Our Global Annual Healthcare Conference at Leerink. I'm Andrew Berens, very happy to have with us Boundless Bio. We have Zachary Hornby, CEO. Thanks, Zachary, for joining us.
Thanks for the invitation as always, Andy.
Great. Hope you enjoyed the beautiful weather.
Absolutely.
Oh, you come from a place with beautiful weather, so.
Still nicer here.
There's definitely a lot of benefits to be in Miami. Why don't you give us an overview of the company before we get started?
Sure. Boundless Bio is a public company devoted to oncology drug development. We were initially formed in 2018 to try to address what we believe is one of the largest remaining unmet needs in all of oncology, and that is patients whose tumors are driven by oncogene amplification. Just a little primer on what that is, probably most of the field is familiar with tumors that are driven by different genetic defects, things like gene fusions. We've all heard of good drugs for ALK, ROS, RET, TRK fusions. There's also point mutation drivers like EGFR L858R or BRAF V600E, most recently KRASG12C . All of these types of oncogenic drivers are pretty well addressed by existing medicines. However, patients who have an amplification instead of a mutation, they now have a wild type sequence of a gene, but just too many copies.
Those tumors have no available therapies. In fact, those same drugs that might work for a mutation, they do not work for an amplification. The net result is you've got patients with significantly worse survival, no standard of care, and we're talking about 25% of all cancer patients, so more than 1 million per year in the major markets. We've identified this as a major unmet need for therapeutic development, and it coincides with some really nice emerging cancer biology that's been advancing in the academic sphere, particularly what is the root cause of these amplifications, what's the underlying pathophysiology.
Our scientific founders discovered that when amplifications arise in cancer, they often do not arise in the expected chromosomal locus based on the human genome map, but instead they arise on distinct little units of DNA that actually physically break off of chromosomes, circularize, and they remain in the nucleus, but they're physically separate from the chromosomes in these little circles called extrachromosomal DNA or ecDNA. They independently replicate, they independently transcribe, and they can allow the tumor to constantly evolve its genome and evade therapeutic pressure. These ecDNA-enabled tumors are more aggressive, they become resistant much quicker, and unfortunately, the patients have worse survival. We have built a company and a platform to try to really understand this biology and identify unique weaknesses or vulnerabilities that we could exploit therapeutically through new targets, new drugs.
Great. It is a phenomenon that's seen in other organisms like bacteria, right? It's not just mammals.
Correct. We think what tumors are doing in this case is basically hijacking some evolutionary biology from microorganisms like viruses and bacteria, because that's exactly how those microorganisms constantly evolve because they too are constantly under pressure, like antibiotics or vaccines. It's a nifty little trick for cancers, but bad for the people who harbor them.
Okay. Before we dive into the different programs, just maybe a little bit about your background. This is obviously not your first rodeo. You've had a lot of experience in the biotech industry.
Yeah. I've been working in the industry for about 25 years, a host of different public and private companies, both in Boston and in San Diego. I've really been dedicated to oncology development for about the past +15 years at companies like Halozyme Therapeutics, Fate Therapeutics. Immediately prior to getting Boundless off the ground, I was with the company Ignyta from its inception, from writing the business plan to taking it public, to ultimately selling it to Roche. I think most rewardingly, the drug that we developed there got approved and is still commercialized globally.
Great. Maybe we could also talk a little bit about diagnosing ecDNA. You had a diagnostic called ECHO. Can you talk a little bit about that and any plans to use that in development going forward?
ecDNA is a relatively new biomarker, meaning that only in the past 10 or so years have people really tried to look at it at scale. I'd say currently what's used most in the academic field is a tool developed by our scientific founders called Amplicon Architect. This is a bioinformatic tool that relies on whole genome sequencing data to basically infer the presence of the circular reads as opposed to linear chromosomal DNA. That Amplicon Architect tool is used virtually every scientific publication. However, because it relies on whole genome sequencing, it's not particularly clinically friendly for robust use because whole genome sequencing is not standard of care.
What we set out to do in the early days of Boundless is try to come up with a diagnostic tool that would more easily or seamlessly fit into standard of care. We wanted to come up with an ecDNA detection algorithm that would sit on top of the standard sequencing data that's already being generated by Foundation Medicine or Tempus or Guardant Health. We built this tool called Echo that you alluded to, and it was specifically validated to detect specific amplified oncogenes of interest to us for a certain program. We validated that for looking at EGFR, FGFR 1, FGFR 2, FGFR 3, FGFR 4, and CDK4/6. We did deploy that clinically for one of our early clinical trials. Indeed, we did detect ecDNA-based amplifications with that tool.
As we move forward with the new program that you and I are probably gonna discuss, we're not initially using ecDNA as a condition of enrollment. We don't necessarily have to apply that ECHO tool, prospectively, though we will certainly characterize ecDNA status of patients who do enroll, and we can do that retrospectively.
I see. Okay, so let's talk about the new program, 940. It's kinesin. What can you tell us about. Give an overview, and why you're interested in that pathway.
Starting with the premise of the biology and that we wanna address oncogene amplifications, and we want to do so through extrachromosomal DNA and trying to leverage vulnerabilities that accompany a cancer cell's reliance on extrachromosomal DNA. We used our Spyglass platform that we had internally developed, and it consists of proprietary cancer models and tools for detecting ecDNA, quantifying them, monitoring them. We were able to run various target ID screens with this platform and we identified a kinesin. This is a novel kinesin. Folks might be aware that the kinesins are a known class. In fact, other companies have previously tried to drug kinesins and have brought some programs into the clinic.
None have been approved to date, though currently, I would say there's some very encouraging early-stage drug development ongoing for one of the kinesins, which is called KIF18A. However, we, Boundless Bio, discovered a different kinesin that appears to be non-essential in healthy cells. You can completely knock it out, and healthy cells will still survive. Knockout mice can become viable and fertile and can procreate. However, this particular kinesin does appear to be essential for ecDNA in cancer. We set about trying to drug this kinesin that we discovered. We generated really nice genetic knockdown data showing that it was impacting our ecDNA models, and then we set out to develop a compound. We ran actually several high-throughput screening campaigns. We screened over 1 million compounds.
We actually got only a singleton hit from that vast screening effort. Our team plugged away, our medicinal chemistry team, trying to optimize the compound, get more potent, more selective, better drug-like properties. Well, long story short, we got down to single-digit nanomolar inhibitors, but when we put those compounds into cells, they were still not having as profound an effect as the genetic knockdown did. We were unable pharmacologically to recapitulate the genetic validation we achieved. Our team then transitioned from pure inhibitor to oral degrader. We started working on a heterobifunctional degrader approach. In the end, we generated what we think is a very nice compound, very potent, very selective, good oral bioavailability, no clear liabilities, and that is our program, BBI-940, which is now our oral kinesin degrader.
Okay. Why are kinesins important, with ecDNA?
Yeah. Yeah, this gets a little bit esoteric, but as probably all of us are familiar, cells divide, and when they do, the chromosomal DNA basically duplicates one time. All the DNA aligns to the middle. You can kind of remember this from high school biology textbooks, and then they get pulled apart into the now two new daughter cells. There's always this duplication and then halving that happens with every cell cycle, and the result is you have the same amount of genetic material, and really what should be identical genetic material in every cell in a multicellular organism.
Part of that orderly process of coming to the middle, duplicating, and then being pulled apart relies on something called the centromere, like a little loop-like structure at the center of a chromosome, and that's where the mitotic spindles kinda grab onto the chromosomes to pull them together and then pull them apart. Well, these little circles of ecDNA, they don't have that centromere, and so they don't have that kinetochore. They don't have that same ability to be bound to the microtubules and pulled one way or another. Instead, they rely on some different aspects of cellular structure to kinda shuttle them around and make sure they end up in the right place. We believe that this kinesin that we've identified is critical to how they segregate. We think that they're kinda hitchhiking or towing onto the chromosomes.
Think of this kinesin like a tow rope that's binding to the chromosome and binding to the ecDNA. When we degrade, so like cutting this tow rope, now the ecDNA are a little bit helter-skelter, and what we see with high content screens is they don't properly align during mitosis. They end up getting left behind or lagging, which leads to aggregation, which ultimately leads to degradation, which ultimately leads to cell death.
That is the mechanism by which degrading this kinesin kinda messes up the ecDNA trafficking and ultimately kills the cells.
Okay. In which tumor types do you think this process can be exploited?
Yeah. We certainly see ecDNA writ large across about 30 different tumor types. It's particularly common in kinda really aggressive tumors like the sarcomas, glioblastoma, metastatic ovarian cancer, esophageal cancer, gastric cancer, breast cancer. What we see with this particular kinesin is it is overexpressed in breast cancer, and then we ran a broad cell line screen, north of 800 different cancer cell lines across different tumor types. Overall, across those 800 cell lines, 15% were exquisitely sensitive to our degraders, but there was enrichment in certain tumor types, and breast cancer was the single most enriched in terms of percentage of the cell lines that were sensitive. We developed some breast cancer in vivo models, and we were able to see some nice sensitivity in vivo in breast cancer as well.
For now, that is our lead indication.
Okay. You don't expect to have to enrich it for ecDNA or any.
We don't intend to do that, at least initially, with dose exploration and with the first few, let's say, dose expansion cohorts that we try. That said, we will have the material to retrospectively assess the ecDNA status and to see whether there's any particular association with the s-ecDNA status. I wouldn't rule out that analysis, but right now it's not a condition of enrollment.
Okay. Which segment of breast cancer?
There's two segments that empirically declared themselves in our models. One is ER-positive breast cancer, which everyone's familiar with. The other is a lesser-known type of breast cancer. It's a subtype of triple-negative breast cancer where the tumors are actually dependent on androgen receptor signaling. This is called TNBC-LAR, and the LAR stands for luminal androgen receptor. We find it kind of interesting that empirically, with this mechanism, both estrogen receptor expressing tumors and androgen receptor expressing tumors are both seemingly sensitive to our compound, our approach. Perhaps that reveals something about the biology.
Okay. Which are you gonna test it in both those settings?
We are.
Okay.
They're both eligible for the KOMODO-1 study, which is our first in-human study that we just kicked off.
These will be HR-positive breast cancer that has failed endocrine, become endocrine insensitive?
Yeah. The inclusion and exclusion criteria is second-line plus, meaning, within the ER-positive setting, they must have failed exactly what you said. It's basically a combo of a CDK4/6 plus endocrine. They must have failed that. There's no other requirements for what they must have failed. On the back end, they cannot have had more than one chemo-including regimen, which could either be pure chemo or an ADC, not more than that.
You expect to see monotherapy apoptosis in responses?
The design of the study in dose escalation is monotherapy. Once we have a recommended dose for expansion, we'll start to break out some cohorts. One cohort will be a biomarker-enriched cohort as a monotherapy, and there we'll be looking at patients with FGFR1 amplification or copy number gain.
Okay.
We will also have a combination arm where we're combining with fulvestrant. The only requirement there is that they're not ESR1 positive.
Okay. The recent news about the persevERA trial failing is probably good, that at least we kinda have some clarity of where the oral SERDs are not going at this point.
Right. I agree.
Okay. Historically, kinesin programs, I think KIF11 had difficulty with therapeutic index. Like, what gives you confidence you're not gonna run into those problems?
That's a precedent that others have asked us about or cited. KIF11 per DepMap would be considered an essential target. I think it does bind at that kinesin core. Andy's correct that other companies have tried to take KIF11 inhibitors into the clinic and ultimately were beset by tox. Our DepMap profile is distinctly different in that for our kinesin, it is considered non-essential. Maybe intuitively you'd expect it to behave differently. I can tell you so far with our preclinical work, it was extremely well-tolerated in the GLP tox at all levels, both species, no morbidity, no mortality, you know, almost hard to find any tox signal at all. I think that gives us optimism for what we encounter in the clinic.
That said, it's a first in human with a totally novel target, so we've gotta go generate the data.
Yep. Okay. You mentioned, I think, some competitors. There's KIF18A inhibitors. How do you think this drug can perform and compare to those?
I'm excited about what's happening with the KIF18A programs. Amgen initially took one into the clinic. They saw some clinical activity. I think it was a little bit sparse, and they couldn't figure out what biomarker defined what they saw, so they ultimately divested their program. There's a private company called Volastra that's been leading the charge with KIF18A inhibitors, and I think they've published some reasonable data in ovarian cancer. There's another company called Accent Therapeutics that's also working and, you know, I've heard they're generating nice data as well. It sounds like KIF18A inhibitors are generating some promising data. From what I've heard, everything's exclusively in ovarian cancer right now, which is a pretty crowded space.
Our program, we're not going into ovarian cancer. Even KIF18A is still considered an essential target, so you would ultimately expect more tox with KIF18A than with ours. But from my perspective, I would love to see some of those programs succeed and make it the distance because I think it could renew interest in the class altogether. You know, I think at this point in our industry, there's only so much more work we can do in kinase targets. I'd love to see, like, a new area that could be harvested.
Yeah.
I'm optimistic that kinesins could become that, and then we might get interest from pharma, not only in our kinesin. We actually have a second kinesin we've identified that is ripe for a discovery program, so I hope this becomes the next class up.
Okay, good. I think you just announced that the phase I trial's up and running.
Correct.
What can you tell us about that and then the cadence of data coming out of that program?
The name of the study I alluded to earlier, it's called the KOMODO-1 study, and that stands for Kinesin oral molecular degrader oncology. Currently we've got about six sites open, and then we'll ultimately up to about 25 sites in the U.S. and a handful of sites in South Korea. We're currently in the earliest phase of single agent dose escalation, and then as we were kinda talking about before, once we get to a recommended dose for expansion, we'll go into those cohorts I mentioned, the FGFR1 single agent cohort, and then a combo with fulvestrant. Then we have some other potential combination cohorts or expansion cohorts as well based on preclinical data we're generating. The single agent dose escalation is a modified BOIN design.
In terms of like what I'm looking for, in the very earliest cohorts, the PK data will be critical because this is an oral degrader. The first question is, well, are you getting oral bioavailability? That'll be the first thing we'll be looking for. As we escalate, we'll be looking for evidence of target modulation. In this case, because it's a degrader, we'd be looking at the expression of the protein pretreatment and posttreatment, and obviously looking for that expression to go down. That would then indicate as we're getting exposure, that we're starting to get an impact on target. As we continue to escalate, I'd be looking for robust exposure, robust target degradation, and at those levels, is tolerability looking decent? Which we expect it to be, but nonetheless we need to confirm that.
If you can check all three of those boxes, good exposure, good target modulation, well-tolerated, then you're really in the game for efficacy. That's where I think we'd be doing those expansions, getting into the right patients, testing our hypotheses. That's how I see the trial playing out over the next year.
Okay. How much degradation you think you need to be clinically relevant?
With our preclinical modeling, where we would do a correlation from dose to PK to PD to tumor growth inhibition, seemed like 70% degradation was our sweet spot.
Okay. All right. Beyond breast cancer, you mentioned some of the other tumors. Where do you think you might take the program after?
Yeah. We're testing some other tumor types right now that through that cell line screen, we saw some other interesting signals. There's not always a strong in vitro to in vivo correlation, so just because we see like 30% of this tumor type is sensitive in vitro, that may or may not recapitulate in vivo. We're going through that work right now. We're running additional tumor type models based on what we see. I don't wanna declare another tumor type of interest yet because it could be that like four weeks from now, when the in vivo models read out, it turns out that wasn't a good one. Bottom line is, we are looking at other both solid tumors and hematological tumors to see which ones do we get that nice concordance of data from in vitro to in vivo.
Okay. Why don't we talk a little bit about the financial, like the runway you have?
We issued our 10-K earlier this week. We have $107.6 million of cash on the balance sheet, and we have projected that to fund our operations into the second half of 2028.
Okay. You're still looking for other targets. You have your Spyglass platform. What else would be interesting to complement this program?
From the Spyglass platform, there's four other targets we've identified, three of which are completely novel, that we think would be promising to be our next programs up. We're not actively advancing them at this moment because with our current resources, with the BBI-940 program, with, I think, the state of the market and where investors' interests are, we've determined that we really need to generate clinical data with this program that's most likely to catalyze interest. At this moment in time, it probably wouldn't be wise for us to be burning a lot of our cash on a discovery program that could still be years from the clinic. In the long term, I would love to work on those programs.
I think there's scientific merit there, and I think they could represent, you know, future hope and help for our patients, but we also have to be disciplined stewards of our cash in this environment.
Great. Well, let me see if there are any questions from the audience before we wrap it up. All right. Well, thanks, Zach, for being innovative and going where no one else has gone before.
Thanks for following the story, Andy, for always maintaining a real scientific interest in it.
Great. Thank you. Look forward to--