All right. Good afternoon, everyone. I'm Stephen Willey, one of the senior biotech analysts here at Stifel. Glad to have with us as part of the next session, CEO of AN2 Therapeutics, Eric Easom. Eric, thanks for joining us today, taking the time. Appreciate it.
Yeah. Thank you for having us.
Maybe before we jump into Q&A, you can just start us off with a brief overview of the company, kind of who you are, what you do.
Sure. Be happy to. You know, AN2 is a boron chemistry platform company. We originally came out of Anacor, so that was AN1, as we like to say. We've been doing boron chemistry for 20 some years. We focused originally on infectious diseases, but, more recently we've gotten into hematology and oncology.
Really the platform is applicable to, you know, any therapeutic area. What we usually do is follow the biology associated with it. We've got three clinical programs. We've got three more coming into development over the next year. We've got a number of really interesting programs, I think, driving us forward.
Okay, great. Maybe you could talk a little bit about the decision to pivot from infectious disease. I know it's not a full pivot. You're obviously still doing clinical development, and you care about infectious disease.
For the purposes of this discussion, you know, that transition into the heme, into the oncology space, I know you just talked about the boron-based med chem platform that you have, but how is that decision, that pivot decision kind of driven by the capabilities you have there? What additional resources, if any, do you now need to either develop or acquire to be able to execute on kind of these new indications within the clinic?
Yeah. No, it's a good question. You know, we have traditionally focused on infectious diseases, and we think that's a really important area. But oftentimes, you know, in this field, biology throws you interesting things, that's how we sort of pivoted over into oncology.
It's very similar to infectious diseases in that you're trying to kill cells in the body and not harm the host and things like that. We, you know, we are expert drug R&D team. We've discovered, you know, probably more than 15 drugs over the past decade. We're really good at, you give us a target and a target especially that's amenable to boron chemistry. You know, we can go.
I think oncology was just a natural thing, and especially when you just follow the biology and you're not chasing targets, so much. That's kinda how we got into it, and it seems like a natural fit for us. You know, that we're kind of running with that. In reality, we're just really, you know, we've been doing R&D and discovering our own internal drugs for 20 years on the boron platform. We're pretty good at that.
Okay. Your first foray into, I guess a hematologic-like setting is actually through this chasing of biology, right?
Yeah
I'm not sure I wanna call it a repurposing, but, you know, your lead infectious disease asset of epetraborole or EBO, you know, you currently have this in phase II development for patients with Mycobacterium abscessus. Can you talk about the clinical observations that drove the decision to now evaluate this in polycythemia vera or PV and in some of the work that you've subsequently done to try to better understand the underlying mechanism?
We've kind of started going into oncology. We were working on some viral targets and ended up working on ENPP1. That was kind of our first taste about two years ago, a year and a half ago. That's a target that's really amenable. We also acquired another boron company that had a PI3K program that was really interesting. We started going into solid tumors.
PV came around a little differently in that our epetraborole, which has been our lead asset for NTM, as you, as you've mentioned briefly, you know, we have known for a long time that one of the side effects of the drug is that it has a very red cell specific interaction that causes a lowering of hematocrit and hemoglobin. We were more interested in NTM for long-term. We had patients who were gonna be on it. Was that, you know, what was the response? We've modeled this and studied it in non-human primates. We've looked at it deeply in volunteers in phase I studies and phase II.
We saw this signal that really is, you know, kind of subclinical, if you will, in NTM patients. They don't even realize it's happening, but it's a very, you know, predictable signal. I think, you know, last year we had an aha moment where we were like, "This could really benefit patients with PV because it's red cell specific."
We've done a lot of bone marrow biopsies and things in NHPs and tox studies and chronic tox, and we know it doesn't affect precursor cells. It's not affecting white cells. It really is in late stage erythrocyte, is the effect. We talked to a number of KOLs and others, and we have a, you know, really a red cell specific, goes down, kind of maintains.
When you remove drug, it returns to baseline. It was kind of this perfect profile, if you will, for potential PV patients. That's how we geared up, now you find us in a phase II-ready situation where we're gonna go test this hypothesis, where we have lots of data from patients over long term, and NTM patients and volunteers and NHPs. You know, now the big question is, will that translate to PV patients?
Okay. Maybe you can talk a little bit about the design of that phase II proof of concept trial that you're looking to now initiate and, you know, what some of the key questions are that you're hoping to address specifically and when you might be in a position to provide some incremental data here to the street?
Yeah. I mean, this is moving pretty rapidly because we had a drug that was essentially almost NDA-ready on NTM, so we're able to move quickly. We had drug product, we've done all the tox, and so forth. The key question we're trying to answer is, does all this observational data we have long term in NTM patients and, you know, the volunteers and NHPs, does that translate to PV patients?
We think it does because of where the effect occurs is late stage erythrocyte. You know, the JAK mutations turn on red cell production, but our block occurs after the red cells. We think it's in the globin synthesis side, which is a unique mechanism. We don't know exactly what that is.
The trial really is to validate that that is in fact, this translates over into PV patients. We're in the regulatory process now. We're gonna get the study initiated in India because it was faster, cheaper, for us to be able to answer this question.
The first part's gonna be a sentinel group of 10 patients at a low dose, just so we can get some familiarity with how the biology's gonna work in a PV patient. If they respond more strongly, you know, we have an idea or not. This is all open-label, we'll be able to see it real-time. This is gonna start in dosing, we believe in the third quarter, we'll have data as soon as the fourth quarter of this year.
Really not very far down the road. Throughout next year, the second part of the study, which will bring on an additional 54-ish patients, so 64 total, will be a dose finding, kind of dose ranging, dose finding study. Then we'll analyze that data.
We think it could be very simple of having a single dose and not a lot of titrations, which would be better for patients. Having an oral red cell-specific agent that we bring into a double-blind kind of part II of the study, then there'll be long-term, you know, kind of follow-up if patients wanna proceed with that. We're following kind of the same study design that was used with rusfertide and published. In the journal. We're gonna get a quick answer on this. Yeah.
Yep. Do you think that there's a chance you could see a reduction in the clonal burden of the mutant JAK allele? Or do you really just expect the benefit here to be, you know, limited to symptomatic improvement and phlebotomy reduction?
Yeah. The short answer is we don't know yet. I guess we can do a lot of arm waving, if you will, until we have the data. You know, it, it depends. If the effect that we see in normal, kind of pre, you know, late stage erythrocytes occurs at a greater effect in PV patients, JAK mutated cells, and reduces those, then you could, you know, you could have a situation where you have normal wild type outcompeting the JAK mutated. That's a lot of arm waving. We'll get the data and report. It, it is possible, to answer your question.
Okay. How would you characterize the unmet medical need and kind of the market opportunity that you see in PV and how do you envision EBO fitting into the treatment landscape?
This is really interesting. I think not being, you know, as familiar with the PV space, you know, there's a lot of drugs, you know, certainly rusfertide and others. What, you know, in working with the KOLs, one of the things I think we, especially, Dr. Aaron Gerds at Cleveland Clinic, has been very helpful in helping us understand the potential here.
I think, you know, there's two primary pillars to control kind of these thrombotic events, and that's hematocrit control and platelets. Hematocrit control, surprisingly, is really poor, even with current therapy, using phlebotomies, using hydroxyurea, adding on other agents on top of that. Frontline with phlebotomies and hydroxyurea in the big prospective trial that he was participating in was something like 25% or less.
You know, that's pretty abysmal. I'm used to areas like diabetes where you're trying to control A1C, and you can do a pretty good job with agents if you have the right ones. To me, that opens up tremendous opportunity for an oral therapy that could be used early in, you know, kind of frontline patients, and you don't get all the white cell effects or other off-target things that you might get with hydroxyurea.
People don't like to take phlebotomies all the time either, that's a major impediment. Frontline, you know, the KOLs will tell us, and then adding it to other agents, where you could, you know, BESREMi, ropeginterferon, for example, takes a long time to titrate. Patients can't tolerate it, things like this sometimes.
Adding it on during that interim while you're trying to get to a target dose that can work. Adding it to therapies later on more in a second line, like Jakafi and other agents are used now. I think what we're hearing and seeing is there's a really potentially very broad use for an agent that's oral red cell specific like epetraborole.
Okay. I know there's precedent for chronic antimicrobial use in non-infectious indications, right? We see macrolides used as standard of care therapy in COPD, just wondering how, you know, this might represent a headwind, if at all, from, you know, either just a regulatory or a prescribing perspective.
Yeah. I mean, we're lucky we have a lot of internal expertise in infectious diseases and, you know, also consult a lot with others. Really there's two main things that you want to make sure is that you don't have any effect on C. difficile, and we've never seen that even in long-term treatment in NTM patients.
I mean, you know, we have 100 and some patients out, you know, months to a year or more. C. diff is one thing, and then the other is just kind of your disturbances in the microbiome and how that, you know, plays out. You know, it's been very mild and subsides and, you know. Ultimately, I think what happens is the GI adjusts and probably develops resistance to a single agent and normalizes.
We don't see any long-term problem with that. In NTM, you know, patients we treated in previous trials had been on them 9- 20 years. You know, these are long-term. Patients. We don't see that being a issue at all.
Okay. Then assuming you were to achieve success with EBO in both abscesses and in PV, how do you think about the ability to optimize pricing for each of these indications? I know it's a bit of a first-world problem that you might be facing here, but, how do you optimize pricing? Would you expect the dosing paradigm to be relatively equivalent across the two indications?
I mean, this would be a good problem, I guess, to have. You know, for NTM, the dose that we anticipate working is 500 mg. The dose that we ran in all of our NTM studies was 500 mg. We suspect that the PV dose, we don't know yet, but will be in that same range. They're both rare orphan-type diseases, so I think that shouldn't be a problem at all for this profile.
Okay. If we can shift gears to the earlier stage pipeline.
Yeah
You've nominated a development candidate, against ENPP1. Can you maybe just talk about the relevancy of this target in the context of solid tumors? I think some of us have seen it in the rare disease setting before.
Yeah.
You know, how the inhibition of this target, just based upon the preclinical data and the biology out there would suggest that you can potentially improve clinical outcomes.
Yeah. I think, you know, this is, this is one of our, you know, lead oncology solid tumor assets. It really is more of an innate immune system stimulator. I know you know, you've talked about the STING pathway, you know, or others have, you know, that was kind of a disappointment five years ago or so. This is a natural.
When the tumor cells signal, you know, to the immune system through cGAMP, basically we have a problem. ENPP1 is sitting on the cell surface, it's shutting down that signaling to turn on naturally when there's a problem, the STING pathway. A STING agonist, you know, a lot of times had terrible drug properties. They had to be injected, you know, straight into the tumor. Could you access tumors?
They over-hijack the immune system, things like that. Whereas this is kind of the innate immune system doing what it's supposed to do and restoring that to normal. We're very intrigued. It's an unproven target. There's, you know, the target risk, unlike, you know, we've got a PI3 kinase pan-mutant program that's highly validated, and everybody knows that. This one's a little more out on the risk curve, but we thought it was.
one worth taking. It's a perfect target for our boron chemistry. You know, we were working on viral targets, and this came about. There's a lot of new data and science around it. There's a number of companies that have looked at this and are working on it. There's two in the clinic right now. You know, we're gonna get some feedback, I think from those programs.
In phase II, for example, there's a company called Riboscience that has two phase IIs in colorectal and kidney cancer. We'll find out how the target works. The drugs that we see from other chemistries have lots of potential issues. You know, we've explored and looked at and profiled those, and we can go into that detail.
This is a target made for our chemistry, which made us able to move very quickly, have good drug-like properties, have good permeability, all the things that we don't necessarily see. We're not affected by acidic environments and things that are important in tumor microenvironments that you have to have. If this works, we'll be pretty excited. We'll see. We've just declared our first candidate there.
It sounds like there's a couple of other drugs that are out there in the clinic right now.
Yeah
not really much in the way of externally generated clinical data for you to say that proof of concept around the mechanism has been established.
Yeah, exactly. This is more of a risk play that we think is, it looks like all the science from the animal models. We've got quite a bit of data. We've put in some of that in our corporate presentation, you know, it could synergize with PD-1s, with radiation, chemo, PARP inhibitors. Anything that damages DNA, this would be kind of an extra, you know, set of hands that would turn on the natural immune system, you know, in a very controlled way that could be hugely beneficial. This one, the jury's still out. To take that risk, especially given we have, you know, multiple other programs.
Anything you can say about the timing expectation around an IND submission, and I guess any sense of what a preliminary phase I might look like? Are you gonna just enroll all-comer solid tumor patients? Are you gonna try to enrich for certain tumor types that might have inherently higher ENPP1 expression?
Yeah. I think, you know, we're kind of in a not getting in a huge hurry with this one, and let some of the clinical data that'll start coming out next year come out. We do think that for this one, you know, it's gonna be paired with other agents that are DNA damaging and so forth. We think that, you know, essentially we'll get in and out of phase I and all comers to make sure you got good safety, PK, all the things, check the box, and quickly get into studies much like the ones in front of us in colorectal and, you know, other cancer types. That'll be the go forward plan.
Okay. Presumably you can incorporate some of those external study learnings into the design of your trial.
Yep
as you move forward. You talked about PI3K alpha being the other medicinal chemistry effort that you have ongoing. I don't think you guys have yet to nominate a DC here.
That's correct. Yeah.
I think as you may have insinuated, right, I mean, this is a fairly crowded development landscape. When you look at the landscape, what are some of the perceived liabilities of the second gen inhibitors, maybe specifically, that you're trying to solve for? How does some of the preclinical data that you've generated to date through your med chem effort kind of inform your optimism here?
Yeah. I mean, this is one we're being opportunistic on. You know, we're used to working in infectious diseases and in fact, you know, we've got this Chagas program, the NTM. There's no FDA-approved drugs in those areas. There's very little competition and so forth. On the other extreme, PI3K, there's lots of competition, drugs, target, validated.
I think, you know, our view of this is kind of the first, you know, alpelisib and the first generation are gonna be displaced by the second generation, which is more like a Relay compound. I think Relay showed that if you can show mutant-specific activity, you can really have progression-free survival data that's enormous. There are kinase against kinase mutants, you know, if you kind of back calculate, you can get a 18-month progression-free survival versus maybe six or seven on the helicase.
They seem to be kinase-centric ones, like, kinda like Qinlock. Relay's data I think is real. It shows the potential of this pathway of getting 18 months. Imagine you could get that for both helicase and kinase. Helicase probably make up, you know, somewhere around 50%, 60% of the mutants. That's what you're seeing with Synnovation.
who was just acquired by Novartis. They've got a pan-mutant with really what appears to be a strong separation over wild type. Give you an example. Relay is about, in our hands, 12-fold better than wild type on kinase and only two, three-fold against helicase. That's kind of their dose-limiting piece. Synnovation's molecule is 50, 60 against kinase and 15-ish, 20 maybe against helicase. That's the profile we're going after. The only people in the world we know that have that, a lot of people have kinase-centric that they call pan-
They're not really. You know, maybe, well, Synnovation is the, you know, the one that's just shown that, but OnKure possibly, and then us. We, you know, we have that. It's also very crowded from an IP. We've got boron chemistry, which is highly unique. It binds to the target differently and gives us something. We think there's a lot of breast cancer franchises out there that want one of these. You know, Lilly's probably back in the game, Pfizer, others. I think we think it's opportunistic, and it could be a huge upside for us and patients if we can create this sort of a profile.
Yeah
This one, we'll have a candidate, we think, late this year and then, you know, move it quickly into development, and then we'll partner it probably.
You see a lot of strategic value in solving for that efficacy bias that seems to exist for a lot of these inhibitors between the kinase mutant activity and then the helical mutant activity.
Yeah
I guess using Synnovation Therapeutics as a reference point in Novartis’ recent $2 billion acquisition, arguably that’s not a terrible thing to strive for.
That's a pretty good outcome for us. That's one of six, you know, we think our other programs in PV, Chagas, NTM, these are all big opportunities that we can, you know, add value and also mitigate risk against ENPP1. We can take that kind of risk now because we have six other programs that could fill that spot. We've really got, for a small company, I mean, we are experts in drug discovery, and we've got a unique tool that nobody else has, which is boron chemistry, and we've been doing it for 20 some years, and we think we can win on these things.
Maybe just to finish up, you can kind of walk us through some of the catalysts that we're expecting between now and the end of the year. Feel free to wrap in some of the infectious disease events if any of those are gonna materialize before year-end. Then maybe you can also just speak to the balance sheet runway and what that allows you to execute on here going forward.
Yeah. Thank you. You know, we have three phase II programs. PV is one of those we're going to get data later this year and into next year. Huge opportunity. I think we're, you know, significantly undervalued, especially if that works. We have high hopes for that. We've got Chagas disease, which is, you know, we call it a mini HCV market, but it's a, you know, potentially a $30 billion U.S. market.
There's no FDA-approved drug, we have a antiparasitic that we've been in three NHP studies with natural infections and cured them. It's a high probability, we think, of success. You know, we're pioneering this market, but it's very similar to a smaller HCV market.
It's a novel target, novel chemistry, and we've proven it on African sleeping sickness, for example, in a different setting. There's that, NTM abscesses. You know, there's 15,000 patients in the U.S., and they're struggling because they're put on IV-only regimens or heavy IV regimens daily for years, you can imagine.
Having an oral backbone therapy, orphan drug, et cetera, is a, you know, a couple of billion just in the U.S.-type market. Anyway, we'll have NTM data late next year. That trial has already kicked off a phase II. We'll have Chagas that's starting late this year, and we'll have phase II data next year. We'll have PV. Those are near term.
We got the ENPP1, we got the PI3 kinase, and, you know, we've got a few other projects we're looking at that are pretty exciting. I think we got multiple near-term catalysts and lots of upside potential and lots of risk mitigation in this portfolio because we, you know, we can do our own research and push all these forward. We're feeling really good about the future.
All right. Very good. Eric, appreciate the time.
Thank you, Steve.
Thanks everyone for listening.
Yep. Thanks, Stephen Willey. Thank you.