Everyone, thanks for joining the Opco Conference. Please introduce our next presenting company, which is Biomea Fusion, and CEO Tom Butler is going to run through some slides, and then we'll take it from there with the fireside. Tom.
Okay, great. Thank you very much, Matt. Thank you very much for hosting us, and pleasure to be here again delivering this presentation. You know, lots going on for the company, a lot of exciting things. I'll be making some forward-looking statements, so please take note. Everybody knows the team quite well. We've been working together for a very long time, working on many successful therapies, and we're excited about Icovamenib and BMF-650's potential in the metabolic space. We are a diabetes and obesity medicines company.
We made that announcement at the beginning of JP Morgan on Monday, and it really was because of two key data sets that crystallized together at the same time at the end of December, which was the COVALENT- 111 top line data, which is a phase II, week 26, primary endpoint reduction in A1C from baseline, as well as key data that came together at the beginning of January, which was our in vivo work of combining Icovamenib with a GLP-1 semaglutide. Here, what we showed was really remarkable and unexpected data where we saw the increase in blood glucose lowering, accelerating the reduction in glycemic hyperglycemia in our animals. What was unexpected is that we saw additional body weight, but that body weight loss was really fat alone. A combination of semaglutide with Icovamenib really drove fat burn alone.
Mechanistically, this is, you know, really driven through menin inhibition, where we see that menin inhibition, not only in skeletal muscle, but also in white adipose tissue, really drives key fat burn alone. We saw complete preservation of muscle mass, which is very important. I think as we get more into the obesity treatment landscape, it's not just about body weight loss, it's about the quality of body weight loss. We have our important secondary endpoint week 52 data, which then completes the study. That will happen early in the H2 . We will have our type 1 diabetes open label data provided also in the H2. We have a type C meeting that we expect to occur in Q2 to discuss and align on the design and the sizing of two key studies for Icovamenib in type 2 diabetes.
That is in the insulin deficient patient population, the SIDDs, they're the lowest quartile of C- peptide insulin production amongst all with type 2. They really are suffering with hyperglycemia because of their C- peptide insulin capacity and not really because of their insulin resistance. They are very high on medical need in type 2 diabetes. We are excited to discuss this potential for late stage development with the FDA. We will also talk about and agree upon the sizing and the design of the GLP-1 combination study with Icovamenib. Here, what we want to look at are kind of two key segments, those who are initiating a GLP-1 and those who are already on a GLP-1 and have not reached their glycemic target. Lastly, the cornerstone of our franchise, BMF-650 for obesity, GLP-1 receptor agonist.
We think this has best in class potential. This would be developed, of course, in obesity, but as well as diabetes. We expect to have IND filing and cleared in the H2 of this year, as well as first patient dosed in the phase I study. Again, another high impact milestone where, you know, data generation is around the corner for this molecule. As I mentioned, our strategic focus in becoming a diabetes and obesity medicines company is really around our core two cornerstones of Icovamenib, which is an oral small molecule covalent menin inhibitor, and BMF-650, which is our oral small molecule GLP-1 receptor agonist. What we see and the rationale for the prioritization is really to go after the unmet needs that are not being addressed with current standard of care. This is where Icovamenib really shines.
We're really addressing an aspect of diabetes that's not being currently handled with standard of care. What I mean by that is that patients experience a depleting pool of their beta cells, not only at the time of diagnosis. At type 2, you've lost 50% of your pool of beta cells. At type 1, you've lost 90%. This pool continues to deplete whether or not you start an antidiabetic medication. Icovamenib would be the first medicine approved to address this depleting pool. Again, as I mentioned, it's really the top line data and the in vivo work that we've done that focuses and highlights where we should develop Icovamenib. That would be in the insulin deficient patient population as monotherapy on top of standard of care.
When we talk about the combination of Icovamenib with GLP-1, that would be really addressed to all phenotypes of type 2 diabetes. We see in our study that the efficacy is not impacted by a phenotype. It is really about GLP-1 receptor expression increases in key tissues that drives the data. It is not dependent on the phenotype. On the right-hand side is again the key milestones that I previously walked us through. This is the really exciting slide. This is what gets us excited internally, also our scientific advisory board and others. I think, you know, this is what really validates the mechanism of action of being a global menin inhibitor. I think, you know, what makes Icovamenib so unique as a menin inhibitor is that it is not a menin-MLL interaction inhibitor. It is a menin inhibitor, meaning we drive down menin protein.
This is what enables us to disrupt not only protein-protein interactions in the beta cells, but also in key tissue types. The reason why this graph is so exciting and so important is that we're showing you just with 12 weeks of treatment. On the shaded side on the left is Icovamenib dosed once daily for 12 weeks, so week one to week 12. The right-hand side is now off treatment of 14 weeks from week 12 to week 26. That's 14 weeks off treatment. Week 26 is our primary endpoint. These are all of the insulin deficient patients, the SIDDs that are the lowest quartile of C- peptide and insulin production. They are continuing to achieve a reduction in their A1C over time. What we, and this is placebo adjusted.
The placebo is basically just kind of a flat line across the zero mark for the full 26 weeks. These are all the arms combined. You can see the dose impact of Icovamenib and really just a strong result. Clearly, it has not plateaued at week 26. We are very excited to see, you know, what week 52 will show. Again, you know, really highlighting that patients are achieving a further reduction or benefiting further from the therapy off treatment, which means we did a very good job to enable the patients to produce more insulin or more C- peptide on their own. That is really something that has not been done before, to really allow a patient to have a tail benefit from your therapy and their A1C to continue to decline despite cessation of treatment.
The next slide is really highlighting the second piece of our effort in developing Icovamenib is the combination with the GLP-1. We did a lot of work internally, and we presented in October the insulin secretion increases that we saw when we combined with tirzepatide and semaglutide. We saw a doubling and a tripling of insulin secretion when we combined the two agents. What we're also seeing now is an acceleration of body weight loss. When we add Icovamenib on top of a GLP-1, once the GLP-1 weight effect and A1C effect has plateaued, we are adding not only glycemic benefit, but also weight benefit. Again, with the in vivo work, we're seeing that the weight loss is really just fat mass alone. Going into our next stage of development in combination, we'll be certainly looking at body composition very closely.
I think the fact that now this combination results in fat burn alone, that this really opens up the door for Icovamenib to be explored in the obesity space. Here, what we showed in December is that Arm C, which is dosing patients for 12 weeks once daily, starting with 100 mg, escalating to 200 mg for the final four weeks, we got about a 1% reduction in A1C. That's on top of whatever benefit they saw prior to receiving their GLP-1. We saw patients achieve up to a 14% additional body weight loss with the combination. Really exciting effects, and I think really drives our excitement to get into a larger GLP-1 combo study soon.
As our, you know, value proposition or development rationale for Icovamenib is potential first-in-class therapy with a novel MOA, we're really focusing on a unique treatment effect that other agents are not able to achieve in patients, which is a durable treatment impact on beta cell function and incretin effect. When you discontinue standard of care, their A1C and their weight comes back. We think with what we're seeing with Icovamenib, certainly after 14 weeks, that A1C is continuing to decline. We're very excited to see what week 52 shows. We enhance endogenous insulin production. We've shown improved beta cell function, body weight loss promotion, as well as preserving lean mass and building lean mass.
For us, the development rationale is getting into these two key patient populations, the insulin deficient patient population, as well as anyone who's about to initiate or already on a GLP-1. We've really demonstrated highly clinically significant reductions in A1C. We are looking also for BMF-650 in the clinic and potentially running novel combinations that are all oral with Icovamenib and BMF-650. Maybe I'll stop here then for questions, Matt.
Yeah. Great. Thanks, Tom, for that kind of high-level overview. I think one of the maybe fundamental misperceptions of the story is that Icovamenib is only a 12-week treatment. This is not a chronic therapy. Can you just kind of maybe talk about how you're trying to hone in on that message here? Because it seems to be getting lost on the street.
Yeah, it does. It certainly doesn't.
I think that's what we try our best with highlighting treatment period and off treatment period. It's really because when we focus our mechanism of action, and this certainly, this graph validates the mechanism of action, is focusing on beta cell proliferation. That's why you see patients are able to have a reduction in their A1C over time off treatment. Beta cells are very long-lived. You don't have to regrow these beta cells continuously. You just regrow the pool. The pool will mature into insulin productive cells, beta cells, and then they will respond to glucose as they should. Beta cells have a half-life on the order of decades. That's why you don't have to develop a chronic treatment.
I think that's what really opens up the door to a more accelerated path for this molecule is that we don't have to follow the chronic therapy path in terms of sizing of phase III, in terms of sizing of a safety database, et cetera.
What are you hoping to see from the week 52 data? Just a continued sustained decrease in placebo adjusted A1C, or do you think you'll hit a plateau?
I think just even, I think a win for us is even if just week 26 holds to week 52. I mean, just to show that there's just a consistent clean benefit for patients would be a home run. If we see a further decline in A1C, I would say that would be a grand slam for us. That certainly can be the case. We don't know how long it takes for the pool to mature and for the response to plateau.
What's currently your internal strategy? I know you have to have the end of phase II meeting with the FDA, but what are you proposing as a potential trial design? Would this be a week 26 A1C or maybe even something earlier?
Yeah. We've had that alignment previously during a type C meeting late 2023 with the FDA that the primary endpoint for Icovamenib is week 26, with the key secondary being week 52. When we're ready for that registration study or when we're cleared to do it, you know, that certainly would be the encompassed kind of timeline for the study would be week 26 primary and then completion at week 52.
Are you looking to hit like a 0.5% reduction, or is there some bar that you need to hit?
Yeah, certainly anything greater than 0.5% is clinically significant and would put us on par with, you know, the current mechanisms of action that are currently being prescribed in this space. Clearly you see with, in this insulin deficient patient population, this is across all arms. We see a 1%, you know, when we went and looked at Arm B, which treats out to 12 weeks and more consistent dosing, we got a 1.5% reduction at week 26.
I mean, it makes sense that this drug would work better in insulin deficient versus insulin resistant patients given the mechanism of action, right?
That's right. Yeah.
I think, you know, when we look at across the landscape of phenotypes, you know, the severe insulin deficient, they're just the lowest quartile of C- peptide production insulin capacity. The reason why they really have diabetes or they have very high baseline A1C, you can see 8.3, is because of their depleted pool. It's not because of insulin resistance. If you look at the insulin resistant population, their HOMA beta scores in the range of 74%-100%. They make a lot of C- peptide in a relative basis. Their median A1C is around target, around 7%.
I think for those individuals, really the GLP-1 combination makes a ton of sense for us with just monotherapy Icovamenib of the insulin deficient patient population, just matches the mechanism of action so well because their HOMA beta score is kind of a proxy for how well their pool of beta cells is responding to glucose. And 49% obviously is highlighting that it's just not making it anywhere near enough.
Is it pretty consistent in the literature that you can screen for these patients? If you actually just go back to that slide. Yeah.
Yeah. You can. And there's a lot of literature support saying that you can do it just based on baseline A1C and BMI alone.
I think, you know, when we actually looked across the literature, we saw that support, but we also did analysis on our own data and saw that if you just use baseline A1C and BMI based on the literature, reanalyze our data, you get to the same data point, meaning you just, you start enriching for up to 90th percentile of all of the insulin deficient patient population. Moving forward as we go to late-stage clinical development, we will use just baseline A1C and BMI alone.
Okay. A future potential label for this drug could, would basically be like Icovamenib for use in insulin deficient diabetes as measured by this on A1C, this restriction on BMI?
That's correct. Yep.
Okay. That's interesting. Do you want to talk maybe a little bit about the decision to rehome the company's focus on just the metabolic space?
Yeah.
You had really nice data from the FLT3 BMF-500 over at ASH. I also kind of like the idea of combining that with Icovamenib given some of the overlapping genotype mutations that we see there. What was kind of behind that decision?
Yeah. Great question. Just before we get there, just to make it clear, the GLP-1 combo strategy with Icovamenib is phenotype independent. That will work across all type 2. That is because just GLP-1 receptor expression is the focus here, not necessarily the C- peptide production. To your question about oncology, we were really agnostic coming into the clinic with Icovamenib because we disrupt menin globally. We drive down menin protein. That allows us to go into liquid tumors, into solid tumors, as well as into diabetes. For us, it is really about delivering where the strongest data is.
As a small company, we have to focus. When we got this data at the end of December and early January, it was very clear that the breakthrough type data is here in the diabetes and obesity space. We agree that Icovamenib oncology did very well. I think the combination of BMF-500 with Icovamenib in AML is extremely attractive. We think BMF-500 is best in class FLT3. We are really out there looking for a partner to run a head-to-head study of BMF-500 versus gilt because the FLT3 suppression that we are measuring in the clinic, we think, delivers that best-in-class profile. The really strong profile for BMF-500 is also that we do not deplete the bone marrow. We do not see, you know, reduction in neutrophils. We do not hit c-KIT .
This makes BMF-500 a really strong combination partner. You know, in AML, you typically see combo strategies because it is a polyclonal disease. There are multiple mutations. The fact that you can really deliver strong FLT3 suppression in the absence of neutropenias and cytopenias just speaks about the best-in-class potential of this molecule.
You are actively seeking partners on that front?
We are.
Okay. Back to the combo strategy in diabetes for the "heavier patients," the insulin resistant patients. Can you just kind of like walk through some of the data, I think, that you presented in October about why this biologically the synergy makes sense? I know it is a bit complex, but I think there was a message there.
Yeah. We really see a dual effect with Icovamenib.
This, again, is just because of the global disruption of menin and driving down menin protein. We see the beta cell quantity and function improvements, as well as GLP-1 receptor expression, which really results in an increase in insulin secretion. We get an increase in beta cell mass and function. We get an increase in insulin synthesis and secretion from just having a larger pool. We also get enhanced insulin secretion from having more GLP-1 receptor expression on the beta cells. We also see an enhancement of the incretin effect because we're increasing GLP-1 receptor expression in the duodenum. There's actually a paper that got published yesterday that really highlighted the effect of menin inhibition and GLP-1 expression. It really corroborated with the work that we published in October.
Let's check that out. On the COVALENT- 112, that's in type 1 diabetes. I've always thought of type 1 as, I mean, it's an autoimmune disease. Like,
yeah,
clearly probably going to need some kind of chronic treatment there, right?
Yeah, we're not sure because with type 1, what's interesting and it's early stages, so we have to see is can Icovamenib drive responses that are durable without an immune suppressant or not. That's TBD. That's what we have to prove in this open label portion. The theory is that, you know, when you look at the staining of islets from type 1 diabetes subjects, you know, it's not like there's a black hole where the islet used to be. It's spotty, right? There are still insulin-producing beta cells in these islets. The reason why they remain despite having the autoimmune attack is that the autoimmune attack doesn't hit all beta cells agnostically.
It really focuses on specific phenotypes of beta cells. Our approach and our hypothesis is that we should be able to proliferate or regenerate the phenotype that's not getting attacked. We want to first complete that work first with our open label and see how much headway we can get, which is monotherapy, and then look at other approaches as we learn about it. Great question.
Getting another question here on the safety profile for Icovamenib, there was kind of the scare with the increased LFTs that led to the clinical hold. You subsequently resolved that very swiftly?
Yep.
Now that you're looking at kind of a lower dose, you feel much more confident about the therapeutic window here?
Yeah. I'm glad you brought that up.
This slide really, really highlights the really the importance of the dose, but also time on Icovamenib to drive responses. This 0.075 to 0.15 really represents the 100 milligram dose well. I would say the 0.3 is about 200 mg. You can see that actually time matters more than exposure in driving beta cell proliferation once you get up to about 0.15 micromolar. We achieve that based on an AUC perspective in our patients with 100 mg daily. You know, when we were doing our dose escalation in the MAD phase, when we got up to 200 mg, we were getting much higher exposure, higher C max. We did not see really a big difference in response of the patients.
What we started to learn is that it's really the insulin deficient patients that just respond the greatest to this mechanism of action because of the C- peptide that we talked about. The clinical hold was based on the dose escalation study, and it was based on those who were starting at a much higher dose in the first 30 days. We think there was just an equilibration period where you have a rapid reduction in glucose and you get the glucose stored in the form of glycogen in the liver, and you're getting these LFT, AST elevations. When we submitted the expansion phase to the FDA, about 40% of the study was completed. That was enough. Once we sent that data, the FDA lifted the hold in 30 days. They knew that the expansion phase was not an issue.
Now we have 100% of the data, the expansion phase, clearly not an issue with LFTs. It was really about what is the dose you use in the first 30 days. I think going to 200 after the first 30 days, like we did in Arm C, also no issue. We think we have this well controlled. Really, the 100 mg is plenty of drug. I think, you know, as we learn about the insulin deficient patient population, as we learn about now the insulin resistant, it really just comes down to how much, how long should the treatment period be for some of these other patients that may need a little bit more boosting to get their pool back.
Yeah. Makes sense. One last one for me because we're out of time is just the financial situation right now with kind of the cash overhang. What are your kind of ideas for maybe creative funding solutions, partnering opportunities, etc.?
Yeah. You know, we really spent the last four weeks, you know, JP Morgan Plus, you know, and really met with a lot of investors to walk them through the data, walk them through the development plan with Icovamenib and then also the high impact milestones that are happening in 2025. We had really strong feedback from investors and a lot of positive comments. You know, for us, we want to make sure that we properly inform everyone of the data and the plan. Certainly at some point, we want to execute a raise that serves kind of as a bridge to these high impact milestones, but also to partnering discussions.
Because you can imagine if we're able to drive pure fat burn alone and drive a durable fat or drive a durable weight loss in patients with diabetes and obesity, that's a really strong development rationale for Icovamenib. If we can lay out kind of an accelerated path for insulin deficient, again, a very strong development rationale. You know, we're certainly, you know, engaging in partnering discussions. I think at the very least, we would like to get a clinical collaboration where we can get these GLP-1 trials up and running with a partner and generate some really exciting data.
Awesome. Tom, thanks so much for telling the story and look forward to seeing the updates this year.
Absolutely. Thank you very much for having us.