrough phlebotomies and so forth. And the other critical point of that study is one of the endpoints that we need to be able to show is kind of feel and function. Function-wise, you can show lack of phlebotomies but feels we have to implement PROs and are they -- those who are getting phlebotomies feel worse. They feel tired and it has an effect on their health. So we -- others have been able to show that, and we'll show that. So that's how that part will work. So we have that kind of double-blind, placebo-controlled part of this trial.

Okay. Got it. Great. And I guess obviously, it's an oral agent, which is pretty attractive. But then again, rusfertide has like a 77% responder rate, I think. So what is the push and pull with that oral route that 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 injectables is obviously not probably ideal?

Yes. So I think -- I mean, oral is a big deal, but also having meaningful control. So in the Phase III non-PV patients with that 105, we have a very tight confidence intervals around that. So 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. So I think there's a lot of ways we can win, but oral will be a big one, particularly in earlier frontline therapy where there's a big -- much bigger opportunity.

Okay. Was there anemia seen for epetraborole in the NTM patient population? Yes?