Perfect. Great. Well, thanks so much to everybody joining us here. The second day of Piper Sandler's annual healthcare conference. I'm Joe Catanzaro. I'm one of Piper's biotech analysts. It's my pleasure to welcome Boundless Bio here for our next session. Joining us is their CEO, Zach Hornby. Zach, so much, thanks so much for joining us here. Obviously, a bunch of questions I wanna run through, but maybe first I could give you a minute or two. You could introduce Boundless and let everybody know what you guys are up to and what we have to look forward to.
First off, thank you, Joe and Piper, for the invitation. Always a pleasure to attend and present at this conference. Boundless Bio is a clinical-stage next-generation precision oncology company that is dedicated to treating one of the largest remaining unmet needs in cancer. And this is patients with oncogene amplifications, about 25% of all cancer patients. We're the only company in the biopharma space dedicated to this patient population. And we're seeking to address this population through a very exciting new area of cancer biology that is called extrachromosomal DNA, or ecDNA. And I'm sure in the subsequent questions I'll get into what exactly that is. But it's the root cause of oncogene amplifications, and we're the world's leading company in this emerging space.
And most importantly, through our understanding of this biology, we've identified multiple novel targets, and we currently have several programs in the clinic dedicated or directed to these targets with near-term catalysts over the next 12 months.
Great. So I just finished up this session where we talked about EGFR inhibitors and actual EGFR mutations. You mentioned oncogene amplifications and the unmet need there. Maybe you could elaborate a little bit more on why there's an unmet need there and why traditional targeted therapies have not yielded the benefits there that they've seen in sort of, you know, traditional mutational backgrounds.
EGFR is a great example, and it's not unique. It's a similar phenomenon would hold for FGFR or other similar targets. But if you look closely at the approved drugs for a target like EGFR, where there have been multiple generations of approved therapies from early on, Tarceva and Iressa, all the way forward to Tagrisso, each of these drugs has been approved for certain types of activating EGFR alterations. These are things like L858R mutation or exon 19 insertion, or now exon 20 deletion. But notably, none of the EGFR inhibitors have ever been approved for amplification of the oncogene. And that same is true for FGFR and really any other target you can think of: ALK, ROS1, RET, NTRK, BRAF, KRAS. No drug approved for the amplification. And so why is that?
The trials have been conducted, the patients have been tested, but the response rates and durability are always significantly lower than the driver mutations or fusions. And our scientific founders here at Boundless, being good scientists, were perplexed by this clinical observation. They wanted to understand what was different when cancer cells had amplification. And when they looked under the microscope and treated these cells with these targeted therapies, they realized that the amplifications could disappear, reappear, change which genes were being amplified very rapidly in a non-Mendelian fashion. And when they further delved to understand how that was happening, what they realized was that the location of these oncogene amplifications was not on the chromosome in the expected location based on the human genome map, but instead were on these cancer-specific circular units of DNA that were still within the nuclei but were physically separate from the chromosomes.
These were the extrachromosomal DNA or ecDNA. And these little circles were leading to the amplification, but were also evolving real-time under therapeutic treatment. And so this helps explain why targeted therapies alone don't work for patients with amplification.
So I think you touched on it a little bit in the sort of non-Mendelian manner of ecDNA. But maybe speak a little bit more to how ecDNA differentiates itself from traditional chromosomal DNA and some of the advantageous benefits to have genes on ecDNA.
First and foremost, the location, the fact that ecDNA is not on the chromosome, so it is a physically separate entity, and then within that entity, one of the unique features of ecDNA, being these relatively small circles, is that the transcriptional machinery can bind onto these ecDNA and constitutively transcribe just over and over again without stop, so these circles of ecDNA are hyper-transcribed, meaning they are optimized to pump out a lot of oncogenic protein. That is one key feature. A second key feature of ecDNA is that, unlike chromosomes, ecDNA lacks centromeres, and the significance of that is that when ecDNA replicate during cellular division, they do not get symmetrically pulled into daughter cells, they get asymmetrically distributed such that you can get copy number heterogeneity from one cell to another.
And what this means over a bulk tumor cell population is that every cell has a slightly different genome than the one next to it, meaning it can have a different fitness advantage, meaning under various therapeutic or other pressures, different cells can become the dominant clones. And so this heterogeneity gives rise to evolution, which gives rise to resistance to targeted therapies.
There's been a, I think, remarkable growth in data supporting the idea that ecDNA plays a really important role in tumor fitness and resistance to targeted therapy. I guess the question then is, how do you go about exploiting that, right? So maybe you could speak to your Spyglass platform and how you guys think about potentially interfering in the processes of ecDNA as potential therapeutics.
This question you're asking is kind of the billion-dollar question. And it was really the first key question when we formed the company, is if we now have this new insight that amplifications are occurring on these ecDNA instead of on the chromosome, and we see that targeted therapies alone can't work due to the heterogeneity resistance, is there a unique way to try to drug this ecDNA? And so the approach we came up with relies on the fact that ecDNA are unique to cancer cells. They are not a feature of healthy cells. So we started to ask ourselves the question, is it possible that there is unique machinery or processes that are being leveraged to enable these ecDNA to form and to function? And if so, could we intervene in this machinery instead of the ecDNA themselves?
So you're correct, Joe, that our Spyglass platform was really built to understand the life cycle of ecDNA. How do they form? How do they function? And where can we selectively intervene in that life cycle?
So, your first, your lead program is BBI-355, a CHK1 inhibitor. What makes CHK1 a suitable target within the context of ecDNA?
Yeah, the biology's pretty elegant and actually, I'm excited to say that we had a Nature publication on this just a few weeks ago, really elucidating the mechanistic biology but what it comes down to, something I said earlier, is that the circular architecture of the ecDNA allows the transcriptional machinery to bind and never come off. Now, that's a problem because when the cells go through cellular division, the replication machinery comes in and it actually collides with the transcriptional machinery, and that's a phenomenon called transcriptional replication collision, TRC, and that leads to a secondary phenomenon called replication stress. Replication stress, if unmitigated, is ultimately lethal to cells so these cancer cells that have this ecDNA have these TRCs, have this replication stress. What do they do? They invoke the DNA damage response pathway to pause the cell cycle, help resolve that replication stress, and move forward.
The way that they invoke the DNA damage response pathway is through the master regulator, which is CHK1, and so these cells, due to their heightened replication stress, have a heightened reliance on CHK1 and therefore have a high susceptibility to CHK1 inhibition as a synthetic lethal target.
So, I know I've long said this to you. So ecDNA's sort of novel, new concept, CHK1, not so much, right? So it's a target that's been around. There's been some challenges there. What are some learnings from the historical clinical experience with CHK1? And how does 355 potentially differentiate from those prior attempts?
CHK1 is a known target for good reason. I think there even today we see a lot of attention on DDR targets ranging from CHK1 to WEE1 to PKMYT1, ATR, and Joe, you cover a lot of these. So the pharma industry has known about this target, and most of the major players tried to drug CHK1 over the last, let's say, 10- 15 years. Multiple molecules made it into the clinic, and some of them did have single-agent activity, including complete responses and durable responses. But the problem was prior to now, pharma didn't have a biomarker hypothesis. They had no way of predicting which patients would respond. And so when you don't know who's gonna respond, what do you do? You dose up until toxicity to try to maximize response.
So up until now, while there were single-agent responses, they were somewhat few and far between. But now you fast forward to 2024 and Boundless's approach, we believe that by having a biomarker, we can predict which patients are more likely to respond. Therefore, we do not need to dose up to toxic levels. And then on top of that, we also believe that we have a best-in-class compound, BBI-355, that we've optimized for potency, selectivity, and oral bioavailability.
So maybe we can move to POTENTIATE, the ongoing trial. There's a couple parts to that trial, the first being monotherapy. What have you learned about the molecule in terms of its PK, PD, its safety, and maybe even potentially the early monotherapy activity?
We've learned that we have a potent CHK1 inhibitor that has good oral bioavailability, does engage the target and show PD impact, and ultimately, if you dose high enough, has the predicted on-target toxicity, which for the class is always hematologic toxicity, namely neutropenia, thrombocytopenia. Importantly, these are measurable and reversible toxicities. So what we've demonstrated as a monotherapy is that we have a dose, by the way, we have a long half-life, 40 hours in humans. So we have a dose that's 60 milligram orally every other day. That gives us very good PK exposure, in the range that was associated with efficacy in our preclinical models, and that has been a well-tolerated dose.
So maybe sticking with monotherapy, and this is something I think about a lot, whether there's a monotherapy opportunity for the CHK1 class. And there are multiple approaches to this patient selection strategy. Maybe just talk to your overall thoughts on whether there is, in fact, a, with the right patient selection strategy, a monotherapy path for maybe not just 355, but, you know, the CHK1 class.
Right. We believe there is a monotherapy path for CHK1 inhibitors in high replication stress tumors, particularly in the GAIN-ONC setting, and there is precedent with both prior CHK1 inhibitors, current CHK1 inhibitors, and current WEE1 and PKMYT1 and ATR inhibitors that all of these targets in a similar class are showing single-agent activity, particularly in indications like platinum-resistant ovarian cancer and endometrial cancer.
So maybe now we could shift to part two, which I think is really where you start to kind of exploit this ecDNA biology. So talk to the targeted combination strategies, which are truly novel there that you're employing, and the rationale behind combining a CHK1 with a targeted therapy.
One of the things we discussed earlier in this conversation is how historically targeted therapies alone don't work in patients with amplification, and what we see reliably across all of our preclinical systems, both cellular and in vivo, is that when you apply a targeted therapy to an amplified tumor model, it elicits more ecDNA and a higher reliance on ecDNA, but that in turn also elicits a susceptibility to ecDNA targeting therapeutics, so what we've been able to show in these models is a combinatorial synergy between a targeted therapy and an ecDNA directed agent, so for instance, if the tumor starts with an EGFR amplification, we apply both an EGFR inhibitor as well as our CHK1 inhibitor, and that shows very nice, deeper and more durable regressions in animal models.
As Joe alludes to, that is now the design of our ongoing POTENTIATE study where part two and part three look at different modules based on the underlying gene amplified in these tumors. We have a module that looks at EGFR amplification in combination with an EGFR inhibitor, a module that looks at FGFR amplification in combination with an FGFR inhibitor, and a module that looks at CDK4 or CDK6 amplification in combination with a CDK4/6 inhibitor.
You had previously expected some additional data in the second half of 2024 that got pushed into the second half of 2025. Maybe just speak a little bit to some of maybe the enrollment challenges that drove that shift in timelines and how you've gone about potentially addressing that to get to a good meaningful data set in the second half of 2025?
There were two factors that contributed to us, pushing our timeline out till next year, one intrinsic and one extrinsic. On the intrinsic side, as we began to enroll these combination cohorts and get them off the ground, they just took a little bit longer to get off the ground than we had forecast in terms of finding the patients, making sure testing's occurring, and that as physicians identified a patient that they were aware of our trial and knew which patients qualified. So we put some steps in place to help overcome those challenges, work with diagnostic vendors, having a small field force, having embedded resources at our leading trial sites, and I'm happy to say that these measures are really paying dividends now that we have a much more capable ability of identifying the patients who qualify for the study.
The extrinsic factor is that as we've looked at data disclosures of other public companies over the past couple of years, we noticed that companies really do not get rewarded for small data sets. Investors prefer to see a larger quantity of data with more durability, and so we thought it would be prudent for us too, that when we reveal a potential efficacy signal, we want it to be something that, that is interpretable and that people can feel confident in.
I think you maybe answered my sort of follow-up question to that for that second half of 2025 update in terms of the scope and breadth of the data set. Maybe first in monotherapy, what questions do you hope to be able to answer? Then maybe for the early combination data, what questions do you hope to be able to answer?
What I hope to be able to answer is with the monotherapy in the GAIN-ONC setting, I'd like to be able to show a reasonable response rate with reasonably durable responses. And really that's the same thing that I would like to be able to show in the combo arms, specifically the EGFR and FGFR arms. And so what we're striving to deliver to the Street second half of next year would be double-digit patients in each of those three cohorts with sufficient durability to see confirmed responses.
Maybe the last point on POTENTIATE, the biomarker strategy, which we haven't really fully delved into, just to talk through how you're going about detecting and quantifying ecDNA and sort of bucketing these patients and amplifications on ecDNA. I know you're also enrolling patients with chromosomal amplification.
Correct. So the part one, including the GAIN-ONC expansion is not limited to any specific oncogene amplification. So basically any patient with a bona fide amplification and no co-occurring driver would qualify for part one. Part two, as I mentioned earlier, is restricted to specific amplifications, either EGFR, FGFR, or CDK4/6. But we don't restrict that those amplifications have to be on ecDNA. We expect that many of them will be. In part three, we're actually applying a proprietary diagnostic that we have developed called ECHO that allows us to specifically discern which amplifications are on ecDNA or are not. And our statistical analysis plan will segment those into two separate buckets such that we can compare ecDNA positive versus ecDNA negative and see whether that does lead to a difference in either response rate or durability.
So maybe this is a good time to ask about your ECHO diagnostic and sort of where that fits in and what differentiates it from other approaches, I guess, that we're trying to quantify replication stress, and as a biomarker.
So the ECHO diagnostic was designed to detect ecDNA in a tumor biopsy, report out whether there is ecDNA or not. If there is, which oncogene is amplified on the ecDNA and at what level? And one of the key strategic imperatives that we designed into it is we did not want to disrupt patient care or workflow. And what that meant is that we wanted our diagnostic to sit on top of standard next-gen sequencing, which is the most common way that patient tumors are processed, in the developed world in this time. So our ECHO diagnostic is a software that is performed purely in silico. It ingests standard NGS data as its input, and then it has a unique algorithm so that its output is what I said, the presence or absence of ecDNA.
So in these next few minutes, I wanna talk about 825, your RNR inhibitor, maybe a more novel target, a new target for some. Maybe speak to it within the context of ecDNA. So where does ribonucleotide reductase, what role does it play within ecDNA biology?
One of the observations we've had clinically is that certain patients, when they start with a point mutation genetic driver, like a KRAS G12C mutation or a BRAF V600E mutation, when they're treated with the standard targeted therapies, including combo regimens, about 50% of patients develop amplification-mediated resistance. So it is the most frequent mechanism of resistance. And we routinely now obtain tumor samples from trial sites to characterize what is the nature of those amplifications. And it's the preponderance of the time is ecDNA mediated. So if we'll stipulate that occasionally patients who have point mutations develop resistance and those are amplification-mediated on ecDNA, then we want to define targets that could help prevent or treat that resistance. And one of the targets we identified is called ribonucleotide reductase or RNR.
The way it works is if you inhibit RNR, you shut off one of the two core processes by which cells can obtain dNTPs for DNA synthesis. So if a cell is gonna have ecDNA or amplified DNA, it must have dNTPs. Like I said, we shut off one of the two pathways. What's critical about this is that this pathway we shut off, it's just called the de novo synthesis pathway, is only essential in cancer cells. Healthy cells do not rely on this pathway.
So you've advanced 825 into a phase one two program. I'd say a sort of similar design strategy to POTENTIATE, but maybe speak to the, the target population you're looking at within the context of 825 and maybe any other important differences in the, in the trial's design relative to POTENTIATE.
You're correct that the trial design is somewhat similar to POTENTIATE. This study of 825 is called STARMAP. Part one is a single-agent dose escalation in all comers. Part two evaluates a combination of our 825 compound, with two different combination regimens and two different patient populations. The first is patients who have a KRAS G12C mutated colorectal cancer and develop amplification-mediated resistance to adagrasib plus cetuximab, which is now standard of care. And the second cohort is patients who start with a BRAF V600E mutated colorectal and develop amplification-mediated resistance to encorafenib plus cetuximab, which is also standard of care. So in our study, once those patients develop that amplification-mediated resistance, they will receive the triple combo of the standard of care plus our novel agent.
I know the first patient dosing occurred back in April. Anything you could say about the early monotherapy experience, what you're seeing in terms of the drug properties, behavior, anything else?
What we've publicly disclosed to date is that we have safely escalated through multiple dose levels, that we're seeing evidence of oral bioavailability, and that the compound has been generally well tolerated so far.
So similarly in STARMAP, it's a second half 2025 update that you're guiding to. Is your thinking there similar to what we spoke about in POTENTIATE in terms of being able to tell a meaningful story with a meaningful data set? And there too, sort of what you want to sort of learn within that early data release?
Yes, it is a similar intention of being able to show evidence of activity. In this case, if patients have failed or have become resistant to a standard of care regimen and have no other options, and then had a secondary response on our regimen, that might require even less data to be convincing, right? So if they're on adagrasib plus cetuximab and develop resistance, we add on our agent, and then they have a renewed response. It might not even take 10 patients to convince you that that's meaningful.
Yeah. Great. Last minute, there's another asset in the pipeline. It's a novel kinesin. I guess my question there is, as we sort of speak about ecDNA biology, where, where kinesins fit in, and what you're looking to try to do there.
Yeah, I'm really glad you asked me about this one with 40 seconds left because this is very exciting. Through our Spyglass platform, we have identified a completely novel target. To our knowledge, no company has ever pursued this compound or this target. It's absolutely first in class. It is a kinesin that is involved with how the ecDNA localize or move around the cell, which turns out to be essential to their function. We have developed an oral degrader. We've had major breakthrough this year, and so we're very eager to push this forward towards the clinic next year. And so I definitely say stay tuned.
Perfect. Well, with that, we're right on time. So thanks, Zach.
Perfect.
Thanks everybody for tuning in. Take care and enjoy the rest of your day. Thanks so much.
Thanks, Joe.