Perfect. All right, let's get started with our next session. My name is Kelsey Goodwin. I'm one of the senior analysts here at Piper Sandler. With me I have the CEO of Boundless, Zach Hornby. Welcome and thanks for joining us.
Thank you, Kelsey. Nice to be here.
Let's start with a quick summary of Boundless and where we stand heading into 2026.
Sure. So good morning. Boundless Bio is a precision oncology company located in San Diego. We've been in existence for about six years, and the company was established to address one of the largest remaining unmet needs in oncology, which is patients who have oncogene amplification-driven tumors. This is about 25% of all cancer patients. And unfortunately, current standards of care, like immunotherapies, targeted therapies, generally do not work for these patients, and they have worse outcomes, worse survival. So the company was formed to try to address this unmet need through a very exciting and emerging area of cancer biology called extrachromosomal DNA, or ecDNA, which is one of the root causes of amplifications. And so what we've been doing over the past half dozen years is identifying synthetic lethal targets in cancers that are relying upon this extrachromosomal DNA to propel their oncogene amplifications.
From that, we have identified multiple first-in-class molecules. We have two that we've brought into the clinic. They're currently in an ongoing clinical trial. Then a third one that we're preparing an IND to enter the clinic early next year. That would be a high-level summary of where we are.
Perfect. So we can dive in a bit, maybe into the background first. Let's have you walk us through the biology of oncogene amplifications in cancer and how extrachromosomal DNA plays a role there.
Sounds good. So as I was mentioning, different types of cancers, and probably folks are familiar with the different types of drivers or root causes. For instance, there's things like gene fusions, like ALK fusions, ROS fusions, RET fusions. Those are eminently treatable with TKIs or other small molecules. Then there's things like point mutations, like EGFR, KRAS, G12C, G12D. Once again, good drugs either on the market or emerging for that type of driver. Oncogene amplifications are a little bit different, where instead of a mutation in the DNA sequence, you simply have too many copies of the DNA. And interestingly, those exact same drugs that are approved or work well for a gene fusion or a point mutation, they almost always do not work in the case of an amplification. So something about that biology is quite different. So why is it that these amplifications respond differently?
One of the seminal discoveries by our scientific founders and others in the field was that frequently these amplifications, when they occur, they're not on chromosomal DNA, so we all learn in high school biology that your DNA is encoded on chromosomes, but it turns out that cancers often have some sort of DNA that's almost more like bacterial DNA. There are these little circular plasmids that are still inside the nucleus of the cell, but these little circles are physically separated from the chromosomes, and these little circles can replicate, like so one becomes two, becomes four, becomes eight, and this is one of the root causes or primary sources of amplification, and so it's really a differential biology in cancer as compared to healthy tissues. These ecDNA, extrachromosomal DNA, they are not found in healthy tissue.
And so once we as a field have this understanding that these amplified cancers are relying on this differential biology, it opens up this new concept of, okay, can we somehow exploit that? Can we somehow find targets or drugs that are lethal when the cells need this circular DNA? Because then they would have no impact on cells that don't do that. And so that's the overarching premise of our company.
Understood, and very cool science. In terms of how widespread this oncogene amplification is, maybe talk to the rates there in cancer specifically and what tumor types this would be relevant for?
Oncogene amplification overall is about 25% of cancer, and it can either be at the initial diagnosis as a primary driver, or it can arise over time as a mechanism of resistance. A nice example recently is with KRAS, G12C, G12D. The better the drugs have gotten from adagrasib to sotorasib to Roche's divorasib and now the Revmed drugs, you're actually seeing more and more amplification as a mechanism of resistance, so basically, the better the chemistry going after the original root cause driver, the more the tumor is going to find a biological solution to evade that chemistry, and so that's just one example where the amplification rates are increasing upon treatment, so that's amplification writ large, and then extrachromosomal DNA, our focus, that's about 15% of all cancers. That's now been studied in two large national cohorts, both the U.S. and the U.K.
So independently verified over about 20,000 patients with the data. 15% have this extrachromosomal DNA. And it's most common in the most aggressive tumor types. So it's particularly enriched in things like glioblastoma, sarcoma, metastatic ovarian cancer, esophageal cancer. Some of the ones with the worst outcomes seem to have the most of this ecDNA. And that's probably no coincidence. That's probably interrelated.
Interesting. And in terms of current standard of care for oncogene amplified cancers, maybe speak to that and the unmet need that we have so far.
Right. In a way, there is no current standard of care, meaning the targeted therapies are almost never approved. The sole exception is HER2, so for breast cancer that has HER2 expression, you, of course, have the HER2 antibodies or ADCs approved, but that's really the only case. For any other oncogene you might be familiar with, think like ALK or KRAS or MYC or EGFR, there is nothing approved for amplifications, and so the current standard of care then would become chemo or whatever other thing is approved more for the tissue in which the oncodriver is found, but it's not specific to the biology, the driver biology, so there's no precision medicines approved when there's amplification.
Okay, understood. And then you have a proprietary platform called Spyglass. What is it and what does it enable for your pipeline?
Spyglass is our discovery platform to first identify new targets that are implicated in the ecDNA biology and then when we identify those targets to validate them and then ultimately for us to prosecute molecules directed to those targets. At a very high level, the way it works is it starts with models that represent the unmet need, so we have more than 100 in vitro, multiple dozen in vivo models that we've established that are oncogene amplified tumors that either have this ecDNA or do not, and so the ecDNA bearing models is like the test set, and the ecDNA negative models would be the control set, and by creating a library of positive and negative models, we can run differential analyses to identify targets that are critical for the first set and not critical for the second set, so let me give you a simple example.
If you've got 10 ecDNA positive models and 10 ecDNA matched negative models, you could run a genome-wide CRISPR knockdown of every gene one at a time and ask the question, which genes when knocked down are going to kill all the ecDNA positive models and have no effect on the ecDNA negative models? That's the type of analysis we run because that's what allows us to then identify the targets that are essential only for ecDNA and not for other cellular processes. So that's kind of the basis of how Spyglass works.
Understood. Okay, great. And so you've already entered the clinic with two programs, BBI-355 and then BBI-825. What have been the key clinical learnings so far with those programs? And to what extent does the data that we've seen so far support the rationale to target these ecDNA pathways?
Yeah. So based on that Spyglass platform and identifying targets that are synthetically lethal in ecDNA, we've now identified more than a dozen targets that we validated, and we can bucket those targets into different classes in terms of how they're interfering with the life cycle of ecDNA, so just as an example, these ecDNA, they need to form in the first place, meaning DNA is breaking off of a chromosome, it's then circularizing, so that's like the assembly of the ecDNA, the formation, then they replicate. They go from one copy to multiple, and they could reach literally hundreds of copies, so the replication is an important facet of the biology. There's the transcription. The DNA needs to become RNA. It needs to become protein. There's the movement, which we often call segregation. How do they move around within the cell? How do they divide during mitosis?
There's even degradation. Sometimes they get degraded into micronuclei, so we've identified targets that can impact each of these elements of the ecDNA life cycle. Some of the early targets that we identified and have prosecuted into the clinic were involved with the transcription and the replication, and in fact, those two things can come into conflict with each other if they happen at the same time. That's called replication stress, and replication stress, if unmitigated, will ultimately kill a cell, and so what these cells do when they have these ecDNA and they have high transcription and high replication, and therefore they have replication stress, they invoke the DNA damage response pathway, and so some of the targets we're working on are involved in the DNA damage response pathway, so as an example, Chk1 is a well-known target. There's no approved drugs.
It certainly had never been understood or prosecuted with this biology or with this approach. So our lead program, BBI-355, we took into the clinic almost two years ago. And we're definitely seeing activity. So we are seeing RECIST responses with that program. It's an active molecule. However, the DDR pathway and Chk1, it is an essential pathway, and therefore there is some toxicity that comes with it. So we've seen some challenges with the toxicity. We've been open about that. But there have been some clues in terms of where we have seen activity. There have been some certain genetic markers or other enrichment factors that we've observed clinically, empirically with that program, which very interestingly, and I know we're about to talk about it, we have a new program that's going to be entering the clinic shortly.
And preclinically for that program, we're seeing the exact same signal in terms of tissue type and some other genetic markers. So our team is optimistic that some things we're seeing clinically are matching really well with some things we're seeing preclinically, even though they're very different targets, very different approaches. But perhaps there's a signal emerging as to where this ecDNA biology can be best targeted.
Super interesting. And a good segue to our next line of questioning around BBI-940. So your new program, walk us through the biology and the rationale for this target and to what extent you've disclosed anything on this program?
This program is something we're really excited about because it's the epitome of the vision of the company from its inception, which was to look at novel biology and hopefully reveal novel targets and then turn those into first-in-class drugs and hopefully establish a whole new category of cancer treatment and that is what is in the early innings of playing out in that through the Spyglass platform, we identified a novel target. It's in the class of targets called kinesins, so the kinesins as a class are known, and other companies have tried to drug certain kinesins, not yet successfully. This particular one we've identified, to our knowledge, has never been attempted by anyone else. There's no evidence of it in the patent literature or scientific literature, so we think we've made a truly first-in-class discovery. Because nobody had worked on it, there was no pre-existing matter.
There were no assays, no protein, no compounds. We've had to do all of it from scratch, expressing the protein, purifying it, crystallizing it, running screens, identifying molecules. It's been a labor of love, but we had some real breakthroughs in the last couple of years, particularly when we started making not only inhibitors of this kinesin, but also degraders. And we think the reason the degraders are essential is this kinesin is likely playing a critical role into how the ecDNA move or segregate or localize to the right place to have their function. And perhaps it's playing a scaffolding role. So just inhibiting it might not overcome that scaffolding role. You might need to actually physically remove it through a degrader. So long story short, we have now developed an oral degrader compound. It's very well along in IND enabling.
We anticipate filing an IND in the not-too-distant future and then initiating a first-in-human study with this molecule oral degrader of kinesin. It's called BBI-940.
Perfect. And maybe just diving in a bit for kinesin, why is it important for ecDNA segregation in cancer cells, but not normal cells? And what makes it a particularly good target?
Right. And this gets a little bit into esoteric biology, so I'll try to keep it somewhat high level, but chromosomes have a centromere, and the centromere is the basis of something called the kinetochore. And so if you go back to high school biology, if you kind of picture the cell cycle, the different phases of the cell cycle, there's the point where the chromosomes duplicate. They all line up at the middle of the cell, and then they all get pulled when the cell divides into two daughter cells. The chromosomes get equally or symmetrically pulled into the daughter cells. Think of like a tow hitch. The way that that happens is because they're pulled by kinesins from this kinetochore at the center. That's how they get pulled apart. Well, ecDNA lacks centromeres. Therefore, they lack the kinetochore. So to use my analogy, they lack this tow hitch.
So then what governs how they move around when the cell divides? How do they get distributed? That's where we've discovered that this kinesin seems to be playing an essential role for ecDNA, whereas it's not essential for chromosomes.
Understood. So you're running IND enabling studies for 940. What have been kind of the key preclinical learnings that you've seen that give you confidence in advancing this program?
Yeah. I'd say two things. One is that, just kind of building off my last statement, it is a non-essential gene. So by DepMap, this is not an essential gene, meaning its removal shouldn't kill healthy cells. And that has been our experience so far preclinically is that our degrader has been very well tolerated in our tox studies. So there seems to be a nice and attractive therapeutic window. Of course, we need to validate that in humans, but at least preclinically, it's looking encouraging in terms of tolerability. The compound's got good oral bioavailability in multiple models. And then on the preclinical side or sorry, the pharmacology side, we're seeing interesting activity, anti-tumor activity in vitro and in vivo. We are seeing activity in a subset of models across different tumor types. Probably about 15% or so of the different cell lines we've run are showing sensitivity.
And we're seeing a particular interesting signal in breast cancer. So that will likely be our initial clinical foray will be into breast cancer just based on what we're seeing both in vitro and in vivo.
That's perfect. And a great segue to the next question in terms of how we should think about potential tumor types that might be best suited in terms of what you've disclosed so far and the preclinical models that you are describing. Yeah, how should we think about this program longer term?
Yeah. In the near term, we should think about breast cancer as probably the first shot on goal that we'll take. The biology is not limited to breast cancer, meaning of course we see the ecDNA and other tumor types. And so this compound has shown activity in models of other tumor types as well. So I think longer term, there could be potential to have more of a basket study or a broader design. But let's say chapter one will likely be breast cancer.
Perfect. Great and that's super exciting. In terms of learnings from 355 and 825 that are in the clinic right now, anything specific that can be leveraged for this program?
Yeah. It comes back to something I said earlier, which is there are some cool things we're seeing with 940 preclinically that we have also been seeing with the other programs clinically. It wasn't intentional or by design. It was more coincidental, but it's somewhat reassuring that some of the signal we were seeing with the programs in the clinic is overlapping with what we're seeing preclinically. So I'd say it helps enrich our confidence for where the biology might be most at play and therefore most targetable.
Perfect. And as you think about the competitive landscape for kinesin degrader, what themes do you see emerging and how do you see the space kind of evolving in the near term?
To our knowledge, there's no competition at this moment. We don't see any evidence of anyone else working on this kinesin, and that's actually why, even in this conversation, I'm only referring to it as a kinesin and not disclosing the target. Because I think we all in this industry are now aware that when a target gets revealed or validated, a lot of competition emerges quickly globally, and so we want to have as much of a head start as possible. I'm hopeful that when we bring it into the clinic, we'll demonstrate robust clinical activity, and then we might have a multi-year advantage because, like I said, we had to build it all from scratch, so I think no imminent competition. Of course, there's other companies working on other kinesins. They don't have the same biology or necessarily even the same tumors they're going after.
I think the competition in a way is other classes of molecules. For instance, if we're going into breast cancer, positive breast cancer, that's a very active space right now. In fact, we've got San Antonio breast cancer next week. There will be new data from Roche with their SERD. There's companies with PI3K pathway inhibitors, the various CDKs, CDK6. So there's just a lot of different ways to impact the biology. We think our target is non-overlapping, meaning it could potentially be complementary or combinable with some of those other pathways.
Got it. And I guess specifically for other programs in the past that have targeted other kinesins, what have we learned from those?
Yeah. One target that has been a kinesin that's been targeted over the last couple of years, and I think is becoming more exciting, is a target called KIF18A. And Amgen first brought a compound into the clinic, a small molecule inhibitor, a few years ago. It had activity. So there were responses, but they were somewhat few and far between, and I don't think there was a biomarker that could predict who. And so ultimately, Amgen divested that molecule to a company called Volastra, who's also developing a KIF18A inhibitor of their own. Perhaps the one that they're developing of their own might be a little bit better than the one that they got from Amgen. So maybe they're seeing some better tolerability. And then we hear about other companies who are also working on even newer ones.
I think probably what happens is over time, the molecules get better, more selective or other properties. And so we're hearing some very promising signs of data with the KIF18A inhibitors in terms of response rates and tolerability. Now, once again, that is a different target. It is not identical to ours. That one's being pursued more right now in the gynecologic ovarian type setting. But I think if those KIF18A inhibitors continue to show nice data, there might be emerging interest in the class.
Understood. And then for 940 specifically, maybe just remind us the timeline there and what's kind of the next step?
Yeah. What we've stated publicly as of our last earnings release is that we will initiate a first-in-human study in the first half of 2026. So we remain on path to do that, to get this into patients first half of next year.
Okay. Perfect. And then maybe just taking a step back here at the end, in terms of just the broader state of the ecDNA field, competition, pharma interest, how are you thinking about that? And what will we see or what do you expect to see over the next few years?
The field has really taken off over the past half dozen years since we started the company. I mean, late last year, there were four concurrent publications in Nature on ecDNA, including the cover. This year, there was an international conference devoted to ecDNA held in London with several hundred attendees. Our company co-founder, Paul Mischel, delivered the opening plenary address at AACR this year, and now he's a co-chair of the conference for next year. Probably most tellingly, if you quantify the PubMed searches that cite ecDNA, it's an exponential curve. The field is absolutely taking off academically, the interest in the science. We are the first and leading company built devoted to ecDNA. There are other emergent companies now, which is exciting to have some brethren. Then Big Pharma is certainly interested.
For instance, one of our company co-founders, a really distinguished scientist named Howard Chang, who was at Stanford, he's now the Chief Scientific Officer at Amgen, so a very prominent position. And he's publicly stated that Amgen would like to work on ecDNA. Certainly, other pharmas have, of course, approached us about it. And certainly, as we talk to them, we know that they have nascent groups working on the biology. So I think, as with all things, the more the academic field leads science, then industry follows.
Perfect. In our last 10 seconds, maybe just remind us cash and runway.
Yeah. As of last earnings, about $117 million of cash, and we have projected that into 2028, so more than two years.
Great. We are at time. Thank you so much, everyone, for joining us. Thank you, Zach.
Thank you, Kelsey.