Great. Thank you so much. My name is Peter Lawson. I'm one of the biotech analysts at Barclays. I've had the pleasure to gather Biomea for the last couple of years, and it's been a thoroughly interesting story. Great pleasure to have Thomas Butler up on stage, Founder, CEO, Chairman of the company of Biomea Fusion. First questions we've been asking, and mostly that kind of no answers, but or no's as answers. Do you envision any kind of supply chain disruptions just as we think about the kind of the new world, more isolated world we're going to be living in?
Yeah, I don't. First of all, thank you very much for having us and hosting us again. We love coming to the annual Barclays Healthcare Conference here in Miami, so thank you very much. No, we don't see any impact to our supply chain, to really our operations, given the current backdrop. We don't see that coming.
Have you seen any change in the communication with the FDA?
No. It's always been very consistent, very steady. These guys are very hardworking individuals. Even our experience back at Pharmacyclics, FDA was always very responsive, very fast, even under furlough. We don't see any slowdown there.
That's a good point, actually. I mean, you're self-funded, but are there other drop-down effects that we may not appreciate as the NIH budget gets cut? Does it create a long-term impact on science? Are there any kind of near-term, mid-term effects, whether it's at clinical trial sites?
I think it won't impact necessarily the sponsored clinical trials. It'll certainly impact innovation long-term because you need the basic research done and funded by the government and done at top academic institutions. That's why we organize these institutions and the research that way. For us, I think it would impact IST development, which I think is a very important part of just clinical development of novel mechanisms of action, is that you rely on label expansion, understanding indication expansion, interesting combinations. There'll be less funding for that from an academic perspective. I think there will be some headwinds there, that it'll be on the sponsor to really do most of the work.
Yep, exactly. New world we're facing. Now, back to your very unique mechanism of action, covalent menin inhibitor and moving it into type 2 diabetes. Just what we should expect to see from what we've seen, the data has been really encouraging and intriguing. Kind of what should we expect to see in the second half when we get an update? I think of the 52-week data.
Yeah, great question. I think icovamenib reduces hemoglobin A1C in all patients treated. That's what we showed in December. It works particularly well in patients with type 2 diabetes that are insulin deficient. They really need a bigger pool of beta cells to produce more C-peptide, produce more insulin to control their hyperglycemia. That's what we highlighted in December. I think we will move from intriguing to very validating data coming up soon at ATTD, where we'll be sharing for the first time all the supporting work and endpoint C-peptide, which is a very important endpoint for us from a mechanism of action perspective of showing how our patients are improving their C-peptide production while on treatment. Is that sustained while off treatment? It's very important to show, right?
If you have a durable pool of beta cells, it should be sustained in terms of C-peptide production. Is the C-peptide production matching the reduction in A1C that you're seeing in your patients so that you're getting this correlation of mechanism of action and driving A1C to support icovamenib's MOA? I think it's just very, very important to share that. We'll share it for all patients that are analyzed in the patient population. It's going to be important for us to get this out and for people to talk about and see why icovamenib's working so well in insulin deficient versus insulin resistant. It's coming up soon in about a week's time.
Okay. That would kind of help us understand the deficient versus dependent.
The resistant. Exactly. That's exactly right. Coming post ATTD, just kind of working through the news flow, we'll be meeting with the FDA in Q2. That's to really align on the design and the size of the next studies for icovamenib in type 2 diabetes. Again, just as a reminder, we want to focus the development in the insulin deficient patient population in one trial. We think that could be a really strong opportunity for icovamenib. The second study will then continue our exploration of adding icovamenib on top of a GLP-1. We had really interesting and supportive preclinical work come out in January that showed not only does icovamenib on top of semaglutide drive further A1C reduction, we saw further weight reduction. That weight reduction was driven by fat mass loss alone. High-quality body weight loss.
What that means is we're really benefiting a long-term outcome, long-term durability from weight loss. We want to see this preclinical work translate into humans. We want to do more work in combination with the GLP-1. We think it's a very exciting combination potential. It really validates this dual mechanism of action of icovamenib, which we know on the one side is beta cell proliferation focused. The second one is GLP-1 expression focused, insulin secretion focused, and muscle preservation.
Gotcha. Thank you. As we think about the FDA interaction in Q2 for the size of the study, what are the bars around that? How should we be thinking about typical studies within?
Yeah, so great question. Because this is not being developed as a chronic therapy, the sizing requirements for our phase three for the safety database are going to be very different. It's going to be much smaller. We really had these type of general discussions with the FDA last year that we would not have to do a chronic type approach. It will be important for us to then, during this type C meeting, to have this alignment. The way we're thinking about it is that it would be on the same order of kind of oncology size phase threes, oncology sized safety database, because again, this is a 12-week course treatment, not chronic therapy.
Okay. And then we get to see updated COVALENT-1 11 in the second half of the year, I believe.
That's correct. Yeah. The final secondary endpoint of the study is week 52, and that'll help us just understand the durability of the response of this 12-week course treatment. We had the top line week 26, so we'll have another 26-week follow-up at week 52, and that's the last time point for the study. That'll be great just to calibrate how durable the response is after just 12 weeks of treatment. That will set the stage for us moving into late-stage clinical development because we aligned with the FDA that week 26 would be our primary endpoint for late-stage clinical development, and week 52 would be the key secondary.
Okay. Do you think that data in any way would change the clinical trial that you're discussing with the FDA?
No, I think the size and the overall design will be really for safety database purposes, not necessarily for efficacy or durability of response. I think we'll certainly be able to share trends of what we're seeing in the data set. Keep in mind when we published the week 26 data, the curves are certainly trending down. They're trending down for the insulin deficient patients, but they're also trending down for the insulin resistant patients. This 0.5% reduction we see in all patients treated with icovamenib, that certainly has not yet plateaued too. That keeps going down. The 1.5% reduction that we see at week 26 is in those that are very insulin deficient. They have a very low pool of beta cells, and they're very sensitive to increases in insulin.
A clinically significant improvement in C-peptide can have a dramatic impact on their A1C. What we want to align with the FDA too is because the insulin deficient patient population is such a high medical need, we think that there's room for an "accelerated path." We are hopeful that we can align on an adaptive design study where it starts as a 2B. If we meet certain safety and efficacy hurdles, this would flip to a phase three and provide data for registration.
Gotcha. Thank you. I guess the depth of the data we should expect to see for that 52-week cut, I guess, is it the gamut of like HOMA beta, C-peptide?
That's correct. Yeah. There'll be A1C, C-peptide, HOMA beta. That will be all in the second half. Just from a timing perspective, that would be towards the end of Q3 from an expectations perspective. For the week 26, obviously we have C-peptide coming at ATTD, and then HOMA beta and additional data we expect to be presenting at ADA.
Okay. Thank you. There are these two groups, sort of group B, group C, kind of if you walk through kind of the do you expect different outcomes for those groups of patients?
We certainly see it at week 26, different outcomes. This is our chance to explore what is the difference between just nice consistent 100 milligrams once daily for 12 weeks versus giving it once daily for eight weeks and then changing to a BID regimen. Obviously, you are disrupting menin differently for those final four weeks. We want to see is that attractive? Is that providing more benefit for the patient? Is it providing the same as just 100 milligrams once daily? Is it less effective, hitting menin twice a day? We just want to see what that does. I think to date, we see it is about the same as 100 milligrams once daily. Let's see with longer follow-up, maybe Arm C catches up.
Gotcha. You have kind of broken that market or segmented the patients into different subgroups. How do you think it kind of ends up performing in the SIDD versus the MARD phenotypes?
Yeah, so it's a great question. At ATTD, we'll be providing the baseline characteristics. You will get the patient demographics, disposition, and the breakdown within the different categories and characteristics. You can just see how the mean baseline A1C looks like, what's the different populations. You can quickly see, and then also C-peptide, but you can quickly see when you just look at insulin deficient, as you mentioned, the SID and the MARD, you have severe insulin deficient, so they have a very low C-peptide. The MARD patient population has more C-peptide at baseline than a SID. That comes out when you look at their baseline A1C. In general, a MARD has a baseline A1C of about 7- 7.5.
They do not have much, they do not have a huge need to have a big drop in A1C to get to target, right? They just need to lose 0.3-0.5 on average to get below 7% because they are certainly insulin deficient, but they are not as severe as the SIDD. You would not expect to see such a dramatic reduction in A1C in that patient population because they are starting with a lower baseline. For the SIDD, a bigger reduction in A1C because they really need it. Certainly from a cardiovascular outcomes perspective, there is a lot of literature that suggests that it is much more important to drive below 8% than to drive below 7% from a health outcome perspective. That is where SIDD becomes really focused as a very important unmet medical need because they really struggle to get below 8% with current therapy.
Gotcha. Thank you. Really helpful. As we move on to type 1 diabetes as well, second half, we get data, what should we expect to see? It is 40 patients or so, but what cohorts, what doses will we see at that level?
Yeah, so for us, the clinical hold that we had endured over the summer last year had a much bigger impact on the type 1 study. That is very much under a reset. What we are focusing on is looking at patients who are a little bit closer to diagnosis, so zero to one years moving forward, just because we think that they have a bigger pool to start with than those that may have had type 1 for many, many years. We want to hone in on this PK/PD relationship of monotherapy icovamenib in this patient population. That data will then come in the second half of this year as well. Obviously we will be sharing C-peptide, A1C, changes in insulin, some of these important measures.
Are there particular subgroups within that? There's type 1s that we should be honing in on or particular doses you think we should hone in on?
No, I think it's really just about years since diagnosis is kind of how we're thinking about splitting up, quote unquote, the patients. Obviously, the closer they are to diagnosis, the bigger the pool that they have. We just want to see how much of the pool can we restore for these patients. I think we've all seen that the FDA has made it clear that if you can slow the destruction, that is a big win, right? They know that if you measure the C-peptide over time in a type 1 patient, it has a nice steady decline because the immune system keeps attacking these beta cells. If you can reduce the decline, that's really the endpoint that FDA is looking for for an improvement because you're lessening the insulin dependency of these patients, which has a big-time impact long-term.
Now, we're hoping that not only do we see a reduction in the decline, we think we can actually halt the destruction of C-peptide. In some cases, we think we can actually start growing C-peptide production in type 1. This is certainly work that we're very focused on. Seeing the SIDD responses that we saw in type 2 gets us really excited about the type 1 potential. This mechanism of action works very well. It's really about just we're trailblazing a new pathway and we're learning as we go. 111 and 112, the way they're designed, gives us so many answers for us to then prepare for late-stage clinical development.
The data will be continuing to flow out in 2025 and getting people excited that we're really honing in on who are the key responders and then how do we get to that now registration study.
Yeah. Did the Sana data that was presented in January, did that kind of set a bar for you or change the way you think or?
No, I think it's great to see innovation in other modalities and thinking about islet transplant and these different pouches. I think people are just trying to find ways where type 1 individuals are no longer dependent on insulin injections. Any way which way we can do it, whether it's through transplant, maybe you combine icovamenib with the transplant, maybe it takes less burden. It takes the burden off of the transplant on sizing, right? Because if you transplant it, icovamenib can replicate those cells that you transplanted as well. I think innovation is needed to drive patient responses and doesn't really change the bar that we set for icovamenib, but we'll certainly keep abreast of how this space is advancing.
Gotcha. Thank you. I guess safety metrics that we should be looking at beyond kind of discontinuation rates. Are there any things we should be honing in on?
Yeah, if you look at the, oh, some additional data that we'll have for ATTD and ADA at week 52, obviously is hypoglycemia, which we've gotten questions about. Is the new beta cells, how responsive are they to glycemic cues? Are they just operating like normal beta cells? They are normal beta cells, so we don't expect to see any hypoglycemia. What about weight change? We got that question quite a bit. We will be sharing weight change for icovamenib in our studies. Just as we'd expect, as patients start to regain their own glycemic control, you'd expect their weight to come off, not gain. I think there was a concern that icovamenib could cause weight gain because they're increasing their insulin production. This is their own insulin. This is a responsive endogenous insulin, not exogenous insulin. We'd expect slight weight loss.
This is not a weight loss drug by any means. It would become a weight loss drug when you combine with the GLP-1. Definitely not weight gain.
The safety metrics for the updated type 1 data, is there anything we should kind of be?
No, safety discontinuation. We saw in December, very strong. No discontinuation due to a TEAE. No study discontinuation. No reduction in study drug. Very strong safety profile, which was great to see coming off of that clinical hold that we picked the right dose levels for the expansion phase. We think the risk-benefit profile of icovamenib is very strong. As we continue this study now marching towards week 52, that safety data continues to look very good.
Are you expecting a similar kind of duration of treatment in type 1 versus type 2?
Yeah, that's a good question. That's something that we have to sort out. We don't know. It's too early to tell what that's going to look like. Certainly as we get to the second half data set in type 1, we'll start to get a better feel for what does that durability look like. Keep in mind that when you look at an islet from someone who has type 1, the islets are not just black holes, meaning all beta cells are gone. They're very kind of patchy or spotty. That's because the beta cells are not having all the same phenotype. The immune system is attacking specific beta cells that are flagged with proteins. They're really targeting those beta cells. They leave other beta cells behind. We will proliferate those beta cells left behind.
Perfect. Do you think you can see an effect in kind of stage 2 patients, ones that are pre-symptomatic type 1?
We do. I think we've gotten a lot of feedback from our KOLs and from our advisory board following the December data set that if you can continue to show and validate this mechanism of action with C-peptide data, with further reduction in A1C, you should really think about trying to move in earlier lines as possible and even moving into pre-diabetes. Because if we can halt or regrow the pool of beta cells, and these patients have already lost 60+% of their beta cell pool, why wait until they're at that low level? Why don't you capture them at 70% or 65% and regrow the pool by a few percentage points so that they never fall below and reach the threshold of type 2 diabetes?
That would be a wonderful outcome that you can just pre-treat and prevent diagnosis of diabetes for those who have pre-diabetes by just replenishing the pool, let's say every 12 months as an example.
Yeah. Okay. Perfect. Thank you. We kind of touched upon it, but your own GLP-1, kind of where do you stand for that?
Yeah, so we have an oral small molecule GLP-1 BMF-650. The IND enabling studies are on track. We expect to file the IND and be in the clinic in the second half and start generating weight loss data by year-end. This is a very good molecule. Our approach is quite unique in that we are going for very flat PK, very high AUC. What that does is prevent this kind of bouncing on and off the receptor and causing nausea and vomiting and GI side effects. We think this type of profile will show a nice blend of efficacy and safety and really be considered one of the top oral small molecules.
Gotcha. When do you know it's early days, but when would you expect to see initial data with that?
Yeah, initial data by year-end 2025 or early 2026.
Okay. Do we get kind of updated, do we get pre-clinical data this year as well for the molecule?
For BMF-650?
Yes.
Yes.
Yeah, the GLP-1 .
We will. Yeah. We'll continue to share our pre-clinical data on the molecule.
Okay. I know January you kind of talked about this migration away from the oncology business and being very squarely focused on diabetes, obesity. Kind of what's the status of those programs and the idea of getting a partner to run those trials?
Yeah, great question. Yeah, 101 and 102, which as a reminder is our liquid tumor and solid tumor trials. Those are being wound down and really focusing icovamenib in the diabetes and obesity space. That comes obviously from GLP-1 combination, but also monotherapy. We will no longer apply icovamenib into the oncology space. I think we made really good traction and people can understand how icovamenib works in these certain mutations. For BMF-500, that's COVALENT- 103. We are very excited about this molecule. This molecule continues to show best-in-class profile for a FLT3 covalent inhibitor. We will find a very good home for this molecule. We want to make sure that we have a nice robust data set to share this year to show people how strong this molecule is.
Gotcha. Just with a given market uncertainty, market volatility, kind of how are you thinking about capital raises versus partnerships?
Yeah, I think trying to get in as much non-dilutive capital. I talked about the importance of ISTs. I think ISTs are important because that allows you to develop your drug in important areas without having a lot of sponsored expenses. We will be very smart there. We want to do a lot of GLP-1 combination with icovamenib. We will look for corporate partners to help us with these combinations because you can imagine there's a lot of different combos that we could do, doublet, triplet type of combinations to really bring a unique mechanism of action to the space. We will be looking to do that with partners.
Perfect. Thank you so much, Tom.
Thank you, Peter.
Always appreciate it.
Pleasure.
The conversation.