Great. Thanks, everyone, for being here. My name is Yanan Zhu, and I'm one of the biotech analysts here at Wells Fargo. It is our privilege to Caribou Biosciences' management team joining us for a fireside chat. With me is Rachel Haurwitz , President and CEO Caribou Biosciences. Thank you, Rachel Haurwitz, for being here.
Thanks for having me. I really appreciate it.
Great. I was wondering if we can start with the big picture question. What role could allogeneic CAR-T cell play, and how Caribou Biosciences' approach differ from others in the field?
Yeah, thank you. I think it's a great, great place to start. You know, fundamentally Caribou Biosciences, we believe the future of the cell therapy field has to be off the shelf, right? As we think about the ability to scale these kinds of therapies for broader and larger patient populations, you really need to be in a paradigm where one manufacturing run can result in many doses for many patients, rather than the personalized approach that's inherent in the autologous strategy today. Immediately, though, I think we have to reckon with the fact that in the off-the-shelf world, these are healthy donor T cells. They're foreign to the patient's immune system, and we have to do something to help enhance the activity of those T cells to bridge the gap, because the patient's immune system will recognize them as foreign and, and will reject them fairly rapidly.
So Caribou Biosciences, we've developed a few different strategies for ways to do what we call armoring, enhancing the anti-tumor potential of our cell therapies. We use different strategies for different therapies as we're really trying to marry the strategy with the disease biology in particular. So for example, in our non-Hodgkin lymphoma program, we get rid of PD-1, really trying to take the brakes off the CAR-T cells. Now, this doesn't change immune-mediated rejection. That will still happen. But what it does, we hope, is prevent the T cells from becoming prematurely exhausted. So during that window of time while they're present in circulation, they pack as much anti-tumor punch as possible. Now in our second program for multiple myeloma, we instead use an immune cloaking strategy. And here we're very directly trying to slow down immune-mediated rejection, buying additional time for additional anti-tumor activity.
I hope we'll have time to talk about our AML program today as well, which is the first chance to actually deploy both of these together. That's a preclinical program, on track for IND this year, and it's the first time that we'll be deploying both the PD-1 knockout and the immune cloaking together in one cell therapy.
Got it. Got it. Thanks for that overview. I think, over the summer, it caught everyone's attention that Pfizer invested $25 million in a company. How did this investment originate, and what did Pfizer review as part of their due diligence process?
Yeah, we were thrilled to have their investment. They approached us in the context of the Pfizer Breakthrough Growth Initiative, PBGI, with a specific strategic interest in multiple myeloma. That meant our program that we call CB-011, which is in an ongoing phase I clinical trial, was their primary remit from a strategic perspective. In exchange for their $25 million investment at a healthy premium, they get a 30-day right of first negotiation on that program. We also get their help. Their head of multiple myeloma development has joined our scientific advisory board, and we're thrilled about that. We have other touchpoints between the companies where we can seek their advice, their feedback, and their guidance as well.
Right. Great. Congrats again, congrats on that transaction. Also over the summer, you reported data from the ANTLER phase I trial, for your lead program, CB-010, in patients with relapsed or refractory B cell non-Hodgkin lymphoma. How do you and your investigators view the data?
Yeah, we were very excited about these positive data. So the data set was all 16 patients enrolled in dose escalation, which is now concluded, and we had a minimum of six months of follow-up on each of those patients. And so it, it allowed us to speak to not only safety, not only overall response rates, but really the durability of response, which we know is so important, in this, this space in particular. So the headlines are 94% overall response rate in that 16 patient cohort, which is obviously quite remarkable. And I think most importantly, we were thrilled to see 44% of the patients achieve durable CRs, measured at a CR at six months or greater.
To put that in context, if you look at the data from the trials that led to the third-line approvals for Kymriah, Yescarta, and Breyanzi, typically about 1/3 of patients achieve CRs at six months or greater. So it's n of 16 versus an n of 100 or so. I wanna be cautious about the statistics here, but I think it is very clear that CB-010 can drive durable responses that rival those of the autologous CAR-Ts. You asked about physicians as well. I'll highlight between the data that we've been able to share and our move into second-line large B cell lymphoma patients. We've actually had quite a number of top-tier sites reach out to us to say that they'd like to be part of the trial.
For anyone who's been following ClinicalTrials.gov, they'll see that the number of sites listed there has increased recently, and it's really a reflection of that.
Got it. That's great. Great to hear. For dose expansion, can you remind us of the strategy for moving into second-line, as you just mentioned, and what can we expect to see initial dose expansion data?
Great question. Obviously, as we look back at the autologous CAR-Ts, they really paved a path, with initial approval in the third-line, additional clinical work that has ultimately moved two of them now into the second-line setting. And so as we step back and look at the evolving medical and commercial landscapes, it's very clear that second-line is where the compelling need and opportunity lies. And so our team has, I think, been very creative and thoughtful, and looking at our initial data, felt that it really motivated a potential move directly into the second-line setting. And so we proposed a protocol amendment to the FDA to do exactly that, to move into second-line large B cell lymphoma patients in expansion, and they greenlit that.
And so all of the patients who are enrolling in the ongoing dose expansion portion of this phase I trial are second-line patients. The objective really is to create the foundational data set that could be used for a potentially pivotal trial in the future. We plan to talk to the FDA this year, to start getting their feedback and their guidance on a potential strategy, to go for a pivotal trial in the second-line. In terms of first data, what we've guided to is that we plan to share initial dose expansion data in the H1 of next year.
Got it. That's quite exciting. Congrats on having this agreement with the FDA, and definitely looking forward for that data. Just.
Just to be clear, we'll have the FDA meeting this year, and we'll share that feedback later this year.
Right. But the expansion cohort.
Yes. Yes.
You know, you can enroll only second-line patients. That's, you know, quite, quite interesting.
Absolutely.
Yeah, glad to hear that. What is the bar for CB-010 in second-line?
We think of the bar in second-line thematically the same way we thought about it in the third-line, namely we believe the response and, importantly, the durability of response has to be in the same ballpark as the autologous CAR-Ts. In the third-line setting, we've talked a lot about six-month complete response rates. I think that's a metric that people are very familiar with in these early-stage trials. But of course, it's not actually an approvable endpoint if you look at these labels. They're far more traditional endpoints like overall response rate or event-free survival. And so, as we look at the second-line comps for both Yescarta and Breyanzi, we'll be looking to measure CB-010's responses and durability of responses, and expect to hold ourselves to the bar of seeing CB-010 in approximately the same ballpark.
Got it. Got it. Will you, you know, will you consider redosing patients or changing the lymphodepletion regimen?
So today it's a single-dose strategy. Certainly, as we speak with KOLs, one of the things they love about the autologous CAR-T space is the one-and-done nature of the therapy, and any departure from a single-dose regimen would be data-driven. In terms of lymphodepletion, in this particular trial, though, not in our other trial, which we'll come to in a moment, we're using a deeper lymphodepletion. So it's the same two drugs that most people will be familiar with. It's a Cy/Flu regimen. It's simply more of each, and this was based on a strong recommendation from our scientific advisory board, recognizing that CB-010 does not have the immune cloaking and therefore will be fairly rapidly rejected, and so balancing that with a slightly deeper lymphodepletion in order to create a slightly larger window, if you will, for initial engraftment and activity.
This has been well tolerated on the study to date, and there are no plans to change it at this point in time.
I see. Got it. Got it. Is there any, you know, according to your interaction with your investigators, is there any indication that the lymphodepletion could have contributed to the response rate and durability of a response?
It's a great question to ask. We ask that of physicians. You know, what, what do you think the outcomes could be if patients simply got this Cy/Flu combo and no cell therapy? And what we hear is that by and large, they would expect little to no response, certainly not durable complete responses. And we can look into the literature and, and look at other trials that have used this combination in the autologous CAR-T setting, and we certainly don't see the same kinds of durable responses.
Got it. Got it. What will be the next steps after dose expansion? Do you plan to evaluate CB-010 in autologous CAR-T experienced patients?
Potentially. So today we're exclusively focused on CD19-naive patients, so not only patients who've not received auto CAR-T, patients who've not received any sort of CD19 targeted agent. But we certainly recognize that the auto CAR-T relapse patient population is a growing one. So our objective right now is really focused on continuing to use dose expansion to ultimately determine the recommended phase II dose. Once we have that dose in hand, we can think about potentially other patient populations, and auto CAR-T re-relapse could be one of them.
Right. And this would be CD19- positive.
Correct.
Relapse.
Correct. Exactly.
Got it. Remind us of the PD-1 genome editing strategy and how this differentiates CB-010 from others.
As far as we know, CB-010 is the first allogeneic CAR-T into the clinic with a PD-1 knockout. And really, the objective, as I mentioned a few minutes ago, is to take the brakes off the CAR-T cells. We're simply trying to prevent premature CAR-T cell exhaustion. And we think this is a particularly relevant strategy in the context of non-Hodgkin lymphoma. The majority of NHL tumors are PD-L1 positive, and of course, they reside in the lymphatics, which are the, the epithelial cells lining that are rich in PD-L1 and PD-L2. So it's an environment where we know the PD-1 axis matters quite a lot in terms of T cell activity.
Our preclinical data, others' preclinical data as well, has demonstrated the importance of the PD-1 pathway in this disease, and I believe it's why we saw such compelling activity even at the very first starting dose on ANTLER. So our very first dose level was only 40 million CAR-T cells, and yet we saw remarkable responses. In fact, the first six patients in that cohort achieved a complete response. And even compared to the autologous CAR-Ts, that's a remarkable response for such a low dose, and I believe it's the impact of the PD-1 knockout.
Yeah. Well, great to hear. Thanks for explaining the rationale why it should work, and congrats on selecting that strategy at the beginning. If we switch gears to CB-011, what is the status of CaMMouflage, and when could we expect to see first data?
Yeah, great question. So CaMMouflage is the phase I trial that we are running for CB-011, our off-the-shelf CAR-T for multiple myeloma. We dosed our first patient earlier this year, and recently, safely concluded dose level 1, and we've moved into dose level 2, so going from 50 million CAR-T cells to 150 million CAR-T cells. We've not yet guided to a specific timing for the data update, and that's simply because it will be data-driven. If you look backwards at our initial approach for CB-010, I think in many ways it will look similar for CB-011 from a communications perspective. Our goal is to really have a, a meaningful negative data that can start to shed light on some of the key questions about this program, both safety and efficacy, and once we have that, we'll, we'll find the right venue to share that information.
Got it. How do you view the competitive landscape in multiple myeloma, and where does CB-011 fit in that landscape?
So we ask KOLs all the time, "What would it take for you to choose an allogeneic CAR-T for your patient?" and what we hear is that they're really benchmarking the emerging allogeneic CAR-Ts against the bispecifics, and that's because the bispecifics are the other approach that is broadly available off the shelf to this patient population. So that's about a, let's call it 60%-70% overall response rate, and so that's the benchmark that we have in mind, as we brought CB-011 into the clinic. As far as I know, CB-011 is the first allogeneic CAR-T to have the immune cloaking strategy that we're deploying, and so we believe it really sets the program apart in the competitive landscape.
Got it. Got it. And, in terms of, I think, you know, you just mentioned, the bar for CB-011. Maybe let's can you talk about, you know, about the editing of the cell, one, why their PD-1 is not, used in this, for this, construct, and two, explain how does the immune cloaking, strategy work, and how does it make, CB-011 different from others?
Yeah, happy to. So maybe taking 10 steps back, as we were initially building our cell therapy pipeline, we were thinking really hard about the different kinds of armoring strategies that might be useful in these kinds of settings. And so we had both the PD-1 knockout approach and the immune cloaking approach, and we wanted to initially evaluate each of these separately to understand their safety and understand their potential utility. And so that means we had to think really hard about the appropriate places to deploy each of these. I talked a little bit about why PD-1 is so impactful in the non-Hodgkin lymphoma setting in particular. The same data don't exist in multiple myeloma, demonstrating the role of PD-1 in that context, and so we felt the immune cloaking approach would make the most sense for this particular disease.
I'll come back to how it works in just a moment, but I will say, you know, of course, hypothetically, there might be situations where you'd want to use both of them, where they could be additive, and in fact, that's what we're doing in the context of our AML program, CB-011. So the immune cloaking is designed to try to slow down immune-mediated rejection by the patient's immune system, and so we use two edits to carry this out. The first is a gene knockout where we get rid of a protein called beta-2 microglobulin, beta-2M for short. beta-2M is necessary for the stabilization of HLA class I on the surface of a cell, so it's kind of an easy way in one step to get rid of all endogenous HLA class I presentation. So that helps to prevent the patient's T cells from rapidly rejecting the therapy.
Then we take it one step further. We site-specifically insert a transgene that fuses beta-2M with HLA-E, and that ensures that our CAR-T cells are decorated only with HLA-E on their surface, and that goal is to prevent the patient's natural killer cells from rapidly rejecting the therapy. So really trying to balance both sides of the immune equation. I should be clear, we don't think these make the cells perfectly stealthy forever, right? This is about buying additional time for additional antitumor activity.
That's very helpful, color on the cloaking. I think, as we talk to different companies pursuing different strategies, and some feedback is that, one, the HLA-E could bind to activating NK receptors on some, a subset of NK cells, and two, perhaps not all NK cells have the inhibitory ligand, NKG2A, for HLA-E. Could you, you know, talk a little bit about those context?
Yeah, it's a great point and a great question. NK cells are not one thing. They're a rich mixture of cells that express a variety of different ligands and proteins. What we have seen in our preclinical work is that CB-011 cells are very nicely protected from the onslaught of both allogeneic CD8-positive cytotoxic T cells as well as natural killer cells. And we've evaluated not only an immortalized line like NK-92, but also healthy donor peripheral blood-derived natural killer cells. So we see that this phenomenon is nicely protective of the CB-011 cells.
Great. Thanks for going into that detail. Perhaps we can switch gears to CB-012. Why is CLL-1 a good target for AML?
So as we got excited about thinking about a cell therapy for AML, we quickly realized target selection is one of the very hard parts of developing a cell therapy for this field. Our objective is to develop an allo CAR-T that could be potentially disease-modifying on its own and not necessarily a bridge to transplant, and so that means you have to find a target that is expressed on AML tumor cells but not expressed on healthy hematopoietic stem cells. So that's why we got very excited about CLL-1. It is highly expressed on AML tumors. It's even expressed on leukemic stem cells, but importantly, it is not expressed on healthy HSCs.
There was some really interesting work happening at Memorial Sloan Kettering on this target, and in fact, Renier Brentjens's lab had developed fully human binders against it, and we've since exclusively in-licensed those for the development of CB-012.
Got it. Got it. And could you summarize the five different genome edits involved in this product candidate?
Yes, absolutely. I think this is a great example of the strength of our underlying genome editing technology. We call it the chRDNA platform. It allows us to do quite sophisticated multiplex genome editing while maintaining genomic integrity, allowing us to carry out the kinds of edits to make something that looks like CB-012. So we knock out a gene called TRAC, and the purpose of that is to get rid of the T cell receptor to reduce the risk of graft-versus-host disease. We knock out PD-1 just as we do in CB-010 to prevent premature CAR-T cell exhaustion, and we also knock out beta-2 microglobulin as part of the immune cloaking strategy and further insert the B2M- HLA-E fusion gene. And of course, the fifth edit is adding the CAR that is specific for CLL-1.
Right. With that many edits, are those done simultaneously, and if so, the double-stranded breaks and chromosomal risk for chromosomal translocation, could you touch on that?
So, very great question. We've not revealed the exact secret sauce for how we do all the editing inside the manufacturing, but I can say about all of that is two things, though. First off, because we're using a genome editing technology that is far more specific than first-generation CRISPR-Cas9, it helps us reduce the risk of off-target translocations. So how do translocations occur? They occur when there are two different breaks, two different edits simultaneously, and that, of course, can happen if you have both an on-target edit and an off-target edit. So by dramatically reducing the frequency of off-target editing, we dramatically reduce the risk of off-target translocations as well.
Now, as you know, we just talked about, we're intentionally making multiple different edits, and so we've further developed a proprietary way that we actually deliver the reagents into the cells that also dramatically reduces the frequency of translocation. We've publicly shared exemplary data of this before showing that if you use kind of a standard approach, you'll see something like 1%-5% of T cells experiencing a translocation when you edit two sites, and when we use our proprietary delivery and our delivery strategy instead, we can drive that down as low as 0.1%. So very excited about the combination of these approaches.
Got it. Got it. What is the status of this program for getting to the clinic?
Yeah, great question. So we recently reiterated it is on track for IND this year, and certainly looking forward to bringing it into the clinic into a phase I trial.
Got it. Got it. I think and perhaps now let's talk about the hero behind the scenes, the chRDNA, sorry, technology. What makes it different from the conventional CRISPR technologies?
Yeah, so chRDNA is an acronym. It stands for CRISPR Hybrid RNA DNA, and it describes the proprietary guides that we've invented here Caribou Biosciences. Obviously, typically, CRISPR enzymes are targeted by all RNA sequences, guide RNAs, to the right site in the genome, and our team instead developed hybrid guides, guides that are part DNA, part RNA. Turns out the inclusion of DNA dramatically improves the specificity of genome editing. We can combine these guides with multiple different enzymes. For example, CB-010 is manufactured with Cas9 chRDNA, whereas our other programs are manufactured with Cas12a chRDNAs. Cas12a is particularly good at gene insertion, and so that's how we're able to do multiplex gene insertion to manufacture programs like CB-011 and CB-012.
Right. Got it. And, you know, I think you touched upon this, a little earlier, but how does the number of edits impact editing efficiency and genomic integrity?
Yeah, so in the context of a primary cell, like a batch of CAR-T cells, you never hit 100%, right? So every edit leads you to multiply the fraction of the cells that got the first edit by the second edit by the third edit. So it obviously puts tremendous pressure on the importance of efficiency and genomic integrity simultaneously. It's why Cas12a in particular has been so valuable for us for manufacturing these kinds of therapies. For example, we can achieve knockouts as efficient as 95%. We can achieve gene insertions as efficient as 80%. So it means we can make something like CB-012 with 5 different edits and know that by the end of the manufacturing run, more than half of all of the T cells can have all five of those edits.
Got it. Got it. How do you think about manufacturing, both for clinical trials and in the long- term?
So internally, we've built out strong process development and analytical development teams. Our PD team is responsible for everything from that initial handoff from the research team through to scale-up and optimization, and then we tech-transfer these processes to CMOs. We have selected CMOs who have not only demonstrated clinical expertise with cell therapies for other clients but also commercial expertise as well, and so we believe we're, we're well-served today and in the future by these relationships.
Got it. Maybe, a question for, you know, future of the pipeline. Right now you are focused on ex vivo. What about in vivo? Can you share some thoughts on there?
It's a really interesting therapeutic area. Certainly as I look at the chRDNA technology and its enhanced specificity, I could see a lot of value in being able to use that kind of high-specificity technology in the in vivo setting. Clearly to be successful there, you not only need great genome editing, which we have, but also great delivery so that you can deliver the genome editing reagents to the intended location and not to unintended locations. So I would suspect that one of our best paths forward in that way could be to potentially partner with someone, to access the right delivery technology for that in the future.
Got it. Got it. You also mentioned Cas12a as a nuclease with greater specificity, and you have figured out how to combine that with chRDNA. I was wondering about the IP for Cas12a specifically, and do you have the freedom to operate on the nuclease?
Yeah, thank you for asking this question. Because enzymes like Cas12a are naturally occurring, there are no patents on just the enzymes by themselves. So really the IP estates are built around the guides and combinations of the guides with different enzymes. A few of my colleagues here Caribou Biosciences actually invented the chRDNA technology, so it means we own the foundational IP for the chRDNA technology here Caribou Biosciences. Our patent team has been quite busy. We already have five issued U.S. patents, one issued European patent, and they continue to aggressively prosecute this in many jurisdictions.
Got it. That's super helpful. How is the AbbVie collaboration agreement progressing?
It's going well. So we kicked this off in early 2021, where they came to us as their first partner in the off-the-shelf CAR-T cell space, and so we're helping them use our genome editing and cell therapy technologies and capabilities to develop two new CAR-Ts against targets they've brought to the collaboration. Now it's their program, not ours, so they control communication about the details, so there's not a tremendous amount of detail that I can share. What I can say is when we started the collaboration, we focused on one program initially, and more recently we've now kicked off the second program, and excited to see that up and running.
Great. Maybe, you know, lastly, financials. Can you talk about your cash position and the expected runway?
Yeah, so we have a strong balance sheet. We ended Q2 with $292.5 million, and since then we actually raised and upsized follow-on financing to the tune of about $135 million net proceeds. That means we're currently holding a little more than $400 million, which gives us a very strong balance sheet and a runway into the Q4 of 2025.
Got it. Got it. And, perhaps could you summarize the expected upcoming milestones, and, you know, what could be achieved within that cash runway?
Absolutely. So within the context of that runway, we anticipate achieving a few key things across our first three programs. For CB-010, that will get us to the dose expansion data set. For CB-011, that will get us to the dose escalation data set. And for CB-012, that will get us to initial dose escalation data. In the near term, what we have guided to is that we hope to be able to share FDA feedback on the potential future path for CB-010 by the end of this year and initial dose expansion data for CB-010 in the H1 of next year.
Right. Got it. Yep. Thanks. That's a lot of interesting near-term and longer-term milestones to look forward to. I was wondering if there are any questions in the audience? Seems like our discussion is clear. So with that, I think I wanted to thank you, Rachel Haurwitz, for being with us and walking us through the initiatives and progress at Caribou Biosciences.
Thank you so much for the invitation. We really appreciate it.
Thanks.