Welcome everyone to the Piper Sandler Healthcare Conference. I'd like to introduce our next company. We have BridgeBio Oncology Therapeutics, and their management team. So welcome, Eli. So we have Eli Wallace, CEO, and Uneek Mehra, Chief Financial Officer. So welcome, gentlemen.
Thank you.
You know, one of the few IPOs of 2025, so congratulations on that.
Thank you.
Maybe for the audience that's not familiar with the story, can you maybe go over your three clinical-stage pipeline assets?
Yeah. Thanks, Darren. Yeah. Thanks for inviting us. Great to be here in New York City with the sunny weather, so you know, our thesis is, it's all about small molecules targeting the two most mutated oncogenes, RAS and PI3K-alpha, and the thesis really is to do both mechanisms and molecules that can drive the high levels of inhibition. Because we know from our years of experience, to give patients the best chance to benefit, that are, you know, driven by these oncogenes, you have to drive the high levels of inhibition, so we have three programs. They're all in phase I clinical development. First one is BBO-8520. That's a KRAS G12C on/off inhibitor. Binds directly to the switch-two pocket of KRAS G12C, but it's able to do it with really high affinity, so that it can inhibit both the on and off stage.
I should mention that all of these assets are discovered in-house, through our scientific team. The second program targets PI3K-alpha signaling. That's BBO-10203. This is called our RAS- PI3K-alpha breaker, and it's a novel way to inhibit signaling from the second most mutated oncogene. It's a protein-protein interaction inhibitor, so it binds specifically and selectively to the RAS binding domain of PI3K-alpha, and it blocks the ability of RAS to activate it. It's really, maybe we'll talk about it later, the differentiating points on that. Then the third program you can think of as the first cousin of BBO-8520. It's BBO-11818. This is our pan-KRAS inhibitor. So it also binds with a very high affinity to the switch-two pocket and inhibits both the on and off states.
Maybe we could start with BBO-8520, the KRAS G12C inhibitor. Can you just maybe comment on its differentiating attributes to first-gen KRAS G12C inhibitors, you know, sotorasib, adagrasib, and talk about, I guess, its differentiating attributes?
Yeah. I think, you know, the first thing is certainly the work that Kevan Shokat did at UCSF to show that you could drug KRAS G12C was groundbreaking. His work showed that you could inhibit that in only what's called the off state, right? And major breakthrough, but the fact that those that work at all, because they're hitting a dead protein, I think was somewhat of a surprise. So the first key differentiating point is we actually inhibit the protein that signals. So our mechanism is different. We inhibit RAS's ability to activate downstream effectors like RAS. So that's number one. Number two is, when you develop resistance to G12C off inhibitors, and unfortunately tumors almost always develop resistance, in the case of an off inhibitor, you don't need to do a genetic modification. You just have to increase the population of the on state.
By inhibiting the on state, we should be able to offset some of that resistance. The third is a very important subtlety of the chemistry. I wanna, you know, spend just a minute on this because it's, I think it's very important when one thinks about differentiating, going forward and where this can fit potentially in the treatment paradigm. That's when you're a covalent inhibitor against the on state, you can act like a hit-and-run mechanism. That means that you can get good residence time and efficacy while you clear the circulation. You have residence of PD, but you can clear the PK. That can give you a better therapeutic index and hopefully minimize or eliminate liver toxicity issues that are certainly present with the off inhibitors.
You know, so you've so far disclosed some data around BBO-8520. Can you maybe review that data set, as well as I think the attribution towards the lower adverse event? Clearly you're seeing activity on the efficacy side without, say, you know, the safety compromises that have, you know, plagued the first-generation G12C inhibitors.
Yeah. What we've released so far is the first handful of patients on efficacy and safety through the first monotherapy cohorts at 100, 200, and 300 milligrams QD, where we observed 60% confirmed overall response rate, so very good, encouraging early activity. Importantly, through those first three cohorts, we had no grade three toxicities observed, and very importantly, no liver toxicity of any grade. Arguably better efficacy than the first-generation G12C and better safety, so both ends of the therapeutic index. We've shown preclinically, and I think this is gonna carry forward into the clinic, that we can get arguably better efficacy than off inhibitors in mice, but we can do it at a fraction of the concentration. We'll disclose the PK when we just do our next data update.
But what I can share is through that 300 mg cohort, our free concentration is 1% of the added in situ. So a fraction of the concentration, 60% response rate, no grade three toxicities, no liver toxicities of any grade.
The next update is expected in Q1?
Yes, sir.
How many patients should we expect on the monotherapy portion? What type of follow-up could we be looking at?
Yeah. We haven't been guided to an exact patient number. I think what we hope to be able to share is full monotherapy dose escalation, and some early combination data with pembrolizumab, where we can, you know, show safety and maybe early efficacy signals in that combination. You know, I think one way to think about BBO-8520, the data I've described, and hopefully the data we're able to show, as we enroll more patients is that BBO-8520 can be positioned as the combination agent of choice with pembrolizumab.
Remind us, what are the dose ranges that you're investigating both monotherapy as well as combination?
Yeah. So what we've disclosed so far, excuse me, is to go up to 500 in monotherapy and also go up to 500 with pembrolizumab, which I think is another important point. Our OFF inhibitors that have shared data in combination with pembrolizumab have had to reduce their dose in combination because of mainly liver toxicities. Liver toxicities that they see monotherapy that get worse when they combine with a checkpoint inhibitor, we are escalating with pembrolizumab. So, you know, we hope to be able to show that we can, have better safety than they do and also be able to achieve that with a dose, a monotherapy dose that's quite active. And that then should lead to better benefit to patients.
the 500 milligram QD dose, I mean, so we would probably expect to see data as well, in the next update?
Yes.
Okay. And then I guess on the combination, we'll probably get some of the dose cohorts, but not all.
Yeah. We haven't provided that guidance, but I think it will be a meaningful update in combination.
In terms of both efficacy as well as safety?
Certainly safety. We'll just have to see, you know, how much efficacy data we're able to generate at that time.
Do you envision disclosing this at a medical meeting or would this be something like a company-specific event?
Yeah. We haven't disclosed where the venue will be, but it will be in the first quarter.
After these data sets are available, the trial clearly continues to those patients. At what point do you make a decision on potential for pivotal registrational studies?
Yeah. I think, you know, I'll answer that question twofold. Certainly as the data matures, that will dictate, you know, where we can position it. We do think there's still white space in the front line, particularly in TPS less than 50, where OFF inhibitors, in combination with pembro, you know, are showing activity in the 55%-60% response rate, which is really what a good G12C inhibitor is showing in the second line as monotherapy. So I think, and, you know, significant grade three toxicity. So I think there's still room there. The other part of that question is really more of a portfolio prioritization. So we, you know, were very successful in the de-SPAC. We raised $380 million, had, I think, 30, what was it?
39% redemption.
39% redemption, which was quite low, right? So that put us in a very good position to turn over the POC cards on all three assets this coming year. We have data releases on all three programs. And so part of the pivotal planning and, you know, which agent we do internally, which we partner, and maybe Uneek can talk more to that, will depend on how also the other programs perform.
Got it. So with the other programs, there's data available next year as well. With BBO-10203, the PI3K breaker, I mean, highly novel program, clearly, you know, differentiated. Can you talk about, I guess, the phase I trial? What type of tumor types are you enrolling? What could we expect, I guess, in first half 2026 from the program?
Yeah. Let me first just describe the mechanism a little bit because it is a novel approach to inhibit signalings from the second most mutated oncogene. And, you know, you don't often get an opportunity to work on such a program, as this. And so the key here is that it only inhibits PI3K-alpha AKT signaling when it's driven by RAS. And so the selectivity here is the biology. And so RAS activation of PI3K-alpha is important in many tumor genetic settings. But RAS activation of PI3K-alpha does not play a role in glucose homeostasis. So the hope here, and it's built upon some nice, elegant studies, genetic studies in mice, and then we've supplemented that now with quite a lot of preclinical data, including a publication that we put out last summer describing the mechanism.
The idea here is that we can inhibit the signal in tumors but not have to worry about hyperglycemia. And so we, you know, our preclinical data is very strong on that point to that led us then to go forward in this trial with no restriction on HbA1c status, which is very novel. No one else inhibiting on this pathway is able to go forward without restrictions on glucose. And so what we will show in the first half, right? A little more there. There's three genotypes that revealed themselves through the preclinical evaluation process as sensitive to this mechanism of inhibition. One is HER2-amplified tumors. We're exploring HER2-amplified breast cancer, both in monotherapy and in combination with trastuzumab. The other, of course, is hormone receptor positive breast cancer.
We're looking at that in combination with fulvestrant initially. And then importantly, KRAS mutants, particularly G12X. Our mechanism here, this breaker, doesn't depend on the mutational status of either partner. So RAS can be wild type or mutated. PI3K-alpha can be wild type or mutated. So you can get the efficacy in that setting, but you can also get the safety. So why is that particularly important? It's really important when you think about addressable patients. One can certainly review the data from a whole series of PI3K-alpha H1047X selective inhibitors. All of those inhibitors, you can argue how good their therapeutic index is, but none of them will be able to address KRAS mutants because 90%-95% of KRAS mutants are wild type for PI3K-alpha.
So if you get in your therapeutic index and one can argue how good it is, but it depends on the mutational status of PI3K-alpha, you won't be able to try to treat KRAS mutants. This is kind of a long-winded answer, but basically to say that first half readout or data release, we should be able to share monotherapy dose escalation across those tumor types that I described as sensitive: HER2-amplified breast cancer, hormone receptor positive breast cancer, and KRAS mutants. Monotherapy across those, and then early combinations with standard of care in those settings as well.
And how do we, how should we compare when you, when you have the data across those three, you know, tumor buckets, HER2-amplified breast cancer, HR-positive breast cancer, as well as KRAS mutants? So, you know, are there good reference points that we should look at to say, "Okay, this is what we need to see from an efficacy signal standpoint"?
Yeah. And so I just wanna, you know, be clear that first half, you know, it's just gonna be early combination data. So, you know, we'll see how much efficacy we're able to to garner by that stage. But each one of them has a separate bench point, right, or benchmark, I should say. So in the HER2-amplified, the way we would think about the breaker is that in HER2-amplified breast cancer, there will always be a role for a small molecule. And we believe the breaker will be well-positioned to be that small molecule of choice. It does have good brain levels in rodents, so it should be able to address the brain metastases that are problematic in the HER2 space. And so that combination, tucatinib would be the comparator, which I know that program very well.
So tucatinib, just with trastuzumab has about a 10% or 15% response rate. Okay? The it's labeled with chemo, so that's a little different. So that might be a benchmark there. In KRAS mutant CRC, chemo in the second line is again in the low teens, maybe 10% response rate. The hormone receptor positive is interesting because, if you know that space, there's a lot of patients that have bone-only disease and are not available for response. So maybe duration is gonna be more important there, so that could take a little longer. I guess what I'm saying is each one of them has their own benchmarks, and, you know, depending on how the trials enroll and so on and so forth, could have their own inflection points as we go forward.
Will we have sufficient durability data, or is that something potentially for a subsequent follow-up?
I think the combinations, it's probably gonna be too early for durability.
In the trial, did you restrict patients that had HISTH1C ?
No, they had no restrictions. So, you know, we're so confident that this will be different on the glucose metabolism perspective that there are no restrictions.
Okay. Then I guess, with regards to the safety data, we'll likely have the blood glucose and C-peptide data sets available when this data's disclosed?
Yeah. We'll definitely have the blood glucose data. I don't know if we're collecting C-peptide, but yeah, we'll definitely, you know, so what we hope to show is monotherapy dose escalation in diverse tumor types where we really show differentiated safety. You know, hopefully we can achieve the mouse target PK levels. And then we also have a target engagement assay in blood because it's a covalent inhibitor. We can show target engagement. So at a minimum, we should be able to have very differentiated safety and confidence in that dose to go into the combinations.
Based on the preclinical data, are there any resistance mechanisms, you know, that you would be looking for with regards to the clinical data?
You know, that work's in progress, but nothing has really jumped out yet. Yeah. So, we really haven't seen anything.
Okay. And then, you know, with regards to the pan-KRAS, clearly a high area of interest. Your thoughts there, as it relates to BBO-11818 and how it potentially differentiates from other pan-KRAS approaches?
Yeah. So I, you know, first thing is, again, it fits this thesis of driving a high dose of inhibition. It is a pan-KRAS inhibitor. We think that is the best approach to drive the high dose of inhibition. That sparing HRAS and NRAS will compensate in normal tissue to allow a good therapeutic index and allow us to drive the high dose of inhibition. And it is an ON/OFF inhibitor. So I think, it's well-positioned. You know, it's the third program to enter the clinic. We're anticipating data release in the second half of next year.
What type of mutations are you enrolling? Is it G12D, G12V, others?
Yeah. I think the dose escalation is G12X. You know, we're not expecting a lot of Cs because of the covalence, but mostly D and V is what we expect to see.
And across, I guess, tumor types,
Pancreas, lung, colon.
Okay. And, so, so data second half of the year, also dose escalation. I assume, are there any read-throughs from the other programs in terms of how you think about dose escalation with this program?
You know, I think the medicinal chemistry, and that's my background, that enabled BBO-8520 is carried over into BBO-11818. Okay? So this ability to inhibit the ON state by binding to the switch two pocket, I mean, now is accepted, but you know, I would argue we were the first to really establish that. And so I remember presenting this program for the first time at the RAS symposium at Frederick National Labs, I don't know, maybe 2022, 2023, and everybody who was in the room, K. Von, others, you know, they didn't believe that one could do that. Now it's accepted, right? So, BBO-11818 uses that same kind of structural biology medicinal chemistry to inhibit the ON and OFF states. The difference, of course, is it's non-covalent. The G12C inhibitor, you know, covalently modifies that G12C residue.
The pan-KRAS inhibitor, it does not have a covalent warhead.
You know, I get this question a lot, Eli. You know, with RevMed and their success to date with daraxonrasib, where does a strategy like this potentially fit in longer term with BBO-11818, given you know, I think they're developing in PDAC? Clearly your opportunity is much more broader than PDAC, but I guess taking PDAC as an example, you know, how would you slot this in if the daraxonrasib is successful?
Yeah. I think, you know, the data, well, BBO-11818 is early in clinical development. We'll see how it performs across tumor types. Certainly, we're not limited, we're not limiting our investigation to PDAC, right? There's opportunities in lung cancer. There's opportunities in colon cancer. And I also think that pan-RAS does have a therapeutic index that looks like a wild type inhibitor. So I would call it a wild type tri-complex pan-RAS inhibitor. And so, you know, we would hope, and our thesis is that by sparing HRAS and NRAS, we can drive to higher levels of inhibition and not look like a wild type inhibitor. So, you know, as the data matures, we'll have to see. Certainly, we agree with RevMed and the importance of inhibiting the ON state. They have a, you know, quite a head start.
But at the end of the day, we'll have to see what is the best approach for patients overall, not only in pancreas but in colon and lung as well.
How do you think about the combination with BBO-11818 with your internal portfolio like BBO-10203?
Yeah. This is a wonderful opportunity for us, so you know, arguably the two most important oncogenic signaling pathways, MAPK and PI3K-alpha- AKT, you know, we've within the field, and I was involved in this research, we've had the thesis to try to inhibit those simultaneously for about 25 years now. I'm aging myself a little bit, but the problem was the inhibitors were not well tolerated in combination because at the time we had MEK inhibitors, we had non-selective PI3K inhibitors, and even in mice, they were poorly tolerated. Some people tried to take them into the clinic, and it was pretty much a disaster.
But now when you have this breaker, which you can think of it as a pan-RAS inhibitor of PI3K-alpha, we think that with our RAS mutants allows us to combine safely and hopefully to a high level of inhibition to do those. And we, even in the space of pan-KRAS, where there are competitors, no one else in that field has a breaker for which they can combine.
I guess you know, more broadly, targeting RAS with small molecule versus degraders, your thoughts there, given I think there's other, you know, multiple programs looking at the degrader approach?
Yeah. I think, you know, the probably the top-level difference will be, you know, can you make an orally bioavailable degrader, and can you cover the target? You know, this idea of TI, it just comes back to therapeutic index and target coverage. And so our view is a small molecule direct inhibitor of the ON/OFF to the Switch II pocket will end up being the best way to get the target coverage. And the one that has specificity, whether it's for G12C, whether it's, you know, for KRAS sparing HRAS and NRAS, we think those are the best approaches to drive the high levels of inhibition, best way to delay resistance, best way to give patients benefit. So, I'll age myself a little more, right? So if you remember the BRAF days, I don't know if you guys remember BRAF versus MEK, right?
Preclinically, MEK looked great. Why even do a BRAF inhibitor, right? Clinically, so different. And that was because in wild type cells, BRAF did not inhibit it, and it could drive to 90% inhibition, where MEK you could never get more than 40%-50%. And, I mean, the efficacy differences was huge. It's all about driving the high levels of target inhibition in a safe manner.
Good. And then I guess maybe, last question on cash runway. You know, three really exciting programs. How do you think about cash management, give you know, to ensure that each program is well-resourced to you know, inflection points beyond the next data set?
Yes. We currently, I mean, as of September 30th, we have $468 million, so that takes us into 2028. Now, the good news for us is all three programs are reading out in 2026 in close proximity. So the capital allocation will be real-time, dynamic as the data emerges. All three programs are well-resourced with this capital right now, pre-registrational, with all the dose exploration and expansion cohorts. But as we move into pivotal and registrational, we will have to then consider other capital formation.
Would you potentially consider one or more programs from a partnering standpoint outside the U.S. or even globally?
Yeah. For a company of our size, Darren, I think it's, I mean, we won't be able to do all three programs with all of it. So as the data reads out, we'll obviously then select the one that is most promising for ourselves and then look for strategic partnering.
Perfect. I think our time's about up. I really wanna thank you. Thanks, Eli. Thank you, Eli, for sharing the BBOT story, and looking forward to the updates next year.
Thank you so much for having us here.