Good morning, everyone. I'm Andy Berens, Senior Biotech Analyst at Leerink Partners. Thanks for joining us on day two of our Leerink Partners Global Healthcare Conference in Miami. We're very excited to have with us BridgeBio Oncology Therapeutics. We have Uneek Mehra and Pedro Beltran. Thank you.
Thank you.
Why don't we start with a brief overview of the company for those who may not know?
Thanks, Andy, and good morning, everyone. Thank you to the Leerink team for having us here. I am Uneek Mehra, Chief Financial Officer, and with me is Pedro Beltran, our Chief Scientific Officer. We'll cover a few slides, maybe three or four slides, just to give an overview, and then we'll dive right into the discussion. BBOT, which went public in August last year and separated out from BridgeBio, is focused on next-generation RAS therapeutics.
Our real purpose and mission is to accelerate scientific medical breakthroughs through not only greater efficacious medicines, but also tolerability. We are focused really on high therapeutic index for all our small molecule targets. We do that through optimized target coverage, which covers two of the main oncogenic pathways, which is RAS and PI3K alpha.
I'll walk you through on the next slide our three main clinical programs, which offer an opportunity for us not only to create superior molecules by themselves, but also synergistic and differentiated combinations that target the KRAS population. We have multiple clinical assets, all three of them reading out in 2026 in the second half, so it's a very exciting year for us up ahead.
We have a strong cash balance at the end of this year, $425 million as of December 2025. That should take us into 2028. These are our three assets. As you see from left to right, we have a differentiated portfolio of these assets. The first is BBO-8520, which is our first direct on/off KRAS G12C inhibitor.
We published exciting data in January, 65% ORR in the monotherapy, 68% six-month PFS, and 83% of patients who were eligible for a six-month follow-up continued to remain on therapy. We also believe we have differentiated tolerability, which has been the bane for these G12C inhibitors, especially with the next generation of on/off inhibitors.
Most of these on/off inhibitors have been dose de-escalating as they combine with pembro. We have identified a 500 mg dose, which is an active dose that we are combining now with pembro, and we continue to see very low liver toxicity. We also see early but encouraging signals in highly resistant STK11 KEAP1 co-mutation population. That's about 25%-35% of the G12C non-small cell lung cancer population. In the middle is our pan-KRAS BBO-11818, which is also a on/off inhibitor. It's a reversible bioavailable oral inhibitor.
Interestingly, it's the first pan-KRAS that we have, which we have announced a partial response. In this field, there haven't been a pan-KRAS that has announced a response so far. We had a pancreatic patient with 56% tumor reduction that we announced in January. We continue to see a differentiated safety profile, and our PK is consistent with the dose as we are now in the dose escalation mode.
Our novel RAS PI3K breaker, which we call BBO-10203, it basically blocks the interaction between RAS and PI3K alpha. We have announced monotherapy data in January of this year, where we continue to see, as expected and from the preclinical studies, no hyperglycemia on the safety level. We have had no HbA1c restrictions in our trial so far.
Interestingly, we also announced that we saw full target engagement as well as we now are opening that up, and we continue to expand on three main dose expansions for BBO-10203. This is the sort of dashboard of the three molecules where we are excited to see individually each of them, but also this creates a potential for us to combine across the three molecules. We hope to have internal combinations of BBO-10203 with our BBO-11818, which is our pan-KRAS and a breaker, as well as BBO-10203 with our 8520, which are G12C. Those combinations should be coming later in the second half. In terms of our final slide, in terms of milestones, in the second half, all three molecules will read out on BBO-8520.
We should have additional pembro combinations, both safety and efficacy data. On 818, we should have additional monotherapy as well as combination efficacy data. On 203, the three combinations that are actively enrolling HER2-positive with trastuzumab, HR-positive with fulvestrant, and KRAS mutant with chemotherapy. These should all be reading out. With that, we'll get into the discussion. Thank you.
Great. Well, thanks. Thanks for the overview. I think we'll hit each of the programs. Why don't we start with 8520 since it's the furthest along? The current G12C drugs have been on the market for a while, and I think, you know, we've used to cover Mirati and so obviously aware of Amgen. Just wondering what you see about the limitations of the current agents that you plan to solve with BBO-8520?
Yeah, I can take that one, Andy. Yeah, so as you know, the off only inhibitors that the main liability they carry is that they only inhibit the protein when it's bound to GDP, right? The off state, that's a protein that is dead. It has no activity by itself. It has to cycle to the GTP on state. These inhibitors work by trapping or sequestering the off state, preventing it to cycle to the on state.
They do not block effector binding to the on state. If you have any on protein, which the cell can bypass that off inhibitor relatively easy, if you have any on protein, those off only inhibitors carry no activity, right? What we've done with BBO-8520 is make an on-off inhibitor, and that works by blocking effector binding.
It's a differentiated mechanism of action. It actually prevents RAF1 or PI3K alpha, the two main effectors, from binding to RAS when it's in its on state. It's a very differentiated mechanism of action, and we think that the ORR we're seeing in monotherapy is certainly, you know, a result of that increased better mechanism of action for a G12C inhibitor.
Okay. One of the challenges that the current G12C drugs have had in lung cancer is sharing the playground with checkpoint inhibitors. Obviously, Amgen had a lot of difficulty combining their drug with checkpoint, and checkpoint is very much entrenched in the frontline therapy of lung cancer.
Even in the second line, you know, we started hearing anecdotal experiences of patients that when they were switched from checkpoint inhibitor that they got on the frontline, that they would have liver toxicity in the second line and fairly quickly, and they'd have to come off of the G12C drug for that reason. I guess how does your drug potentially gonna, and you've had some data, so maybe we can talk about that. Hypothetically, why would your drug be better able to combine with a checkpoint inhibitor?
Yeah. If you think about the mechanism that I just mentioned, right? Because it is sequestering that cycling, that drug, that off inhibitor needs to be present every time that protein cycles. That means that even though it's a covalent inhibitor, you do not get the benefit of decoupling PK from PD. You have to be present all the time at high concentrations. The hypothesis is that high levels of covalent drug that binds to proteins non-specifically creates these hapten that then the immune system sees as foreign entities. When you put a pembrolizumab-like ICI, you drive an immune response in the liver that triggers toxicity.
What happens with a covalent inhibitor is that because you're binding all RAS G12C, whether it's on or off, you are removing all mutant RAS from the system, and that allows you to capture that PK/PD benefit of a covalent inhibitor. You target a protein, you clear that protein out. You don't need to be keeping the high level of inhibitor in circulation all the time.
What that has translated for us is that if you look at the amount of free drug that we need to achieve 60%, 65% ORR, it's, you know, 1,000 times less than the first generation of inhibitors, 20 times less than second generation of oral inhibitors. That allows us to have much lower drug present. When you combine with PD-1, you don't get the liver toxicity.
You know, we made the hypothesis, we have translated that into mice, and now we have human data that is also pointing, you know, very strongly in that direction. We're very excited about that combination because it allows you to do something that nobody else has done, which is do that combination at a full dose, full efficacious dose, get the benefit of the G12C inhibitor, get the benefit of pembrolizumab, get them combined, and get, you know, a clinical benefit that we haven't probably seen yet with the off only inhibitors.
Specifically building on that in terms of the data we shared, we had 15 patients combining at an active dose at 500 mg, and we saw just one case of Grade 3 liver toxicity, and that too was deemed to be a co-medication. It was an anti-arrhythmic that the patient was on. It's very clean, and I think that hypothesis pre-clinically has now started to validate in the clinic.
Right. Okay. It seems to be playing out the hypothesis that lower doses will lead to less liver toxicity, which should combine better with checkpoint inhibitor and facilitate usage, I guess, after a checkpoint inhibitor.
That's correct.
Okay. It's interesting that Amgen chose to dose their drug once a day too. I've always thought that they should have dosed that one twice a day, and then they pushed back on that concept.
Yeah.
Okay. I guess the next updates for BBO-8520 are what?
Next update is, we will continue to show more durability on the patients currently enrolled, as well as more combination data with pembrolizumab safety and efficacy in the second half.
Okay. Why don't we shift gears to one of the other two programs. When I initiated coverage, there was a lot of interest in the breaker. Then one of your competitors or one of the other RAS companies had, you know, had some speculation that there was gonna be strategic value unlocked very quickly. Would you say now that the next most important program is the pan RAS inhibitor or the breaker?
I think, or both are very important to us, and the combination of those two internally is even more important. It's just from a time sequence perspective, we are seeing pan-KRAS just clinically move forward quicker. Breaker is absolutely a cornerstone of our strategy.
Yeah. Okay, why don't we start with the pan-RAS inhibitor.
Pan-KRAS, Andy Berens.
Pan-KRAS. That's right. Let's start with that question first. What is the benefit or disadvantage of a pan-KRAS versus a multi-RAS inhibitor since the competitor I'm talking about is multi-RAS?
Yeah. Okay.
I mean, obviously, we have chosen the pan-KRAS strategy. We, you know, believe that KRAS is the driver, the mutant RAS that drives cancer. What that leads you to conclude is that then adding H and N do not add as much benefit on the efficacy as they add, you know, liabilities on the safety side of things, right? We and others, I think, believe that if you can inhibit mutant KRAS in the carcinomas that we usually talk about, lung, pancreatic, and colorectal, you can get all the efficacy, and you can get away from the liabilities of safety that have already been shown in the clinic, mainly, you know, stomatitis, rash, which are driven by a more wild-type RAS, MAP kinase, MEK-like, you know, pathway inhibition.
That is the main benefit. The other benefit is we maintain activity on wild-type KRAS. We think that is important in allowing that tumor cell to adapt and survive inhibition. Finally, I think, being able to inhibit KRAS when we say pan-KRAS, right? It's not a dirty kinase inhibitor. We're not inhibiting ALK and EGFR and RET.
We are inhibiting mutations of the same protein, right? G12D, G12V, G12C. They're all big drivers. Having one molecule that is able to inhibit all these mutations, think about it as having one molecule that inhibit all mutations in ALK or all mutations in EGFR, right? We know what the benefit of that is. It really prevents resistance, adaptation, you know, clonal selectivity.
You know, we believe the best phenotype, the best profile for a drug that targets RAS is to really focus on KRAS, but be pan-RAS, pan-KRAS, so that you can inhibit G12D, G12V, G12C, and the other mutants and stay away from the main liabilities that come out when you have a pan-RAS inhibitor.
Like BBO-8520, it is an on/off also.
Absolutely. Everything we've learned from BBO-8520, we brought into BBO-118. You know, the most important thing there is on and off activity.
Okay. In terms of the therapeutic window of the competitor multi-RAS inhibitor, can you talk a little bit about the toxicities that they've disclosed and how that may be eliminated by going more narrow towards pan-KRAS?
Yeah, I mean, I think the obvious biggest difference on the safety profile is stomatitis and rash, right? We are not seeing those with a pan-KRAS inhibitor. You know, how are those being driven? Obviously, stomatitis is very prominent when you inhibit the PI3 kinase pathway on a wild-type setting. MTOR, PI3 kinase inhibitors are very well known for stomatitis.
When you have a RAS inhibitor upstream, and you're inhibiting all that flow from the PI3 kinase pathway and from the MAP kinase pathway, that is what's driven that stomatitis, which I think, you know, it's certainly dose-limiting in the clinic, a big issue in the clinic with patients. Pan-KRAS, you know, shows none of that. I think that's gonna be a differentiator, you know, huge differentiator if the hypothesis on the efficacy, which means KRAS is the real driver, you know, turns out to be true, and I think all the mouse data, genetic data shows that.
Do you think that you're leaving any efficacy on the table by not targeting beyond KRAS?
I personally don't. You know, if you look at G12C inhibitors, right, in the clinic, multiple of them have been put into patients for a long periods of time. One thing you don't see is the emergence of mutant N and mutant H, right? If these were really the drivers of resistance that seem to be in vitro, when you do these in vitro experiments, clearly N and H show up.
We believe that's really driven by the fact that these cells are bathed in 10% FBS. They have access to growth factors, so they quickly reactivate through those RAS pathways. In vivo or in patients, we don't think that happens. We think the best evidence is, you know, any or very little H or N mutations when you inhibit KRAS G12C.
Okay.
That should translate to all their mutations in KRAS.
Okay. I think, you know, the indications that the competitor is pursuing, you know, is likely gonna require combination therapy. What does the profile of your drug do or not do that could impact the ability to combine with other therapies? Like, what do you think the most likely combination partners are?
Yeah. You know, clearly a better safety profile allows you to do better combinations, and that's what we're seeing in the clinic today with 118. You know, for us, our main combination, as Uneek said, is with the breaker. Right? That is the beauty of being able to have two molecules, one that inhibits a PI3K driven by RAS.
We can talk about that one, and then MAP kinase pathway driven by KRAS-mutant KRAS. The ability to do that combination without the liability, we believe is gonna be a game changer, an experiment a lot of people have been trying to do, you know, for 20+ years. We believe we're in a unique position to be able to do this combination where we can get the efficacy and stay away from the safety liabilities.
Of course, you know, any chemotherapeutic combination, cetuximab combination, you know, that should be much better in a pan-KRAS inhibitor because you're leaving the wild-type NRAS, as the mice have shown, allowed to signal, while with a pan-RAS, you are inhibiting all three pathways.
Yeah. EGFR, one of the key toxicities is skin rash, right?
Absolutely. Yes.
You wouldn't wanna have a drug that also has skin rash as a combo.
Yes. The least you can put those together for the better.
Oh, that could open up, I guess, using a pan-KRAS agent in something like colorectal cancer.
Absolutely. Yes.
Yeah. To be clear, I mean, we are pursuing all three. PDAC with chemo, cetuximab, colorectal-
Yeah
... pembro combination in non-small cell with our BBO-11818 pan-KRAS.
Okay. Where you've presented some data. You mentioned I think you had one response in PDAC-
Right
...which was as a monotherapy. Where are you in the dose escalation process now?
We're still continuing to dose escalate. I mean, so far we've shown data across up to 600 mg BID. Our safety data set went all the way to 800 mg BID. We have still not fully closed out on that. Once we determine that, we'll announce that in the second half as well as combinations that we've spoken about. That should come through in the second half.
What will be the dose limiting toxicity that you predict?
So far we haven't seen anything. I think we've seen two cases of GI. We haven't seen any dose-limiting toxicity, and those two were patients with pre-existing conditions. We think it should solve the Goldilocks problem of having exposure across multiple alleles, but having safety of a mutant selector.
Okay. Anything else you wanna mention about the pan-KRAS before we move to the breaker?
No, I think we've covered it. It's again, one of our pillars to be able to combine and we'll come to the breaker because our goal is to get high therapeutic index across multiple pathways, and I think pan-KRAS helps us do that.
Yep. Okay. All right, let's talk about the breaker. You gave a little overview in the intro, but can you walk us through what the hypothesis is there with that drug which prevents communication between the MAP kinase pathway and the PI3K pathway?
Yeah. Going back to the main message on mechanism, right? We are trying to bring mechanism to RAS that blocks effector binding. If you think about breaker blocks PI3K alpha and effector of RAS from binding to RAS, in this case, any RAS, because the small molecule is binding to PI3K alpha and preventing any RAS, so in this case it's pan-RAS inhibition of only the PI3K alpha pathway.
That's a very clear distinction from a pan-RAS inhibitor, which is also blocking the MAP kinase pathway. This is a small molecule that binds to PI3K alpha, prevents activation from RAS. It is not a kinase inhibitor, so it differentiate it from all the kinase inhibitors. That's key because when you inhibit the kinase activity, you block insulin receptor signaling.
When you block insulin receptor signaling, you get hyperglycemia, which is dose limiting and really a problem from inhibiting this pathway, you know, outside of cancer, it gives you DLT. Very differentiated mechanism of action allows you to inhibit the PI3-kinase pathway. When you combine it with a KRAS inhibitor, think about BBO-8520 and BBO-11818, then you now get the benefit of inhibiting the MAP kinase pathway and the PI3-kinase pathway together, but in a tumor selective manner. That again, we believe is gonna give you a therapeutic index that for the first time we'll be able to do this experiment where we inhibit these two main oncology pathways, get the benefit of the efficacy without the liabilities or the safety problems.
Okay. Can you walk us through what you showed in the data update you had around J.P. Morgan?
Yeah. We had about 32 patients worth of safety data. First, our goal through monotherapy was to get through as quickly and find the dose for combination, which we've determined now is 500 mg. We weren't expecting too much activity on monotherapy as is consistent with the inhibitors of this pathway. On the safety side, it confirmed what we saw pre-clinically, that even with no HbA1c restriction, we didn't see any case of hyperglycemia.
I think that leads us to believe on the activity level though, I mean, just from a statistical perspective, a disease control rate of 62%. We did see tumor reductions, although we didn't see a response as yet, but it has confirmed to us that, hey, this pathway is really safe and like all the other mutant selectives or pan PI3Ks which even despite having HbA1c restrictions continue to show hyperglycemia, we see none of that.
Right. Okay. What, let's talk about the different combination approaches that you're testing. You mentioned you wouldn't expect to see monotherapy activity. I think what we heard when we were doing diligence with our Medical physicians was that HER2- positive tumors should could see some monotherapy activity. If there was gonna be monotherapy activity, it would be in that tumor type. You, I don't think you enrolled any HER2- positives-
No
...in the monotherapy.
Most of our patients were later line CRC patients. Because our goal was to go through dose escalation quickly and a few HR-positive, so we didn't have any HER2-positive.
Can you walk us through the different combination approaches that you're trying?
We have three combination approaches we are trying, which is HER2-positive with trastuzumab, and we have HR-positive, HER2-negative with fulvestrant, and then we have chemo for KRAS-mutant.
Okay. You're not limiting it to PI3K mutations at all?
No.
No. Okay.
This is a novel mechanism, right? Just inhibiting RAS and PI3K alpha interaction. We run a cell line, unbiased cell line screen, and the very strong signals are PI3K alpha mutation, G12 RAS mutation, and HER2 amplification. Those three signals is what we're taking into the clinic to interrogate that question.
Okay. Where are you in the dose with that drug now? Or you think you have the dose?
Yes.
We have the dose, and now these cohorts are rapidly enrolling, and we hope to provide an update in the second half.
What will be in that update?
It should show all three combinations, safety and efficacy. It will depend. We haven't figured out how many patients, but it all depends on enrollment rates, but we hope to show some perspective on that.
It'll be full dose with the combination partners?
Yes.
We should expect to see some formal responses in that update.
We do hope to see that.
Okay.
I mean, from the preclinical data, you know, you have a high rate of regressions in the animal models. You know, at least for the two HER2 amplified and PI3K alpha settings in breast, we should see a level of response.
Okay. Really this next update that will be probably both with the pan-KRAS, you know, that there'll be hopefully more responses there, but the breaker could actually be the big change, the big new data set.
Not to forget BBO-8520, I mean, our G12C with durability because if the durability continues to hold with the liver tox that we are seeing, I think it could differentiate itself to be best in class.
Yeah. No, that we were the most encouraged by that at the update in January. All right. Well, let's see if there's any questions in the audience before we wrap the session up.
Yes.
I was interested in your liver tox explanation. I had always thought that some of this was related to sustained with ALT and depletion of glutathione. You brought up the Goldilocks hypothesis.
Yeah.
I guess it's a couple years later since we've seen what people have attempted to explain liver tox. Can you go over that a little bit more? I guess it's not related to glutathione.
So-
Maybe it is the same.
...it could be. Unfortunately, there's that observation as far as I know, nobody has an animal model that recapitulates it, and so the experiment cannot be done in animals to really get deep into the mechanism. Nobody really knows the answer of what drives it. One of the hypothesis is the hapten creation. Certainly another hypothesis is the glutathione depletion. Right now, because of the hypothesis, the low free drug would lead to less tox, and that is what we are seeing. That's what we saw in animals, and that's what we're seeing in humans. You know, we believe that that's the likely explanation, but we don't have data that proves that.
Okay.
Yeah. Yes.
In a future where you have a big pan-KRAS inhibitor available and then you've got a G12C available, how do those two play with each other? Where do they fit in development?
Yeah. You want me to take that one?
Yeah. Take it.
I mean, I think from a biology point of view, it's very hard to make a KRAS G12C inhibitor that is as potent as a covalent inhibitor that is not covalent, right? I think always the most potency you're gonna get against G12C is gonna be with a covalent mechanism. We believe that's the best approach to get the most cell killing, especially in combination with pembrolizumab. You know, you want to be able to get that killing. If you can do the combination with a full dose of your inhibitor, then that's great. That's where we believe we are. There's no need to use a less potent inhibitor that comes with a pan-KRAS inhibitor that has no covalent activity.
The pan-KRAS is then for the rest of them?
For DV, yes. That was the design, and nothing we have seen today that makes us change our mind on that.
Well, I'll take that question to the next level. What about relative to the G12D drugs that are in development, like in PDAC? Do you think that that's gonna be more prevalent usage than. Because it seems like the multi-RAS seems to be the one that the doctors are the most excited about in PDAC.
I mean, if you have a multi KRAS inhibitor that targets G12C, G12D, G12V, G12S, G12A, and it gives you a great therapeutic index, great profile, why wouldn't you use that instead of an isoform-specific G12D-only, where G12V could then become resistant or G12C become resistant, right? That is the main reason. Then there's some wild type activity there where the isoform specifics don't inhibit wild type. We believe again that wild type KRAS can provide resistance. Again, we believe that's the ideal profile is that pan-KRAS with wild type activity.
Yeah
That's what we've made.
It's the difference that lung cancer is a little more narrowly selected-
Yeah
...with the G12C. Okay.
Yes.
Yeah. Any other questions?