BridgeBio Oncology Therapeutics, Inc. (BBOT) September 10, 2026 Conference Transcript

Citi's back-to-school biopharma conference. I'm Eric Joseph, Senior Biotech Analyst with the firm. And our next fireside discussion is with BBOT, Bridge Bio-Oncology. And joining me today are CSO, Pedro Beltran, Chief Operating Officer, Edan Mellick, and Ben Young, Chief Medical and Development Officer. Thanks, gentlemen, for joining us. I thought maybe just, you know, by way of starting out, it would be good, helpful to have you guys sort of provide us with a high-level overview of BeBot, where things are today, and, you know, maybe walk us through your updated strategic focus announced earlier this week.

Yeah, thank you, Eric. Thank you for the welcome. Yeah, excited to be here and share our strategic focus and how BOT is doing. So we are a clinically staged biotech company. We are focused on next generation RAS, small molecule therapeutics, and we have three assets essentially in late phase one development expansion, BBO8520, which is our KRAS-G12C specific inhibitor that it's a first in class molecule because it brings the ability to inhibit the on state, so inhibit GTP bound KRAS-G12C. And that molecule, we shared updated data yesterday. day. In that update in the second line, naive treated patients showed 63% overall response rate, and then shared data in the second line, pre-treated patients, Kerochitof-C, which we can talk about a little bit later, showing there's a 75% response rate at a 500 QD dose in combination with Pembrolizumab. That molecule also differentiates itself because it can be combined with pembrolizumab with no hepatotoxicity, so that allows us to do that combination. The second molecule is BBO11A18. This is our pan-K-RAS inhibitor, so it's mainly designed to go after D and V-K-RAS mutants. And that molecule, we shared initial efficacy data earlier in the year at J.P. Morgan, showing initial hints of efficacy in PDAC. That molecule is differentiated because it targets only KRAS. There's a pan-K-RAS inhibitor that allows you to have a much better therapeutic index. In that same update, we show no or low skin toxicity, no stomatitis. And the goal there with a molecule is to really open up combinations. We're a small molecule oncology company. We believe in combinations being the key to success in oncology. And a PAN-K-RAS inhibitor, we believe it's much more combinable than a PAN-RAS inhibitor. And then finally, our third molecule is BVL-10203, which we also call breaker. And that's because it breaks the interaction between pediatric kinase alpha and RAS. And the way we like people to think about this molecule is a PAN-RAS inhibitor, but only for the pediatric kinase pathway. And so that molecule allows you to inhibit any RAS from activating the pediatric kinase pathway, which is used as a salvage pathway when you inhibit the MAP kinase pathway. And that molecule, we also show data earlier in the year, you know, have a great safety profile. Main key there is that because the insulin receptor does not depend on RAS, we do not have hyperglycemia. So we're able to inhibit signaling from pediatric kinase alpha without hyperglycemia. And then it presents a unique opportunity to combine with KRAS inhibitors, and that's because most KRAS mutant tumors are wild type for pediatric kinase. And so it allows you to combine and do that double pathway inhibition without any safety liability. So those are the three molecules. Again, we believe combinations are key here, and these three acids are designed to be combined amongst themselves and also to be combined with a standard of care therapy. So strategically, what we presented yesterday are essentially two areas of focus. So as the new management team here got together and we prioritized what we want to do, we're really allocating capital based on probability of success, very clear regulatory path, so path to registration, and then obviously patient benefit, right? So the two areas of focus here are putting 8520 in the second line plus KRAS-G12C experienced patients. And this is, again, because we can combine with Pembro. And because we have the own activity, we believe we can have activity after a G12C off inhibitor. And we don't believe that we should be competing in the first line. We can talk about a little bit of that commercial challenge there. But, you know, five large companies in the first line, they'll be, you know, those patients will be coming off first line. there will be GTOF-C pre-treated. We think that will create a wide space for a new regimen there that essentially will be competing with docetaxel. So you're a very low hurdle for competition there. And then the second strategic imperative is to focus on the combination of pan-KRAS 11A18 with a breaker. You know, as we described, that's an aspiration for the company. We believe inhibiting both of these pathways is key in inhibiting mutant KRAS signaling. and so whether they're in their combination by themselves or with or without standard of care uh in kras mutant tumors very focused on pdac and crc uh is the second uh you know strategic uh imperative for the company okay great great um maybe maybe let's just pick up on the the second line g12c uh long opportunity that you're you're honing in on um first just from a sizing standpoint Right.

Obviously, you know, this is almost going to be an evolving market, I'd say, right, when we think about where front line is going to move with G12C plus Pembro combinations over time. So, you know, how to think about not only, you know, the overall size of what second line looks like, but, you know, is it all sort of previously G12C experienced patients that you think would be eligible for an on-off inhibitor in that setting, right? I guess what I mean to say is, would the altimers be expected to remain sensitive to further G12C inhibition, or would you kind of need to select or enrich for patients that would be more likely to respond?

Yeah, I'll touch a little bit on the science and then let you then talk about that commercial opportunity. So, yeah, so the way we see it is because the first line, those G12C off-only inhibitors to combine with Pembro, they need to lower the dose of that inhibitor, right? So it's a suboptimal dose that probably has an aura around 20%, right? if you look at all the biology and all the data from the clinic adaptation to that is not going to happen by switching away from g12c right even when you have full dose g12c inhibitor at least 50 of those tumors are still very addicted to g12c if you lower that dose that's going to be adaptation either through pushing us into its own state or changing sensitivity or affinity of some of those molecules to each other it's not going to go but it's not going to change by you know be in a mutation on D or doing something that a C inhibitor is not going to be able, you know, a stronger C inhibitor won't be able to overcome. And then, you know, just on explaining why we believe 8520 plus PEMBRO will work after, you know, we just see it as driving a new immune response. So 8520 will get you a new wave of cell killing, a new wave of epitope release, and then a new T cell response that in the presence of PEMBRO will have durability. right so essentially doing the same thing that you did in that we know works in the first line right you'll do it again in the second line and because we can add pembro because we have this safety liver signal where we don't have alt and ast in combination we think we can do this in the second line add durability and really grow a market that will be meaningful and i'll let it and talk about that yeah thanks so we do think this is a significant and underappreciated growing market there we go uh so we do think this is a a significant and underappreciated growing market

he said this is a market that is emerging but we think with six phase three trials currently in the first line with off inhibitors um you know there is a very very high chance that by 2028 2029 2030 the majority of first line patients are actually going to be treated with a g12c off inhibitor and so you get this growing market i mean diagnosis of metastatic g12c nsclc in the u.s alone about 15,000 patients annually, we think that as this market grows and matures, 5,000 to 7,000 patients will be eligible for this regimen in the second line if we progress to registration. And so I think the key things to remember here are, you know, one is this transitioning market where actually the current second line for G12C inhibitor-naive patients is shrinking. And the second part that we have to think through, um, and we'll see this as the data emerges further is really duration of treatment, right? A lot of oncology, especially later line therapies are limited on revenue because of short duration. Um, what we're seeing here and the inclusion of Pembro in the regimen is part of this, uh, angle for extending duration on these patients with very, very high unmet need, um, is actually, um, having that, that duration of treatment, to build the market size. And we can see early indications of that in the data we released on Monday.

Yeah, I mean, so in fact, your combination with 85, so your PEMBRO combination data with 8520 do speak to activity in a G12C experienced population. I guess, can you kind of further characterize those data, particularly the experience of patients to their prior G12C inhibitor outcome. I guess what I'm trying to get at is whether patients that came on to that combination study were refractory or prior responders to their G12C inhibitor and whether that you think is predictive of whether they're going to be responsive to an 8520 regimen.

Yeah, maybe I can take that. Great question. You know, we have done some subgroup analysis to understand that better. So whether it's refracted to prior GTO-C versus progress on intolerable, there's no difference in terms of response to this particular combination.

Okay, great. And you touched on it a little bit, Pedro, but just, you know, you have an expectation that sort of re-treatment with immune checkpoint, I guess this would be sequential, right, or successive treatment with a checkpoint inhibitor, would be clinically additive. Maybe you can just sort of, you know, speak to that a little bit further, right? Whether sort of you are seeing or had the ability to see in your own data that sort of immune or, yeah, sort of that immune reset or sort of reactivation with anti-tumor, maybe anti-tumor activity driven by 8520 that sort of, you know, may drive responses and durability.

Yeah, I mean, clinically, you know, we don't have evidence that there's a new immune response triggered by 8520, you know, after the previous GTOF-C pretreatment. You know, however, you know, pre-clinically, we certainly have evidence that 8520 can drive deeper regressions after a GTOF-C inhibitor. uh and and really i mean again if you think at the if you think about the data you know pembro after pembro probably is 10 percent response yeah um and so you know i i think there's the only way to explain this data is is by um you know looking at a second response after a G12C inhibitor that gives you new immunogenic cell death. Then again, then you have PEMBRO on board, right? You get those T cells activated, and then you get a prolonged immune response that is giving you that durability. I don't see how else you would explain the clinical data.

Well, yeah, I guess the experiment really hasn't been done because your monotherapy data is in primarily G12C naive, you know, pretreated patients. and here it's a combination of new i mean if you don't have a new you know release of antigen right by 85 20 getting some cell killing it's very hard to see how pembro will drive a new immune response okay so i guess maybe maybe i'm perhaps a little bit unclear as to what the development strategy is is it the combination cohort that you want to drive forward in second in line yeah okay and uh and so i guess i'm getting at the question of like how confident are you that pembro is additive on top of 85 20 uh and yeah yeah i mean we don't have that contribution of components later right which is what you would you would need to answer that question but again based on what we see from pembro after pembro right uh you know we believe there has to be a synergy between these two agents working together okay great um um maybe just from a um a tolerability standpoint right um you know we're aware that historically there's been issues with g12c off inhibitors when combined with pembro you spoke to it earlier where in many cases you know you have to sub-dose patients uh in the first line setting uh maybe can just sort of speak to uh how 8520 is differentiated in that point and um i'll

follow up i guess and just with a more detailed question as it relates to your data sure um you may recall we shared earlier data uh back in january fiber this year about the monotherapy data where uh you can see the safety also uh differentiated uh from the liver toxicity a perspective and the main safety is around the gi which is a class effect if a while similarly as a combination with pambolizumab uh deliver uh safety profile uh holds up nicely uh where we we don't have uh you know a high percentage of astl the elevation still like a single-digit or low-double-digit, the only grade-3 STLT elevation, according to the principal investigator's medication contribution to that AE, high-grade AE, otherwise still remain quite clean. So that side, I think the safety profile seemed to be quite tolerable and manageable as well.

Okay. Okay. The data that you reported yesterday in terms of the safety profile, I guess really considers a valuable patient if I have it correctly, right? Those who had at least 12 weeks follow-up, kind of similar to the efficacy, the patients that were eligible for efficacy evaluation, right? So just to try and more fully understand the clinical profile of the 85-20 plus Pembro combination, I guess, can you speak to, you know, total numbers of patients that have been treated to date with the combination and whether sort of, you know, there are any AEs or earlier discontinuations early in the treatment regimen that are worth considering?

Yeah, great question. So we have this efficacy-valuable population for the reason, for the purpose of reading out the efficacy. see. And you can imagine we do have a couple more patients enrolled. That's still early, has not passed the 12-week landmark for the efficacy analysis. The number changes every day. But what I can say is we don't have any early discontinuation due to either reverse event in those newly enrolled patients. Okay.

All right. So, I mean, the safety data from the patients that we're not seeing yet with immature follow-up is all consistent with whatever what's uh reported yesterday great um all right so i guess looking forward how should we be thinking about what the you know uh will comprise the next update and sort of when you might hope to come back to the street you know how should we think about total treated patients and meeting and follow-up at that time point yeah so we're looking uh obviously into you know confirming this signal uh so the guidance for that is is mid-2027 uh you know we hope to come back with with you know a larger cohort of patients and a strategy for for registration if you want to add anything to that um and looking further still i mean uh i'm wondering what sort of you know assuming all the uh you know everything kind of proceeds as hoped um what does the registrational path look like for the combination and the second line setting?

Yeah, we haven't really guided all the specifics. I think the data is still being generated to answer a couple of questions around the dose and also the contribution component, which is required to have a meaningful conversation with the agency. So, but one thing you probably can tell based on the information we provided in the corporate deck the current standard care uh single agent chemotherapy uh activity and then safety is not ideal so you're talking about a single digit uh maybe low 10 percentage or a very short pfs so you can imagine in order to show superiority to the current standard care the bar is pretty low so it'll be very capital efficient in terms of the pivotal study design yeah so it'll be a large huge phase three you can imagine from that perspective uh so again uh you know once we

have uh more data available and have opportunity to talk to the agency we'll guide us specifically around the pivotal design okay okay um great let's let's turn to um the pan k ras and also the the ras pi3 kinase breaker um part of the pipeline um maybe just sort of you know at a high level walk us through the rationale to each of these molecules and also using them in combination. You spoke to a little bit earlier, Pedro, but maybe just, you know, kind of just delineate a little bit sort of where, you know, this idea of, I guess it's more reflexive induction or feedback induction of pi3 kinase ras media pi3 kinase signaling is you know problematic i guess in managing uh you know getting full full efficacy uh in in treating cancer yeah so i think these two molecules really go back to two pillars of the science of dvlt right so the first one

is that we believe that the driver oncogene is mutant kras right so this is the the protein that needs to be inhibited to get efficacy. It's not wild type KRAS, N-RAS, H-RAS. It's really the mutant KRAS. And then the next step to that is that one thing that we are very confident on is that the real ability of KRAS, mutant KRAS, to be such a transforming oncogene is because it's able to activate both the MAP kinase pathway and the Piatrikinase pathway. If you look at all literature, you'll see that actually it's very difficult to transform cells with RAS if you don't have piatricinase alpha signaling. The cell actually chooses to die, go on their oncogene-induced senescence. So if you take those two concepts, then what we try to do here is reach a point where we can inhibit both pathways, but do that with a therapeutic index. And that's something that we as a community have tried to do in the past by combining MEK inhibitors with piatricinase inhibitors, for example. So, you know, the efficacy is great, but then also half of the mice are dead. And then we moved that in the clinic, you know, failed in phase one, right? Now we are in a position where we believe we can do this combination with a much better chance of success from a therapeutic index point of view with these two reagents. So A1-8 addresses mutant KRAS, right? DMV really gets you ability to go very deep into the inhibition of that pathway, a MAP kinase pathway, because it's not limited by all the toxicities. You're only inhibiting the mutant, you know, KRAS allele. We know that when you do that in a lot of tumor cell lines, especially in the pancreatic lung and colorectal fields, you get activation of piatric kinase alpha, right? And that activation probably keeps the cell alive until it's able to adapt or come up with a resistance mechanism. And so the key here is to try to inhibit that piatric kinase pathway that is getting activated in response to the MAP kinase inhibition to get cell death right and we have shown pre-clinically that when we do this combination you know we get we get regressions we get long-lasting regressions in tumor models and so that's that's what we're trying to now do in the clinic we have now moved both of those agents uh into the combination that's you know currently ongoing uh in the clinic okay um and maybe it's it's captured in the indications that you're looking to pursue the combination in but um just uh is is it is is is activation of pi3

kinase as a result of inhibition of map kinase signaling something you see uniform across different uh histologies and um not only across different histologies but within a given histology I would say it's very common.

It's not every single tumor doesn't do this, but I think it's very common. And it's driven likely by a wild-type RAS, like NHK. And so that is the beauty of the breaker is that it is a pan-RAS inhibitor. So you don't have to worry in that histology and that specific tumor, which is the RAS that is stepping up to activate the pediatric kinase pathway because the breaker by binding to pietrokinase itself acts like an effector broker, right? Preventing any RAS from binding and activating pietrokinase alpha. So that's the beauty of that combination.

So both molecules are in phase ones with monotherapeutic phase ones currently, right? And I guess we're looking toward an update in both trials in fourth quarter, I guess. What should investors focus on in those data sets that, you know, would allow them to better, you know, evaluate the molecules independently and just think about the, you know, maybe get how to think about that carry four as a combination regimen and for development.

Yep. So I think, you know, we're releasing, we've got TQ4 on monotherapy datasets for both 10203 and 818. 10203 is going to be updated on the initial escalation data we shared back in january of this year 818 you know we took in a very early con disclosed it uh escalated through 600 mig uh bid uh just three patients out of that dose back in january and so what we've disclosed now is that we've escalated through 800 mig bid no dlts cleared that cohort and then backfilled and so what we're aiming to share is sort of a cohesive data set in second line pancreas plus pancreatic cancer um which will show an efficacy benchmark uh you know which you been taken and compared to other phase one trials from other RAS inhibitors. In tandem with that, I think a big point of differentiation here for the molecule and a thesis across the entire portfolio is really the tolerability of these agents, the combinability or potential combinability. And so I think seeing a safety signal or a safety data package across a larger set of patients here is going to be really meaningful in terms of helping us and the community here identify, you know, the potential for this agent as we look towards registrational combinations.

In thinking about just sort of the, you know, the updated efficacy look with 10-203, just from an efficacy standpoint, how should we replace expectations?

I imagine, you know, monotherapeutically you know the real effect of it this value is kind of seen in the combination regimen i imagine right so i guess should we expect much from an efficacy standpoint as from its monotherapy monotherapeutic profile yeah i think i mean inhibitors of the pi3k alpha pathway um you know it's a g1 rest pathway so so typically monotherapy don't show much i think the other point here is um you know you can look at the the patient types that we enrolled in that dose escalation study, largely third line plus CRC patients where standard of care or R is low single digits. And so I wouldn't expect too much in terms of response. We did disclose in January DCR of 62%, which is above benchmark for standard of care. So you could see follow up there, but largely oriented around continued safety, the lack of hyperglycemia. Remember, we have no restrictions on HbA1c or glucose status for these patients. And so it's largely going to be confirming that initial signal will be shared in January.

Okay, excellent, excellent. So I guess thinking about just, you know, an initial combination trial going forward, I guess where do you anticipate sort of focusing, or would you focus in a particular histology to start there maybe? And I guess, how are you thinking about where you want to establish proof of concept, basically, when it comes to the combination of these two agents?

Yeah, both the combination of A1A and DEN-203 is ongoing in pancreatic and colorectal. So for pancreatic, you know, we believe this could be the approach that breaks colorectal for KRAS inhibitors, right? As you know, CRC has now been sensitive to monotherapy KRAS inhibitors. and you know one of the possibilities to explain that is that you have a very strong pediatric kinase alpha pathway right and that's highlighted by the fact that out of the three is the only indication that has a you know good number good prevalence of pediatric kinase alpha mutations right so about 15 percent of crc is pediatric kinase alpha mutant so i think that gives us a very you know a very strong signal that the biology there is probably super important and maybe the reason why it doesn't respond well to RAS, K-RAS inhibition monotherapy. So that combination there, obviously, we're looking forward to maybe breaking that resistance to RAS therapies in CRC. Okay, got it.

I'm just thinking about, since the trial is up and running, I mean, how are you kind of proceeding with dose escalation?

I guess maybe we can just talk to this dose escalation scheme. is it is it has has a go forward dosing but established for both regimens or you kind of max max on one and then escalating the other can you just speak to that a little bit yeah um breaker uh we have a uh shared the monotherapy data and then we also share the recommended dose for expansion especially in combination with other standard carriers 500 milligram qd dose so that'll be the dose for breaker cactosumab a standard dose uh so according to the label okay yeah great great um excellent all right well um maybe just you know as we look

to wrap up here you can just sort of speak to um where you know your cash position is today and sort of you know the runway what is encompassed in the runway looking forward here in terms of you know milestones that can be uh accomplished within that runway yep so we ended q2 of this year with 344 million dollars in cash um this provides a runway based on our guidance into 2028 obviously that's uh you know a broad time frame but encapsulated in that runway is full phase 1a 1b um enrollment for all three of our clinical programs and so essentially as we begin to think about registrational trials, that's when we'll later those in and that should come as we initiate these combinations and start seeing data and making decisions about what will be a compelling registrational strategy across these programs.

Excellent. All right. Great. Well, thanks again for your time this afternoon. We really appreciate it and thanks everyone for tuning in. Thank you.