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

Hello, everyone. This is Eun Yang, a biotech analyst at Jefferies. It is my pleasure to host a fireside chat with Biomea Fusion at the Jefferies London Healthcare Conference. So joining me from Biomea Fusion is Thomas Butler, CEO of the company. So Thomas, thanks for joining me today.

Thank you very much for having me.

Sure. So before we start the Q&A, maybe we can start with a kind of overview of Biomea Fusion, how was it founded and the history of the company as well as the people that you have gathered in the management.

Yes, absolutely. So Biomea Fusion is now about 4 years old, and the company was formed actually through a reverse inquiry. Myself and the COO of the company, Ramses Erdtmann, we were in Palo Alto running an innovation fund coming off the transaction of Pharmacyclics and AbbVie, and a computational chemistry company called A2A out of Boston had this menin program. And they came to us because they knew that we were drug developers by expertise, by training. I'm a medicinal chemist, organic chemist by training. And they had this -- they were really excited about menin as a target. And myself and Ramses knew very little about menin at the time. We were just always aspirational or always admired companies that were going after these mutations called translocations because it's not just one of many mechanisms that's controlling the patient's cancer, it's the central node. And so typically, if you develop a drug for these translocations, you not only have a very streamlined effort from a drug development perspective because you understand the biology extremely well, the driving force behind the cancer very well. And so you can go through and target that specific protein or protein-protein interaction in this case. And then typically, the end result is a medicine that has very high response rate. And it's because you can biomarker the patients, you don't have to guess or hope that it's going to work. You can check to make sure these patients have the mutation upon screening. And so we thought that the overall potential is -- was wonderful. We just had to learn what is menin. In the literature, it's described as a tumor suppressor. And so Ramses and I looked at each other like, why wouldn't you want to inhibit a tumor suppressor? That doesn't make a lot of sense. And so we learned over time that literature didn't have it quite right and that we learned that menin is actually a toggle switch, and it needs a protein to tell it what to do as part of a large complex. And in the cases with acute leukemias, this protein complex has pushed the toggle switch into the on position so that you get continuous growth of these white blood cells that survive longer than they should and give you this leukemic state. And so as we learned, we started the program, we said this menin project as a research program. And it was because we only had about 3 molecules made at the time and that we started though with a very interesting novel scaffold. And it was through that computational chemistry effort that we were able to get interesting engagement with menin with relatively low molecular weight. And myself as a chemist, I thought this is a great starting point because you have a lot of real estate left over to build in your drug-like properties. And so we set out to build a reversible menin program. And it was through that effort that we learned that we saw concentration dependencies that gave us a little bit of a pause. We just came from ibrutinib and BTK, and we understood the stair-step concentration requirements to control the pathway. And we didn't get that same result with the menin/MLL interaction. We thought, well, maybe we can make the molecule more sticky. Maybe there's another way to control menin. And it was just through one of our nightly chemistry meetings that we were looking around at the protein and saw that there was a cysteine sticking in the active site. And I had just hired folks from Solera and Pharmacyclics very talented chemists, and we looked at each other and said, do you see what I'm seeing? There's a cysteine. This is a way that you can build a covalent inhibitor or build a molecule that's sticky. And as soon as we did that, the PK/PD or the pharmacology started to fall into that normal stair-step concentration effect that we're accustomed to as drug developers. And as soon as we did that, we felt much more comfortable about going after menin with a small molecule and then being able to not only shut down menin with MLL with a fusion partner, but any fusion partner and even in the wild-type setting. And that's how we got to the advent of BMF-219. We were accepted into JLABS late in 2018 and started to build out our platform, which is a covalent engager matching process. And we just continue to build up the team, build up our expertise in learning how to shut down this protein-protein interaction and then also learn, beyond acute leukemias, what does menin do. Because if you also look in the literature, it looks like menin can implicate other liquid tumors and other solid tumors, but how, why, how does that happen? And so we had to go to great lengths to kind of unravel that internally. And that's exactly what we're executing with our development program for BMF-219. And really, the team and the way the company has formed is really chemistry first, biology first. And we continue to build up the team, so we have an R&D engine behind us. That way, we can create our own future. What does that mean? That means that we can continue to discover interesting biology, pick interesting biology targets that have a cysteine or another amino acid that you can dock on to and continue to build novel covalent inhibitors.

Great. Thank you.

So there are 2 other menin inhibitors in development. So you are going to enter into clinic pretty soon. So based on the kind of a preclinical in vitro data, can you compare how yours is a differentiator from the other 2?

Yes. I think we're really leveraging the benefit of what a covalent inhibitor can do. And so we coined the term internally ligand efficiency or how much drug do you need in the body to control the pathway or to engage with menin as a target. And for us, the ability to go in and not only take advantage of non-covalent interactions with the target, we actually drive deep target and activation by forming a covalent bond within the site. And so we're very much independent of other mechanisms. Our covalent inhibitors have very direct control of menin, and that allows us to be very efficient from a pharmacological perspective. And so those key differences, we think is really, first, from a chemistry perspective, when you're able to use a molecule that stays within Lipinski's rules, the drug-like properties tend to be in your favor, first. And then second, from the ability to shut down the target, we're not really dependent on binding affinities with other proteins. We're independent of that because we can control the binding engagement with just the cysteine warhead engagement.

Okay. So you had this [ ligand ] candidate 219, you had the IND cleared in September. So yes, and then you actually put out the kind of clinical design that's in Phase I and II, so -- I and Ib. So can you talk about your clinical trial design? And when -- what do you want to show there? When we [ might see it ]?

Absolutely. Good question. And so you're correct that the IND cleared in September. And typically, the timetable from IND cleared to FPI is 3 to 6 months. And I know with COVID, it tends to trend in the 6-month category. We think we can do much better. And so we're very much looking forward to updating the community with our FPI. And then from a trial design perspective, it's an adaptive design so that we can use one patient per dose level until we need to expand to 3 plus 3 traditional design. And that way, it allows us to go through some of the lower dose levels as we explore the PK properties of 219 in humans because this is our first time of getting 219 in patients. And so we'll have to understand what those PK properties look like and get through that kind of dose escalation phase to begin with. And then as we identify the optimal biological dose, we have a nice effort to look at various PD outcomes to see how we can measure that in a very accurate way. And then that will allow us to expand into targeted patient populations that really have mutations like NPM1 has the translocation on MLL. And we've also identified other mutations that acute leukemic patients typically present with that we feel a menin inhibitor could be very impactful. So it starts with that dose escalation and then into the expansion phase once we determine our optimal biological dose.

I see. So dose escalation phase, I mean I understand it's a safety PK/PD. So do you think from the dose escalation phase, would we be able to see some differentiation compared to competitors? Or do you think we should wait for the expansion phase in order to really compare the response rate?

Yes, I think it's going to depend on how many patients we have at an efficacious dose or efficacious exposure to be able to tease that out. So it will be very much dependent on your end. And so depending on the time it takes and how many dose levels do you have, we allow patients to dose up from an inter-patient perspective. And so there is potential that we see enough that gives us confidence in what mutation subsets look good. But certainly, the expansion phase is meant to look more in depth and have a much higher end so that you have confidence in where you see activity. Is it NPM1, is it MLL rearrangement and the other mutations that we've identified.

I see. So there are 2 other competitors in development. So how do you think about patient enrollment pace? And where do you see the trial going to be conducted?

Yes, I think there's -- yes, there's a few reversible menin inhibitors in development, I think now 4, maybe more to come. Because I think the excitement for menin is growing, and people are learning that menin has this multifactorial function, which gets a lot of people excited. And so as we proceed into the clinic and as we reached out to various sites around the country, what we've learned is that there are a lot of patients in need and that the ability to enroll patients that we're looking to enroll, there is no issue. And it just gives you a sense for that unmet need. The unmet need is still very high. And so we're very excited to have the ability to get 219 into the clinic. We've even got pushed back on how many sites do we need for the Phase I. And a lot of investigators said, look, there's so many patients, you don't actually need that many sites. And so I thought that was interesting feedback given how many other menin inhibitors are in the clinic. And I think it...

So how many clinical sites are you going to be utilizing?

Sorry?

How many clinical sites that are you going to be utilizing for this trial?

Yes. For the Phase I portion, I think it will sit around in the half dozen range. But most likely, the pushback we get is that you don't even need that. That's probably twofold more than you really need. And I thought that was interesting feedback that we got from investigators.

So all the sites are going to be in the U.S.?

Yes, all the sites are in U.S. at top academic sites and really in the hands of folks who know how to treat these patients and how to handle it.

I see. Okay. And then you also mentioned that not just the leukemia, this menin target could be applicable in other liquid as well as solid tumors. So can you talk about what are the kind of other indications that can be explored?

Yes, absolutely. And this kind of speaks to the abstract that we published last week. And as we learned about menin disruption, it looks like 219 is not limited to menin/MLL. Menin is also involved in other complexes like with MYC. And so if -- as we kind of learned about our effects in these leukemias, we started to see this impact also in MYC and other protein complexes that menin is involved in. And certainly, as you start to disrupt other complexes, that opens up the door to other liquid and solid tumors. And so that's how we started discovering the DLBCL connection looking at MYC. So that's double-hit lymphoma, triple-hit lymphoma and double-expresser lymphoma. That seems to be a very interesting subset of DLBCL. Multiple myeloma also has an interesting subset that we're exploring in and we'll talk about later. And also KRAS-activated tumors. And really, it's not a KRAS thing; it's a RAS/RAF thing. And again, we're thinking about MYC, right, and how we can disrupt MYC's engagement with menin. And so this, I think, is turning out to be a beautiful story for BMF-219 and really showing you its broad potential. And so as we work through not only our in vitro work and ex vivo work with patient samples, we obviously won't need to do our PK/PD, so we can take a look at the exposure required to shut down the pathway and then translate that into the exposure needed to shut down the pathway for those other tumor types then into the clinic.

So how about DLBCL? I think you talked about DLBCL in the past as well. So can you give us a kind of update on that program?

Yes. So DLBCL and multiple myeloma, that development program is moving at a rapid clip. And so we learned at Pharmacyclics that you don't want to do things in sequential. You want to try to be in a parallel mode so that you can quickly understand your molecule. And so we're looking forward to updating the community with our efforts in the other liquid tumors.

I see. Okay. And then -- so you -- so Biomea is the only one who has the covalent irreversible inhibitor and others in development are all reversible, correct?

That seems to be the case in terms of announcing that they have an IND filed or close to IND filing into the clinic. We know that, obviously, there's the team at the University of Michigan, who are quite smart, has done a ton of work looking at both reversible and irreversible. But I think just like BTK, as you show success, they will have much more interest. And I don't think that the 5 people in the clinic here in the short term, us included very soon, that we're going to see more people because we think menin has such broad applicability. And the therapeutic window that targeting menin provides, provides again a lot of opportunity.

I see. And then you also talked about menin's role in diabetes, which is kind of far from an oncology setting. But can you talk about the rationale over using menin targeting diabetes? Also, this is a totally different patient population than very rare cancer-targeting indication, right? So when you think about like if you get successful in every indication, then there's pricing dynamics and number of patients. So for diabetes, are you planning to develop second-generation inhibitor for different indications?

Yes. So I think in terms of which molecule, we'll have to sort through that. Pricing dynamics, that will sort itself out. But for us, it's really about creating innovation and trying to create disruption and help patients at large. And I think diabetes represents another significant opportunity not only in the type 2 setting, but also the type 1 that need a therapy. And so the way we look at it is -- and what's kind of a funny story is when we first started this menin program, we met with various investigators that we had a relationship with from our Pharmacyclics days. And we talked about acute leukemia, and they agree that acute leukemia makes a ton of sense for development. But we got several pushbacks saying, you better develop this drug in diabetes. And we thought, well, that's interesting coming from a clinical oncologist talking about diabetes. But they were right, there's a growing body of evidence. And there's research being conducted in our backyard here at Stanford and at other academic institutions that's looking at how menin can help repopulate or regenerate a pool of healthy beta cells. And as you look into the literature more and more, it's been described that -- well, it's clear that GLP-1 is the gas, and it looks like menin is the brakes and naturally co-localize and interact with each other. And so all we're trying to do is take the brakes off a little bit and allow beta cells to turn over. Typically, they don't turn over. And that's why after 20, 30, 40 years of a hyperglycemic state, you get insulin resistance. And so you -- not only do you not react to glucose, your insulin is less functional, and the beta cells just get exhausted. And so for us, as a menin inhibitor or have our suite of menin inhibitors, what we see is and what we want to validate internally is how can you repopulate that pool of beta cells. And if you can do so efficiently, perhaps you -- since the cells don't turn over, once you stop treatment, maybe this could be a finite type therapy. Maybe you can repopulate the cells and then do maintenance every 6 months or 12 months or even further. And so that's what we really want to understand is, how do you grow the pool of beta cells? How much can you grow? You don't need to grow a lot. There's a lot of literature that says 10%-plus growth leads to a significant impact and reduction of hyperglycemia. We're trying to normalize the glucose levels. And how do you then check the maintenance of those beta cells? And so that's exactly what we're doing here internally to validate it. And so from a disruption perspective, I think that would be huge to have an oral molecule and that is finite. And again, a really novel interesting approach. We don't know if it's a type 1 or type 2 phenomenon. That's something that we have to continue to explore. But we know that, obviously, type 1 involves not only beta cell deficiency, but it's very much autoimmune or the community has always supported the autoimmune part of type 1. I think that's starting to shift a little bit because they're showing you over time in recent literature that if you can uptick beta cell proliferation, you can overwhelm the autoimmune piece of type 1 diabetes and get patients back to a normal glucose level. So I think it is a quite interesting opportunity for a covalent menin inhibitor. And perhaps this leads to an incredible therapy for patients.

So if it turns out the menin inhibitor mechanism of action works out in diabetes, how is it going to be positioned in the market? And then will that be more in the prediabetic patient population? Or is it going to be like in conjunction with other diabetic drugs?

Those are all things that we kind of have to sort out, right, is it depends on what's the A1C level of a patient, right? What do they present with? How far do we have to go below to get below 7, get to 6 or even 5 if you're lucky. And so we have to learn first what's the magnitude of A1C lowering that a menin inhibitor can do. And then we have to learn -- and that will tell you, right, if you have to -- if you're a single agent or if you have to go in combination. And typically, patients get metformin and then there's a 1% to 2% lowering. And then to drive it further, they have to add a GLP-1 or others to try to get you into that normal state. We have to learn that. And then you asked about, at what stage of diabetes would you introduce a menin inhibitor? Would it be early onset versus late stage? I think we have to explore that. What we've learned is the alpha -- is menin inhibition differentiating alpha cells? Or is there an existing pool of beta cells irrespective of the advancement or the maturity of your disease? When -- at what point do you lose the ability to regenerate the beta cells? That's something that we have to learn. We don't know.

So I think you guys mentioned that there is -- like in preclinical study in treatment of type 2 diabetes, there is a pathway of validation in the first quarter next year. So what are we going to see in first quarter next year on this program?

Yes. So what we want to show is from a pathway validation perspective is with a menin inhibitor, can you repopulate beta cells? Can you increase beta cell mass? And what is the impact not only while on drug, but when you wash out drug, what's the impact? And so we want to understand those findings. From an in vitro perspective, it's hard to measure diabetes. You really have as a gold standard in vivo animal models. So in Q1, we'll start to share some of our in vivo animal model work.

So do you think other companies are developing menin inhibitors? Are they also looking at type 2 diabetes or type 1 for that matter as a kind of a potential indication?

I'm sure they are. I mean there's been a lot of literature for menin inhibition. I would say, though, that you have to make sure you have a very good molecule that not only can pass kind of the oncology toxicity studies, but now you have to pass the non-oncology toxicity studies. And so you have to have a molecule that is very clean. And you have to go into developing, obviously, non-oncology disease knowing you have to have a very clean molecule. Most oncology drugs, I don't think can pass those non-oncology tox studies.

So let's just say, preclinical data is compelling. So you go into the clinic and you're pursuing the late-stage development in diabetes, that's a really large trial. So do you think that this is the kind of indication that you might be interested in partnering out?

Yes, it's a great question. And so would we even want to develop it if it ended up just being a chronic therapy? I don't think so. I think that we would be really excited and engaged to develop and have a diabetes program if it was finite therapy, if it was short term. And I think that lends to a very different type of regulatory pathway. Obviously, that's something that we have to work with the FDA on is, what would the sizing of the trials look like? If we're doing finite therapy versus chronic, what are some of the supporting studies you need to do? Certainly, it's -- these studies, even if you are doing finite, you'll have to do much larger patient populations in target oncology. And I think we could certainly, on our own, get to a Phase I or a Phase II. But I don't think on our own, we could do a Phase III. And so I think maybe you're right, maybe it would take a corporate partner or some type of relationship to try to tap into those resources to have a large global study.

Okay. And then also, you guys are doing other oncology target validation and indications, and we have only like 1 minute left. So can you talk about when we might expect update from kind of pipeline expansion from new targets that you could announce?

Yes, absolutely. So we learned a lot about menin. We learned about complementary pathways. And so what we did was try to attack these complementary pathways, knowing that down the road, we would love to do proprietary combinations. And shutting down multiple mechanisms, I think, is the best way to eventually get to a cure for cancer patients. I think with single agent, it's very difficult because other pathways start to turn up. And so as we start to introduce the folks to our pipeline, we'll announce our second program in the first half of next year. Again, this is a covalent inhibitor. We're going after a clinically validated target. And we pick targets that folks didn't either realize that there was a cysteine or ammino acid to form a covalent bond or the people knew that there was a cysteine, but the design kind of missed the mark and left a lot on the table. And so you'll see that with an example with our second program in the first half. We will -- and keep in mind, we'll announce the program when we have an IND candidate in hand, meaning we will start toxicity studies and then be close to IND filing. With the announcement, you'll get the target, you'll get the molecule and all of the preclinical work that we did to validate it as an IND candidate. And the third program is right behind it.

I see. So third program, we are getting update in the second half of next year?

We haven't put a timetable on it, but we'll update you as soon as we announce the second program. But it's very close behind the second one.

I see. So our time is up. Thomas, thank you very much for your discussion, and I look forward to chatting with you more in the next coming months.

Sounds good. Thank you very much.

Take care. Bye.

Bye-bye.