Hey, good morning, everyone. Thanks for joining us. I'm Matthew Biegler, an analyst here at Oppenheimer. I cover these guys, BBOT. Happy to have Eli Wallace and Uneek Mehra here from the team. You know, I guess for those that are less familiar with you guys, spin out of BridgeBio or the oncology spin out of BridgeBio. Motto is, "Best in RAS." Just kinda explain with the pipeline how you plan on fulfilling that motto.
Yeah. Thanks, Matt. Thanks for having us. We're really pleased to be here this morning. Our thesis, and it's important to note, all of our programs were discovered and are being developed in-house, is that to provide patients with RAS-driven tumors, the most frequent and deadliest oncogene, you have to derive molecules, inhibitors, and targets that can provide optimal target coverage for patients. We do this through a couple different ways. One is we tackle RAS inhibition directly by designing inhibitors that are able to inhibit both the on and off state. On the RAS activation of PI3Kα, which is our RAS PI3Kα breaker, we do this by only inhibiting very important PI3Kα tumorigenic signaling, where it's activated by RAS. This provides a very novel approach that avoids hyperglycemia.
Okay, it kinda seems to me like there's two pillars to the story, right? One is on, one is on/off binding. Why on/off is the future? Number two is rational combinations. I think that's where the dimer breaker can come into play, which is one of two or three. Both of these themes kind of fit together, right? As you kind of think about how you wanna build out the pipeline, you know, walk us through the three assets from a high level and what they are and what they do.
Yeah. The 8520, BBO-8520, is our direct KRAS G12C on/off inhibitor. I think it's important to note, when we first started this program and started talking about it, first of all, people didn't believe you could inhibit the on state directly. Now it's accepted dogma. I think a lot of our work set that foundation. The other thing was that people thought it was a done deal, G12C. It is absolutely not, right? Inhibiting the on state is actually the protein that drives signaling. The off state is a dead protein. It doesn't have any biological consequence. It's basically resting state. For 8520, we're able to very potently inhibit both the on/off state. What that has enabled us to do, and we've shared this clinical data, is to drive very strong efficacy with 65% response rate.
83% of patients that were eligible or had for a six-month follow-up, passed that six-month timeframe. Overall, across dose levels, 68%, six-month PFS. Very importantly, we can do this arguably stronger efficacy with a better safety profile. It's highly active and safer, and that's really, we can get into that, a power of the on state as well. The other KRAS inhibitor is our pan-KRAS inhibitor. We took our learnings from structure-based design and medicinal chemistry of BBO-8520, and we applied that to pan-KRAS, where 818 is really a close cousin to BBO-8520. It also directly binds the KRAS and is able to inhibit the on/off state with very potent inhibition, importantly, of KRAS G12D and V, as well as other alleles.
The third program, as you mentioned, is, you know, an orthogonal approach that gives us a unique opportunity to combine both with standard of care and with our own pipeline, and that's BBO-10203. This is our RAS PI3Kα breaker. It's a protein-protein interaction inhibitor, where we're clearly first in class here, where it blocks the ability of RAS to activate PI3Kα, but it is not a kinase inhibitor. The selectivity in the therapeutic index comes from the biology, where RAS activation of PI3Kα is very important in tumorigenic settings, but it doesn't appear to play a very important role in normal physiology, and certainly not in hyperglycemia, which has plagued inhibitors of this pathway from day one.
To me, the RAS axis, it's hard to hit. I mean, now we can finally hit it with these molecular approaches, but there's just a lot of, like, feedback amplification. There's a lot of crosstalk. I guess my question to you is, obviously, there are probably some indications where a monotherapy, be it 8520, better than Lumakras, like it's gonna work there, lung cancer. High... You know, if you think about colorectal, if you think about PANC, do you think you need combinations? That's kind of why I wanna get into, like, the, your modular approach here, where maybe your dimer breaker, all of a sudden, is, like, the ace in the hole, that that's, like, what you have that all the other RAS-focused companies don't have, that you can really kind of target all of those different offshoot escape mechanisms.
Thanks, Matt. I think you framed that quite well. I think there's two ways to think about the combination approach. Let's be clear, oncology is all about combinations, particularly when you move into earlier lines of therapy. If you have a targeted therapy that has very good therapeutic index and combinability, you can combine that either with standard of care. Let's talk about that first. For BBO-8520, I described some of the monotherapy activity. Also, very little liver toxicity as monotherapy.
Yeah
Very, very little in combination with pembrolizumab. We think that's directly a result of the science. When you're a covalent inhibitor of the on state, you can get that promising efficacy at a fraction of the free drug levels, which leads to better therapeutic index, because you don't have a lot of covalent inhibitor driving liver toxicity. We can combine with pembrolizumab at active optimal doses of 8520 and have better safety than off inhibitors. We think that this will be the combination agent of choice as you move into frontline. With 818, first talking about standard of care combinations, you know, earlier stage program, but so far very promising early efficacy and safety. You know, we haven't observed rash, and so certainly, you mentioned colorectal cancer. There has been validation, I think, in the G12C space.
When you combine the G12C inhibitor with the EGFR antibody, you can improve efficacy. There, of course, G12C is not the major player in the colon cancer space, right? It's IND. If the data continues to progress as it has so far with the pan-KRAS inhibitor eight one eight, we certainly have an opportunity, I think, that maybe other mechanisms don't have, where we can combine with an EGFR inhibitor in colon cancer, which, you know, seems to be harder to hit, as you mentioned, and, you know, you're not seeing a lot of data yet in that space. You know, hopefully, that's something that pan-KRAS inhibitor can thread the needle, where you can get both inhibition against D and V, but avoid some of the side effects of less selective approaches, and therefore, being able to combine with cetuximab.
Yeah
O r other EGFR inhibitors. Then the last thing, of course, is the breaker.
Yeah.
The breaker, we have cohorts open with standard of care combinations, where our preclinical data is very strong in all three settings. That would be HER2 amplified with trastuzumab, hormone receptor-positive with fulvestrant, and then as well in KRAS mutant space with chemo. I think what's even more exciting is something that the field and myself personally have tried to do for 25 + years, and that's drive to high levels of inhibition of MAPK and PI3Kα simultaneously.
Mm.
We attempted that in the early days with MEK inhibitors and PI3Kα inhibitors. When we could get it tolerated in mice, the efficacy was very impressive. The combination is just too toxic to move forward successfully in patients.
Yeah, and-
The breaker mechanism gives us that angle, where it only inhibits where RAS activates, and the preclinical data is really strong, and the clinical data on our assets so far really suggests that that combination will be something we can achieve finally.
Yeah, exactly. We will talk about one of two or three in more detail. Just to highlight, you're not seeing any hyperglycemia like you would with a typical PI3Kα inhibitor. I thought that was really cool. That's kind of like... You know, I think we've been talking more about, like, the big picture here and, like, what's coming maybe couple years down the line when you start thinking about combinations. Where we are right now with 8520 is some, I think, really impressive data as both a monotherapy and in combination with PD-1. Could you just kind of lay out why you think the on/off thesis of this drug is starting to pan out already in the data that we've seen, lower exposures, nice response rate, no liver tox, et cetera?
Yeah, I think that's it right there, right? We have encouraging early durability data as well, which we'll be monitoring as we continue to advance the program. 65% response rate, 83% of patients that were eligible to be on the study for six months, achieved that landmark. Then, you know, as monotherapy, less than or roughly five cases of low-grade liver toxicity, and then in combination with pembrolizumab, all three first-line patients responded, even those with very low TPS score.
Then we have about a 40% response rate in heavily pretreated lung cancer patients that had both experienced checkpoint inhibitor and G12C, and that's in combination with pembrolizumab as well. It's important to note, this is achieved with a highly active dose of 8520. We're going forward with pembrolizumab, an expansion at 500 mg. We did not have to deescalate, as all the off inhibitors have, because of liver tox when they combine with pembrolizumab.
Mm.
Every single one of them has had to do that has shared data. Even when they do reduce the dose, they have 40%-70% grade three toxicities. We have very low toxicity. The single case of liver toxicity that we have observed with the pembrolizumab combination really was believed to be due to co-medications. Very different efficacy as well as safety, and particularly when you move to earlier lines, that combination, the ability to combine, is gonna be very important.
Yeah
P articularly when you look across TPS scores.
Yeah, I would agree. I mean, I think the holy grail is obviously to combine in the front line. That's the majority of the patients are before they kind of drop off in the later refractory lines. It sounds like you think, as an industry, we've just been underdosing because we just haven't been able to combine yet with PD-1?
I do think that's supported by the data we've seen to date, where off inhibitors at that reduced dose because of the liver toxicity in combination with pembrolizumab in the front line, their efficacy in TPS less than 50 so far is, you know, not necessarily, or maybe it is lower than what we're seeing, at least from a response rate, in monotherapy in second line. They do have stronger activity in TPS greater than 50.
Mm-hmm.
A thesis I believe that is shared by others is that in TPS greater than 50, the checkpoint inhibitor is carrying a lot of the weight. You can maybe get away with suboptimal dose of the G12C inhibitor.
Yeah.
In the 50% or more patients that have TPS less than 50, the G12C inhibitor needs to bring something to the table.
Yep.
That, you know, that's a big difference between the on/off inhibition that you can get with 8520 compared to off-only inhibitors.
I'd agree. I guess as you look ahead to the second half of this year, we'll get more data. What kind of, you know, maturing of the data do you think would cement 8520 as best in class?
Uneek, you want to take that one?
Yeah. No, I think. Thanks, Matt. Based on what Elijah said, you know, the key question in front of us is that as long as the durability continues to hold, I think we've shown great efficacy to date. Safety is definitely holding up.
Mm-hmm.
To reiterate, if we can continue to combine 8520, which we are doing right now at an active 500 mg dose with pembro, and we continue to see the durability pan through, I think this would solve really the unmet need in the G12C space, which is: Can you combine at an active dose while minimizing liver tox? I think that would cement 8520 really as best in class. We've started to get that anecdotal reference that, "Hey, your profile is shaping up to be best in class." I think for us, we continue to monitor it largely for durability benefit at this stage.
Yeah. Makes sense. Let's switch to 11818. I mean, I like to think of it basically, it's 8520 without the covalent acrylamide, right? That opens up pan-KRAS. It opens up indications like colorectal, like PANC, where G12C isn't as common, and some of the other isoforms are. Yeah, I mean, like, give us a brief overview of how you discovered it, and then I really wanna talk about how that's different from Adagrasib. There's obviously a lot of excitement, I think, in the field about Adagrasib and the tripartite kind of cyclophilin binding structures. This is different from that, kind of how do you differentiate yours versus some of the other competitors out there?
Thanks, Matt. 8520, you know, as I mentioned, we changed the paradigm by directly binding and inhibit the on/off state. That's really achieved through what I would call KI, binding affinity. It's not a covalent inhibitor, but it's not by souping up the covalency. As you alluded to in your question, okay, if I can now remove that covalency and have a group that has, you know, positive interactions for DNV, can I make a pan-KRAS inhibitor? You retain the elements of the inhibitor that enable you to inhibit the on/off state directly, but then you remove the covalency. I mean, a lot more work than that. My medicinal chemist colleagues would probably frown upon this, the explanation, but that's it in a nutshell.
You know, our thesis here is really built upon important work in mice generated by Professor Barbacid in Spain. He's one of the founders of the RAS field, along with Professor McCormick and others. What he showed, and, you know, I don't know if this is always on, if everybody remembers these important studies, but what he showed that in mice, in adult mice, if you knock out all RAS, that's lethal.
Mm-hmm.
It's not compatible with life. However, if you knock out only KRAS, that is efficacious in germ models of cancer. In adult normal mice, the other RAS is compensated in normal tissues. If you think about that, think about pan-KRAS versus other approaches. In the tumor types of interest that you described, where KRAS G12D and V are really the drivers, whether that's pancreas, colon, or lung, and a smaller set of lung than KRAS G12C, but still important there.
Mm-hmm
I t's KRAS that's driving.
Mm-hmm.
You couple that that's the driver in these settings with the difference in the safety profile from pan-RAS inhibition versus pan-KRAS inhibition. Getting back to my introductory remarks, we really believe that the best way to drive to high lows inhibition in a tolerable manner is by focusing on pan-KRAS.
Yeah. Yeah, I'd agree. I mean, so relative to kind of tripartite structures, the cyclophilin binders, they are definitely seeing a lot of skin tox, which is probably EGFR, I guess, driven, maybe HRAS, NRAS. How do you think you differentiate from that from a safety perspective, based on the early clinical data that you've shown?
Yeah, I think from our early clinical data, what we've shown is we don't have any rash, we don't have any stomatitis and mucositis. you know, I think from MEK and mTOR inhibitors, those are kind of what's been seen, in patients. In a way, you know, maybe not surprising if you're, if you're a wild type agent as opposed to a selective agent. you know, we need to see, you know, more data with 818, but if that holds up, we think that will be different, and it could be a better option for patients as we generate data. you know, that's the thesis. I think we're on track for that, so we're just gonna keep marching forward.
I think one of the concerns with the pan-KRAS is that by sparing H and N, maybe tumors can bypass. You know, we know CRAF bypass is an issue with MEK inhibitors, right? I'm just kind of wondering if you think that's gonna be an issue, and if so, maybe that's where BBO-10203 kind of combination comes in. There was a recent paper that was published in Science by [Slowey] and all about how HRAS and NRAS kind of signal through PI3K, and it was actually kind of a resistance mechanism that they saw pop up in some of the direct on RASIB studies. I also definitely wanna get your thoughts on that too.
No, I think that's very, very important and important point here. You know, there are some papers in cell culture that show rapid rescue of KRAS inhibition, whether it's G12C or, you know, that's where most of the work's been done, I think, that H and N compensate. I've yet to see a study where that's shown in mice, right? If you had rapid recovery of H and N, in, in models or animals or in humans, you wouldn't think you would have any efficacy, and that's certainly not the case. I just wonder if that's a cell finding phenomenon. The other thing that's important, right, is we completely agree with the findings you described.
We do think other RASs get activated, we believe their role is activation of PI3Kα as a survival pathway, that has been shown with other MAPK inhibitors years ago. I think it's, you know, this is a study we've done, and we've shared it before. This happens to be a G12C model, the thesis on the RAS side doesn't change. In a fairly hard to treat G12C model, we can combine 8520 with 203 and turn that into regressions. All 203 does, we'll get to that, is inhibit PI3Kα. It doesn't touch MAPK.
Mm-hmm.
That activity, by a study shared from Revolution Medicines, where they did pan RAS versus G12C, the efficacy is almost identical. Our conclusion is that all that resistance is coming from PI3Kα, and you don't need the additional MAPK inhibition that a pan RAS brings to a mutant selective. You know, this will have to play out in patients, that's the thesis that's supported very strongly by our preclinical data.
Yeah. It's a good segue into 10203. Again, I mean, this is not a mutant selective PI3K like we've seen from Scorpion and from Relay. It really works differently than I mean, it's a really out-of-the-box approach, right? Describe it again mechanistically, again, you know, maybe for those that earlier on, it kind of went over their head. You know, how is it so different from anything else that's out there, and why could that be such a major finding for the field as we think about future combination therapies?
It's a fascinating program, and I think, you know, we're at the cutting edge in person class here. It's a protein-protein interaction inhibitor. It binds specifically and selectively in a covalent manner to what's called the RAS binding domain of PI3Kα. It's selective for PI3Kα. It's a highly specific compound, and it blocks the ability of RAS to activate it. That's all, as far as we know, that's all the compound does. That's important then, because the selectivity that we get and the efficacy we get is all about where RAS activates PI3Kα.
Right.
RAS clearly is important in activating it. In tumors, we found that's very important in several settings, HER2 amplified, HER2, hormone receptor-positive, as well as KRAS mutants. Glucose homeostasis and signaling, that is, that PI3Kα kinase activity is absolutely required. That can function fine in the presence of our compound. Preclinically, we certainly showed that, but most importantly, to date, we have seen zero hyperglycemia, zero elevations of glucose, and that's enrolling patients irrespective of their HbA1c status or glucose levels. All other inhibitors of this pathway that I'm aware of have restrictions, and even with those restrictions, they see, depending on the molecule, anywhere from grade one to grade three hyperglycemia.
Yeah.
No restrictions and no issues. We're set up very, very well to test this thesis in combination. I think I mentioned earlier, the standard of care combinations are open and enrolling now.
Yeah, it's interesting to me that the preclinical data looked really good in indications like CRC or PANC, or in breast, in a HER2 positive setting, as well as HR-positive, we always think about PI3K inhibitors being used in HR-positives, just 'cause that's where PI3K tends to be mutated most often. Do you think you could compete with, like, a mutant-selective PI3K inhibitor in a HR-positive setting, or is that not really the intent of this molecule?
Yeah, I think we can. You know, we'll have to see how the clinical data holds up as we go forward. What's important to note, our preclinical data shows that the breaker is agnostic to the mutational status. It will work where KRAS is wild type or mutated, or PI3Kα is wild type or mutated. I think the data that is maturing with mutant selectives show that they're tilted to the kinase mutant, and I think that's completely expected by their preclinical data, their cell data, and their biochemical data. It makes sense.
Mm-hmm.
You know, if our thesis holds, we'll be able to address both of those key hotspot mutations and not have a restriction on HbA1c status and be an oral agent. Another very important differentiation is that the breaker, because it's mutant-agnostic, can address KRAS mutants in combination. I mentioned that earlier.
Yeah.
If you're a mutant-selective PI3Kα, you cannot, because of roughly 95% of KRAS mutants are wild type for PI3Kα.
Yeah.
No, I think it's a larger addressable patient population in breast because you don't have restrictions on glucose status. Hopefully, we'll be able to show activity in both mutants, possibly a larger addressable patient population there. The KRAS mutant space, we have that space to ourselves.
Yes. I mean, it could potentially expand the addressable population 20-fold or more if 90%, 95% of KRAS mutants are wild type PI3K. I think it's really exciting. PI3K inhibitors don't tend to have very strong monotherapy activity, though. Anybody that covers the space kind of laments this, and I wouldn't necessarily expect one or two or three to either, but I just wanna understand kind of where you're setting expectations for this drug before you start to think about combination trials.
Yeah, real quickly, right. Our thesis was to get through monotherapy quickly, and we did that. We enrolled a diverse set of patients. Right, preclinically, these inhibitors are G1 arrest, and then clinically, you know, the highest you'll see monotherapy in well-defined patient population is in the teens. Many of them are less than 10. You know, we did not expect monotherapy. The field generally doesn't.
These indications we talked about, you're always gonna go in combination. We're very pleased with what we've achieved so far from a monotherapy. We hit our goals. Now all these combinations are open. Importantly, also, later this year, we'll open combinations internally. We'll do two or three with 8520, and we'll do two or three with 818. All of that is rolling. It's a big execution year for us. You know, we're excited to continue to enroll patients, generate data, and see where we land here.
That sounds like a great place to leave off. Just in the few remaining seconds we have, we could just talk about some milestones as you think about the back half of this year and into 2027.
Yeah. Uneek, you wanna take that?
Absolutely. Very quickly, I mean, I think, fortunately, or convergence-wise, all three programs are supposed to read out in second half of this year, so we have rich set of data coming in. For 8520, it's the, as I said, more data on the combination with pembrolizumab to give folks the further visibility on the durability aspect. On 818, it's the combination that we want to test specifically is also on, in CRC with cetuximab. You should see some data, as well as the monotherapy progression. On 10203, the three open combination cohorts, should be able to provide perspective on the, on that, and we're pretty excited, with data coming out in the second half of 2026. We have a strong, I'll also mention, Matt, we have a great cash balance right now, $425 at the end of the year, to be able to prosecute these combinations ourselves.
Awesome. Thank you so much to the BBOT team, Eli and Uneek. It's always fun talking to you guys.
Yeah, thank you.
Thank you, Matt.
Thanks so much.
Thanks for having us.