Welcome to the conference. My name is Astrid, and today I'm pleased to introduce to you Rachel Haurwitz, President and CEO of Caribou Biosciences.
Thank you very much, and thank you all, and thank you for the opportunity to participate today. As mentioned, my name is Rachel Haurwitz. I'm the President and CEO of Caribou Biosciences, and one of the co-founders of our company. Of course, I'll highlight that this presentation includes forward-looking information. Caribou is a CRISPR genome editing company spun out of Jennifer Doudna's lab nearly a decade ago. We have invented our own next-generation CRISPR technology, called the chRDNA technology, that is far more specific than first-generation CRISPR-Cas9. With the chRDNA technology, we can carry out quite sophisticated multiplex genome editing while maintaining genomic integrity. This is a very important technology that today is allowing us to advance a wholly owned pipeline of off-the-shelf cell therapies, including three clinical-stage allogeneic CAR-Ts for hematologic malignancies.
Across the board, you'll see that we use our genome editing in order to really enhance or armor the anti-tumor potential of our cell therapies, including a variety of strategies such as checkpoint inhibition, immune cloaking, and cytokine support. I believe we are well-resourced to continue driving this pipeline forwards, and we'll dig into some of the key details of our clinical programs today. We have just shy of $400 million cash on hand, allowing us to fund our programs and our current operating plan into the fourth quarter of 2025. I'd like to highlight that just a few months ago, Pfizer made a $25 million equity investment in our company, and this was driven by a strategic interest in CB-011, our CAR-T, targeting BCMA for multiple myeloma.
In exchange for their investment at a healthy premium, they received a 30-day right of first negotiation on CB-011, and we also benefit from their assistance. For example, Sriram Krishnaswami, their Development Head of Multiple Myeloma, has joined our scientific advisory board, and we are already grateful for their advice and their assistance. Our pipeline today is composed of assets from two different platforms: allogeneic CAR-Ts, with a focus on hematologic malignancies, and allogeneic CAR NK with a focus on solid tumors. Our first three programs, all allogeneic CAR-Ts, are clinical-stage assets, and I'll be excited to dig into some of the details for each of them with you today.
I'll highlight, in particular, some of the data we shared in July of this year from CB-010, our lead program for non-Hodgkin lymphoma, demonstrating that CB-010, an CAR-T, can drive durable responses that rival those of the approved CAR-Ts. to begin, I'd like to introduce you to our chRDNA technology, and then I'll walk you through how we use this to make our CAR-T cell therapies that are in the clinic today. chRDNA is an acronym that stands for CRISPR hybrid RNA-DNA, and it describes the proprietary technology we've invented here at Caribou. As I'm sure you're well aware, typically, CRISPR enzymes are targeted by all RNA molecules, guide RNAs, to the right site in the genome to edit. What our team did is instead invent hybrid guides, guides that are part DNA and part RNA.
It turns out the inclusion of DNA dramatically improves the specificity of genome editing, and I'll share some example data with you to demonstrate exactly that. What you're looking at here is examples of editing using the chRDNA technology on the left side of the slide to knock out genes, and on the right side of the slide, to actually insert new genetic material at targeted sites in a T cell genome. Starting on the left side first, we're actually comparing the ability of the chRDNA guides side by side with all RNA guides in the context of Cas9 mediated editing. What you can see is that both guide types result in very efficient gene knockout at the targeted site. However, the all-RNA guides also result in multiple, quite significant off-target events.
Yet, when we use chRDNA guides to edit the exact same site in the genome, we observe no off-target editing down to the limit of detection. Similar story when we pair chRDNA guides with the Cas12a enzyme. We can achieve incredibly efficient gene knockout and no off-target editing down to the limit of detection. Now, as I'm sure you can appreciate, gene knockout is a critical piece of the puzzle, but so is gene insertion, and this is where the chRDNA guides, in combination with the Cas12a enzyme in particular, really shine, and we're able to achieve quite high gene insertion efficiencies. In fact, so high that we're able to carry out multiplex gene insertion. This is really mission critical as we think about the ways we need to armor and enhance our cell therapies to improve their anti-tumor activity.
And so what we're showing on the right side of the slide here is a batch of CB-011, our multiple myeloma asset in clinical evaluation today, made by our CMO at scale, where we actually insert two separate genes at two different locations in the genome, both at incredibly high efficiency. And it means that once we're done making a batch of CB-011 cells, in this case, approximately 63% of all of the cells have all four edits. So this platform really unlocks our capacity to be quite sophisticated as we think about how to armor and enhance our cell therapies. Fundamentally, we believe this kind of engineering is necessary to really unlock the broader potential of off-the-shelf, off-the-shelf CAR-T-cell therapies. We fundamentally believe that taking a healthy donor T-cell and adding a CAR alone is, is insufficient.
These off-the-shelf cells will be recognized as foreign by the patient's immune system and fairly rapidly rejected. And so we have articulated a strategy of multiple different approaches for how to armor and enhance the anti-tumor potential of our cells. For example, our lead program for non-Hodgkin lymphoma benefits from the disruption of PD-1. Really, our goal is to take the brakes off the CAR-T cells themselves and prevent premature CAR-T cell exhaustion. I believe the PD-1 knockout is why we've seen such robust anti-tumor activity from CB-010, including at our very first low starting dose in our ongoing phase I clinical trial. We've also developed an approach that we're using today in multiple myeloma for immune cloaking.
This is manipulating the expression of HLA class I on the surface of the CAR-T cells in order to slow down how the patient's immune system can recognize and reject the cell therapy. The goal is to buy additional circulation time for additional anti-tumor activity. Now in our third program, for which we recently received the green light from the FDA to begin a phase I trial, an AML CAR-T, we're actually combining both of these strategies together, both the immune cloaking and the PD-1 knockout. That program, for example, requires five genome edits for its manufacture, three separate gene knockouts, and two separate site-specific insertions, which I think really allows the underlying chRDNA technology to shine and allows us to be quite sophisticated in the ways we address the needs of these cell therapies.
So I'd like to spend the remainder of the time digging into our three clinical-stage off-the-shelf CAR-T cell programs. CB-010 is our lead program being evaluated in the ongoing ANTLER phase I clinical trial. This is a CD19-targeted off-the-shelf CAR-T, and as I mentioned, this is where we use the PD-1 knockout strategy in order to prevent premature CAR-T cell exhaustion. Earlier this year, we disclosed data from the now concluded dose escalation portion of this trial. We enrolled 16 patients across three different dose levels: 40, 80, and 120 million CAR-T cells, and demonstrated quite promising data both on safety and efficacy. In fact, from an efficacy perspective, we've been able to demonstrate that CB-010 can drive quite durable responses, rivaling those of the autologous CAR-Ts, and we'll dig into some of those data in just a moment.
Based on these initial promising data, we proposed to the FDA that we focus in dose expansion on second-line large B-cell lymphoma patients. Our initial dose escalation work was largely carried out in third-line or later patients. We recognize as we look across the space, that second-line is really where the commercial and clinical unmet need opportunities are evolving, and so we were very excited that the FDA was supportive of that. Today we are exclusively enrolling second-line large B-cell lymphoma patients in our ongoing dose expansion work. And to my knowledge, CB-010 is the only allogeneic CAR-T being clinically developed in the second-line setting today. Here's a quick snapshot of the 16 patients who were enrolled in dose escalation. The majority of them, 10, had different forms of large B-cell lymphoma, and six had other forms of aggressive types of non-Hodgkin lymphoma.
Thus far, CB-010 has demonstrated a generally well-tolerated safety profile. I'll highlight, in particular, three AEs of special interest in this setting: of course, CRS, ICANS, and infections. Very pleased to see actually no patients experienced Grade 3 or higher CRS. Only two patients experienced Grade 3 or Grade 4 ICANS, and only one patient experienced a Grade 3 infection. If you take these data and then compare them against the safety data from the initial trials in the third-line setting that led to the initial approvals of the autologous CAR-Ts, you can see that the CB-010 safety profile compares quite favorably against the autologous CAR-Ts. So we're really pleased to see these initial data. From an efficacy perspective, very proud and excited to see how robust the responses have been. Across these 16 patients, 15 achieved a partial or complete response.
In fact, 69% of the patients achieved a complete response. I think the next number is the most important number in the deck. 44% of these patients achieved a complete response at six months or greater. The six-month mark is an important mark in the Non-Hodgkin lymphoma setting, especially in third-line patients. It's really become an important objective as people think about how to predict longer-term outcomes for these patients. So we were very excited to see that 44% of these patients achieved a complete response at six months or greater. Again, putting these data in the context of the approved autologous CAR-Ts. Now, I wanna be cautious, right? Our data set is an N of 16, and these were the initial pivotal trials with an N of more like 100± .
But I think fundamentally you can see that CB-010 compares quite favorably, favorably in terms of overall response rate, CR rate, and most importantly, this metric of the six-month CR rate. As you can see, the approved autologous CAR-Ts result in about a third of patients achieving a CR at six months or greater. So very pleased to see that 44% of these patients achieved a CR at six months or greater in the ongoing ANTLER trial. As I highlighted a few moments ago, we're very excited about the opportunity to expeditiously advance the clinical development of this program, and we've really focused our sights on the second-line large B-cell lymphoma population. As you can see, there are more than 2x the number of patients in the second-line setting as there are in the third-line setting.
Certainly, as we think about the evolving landscape of available treatments, we believe the biggest opportunity and the biggest need relies in the second-line setting today. Very excited that the FDA has supported our request to focus exclusively on second-line large B-cell lymphoma patients in our ongoing dose expansion work. In dose expansion today, we are continuing to evaluate multiple of the doses that we evaluated in dose escalation as we continue to really refine and optimize our dose-finding work, with the objective of using these data in order to inform the selection of the recommended phase II dose. So to wrap up, very excited about the data we were able to share earlier this year, demonstrating that CB-010 can drive durable responses that rival those of the autologous CAR-Ts. We've committed to two important updates in the near future for CB-010.
One is regulatory, and the second is data. On the regulatory front, we've committed to providing feedback from discussions we are having with the FDA related to the potential pivotal strategy for CB-010 in the second-line setting by the end of this year, and we've also committed to the initial update on dose expansion data in the first half of next year. I'd like to switch gears now to CB-011. This is our off-the-shelf CAR-T cell therapy for multiple myeloma being evaluated in the ongoing phase I CaMMouflage trial. And I'll remind you, this is the program that drove Pfizer's strategic interest, and what led them to make a $25 million investment in our company a few months ago. CB-011 is an off-the-shelf CAR-T targeting BCMA, and it benefits from the immune cloaking strategy that I highlighted a few minutes ago.
In fact, I'd like to highlight for you exactly how this strategy is designed. Our goal is two-pronged here. The first is carried out through a gene knockout. We get rid of a gene called Beta-2 microglobulin. You can see why I call it Beta-2-M for short. And Beta-2-M is necessary for the presentation of HLA class I on the surface of cells. So removal of Beta-2-M wipes out all endogenous class I presentation. You'll see that some people in the field stop there. What that does is help prevent quick rejection by the patient's CD8 positive cytotoxic T cells. However, cells that completely lack class I presentation actually set off the alarm bells of natural killer cells, part of the innate immune system, which are specifically designed to recognize missing self or the absence of class I.
So we've taken our engineering a step further. We then site-specifically insert a transgene that fuses Beta-2-M with HLA-E. Our goal, therefore, is to have CAR-T cells that lack all endogenous class I presentation and only present the HLA-E transgene that we have provided via our genome editing. Our goal is to prevent both the patient's T cells and the patient's natural killer cells from rapidly rejecting the therapy. I'd like to share with you a bit of our preclinical data demonstrating that we can achieve exactly that in vitro. So what we've done is taken CB-011 cells and evaluated their ability to resist both NK and T cell-mediated killing in a variety of different contexts.
So looking at this slide, starting on the left side, what we've done is actually take three different flavors of T cells and evaluate the capacity of NK cells to kill these or not. So if we begin with unmodified T cells, we can see that there's some low level NK-mediated killing. And then if what we do is knock out beta-2-M alone, we make the situation far worse. Those Beta-2-M knockout T cells are highly susceptible to NK-mediated killing. And now if we come in and make CB-011 by actually inserting that Beta-2-M HLA-E fusion, we're able to nicely protect these CB-011 cells from NK-mediated killing. On the other side of the equation, on the far right side of this slide, similar experiment where we are taking different kinds of T cells and mixing them with T cells from yet a different donor.
Again, we can see CB-011 is nicely protected, in contrast to unmodified T cells. I'd like to highlight that in addition to the immune cloaking strategy that we are deploying for CB-011, CB-011 also benefits from a proprietary binder that we have used to build our CAR. We ran a campaign several years ago evaluating a number of different BCMA binders, and this one landed at the top of the list. It is a humanized anti-BCMA scFv. We've actually acquired it and the IP rights there, too, and we've demonstrated a number of assays. An example of one of those is shown on the left side of the slide here, that this binder results in a more potent CAR-Than some of the other binders that have been explored clinically to date.
So putting this all together, we're very excited about the potential of CB-011. It is being evaluated today in the ongoing phase I CaMMouflage clinical trial. We have successfully concluded dosing at dose level 1, which was 50 million CAR-T cells, and we are now actively enrolling patients at dose level 2, 150 million CAR-T cells. Stay tuned. We have not yet circled a date on the calendar for the initial data disclosure on this program, and it will be a data-driven disclosure decision. To wrap up, I'd also like to highlight CB-012, which will be our next program to move into the clinic. CB-012 is an off-the-shelf CAR-T for AML, targeting a tumor antigen called CLL-1, and we recently received the green light from the FDA to proceed with this phase I clinical trial.
We believe CLL-1 is a highly compelling target for AML because it is highly expressed on AML tumor cells as well as leukemic stem cells, but importantly, it is not expressed on healthy hematopoietic stem cells. And so that means, CB-012 has the potential to be disease modifying on its own and not necessarily or inherently a bridge to transplant. As I highlighted a few minutes ago, CB-012 benefits from the combination of strategies that we are deploying in each of CB-010 and CB-011. It benefits from both the PD-1 knockout in order to prevent premature CAR-T cell exhaustion, as well as the immune cloaking strategy to try to slow down immune-mediated rejection. This program also benefits from a binder, a fully human binder, I should note, that was developed at MSK and that we have exclusively in-licensed for the development of this program.
I'd like to highlight a little bit of the preclinical data for you, and in particular, focus your attention on the right side of this slide. We wanted to really convince ourselves of the appropriate armoring strategies for this particular cell therapy. And so what you're looking at on the right side of the slide is an in vivo model, where we're evaluating basically two flavors of CB-012. One is the CB-012 we know today that has all five edits, and one is the CB-012 that does not have the PD-1 knockout. It still expresses PD-1 and can still become exhausted through the PD-1 pathway. And what I hope is readily apparent by looking at this graph, is that the PD-1 knockout leads to a profound increase in the survival and the antitumor activity that we see in these models.
This was some of the very compelling data that convinced us that including the PD-1 knockout in this particular disease setting could be impactful. As I mentioned, we recently received the green light from the FDA to proceed with this phase I trial, and so we are hard at work getting sites activated and ready to go. The AMpLify phase I trial will evaluate AML patients with relapsed or refractory disease, and we're focused on patients who have had at least one, but no more than three lines of therapy. We'll be excluding anyone with prior CAR-T exposure or prior CLL-1 targeted therapeutic exposure. We will be allowing patients with stem cell transplant, allo or auto, to enroll on the trial. The overall approach looks quite similar to what we've discussed for both ANTLER and CaMMouflage.
Patients will undergo lymphodepletion, a combination of cyclophosphamide and fludarabine, and then one single dose of the cell therapy. And so to wrap up, again, I'd like to thank you for your time and your attention, and quickly highlight that we have made significant progress as of late, and I'm very excited about the steps to come in the not-too-distant future. As I highlighted, we were able to share quite positive data from the now concluded dose escalation portion of the ANTLER phase I trial, demonstrating that CB-010 can drive quite durable responses, rivaling those of the autologous CAR-Ts. And we'll be on the hook for providing both, regulatory insights by the end of this year as we think about the pivotal strategy forward, as well as initial dose expansion data in the first half of next year.
We are actively enrolling patients in the ongoing CaMMouflage trial. We dosed our first patient at the end of Q3 this year, and excited to continue that progress, and very much looking forward to getting sites activated and dosing our first patient for CB-012 in the AML setting. We are well-resourced to continue our work here. We have just shy of $400 million cash on hand, giving us a runway through Q4 of 2025. With that, thank you very much for your time, and I'd be happy to take any questions.
Thank you. I was gonna ask a question on CB-010 and the regulatory update. Maybe just bookend scenarios for what a registrational path could look like and, I guess what, talk about size of the study and, duration and what FDA's expectations could be.
Yeah, [inaudible], thank you. You know, as we look at the autologous CAR-T landscape, all of those programs were initially approved in the third line setting off of single-arm trials. Our objective here is to go straight into the second line setting in LBCL. So as much as I think our CFO might appreciate if it were a single-arm trial, I think that's unlikely. I think there's a tremendous amount that we can learn from looking at the successful approvals of both Breyanzi and Yescarta in the second line setting. And so I would encourage people to take a look at both TRANSFORM and ZUMA-7, because I think they paint a really important starting point.
Got it. That's helpful. And for the data update for half of next year, talk about number of patients and how much data you could report there.
Yeah. Thank you. So our goal for dose expansion is to enroll about 30 patients. So for that update, it, it won't necessarily be all 30. It'll be a, a meaningful chunk of those 30, and of course, some of them will have been on study much longer than others. And so we'll be looking at the big picture in terms of overall response rate and, and complete response rate, and for those who've been on study long enough, really, understanding the duration of some of those responses as well.
Got it. And maybe last question for CB-011 multiple myeloma. Talk about competitive positioning there and where you see CB-011 fitting in.
Yeah, thank you. And I'll maybe compare and contrast quickly with CB-010. So our goal for CB-010 really is to develop an off-the-shelf CAR-T that can meaningfully rival the responses and the duration of responses of the autologous CAR-Ts. As we look at the multiple myeloma setting, as we talk to KOLs and ask them, "Where could an allogeneic CAR-T fit in the evolving landscape for myeloma patients today?" What we hear loud and clear is that their benchmark is the bispecifics. And what they tell us is that's really because it's the other asset that is broadly available to that patient population. And so that's really guiding the focus of our ongoing clinical development.
Thank you.
No further questions, and thank you, Rachel.
Thank you.
Thank you, everyone.