Everyone, my name is Lisa Bayko. I'm one of the SMID Cap biotech analysts here at Evercore ISI, and I'm really pleased to be joined by Rachel Haurwitz, who is the founder and CEO of Caribou. Caribou is working on some novel cell therapies, and so we're going to dig into that today. They've got at least three programs going on that we're tracking, and I think more beyond that. So with that, Rachel, I want to turn to you, and just we can start with a company overview.
Great. Well, Lisa, huge thank you for giving us the opportunity to be here today. We are a CRISPR genome editing company, and that next-generation technology that we've invented called the chRDNA technology is at the heart of our research organization. And we're using it today to develop a wholly owned pipeline of off-the-shelf CAR- T cell therapies for a variety of heme malignancies and autoimmune diseases, and I look forward to chatting about both of those with you today. We have three ongoing phase I clinical studies in oncology: non-Hodgkin lymphoma, multiple myeloma, and AML, and we've committed to three data readouts across those first two programs in the first half of next year. So that includes a 20-patient cohort in second-line large B- cell lymphoma.
We'll use those data to hopefully launch ourselves into a pivotal trial by the end of next year in the second-line setting: a new cohort of patients who've had prior CD19 targeted therapy, either a bispecific or an auto CAR- T, to see if CB-010 has potential with those patients, and then our first look at CB-011 data and myeloma, and we recently disclosed that we're seeing some encouraging efficacy with that program, and excited to dig into the details.
Good. And you've got these are all very different edits going on all these programs. Maybe you can kind of walk us through the differences and how it leverages your chRDNA platform.
Sure. I mean, maybe I'll zoom out for a moment and say our fundamental thesis is that the CAR- T cell therapy field has to move to an off-the-shelf paradigm.
Agree.
And really, that's just driven by a goal of getting more of these therapies to more patients and recognizing that an N-of- 1 bespoke strategy won't do it.
It's just been such a struggle, though. I mean, you're not the only ones to try to do this. We just haven't seen that sort of... but I'm optimistic. I mean, usually there's like a lot of iterations that have to happen before you have a big breakthrough like this.
Which sets me up perfectly for editing strategies. Thank you, Lisa. You know, I think it's not as simple as just taking a healthy donor T cell and adding a CAR, which describes a lot of the first-generation allo assets that came to the clinic. Our thesis from day zero was built on an understanding that those are foreign to the patient's immune system. These allo CAR-T cell therapie s are going to be rapidly rejected compared to the auto CAR-T cell therapies, and you have to do something to bridge that gap. And so we've thought about a number of different editing strategies to really bridge that biology, and we deploy them in different ways across our different programs. So our lead program, CB-010, we use a PD-1 knockout strategy. So this actually has nothing to do with immune clearance.
It's really about ensuring that we take the breaks off the CAR- T cells to ensure that they retain as high an anti-tumor activity as possible during that window of time while they're present. Our preclinical data allowed us to hypothesize that a PD-1 knockout could result actually in a better therapeutic index relative to other CAR- T cell therapies, and I think we've seen that borne out in our clinical work already. Moving to myeloma, we actually went in a different direction. Whereas in lymphoma, there was very clear preclinical evidence that manipulating the PD-1 pathway could be quite impactful, those same data didn't exist in myeloma, and we focused instead on the immune rejection.
We've deployed an immune cloaking strategy where we get rid of all endogenous Class I presentation and then further engineer the cells so that they only express HLA-E to try to prevent both the patient's T cells and their natural killer cells from rapidly rejecting the therapy to buy additional time for additional anti-tumor activity. Moving then to AML, we actually put all of those things together in one therapy, both the PD-1 knockout and the immune cloaking. That asset actually requires five edits for its manufacture, three separate knockouts, two separate gene insertions, and I think it's really a testament to the strength of the chRDNA platform because it allows us to do all of those edits at quite high efficiency while maintaining genomic integrity, which is mission critical.
Okay, great. So starting with CB-010, the CB-010, I guess, the PD-1 knockout, do you think you did enough there? Because I know now you're going to be employing this HLA-E kind of matching strategy. Is that in a way a workaround to sort of not having the immune cloaking on there and that kind of thing? And why didn't you, I guess, in hindsight, employ an immune cloaking strategy there?
Yeah, so zooming back to the early days, as we were thinking about these different strategies to approach the allo CAR- T space, we also wanted to make sure that as we initially clinically deployed them, we could really understand their safety and their utility. And so we wanted to evaluate each of them separately and really paired them with diseases where the biology made the most sense, hence PD-1 in lymphoma and immune cloaking in multiple myeloma. Now moving forward, certainly intrigued to see how the combination of the two might work, especially in the context of a disease like AML, which is obviously so incredibly challenging. As we think about the lymphoma setting, I do think we've done enough, right? Our objective is to meaningfully rival the autologous CAR- T cells.
In data we shared at ASCO earlier this year, we see that for patients who by chance received a dose of CB-010, where they and the donor share four HLA alleles, that's four out of 12, so a fairly modest match, we are able to see outcomes that do rival those of the auto CAR-T cell therapies. Our 20-patient confirmatory cohort that we're enrolling right now, we're explicitly intentionally providing that four-plus match product to these patients to hopefully confirm the signal that we've seen thus far.
How confident are you? Because there's always the kind of concern that when you kind of look back, it's a retrospective analysis and all that kind of stuff that maybe that isn't necessarily a real thing. Like, how confident are you that this is really the solution that on an a priori basis is going to work out?
Yeah, look, first and foremost, we're doing the homework to continue the confirmation, right? So I think that's critical to build the N to really gain enhanced confidence in what we've seen. But I think in this case, the biology, the translational biology really supports the observations. So the observations are based on the efficacy and that we see enhanced efficacy and durability of efficacy, in particular with these higher matches between the product and the patient. That correlates really nicely with the PK. What we can see is that if there are few matches, let's say zero or one, between the patient and the donor, the PK is dramatically negatively impacted. Peak is hit by multiple orders of magnitude, and durability of persistence is dramatically shorter. And it scales from there: two to three matches, higher PK, four-plus, even higher PK than that.
So I think the fact that the translational biology, A, makes sense, and B, is so consistent with the efficacy, I think it de-risks the smaller end of the initial data.
There's almost a dose response. I guess it's a match response or something.
Exactly. Exactly.
Okay. And so then you're not employing this, though, in some of your other programs. So is that because you have these other edits that make it sort of like, you think, unnecessary?
We're deploying what I'll call our best match strategy for 11 and 12. We don't have the wealth of data for those two programs yet that we had for 10 that allowed us to do such a sophisticated retrospective analysis. With 11 and 12, we're building those data sets. And so what we do today is actually take the HLA type of the patient right up front, and then based on our inventory in the freezer, we deliver to them the best match product that we have that's allowing us to build this data set to then dig in and understand within the Class II alleles what level of matching could be most helpful.
Okay, interesting. That's very interesting. Okay. And I guess if this works out, do you think that's something that you're sort of pushing the envelope for the field in a way? Others may kind of look to do the same thing. I mean, in a lot of ways, it does make sense.
I don't think the biology is unique to CB-010 or our platform. I do believe this is a fundamental component of what could make Allogeneic CAR-T cell therapy successful for patients.
What kind of impact does it have on the whole notion of off-the-shelf?
Yeah, this remains very much off-the-shelf. What's so nice is we're talking about a threshold of four out of 12, which obviously pales in comparison to thinking about, say, bone marrow transplant, where you might need 10 out of 12 or 12 out of 12. So to do some quick math here, to have a supply that could be broadly useful for the second-line population here in the United States, we only need 13 different donors to be able to provide 90% of patients with a four-plus match product.
Okay, okay. So walk us through the data that you've then seen sort of using and how this compares to just broadly without overlaying the HLA matching and how that compares, and then we can talk about upcoming data as well.
Yeah, absolutely. Maybe just a quick trip through history. So we started what we call the ANTLER trial, very traditional three-plus-three dose escalation in third-line and later patients, sometimes much, much later, as you typically see in these first-in-human studies. And we ultimately evaluated three different dose levels: 40 million, 80 million, and 120 million CAR- T cells. What we saw with those data that we shared quite some time ago now was really quite compelling in terms of outcomes for patients. And I'll point in particular to the six-month CR rate. 44% of those patients achieved a CR six months after receiving a single dose of CB-010. To put that in context, in the third-line setting for the auto CAR- T cell therapies, on average, about 35% of patients achieve a CR at the six-month mark. So incredibly encouraging for what CB-010 can do for these patients.
We actually took those data to the FDA, and we asked permission to move into an earlier line, to move into the second-line setting, recognizing that's really where the evolving unmet medical need and commercial opportunities both sit. They greenlit that. So all of our work since then has been explicitly in second-line large B- cell lymphoma patients. Now, that is also where the two auto CAR-T cell therapies that have gotten the most traction, Yescarta and Breyanzi, are approved. As we moved into the second-line setting, we've certainly seen a significant shift in the patient characteristics. Actually, our second-line patients are on average dramatically sicker than the patients we were enrolling in our initial work. In aggregate, our data for dose escalation were not quite as shiny and snazzy.
I should say dose expansion were not quite as shiny as the data from dose escalation, and yet, when we then layer on this HLA analysis, what is so fascinating is that subset of patients who received the partially matched product, they have outcomes that rival those of what we see from the autologous CAR-T cell therapies, and that is in spite of the fact that these patient characteristics are quite a bit more severe than the initial cohort of patients we saw, so it gives us a lot of optimism for what CB-010 can do for this patient population, and as we zoom forward, our objective is to meaningfully rival the auto CAR-T cell therapies, so in the commercial marketplace, we see that as potentially two shots on goal. One is to compete for the fraction of patients who are currently being served by autos today.
And the second is to really meaningfully grow the market and to deliver cell therapy to patients who, for a wide variety of reasons, aren't getting it. And to put that in numbers, today in the second-line setting, only about 20% of second-line patients are getting a uto CAR- T cell therapies. That's in spite of the fact that the a uto CAR- T cell therapy data are superlative, right? These are incredible therapies, but there's so many fundamental challenges that just cannot be overcome in an N- of- one bespoke strategy. And we know an allo can be a key to unlocking a lot more of that.
Okay. So you're going to have your confirmatory set of 20 patients. And just remind us when that will be?
First half of next year.
Okay. That's very exciting. And then what are the next steps from there, assuming that kind of confirms what you've seen?
Yeah, assuming what we've seen before holds true, we intend to initiate a pivotal phase three trial by the end of next year.
Are you getting any data on a real-time basis as these patients roll through?
These are open-label trials.
Okay. So how are you? How are you feeling about it?
It's a great question that I can't answer. So I'll say stay tuned as we approach the ability to share the data in a more fulsome way.
Okay. Okay, great. So you're also looking at CB-010 in autoimmune disease.
Yes.
Tell us a little bit more about that.
Yeah, absolutely. Look, all of the work that we've done in oncology, we've now dosed well north of 50 patients with CB-010, has given us a lot of confidence in what that asset can do to kill B- cells. And so I think it's really meaningfully de-risked our ability to bring CB-010 now into the autoimmune setting, specifically in lupus for our first step. As you think about what CB-010 needs to do in oncology, it needs to kill off all of the diseased B- cells, not only in the lymph nodes, but potentially extranodal tumors riddled throughout the body. There's quite a lot of difficult biology it has to navigate. And we've seen some very compelling examples of quite long-term responses in these patients. So it tells us CB-010 can get to where it needs to be. And we also have a wealth of translational data.
And specifically, as we look at PD, we can see in the oncology data that CB-010 drives profound deep B- cell aplasia that lasts on average about 114 days. So to put that in context, Dr. Schett and his colleagues have shared that they see their patients in the autoimmune setting experience B- cell aplasia for about 112 days. So let's call that the same. So we think very encouraging signals for what CB-010 does in oncology that will help to de-risk its potential in autoimmune. We got our IND cleared earlier this year. We'll be able to enroll two patient cohorts in parallel, one for lupus nephritis, the other for extrarenal lupus. And we are on track to initiate that study soon.
Are you going to be using HLA matching there as well? It makes sense, I guess.
Yes, we will. Absolutely.
Okay. And then the space, there was so much excitement about CAR-T cell therapies and autoimmune, and then there's some sort of diminution when there's been some relapses and stuff. What is your perspective on that?
Yeah, I mean, look, the original data from Dr. Schett and his colleagues were superlative, right? Just truly extraordinary, and I think lit the field on fire in a really exciting way to demonstrate what CAR- T cells can do for these patients. I think probably many people also expected that, as is often true with very initial work in an academic setting, it was pristine, and that as you start to get out into the wild, maybe expecting perfection is not the best expectation, and certainly, as we look at what CB-010 has done in oncology and how we think about its potential in lupus, we are as excited as ever for what we think CB-010 can do for these patients, and I'll say that enthusiasm was echoed and then some. Many of our team members were at ACR recently.
We shared a poster on a lot of the preclinical data for CB-010 and actually some of the clinical data in the oncology setting as well and heard tremendous enthusiasm from rheumatologists and other KOLs who are really eager to get a hand on an off-the-shelf approach for these patients. And maybe I'll take a moment to talk about the relative opportunity for auto versus allo in this population. I think it's very different from oncology. In oncology, speed to transplant is critical. Speed to therapy, I should say, is critical and drives so many decisions. And so it's readily obvious that an off-the-shelf approach is critical for that patient population. That story actually doesn't translate to, say, lupus. You probably don't need a therapy today versus six weeks from now.
But really interestingly, we're hearing this really enthusiastic pull from KOLs for off-the-shelf because lupus patients are on all kinds of maintenance meds. To undergo apheresis, to have their product made, they have to go off basically all of their meds. They have to go through a washout period, high risk of flare. Then, depending on how long manufacturing takes, maybe you go back on some of them and come back off again to receive your therapy. That is untenable for a huge fraction of patients and/or means those who go through it are at risk of being in flare in the midst of receiving a CAR- T cell therapy. So they're very attracted to the idea of a readily available product that does not require this washout period for apheresis.
Okay. I want to turn to CB-011 for multiple myeloma. Just kind of walk us through where we're at, kind of what's coming next.
We've made tremendous progress executing on this clinical trial, so 3 + 3 dose escalation design, as you might imagine, and we started with what I'll call standard lymphodepletion, so it's the LD you would get before, say, Abecma or Carvykti. We walked through three dose levels, creatively called dose levels one, two, and three, and then really driven by some interesting observations in the field, decided to go to a slightly deeper lymphodepletion, so same dose of fludarabine as what we've been using, and then going from 300 Cy- 500 Cy, and we're very encouraged by the initial efficacy that we've seen with that, so we started that at dose level three. Our protocol actually allows us to backfill additional patients into a dose where we see efficacy, so we are very actively enrolling into that dose cohort right now, at the same time that we're continuing to escalate.
So we're also enrolling patients in dose level four with a deeper lymphodepletion. Given that myeloma is a field that has a lot going on and has, I think, mature expectations for what success looks like, we wanted to make sure we had a sufficiently robust data set, A, to make our own decisions about the best next steps for development, but B, to then have a story that's clearer to share with our external stakeholders. So we are looking forward to sharing really the first meaningful update in the first half of next year. We've committed to at least 15 patients from efficacious dose levels, and we're excited to talk about what next steps for the program will look like.
Okay. Wonderful. Okay. And then CB-012, I've heard from some people this is like the most exciting program just because, as you mentioned, there's like five edits there.
Yeah.
You're doing a lot. By the way, just a separate topic, would you ever come back and kind of come out with a CD-19 with some of these edits in there as well?
Never say never. Right. Depending on what we learn in the clinic, there might be reasons for future attributes that look like.
Just for the immune cloaking and all that kind of stuff. Okay. So discuss your kind of AMpLify trial design and timing there.
Yeah, so this is our program targeting CLL-1 for AML. Obviously, incredibly compelling unmet medical need, relapsed refractory AML. There's effectively nothing for these patients. In fact, the patients who, say, might be on a waitlist for our study and don't get in for timing reasons, hospice is usually the other opportunity that they have, so incredibly humbling, lots of opportunity for these patients. We started this study earlier this year, have made great progress. We've cleared dose levels one and two, no DLTs. We're actively enrolling at dose level three, and as we look at the landscape, how do you define success? What we hear from KOLs is that a CR rate of 20%, 25%, that would be really exciting for them for this patient population.
Okay. When will we get data from AMpLify?
Stay tuned.
Okay. All right. Okay, good. So we're out of time, but I just wanted to ask quickly about cash runway.
Yes. We ended Q3 with $281 million cash on hand. That gives us a strong balance sheet and the opportunity to invest in all the programs that we just talked about and runway into the second half of 2026.
Okay, great. Rachel, thank you so much for your time today.
Thanks, Lisa. Appreciate it.
Sure.