Biomea Fusion, Inc. (BMEA) Earnings Call Transcript & Summary

Okay. Perfect. Well, thanks, everybody, for tuning in and joining us here at Piper Sandler's Annual Healthcare Conference. This is Joe Catanzaro from the Piper Biotech team. It's my pleasure to welcome Biomea Fusion and their Founder, Chairman, CEO, Tom Butler.

Tom, thanks so much for joining us and making the time. Lots of run through, but I think maybe a good place to start is just a quick high-level discussion around the idea of irreversible, reversible inhibitors and how you guys think about it, and maybe what you see as some of the benefits of targeting with a covalent inhibitor over a noncovalent inhibitor and how Biomea approaches that?

Yes. Great question, Joe, and thank you for having me. This stems from just the makeup of who we are at Biomea. Keep in mind that we assembled an R&D team that composes of people from Gilead, from Solera, from Pharmacyclics. And these are folks that have built covalent inhibitors over several decades who have been very successful at doing it. It's all based on the target, right? You have to pick the right target, and the target has to have an amino acid in the active site or the allosteric site that has a cysteine or another engaging amino acid. What we've learned is that if you can select a target that has this or you find a way to build your covalent inhibitor against the target, the benefits and the profiles come first from selectivity or higher selectivity because you still take advantage of the actual 3D contouring of your target. You have spatial orientation of your target. And what you're doing is essentially building the small molecule, then orienting a particular warhead at a certain angle, but also a distance to form this covalent bond. Once you get this covalent bond to form, you have deep target and activation. What does that mean? That means direct engagement with your target. You don't have to rely on continuous exposure to disrupt the target. And what we've learned is just build a profile where you can get optimum impact to the target or occupancy of the target without needing constant exposure. And whether that exposure is in short burst or in hours of time based on half life of the target, you can really start to leverage the benefit of a molecule because it's not continuously exposed to the patient. And we've just seen this benefit happen really over and over again, whether it was BTK, whether it was a polymerase inhibitor for a virus, you're really trying to limit the exposure and have maximum impact, and covalent inhibitors afford you that.

So it seems like historically, there's been perhaps a version or a challenge to developing covalent inhibitors. What has changed over, say, the last 5 or 10 years that's driving more and more activity in developing irreversible inhibitors?

I think we've learned a great deal. We've -- I mean if you think about it, it's been since the early 1900s when we first started building covalent inhibitors. But what we've learned most recently is we just have much more computing power, we have much more information about the target, and we get great information again at this 3D contouring. It's very difficult if you don't have x-ray accurate crystal information in terms of is the amino acid even approachable and how do you approach it. And so we use several techniques internally, not only from an x-ray crystal generation perspective, but also from the visualization perspective, whether we use virtual reality or we use software to basically look and expand the active site, expand the target so you can actually walk inside it and start to appreciate that approach and how to build your warhead against the target. So computing power has helped us tremendously in terms of being able to get more information on your protein. And then we've had a lot of lessons learned in terms of how to build the right warhead. And keep in mind, just like a noncovalent or reversible inhibitor, the warhead is completely tunable. So you can tune how hot the warhead is. And think of it just like 2 magnets coming together, you can tune the magnet strengths. And that's really developed over the last, I would say, 5 to 10 years.

So as we think about the need to have an appropriate amino acid for the covalent inhibitor to target, it sounds like when we think about targeting enzymatic domains, maybe your array of amino acids that you could work with or perhaps limited. So with that, in general, are disrupting protein-protein interaction to more amenable to covalent inhibitor design because you're working with maybe a larger surface area that you're trying to disrupt?

Yes, certainly, that provides added benefit is because when you're engaging with protein-protein interactions or protease inhibitors is another great example. You typically have to build a relatively large molecule. And when you're a molecular weight of your small molecule continues to grow, you're doing so to basically act like a blanket when you don't have a very deep pocket that you can design and latch on to, like hinge binders, for example, for kinases. Protein-protein interactions, you don't have that ability. So as you build a larger molecule, your noncovalent inhibitor starts to lose drug-like properties. And so as a covalent inhibitor, you can maintain target activation without having to build a lot of surface area. And I think that -- so that really lends to an added benefit for a covalent inhibitor.

So maybe that's a good segue to BMF-219, your menin inhibitor and [ Leap ] program. Why did you select menin/MLL as a lead target to establish proof-of-concept for your covalent inhibitor approach?

Yes. Great question. So we started the menin program actually through a reverse inquiry, a computational chemistry company called A2A came to us and had this great program. At the time, myself, Ramses and rest of the group knew very little about menin. And so we had to learn ourselves first, the target, what is menin? The literature describes it as a tumor suppressor. Is that the whole story? Certainly, not with acute leukemias, and so we wanted to learn where else is a story wrong in other tumor indications. And we also had to learn how do you design a drug for menin. The company that approached us has started their program with reversible inhibitors because that was all that was known at the time. And they had made a few compounds using their computational software. And what I thought was really interesting from a chemistry -- from a chemist perspective is they were able to engage with menin with very low molecular weight, and I thought that was quite novel. And I thought that gave us a lot of real estate, a lot of opportunity to build a drug-like properties around this molecule that had great engagement because like molecular weight the rate is so small. And so we decided to take this on as a research project. It was a very early stage program. And so we first had to get comfort around the target, really learn about the biology of menin, and then we had to figure out what's the right way to disrupt menin is that we think is the right way. And as we learn more about designing a reversible inhibitor for a menin, it was just based on our experience that these concentration dependencies seem to be a little bit out of whack. We're used to this kind of rule of thumb of tenfold stair step area in concentration. As you move from biochemical or target inactivation all the way to in vitro proliferation or potency and then to in vivo potency, and we didn't get that tenfold stair step each way. We got about 20- to 30-fold in the first stair step and then 100- to-200 fold in the second. And I think as we realize you have to go higher and higher concentration and maintain it as a reversible, we thought this is going to be a very high hurdle to accomplish, not only for your lowest-hanging fruit, but what if you want to get into other tumor types outside of the MLL rearrangement, which may need more drug as a reversible inhibitor. And so what we tried to do first was develop reversible inhibitors that were more sticky and would kind of wedge themselves into the pocket. And that seems to work okay. And what you can do is just measure what your K off is. When you gauge with the target, the longer the K off, the better you're doing it kind of wedging or creating propellers to stick into the target. And then it was just through a nightly chemistry session that we were rotating the protein around and we saw the cysteine. And I literally had just hired a few folks from Solera that led the team to discover ibrutinib, and we kind of looked at each other and laughed and thought, maybe this is it, maybe this is the trick that can solve those concentration dependencies. And as soon as we started to redesign the molecule, reshaped the scaffolds and then start building in our warhead covalent engager technology, all of the concentration dependencies got compressed. We got much better ligand efficiency and much better pharmacology. And we were really excited because not only did we get better pharmacology, we seem to get better disruption of menin that opens the door to other tumor types outside of acute leukemias. And then that really created a tailwind or momentum for us. to take the -- to really make this a real not just a research project, but make this a real program and make this a company.

So I do want to obviously discuss potential beyond acute leukemia, but maybe sticking first with acute leukemia. So we've seen some clinical data generated across 2 menin inhibitor programs to date. Those are reversible inhibitors. When you look at those data sets, what do you see as the most important learnings for the class?

Yes, a great question. I think it's been great to see that menin is proving itself in the clinic. And we took on this program in 2017 before really most people knew about menin. And so it's great to see that menin inhibitors are seeing effect in the clinic and giving us great proof of concept. What we're learning is, first, you learn this PK/PD, right, is how much exposure in the patients do you need to get your complete response. In acute leukemia, you need complete response. Anything short of that, most likely ends up in very low durability or a low time of response, very short, I should say. And so what we're learning is what can the current inhibitors in the clinic do in terms of what's the complete response rate, and then what's the durability of response. So that's kind of what we've learned the most to date. And then we're learning what about other tumor types. And so it seems like they're very -- they're developing their clinical plan within just acute leukemia to see how that unfolds down the road. But it's also great as a molecule that's about to enter into the clinic that we don't have to educate all the investigators about menin. They've heard about it now. And so they're really excited that we're coming with a differentiated profile. And what's great to hear is, as we interact with sites around the United States is how much help and how excited they are to be able to have a new molecule like BMF-219 come into the clinic and hopefully lead to disruption. I was quite shocked by it actually, how much effort is put in to help you and help the company and help the molecule really get into the hands of patients, and we've got tremendous support from many, many sites. And so we're excited to really show the world that BMF-219 can do.

Yes. And I want to talk about the recently initiated trial. But maybe first, when you look at, again, the sort of competitive landscape and how we've seen these programs advance here, knowing what you know about 219's preclinical profile, where do you see the biggest opportunity for it to establish investing-class profile? It sounds like we should be thinking not only about efficacy, but also perhaps safety as we think about a smaller structure, better drug-like properties. How should we think about that?

Yes. I think -- and that's why we put in our new corporate deck, some of those features of pharmacology and really highlighting ligand efficiency. And so what we've observed is you don't need a very high AUC or exposure to demonstrate pathway control, and what that does is just allow a very wide therapeutic window. We had no histopath findings in our tox studies. That's unusual for an oncology drug. And I think it just speaks to how special BMF-219 is. And what we're learning from our preclinical experience is 219 at very low concentrations does a great job in acute leukemias, but at the same concentration, we're disrupting other tumor types, other liquid tumors like DLBCL and multiple myeloma as well as KRAS-activated tumors. And what's so interesting about BMF-219 in the KRAS solid tumor setting is KRAS inhibitors that are targeted for KRAS. They reached this kind of plateau effect because there's a certain pool of K on and K off. And so -- sorry, KRAS on and KRAS off states. And so the molecules can never rid the pool. And so they plateau at about 70%, 75%. 219 doesn't have a plateau effect because we're not targeting KRAS or targeting menin. And so where you see the KRAS inhibitors kind of missed the mark in terms of IC90, IC95, 219 clouds right through. And again, this is at the same concentrations will be disrupting the acute leukemic patient population. I think that's quite unique.

Yes. So you've -- your IND recently are for the Phase I trial in acute leukemias. What can we expect a little bit more details on the design of that trial and the dose escalation and expansion cohorts? I presume it will mirror closely what we've seen for other menin inhibitors. And what are some PD biomarkers you can look at to show this pathway engagement in that you are, in fact, hitting this pathway much more efficiently than we've seen from others?

Yes, I think the Phase I is no longer about MTD. Really the FDA wants you to do a really good job to identify what's called the optimal biological dose, and it makes a ton of sense. And it's kind of surprising that we waited so long to do it. We're just trying to be more precise at what's the right dose for patients. And it stems from, let's not just overdose them unnecessarily and try to create an umbrella effect to cover maybe not only your target, but other targets that can help your response. Let's be very precise. And so we have several PD assessments built in to this Phase I because we're not quite sure with this molecule and with a menin inhibitor, right, what's the right PD assessment. So we're doing several approaches like a plasma inhibitory assay is one. We're looking at gene expression changes, protein levels, all these key PD assessments occupancy that you would do for a covalent inhibitor, and we'll tie that obviously to exposure into the response that the patient hopefully achieves with BMF-219. In terms of study design, it's very similar to what we've seen with other targeted oncology agents. It's an adaptive design. It's 1 patient per dose level until you see an adverse event, and that goes into a traditional 3 plus 3. And then we go into the expansion phase once we feel that we've reached the optimal exposure to generate reproducible efficacy.

Great. What are your expectations around potential first patient dosing it? I know it's hard to talk to project out, given that first patient dosing hasn't occurred. But when is a possible initial look at the dose escalation data?

Yes, I think the IND was cleared by the FDA towards the end of September, and ballpark estimates to get an FPI is usually 3 to 6 months. And I would say during COVID times, it tends to lean closer to 6 than 3, but we want to be much better than that. And so we're working very hard to beat those time lines, and we look forward to updating the community soon.

So as you've noted, I think, a couple of times here, right, there's a big emphasis from you guys on opportunities outside of acute leukemias. I think you recently released a little bit of data, preclinical data in the setting of DLBCL. Maybe you could describe the role of menin in that defined subset of lymphomas that you're looking at, and why -- and you sort of touched on this a little bit, why your molecule or covalent inhibitor could have broader utility in a setting like this that maybe is a reversible inhibitor?

Yes. I think what we did was just start to profile out the acute leukemic cancers that we were exploring with BMF-219. And so that includes, obviously, ALL and AML. And I think it's important to know what does your drug do in ALL? And what does it do in AML? And not all drugs are created equal and not all drugs hit different tumor types equally. So we had to then discover that ourselves for BMF-219. And as we explore both ALL and AML -- as we explore AML more in depth, we saw these changes and these changes extend to not only reduction in MEN1, we saw a significant reduction in HOXA9, HOXA10, these homeobox series gene sets. And this is unique to 219 as a menin inhibitor to see a significant reduction in MEN1, significant reduction in HOXA9 and HOXA10 and so forth. Then what we saw interestingly, as we started to kind of -- we just saw a string, we started to pull the string to see what else is there for BMF-219. We saw that MEK was coming down significantly. And so we thought, well, that's interesting, why is MEK coming down? And as we started to learn, we started to see that there was control alongside this menin MEK complex. We wanted to explore what would that mean for additional tumor types or additional indications that we could explore. And so when we talk about DLBCL, when we talk about multiple myeloma, this is very much along the MAP kinase pathway, right? This is very much MEK central. So menin engages with MLL, of course, which we're all familiar with acute leukemias, but menin engages with many proteins. And menin and MEK is just an example of another protein complex that cancers can leverage to have continuous cell proliferation and continuous survival. And so as we look at subtypes within, for example, DLBCL, we are looking at double-expressor, triple hit and double hit. And these are all driven through MEK, whether it's just MEK high expression or MEK has been translocated.

So when we think about the degree of menin dependency with maybe MLL fusion leukemias at the top of that list, how should we think about how translatable the dose and exposure levels that you will identify in the acute leukemia setting? And how will that be translated into these other settings and whether there's some additional dose-finding work that will need to be done or could you simply take what you found in the acute leukemias and apply it to say triple-hit DLBCL?

Yes. Great question. And what we've found in our preclinical studies, at least from a patient sample perspective, it's the same dose, it's the same exposure. And that's what gets us so excited is that you don't have to reach too high of an exposure to try to address these other tumor types. It's the same concentration as a single agent. That's very exciting for us. And the reason why you start to see now is have a publication in ASH, and then we'll start to see more information come out in these other tumor types because we want to start to engage the community at large in terms of what 219 can do as a menin inhibitor and then start to get folks ready for what does this mean for our clinical development plan. We want to do things in parallel not sequential. And so you'll see us not only update you with our acute leukemia trial but other trials.

Is it possible that the -- this initial Phase I study could include an expansion cohort outside of acute leukemias?

It could. Absolutely.

Perfect. So the other opportunity that you've mentioned is type 2 diabetes for 219. Why are you interested in exploring there? And what's the biology behind menin in type 2 diabetes?

Yes. Good question, and we're learning ourselves. It's another scenario where there's a growing body of evidence of the use of menin inhibition or what menin inhibition can do for diabetes. Type 2 diabetes or type 1, we still don't know if it's one or the other or both. But what's coming out in literature is that menin acts like the brakes for beta cells and GLP-1 acts like the gas. And it seems that they actually co-localized and work in tandem, which is really interesting in the pancreas, which is actually quite novel. And so we're learning is and what publications have been proving out is if you take the brakes off and you allow the beta cells to turn over, you create a new pool of beta cells. So your metformin, GLP-1, these other agents, they do increase beta cell mass. So make no mistake, they do, do this. but they do it at a very, very low rate. And so it's not contributing to the majority of their efficacy or their effect. And so -- what's kind of surfacing is that this is the core source of efficacy for menin inhibitor. And if you have these beta cells that have been subjected to hyperglycemia for such a long time, what happens is that you just have insulin that's less responsive or less reactive and you just get insulin resistance built in, and the cells just get exhausted. And they don't turn over because of menin. And so if we use a menin inhibitor, we turn over the beta cells, we create a fresh pool of beta cells that have a very, very long path life of not just days or weeks or months but years. And so that's what gets us so excited is the potential that this wouldn't be a chronic therapy that you would just regrow the pool. And hopefully, there would be just some kind of maintenance built in to treat patients to make sure that their glucose levels never rise. They keep the normal range, and it would be actually a significant disruption to the space if it can be accomplished. That gets us extremely excited. And there's literature out there where it states, look, you don't have to increase the beta cell mass by 50% or 60% or 70%, you need to double the size. And I think that was kind of on our minds as we started to explore this. You actually increase it by 10%. 10% to 15%, you start to see lowering of A1c. And I think if you can lower A1c by at least 1%, you have a $1 billion drug on your hands. And so we're really testing our molecules. We really want to explore this and see if we can create what potentially could be a big disruption for diabetes.

So last question as we're just about out of time. What other targets are you interested in to leverage your covalent inhibitor platform against it? And what we could expect the next program disclosure?

We learned a lot about the biology of menin and some of these complementary pathways, and menin has a scaffold protein. And so what we did was build a nice pipeline. And a second and third program, these, again, are validated targets. We know that if you hit them, you're going to have success in the clinic and beyond potentially. And what we've seen is that the use of a covalent or the use of covalent inhibitor or just using our scaffolds platform just creates superiority. And so what we want to do is build out the second and third program and stand-alone single agents, and then over time, build this into our pipeline as a whole and build proprietary combination. We think that's really the only way to cure cancer. That was what was accomplished at a Gilead in terms of curing viruses, and it's because you have so many mechanisms going on at one time. It's very difficult to do it single agent, and I think it's going to take multiple mechanisms that work in tandem, and it has to be almost a fit for purpose. You have to really understand the biology of the patient and have fit-for-purpose proprietary combination. The second program, we'll announce when we have an IND candidate that has all the preclinical work in development done, and we'll announce when we're starting some of our GLP tox work. We'll disclose the target, and we'll disclose all the supporting data for that program. And that will happen in the first half of next year for the second program, and the third program is right behind it. So Biomea will be a company with multiple programs with multiple molecules in the clinic, and we're very excited to update the investors in 2022.

Perfect. Well, we're just about out of time. So Tom, I do want to thank you for your time. Very insightful discussion, and thanks, everybody, for tuning in. Take care.

Thank you.