Good morning, everyone. I'm Farzan Haque, 1 of the biotech analysts in the Moray Raycraft team at Jefferies. It's my pleasure to introduce Rachel Haurwitz, CEO of Caribou Biosciences. This is a fireside chat format, so thank you for joining us today.
Thanks, Farzan. Really appreciate it.
For those new to the story, can you provide a one-minute overview of your platform and the programs?
Yes. Caribou is using our proprietary next-generation CRISPR technology, our chRDNA technology, to develop two off-the-shelf CAR-T cell therapies, one each for lymphoma and myeloma. These are both clinical-stage programs, and Farzan, I'm certainly looking forward to chatting with you today about the ongoing progress for each of those programs and the data readouts we've committed to in the back half of this year. We're really excited by the continued advancement of each of these. With our lead program, CB-010, which is an off-the-shelf CAR-T cell therapy for lymphoma, we continue to see evidence in the ongoing study that CB-010 has the potential to be on par with auto CAR-Ts, which is our goal for that program and something we're very encouraged by.
CB-011, which is our off-the-shelf CAR-T cell therapy for multiple myeloma, will put a first data set out for that program in the back half of this year. What we've shared from an editorial perspective thus far is that we're seeing quite encouraging efficacy. Looking forward to sharing these data later this year as well.
Great intro. Maybe for a bigger picture question, like, what is your view on the current state of the CAR-T cell therapy field? Like, how does allogeneic CAR-T cell therapy fit in the treatment landscape given the approved autologous therapies and bispecifics as well?
Yeah, I mean, certainly looking at both lymphoma and myeloma, what the auto CAR-Ts can do for patients is transformative, right? It's absolutely incredible to see the kinds of long-term outcomes driven for some patients, obviously not all patients, but a meaningful fraction of patients who are able to get auto CAR-Ts. That last piece is the critical piece, right? It's actually a pretty small minority of patients, even in the U.S., who are able to access the commercial auto CARs. In lymphoma, it's about 20% of patients. In myeloma, it's only about 10% of patients. We see a really significant opportunity to address that unmet medical need with allogeneic CAR-T cell therapies that are readily available off the shelf. If you look, for example, in the lymphoma setting, the commercial auto CAR-Ts are remarkable, and yet 80% of patients are not accessing them. Why?
Often, it has to do with either where the patient is or how quickly their disease is progressing. There are some academic studies that suggest something like 40% of lymphoma patients have a disease biology that is too significant, moving too rapidly to ever wait for an auto CAR-T, and they need more urgent therapy. For those patients, an allogeneic CAR-T could be an obvious win to have much readier access to an off-the-shelf CAR-T cell therapy. The other 1 that I highlighted, of course, is geography, right? A meaningful fraction of patients are treated in the community setting, and yet the auto CAR-Ts are largely only available at large, top-tier academic institutions. I think it's a lot easier to see how you could get an allo CAR-T into the clinic, and we're excited by that potential as well.
Great. For the 2 program updates in the second half, do you plan to do a corporate event or a medical meeting is the preference?
Yeah, I think we'll use a corporate event for these disclosures.
Got it. For the 20 patients in the LBCL, the second line setting, you're enrolling in the ANTLER study. How much follow-up do you expect to have, and what do you need to see in the data set to advance to the pivotal phase?
Yeah, great question. Maybe I'll set the stage for any folks in the audience who are unfamiliar with that particular cohort. This phase I study, ANTLER, for CB-010 in lymphoma has been ongoing for about 4 years at this point. Actually, I'm really excited to share that the first patient ever dosed in that study remains in complete response, which I think is a really compelling example of the kinds of really long-term outcomes that CB-010 can drive for these lymphoma patients. About a year ago at ASCO, we shared data on the first 30 patients enrolled in the dose expansion portion of this study. Those data, plus our historic dose escalation data, allowed us to really appreciate the role that partial HLA matching plays in outcomes for these patients. What do I mean by that?
HLA matching, of course, is something we think a lot about in, say, transplant biology. When you're talking about, say, a bone marrow transplant and you're looking for a matched donor, you're looking for someone who ideally has the same 12 HLA alleles as the patient to drive the best outcomes for that patient. We're not talking about that same level of matching. What we saw in our data at the time is that if the patient and the donor shared 4 or more, so 4 or more of the 12 alleles, then the outcomes achieved by those patients looked to be on par with auto CAR-Ts. We're really encouraged by that. Of course, that's the profile that we're looking for, and also wanted to really try to confirm that initial retrospective analysis.
A year ago, we created a 20-patient cohort, and we designed it specifically so that each of those patients would intentionally receive a dose of CB-010 where the patient and the donor share at least 4 HLA alleles. We've now fully enrolled that cohort. As your question alluded to, I think that will be the key area of focus for investors in terms of our data disclosure in the back half of this year. What we've committed to is that a majority of those 20 patients will be at least six months post-dosing, and obviously, some will be meaningfully past that. We understand that that six-month mark is an important metric as investors really try to wrap their heads around not only overall response rates or CR rates, which of course are quite important, but also the durability of responses that can be achieved.
Obviously, those 20 patients will be a critical focus of this data disclosure. Now, of course, there are many other patients who remain on study and will be in a position to update on really kind of the totality of data as well.
Got it. How should we expect about the bar for success for ORR, CR, and PFS?
I'd say the way to describe it is our overall objective is to see data that look like they're on par with the auto CAR-Ts. It's a combination of all of those things. Perhaps a valuable visual tool for any people who are looking at our corporate deck is to look at the slide where we're looking at PFS for CB-010 compared with PFS for, for example, Yescarta, 1 of the approved auto CAR-Ts. I think that's a really nice way of capturing multiple of these metrics together. Of course, all of these data points matter in terms of informing that fundamental understanding. Ultimately, these data will drive our critical go-no-go decision for whether to take this study forward, this program forward, I should say, into a pivotal study.
Got it. You have an additional cohort of 10 patients who have relapsed following any prior CD19 therapy. How are you setting expectations for that cohort?
Yeah, this is obviously an area where there is even more drastic unmet medical need. Patients who have lymphoma and they're now post a CD19 CAR or some other CD19 targeted therapy, there's really no standard of care for them. I'm not sure that I have a quantitative metric to share with you, but certainly, we're eager to understand whether CB-010 has the potential to help this patient population as well. You're right, we've guided to sharing data on up to 10 patients in this cohort in the back half of this year as well.
If you do see a meaningful improvement, would you consider running a separate arm in your pivotal study?
Yeah, great question. I think future development for the CD19 relapse setting would probably be a separate trial from the pivotal that I was talking about a moment ago, which I expect would be centered on second line large B-cell lymphoma, which is where all of the dose expansion work is being done right now.
How big is this relapse refractory population?
Oh, I'm not sure that I have that number off the top of my head, but I can certainly highlight it is growing rapidly, right? As more and more patients are exposed to auto CARs or the increasing number of other CD19 targeted therapies, obviously, that patient population will continue to grow quite rapidly in the next few years.
Okay. For a potential pivotal trial regulatory path, will you have these additional discussions with the FDA prior to the data release? Is there more on the timing for a potential FDA meeting that you can comment on?
Yeah, really important question. In the back half of the year when we disclose these data, we also plan to share our pivotal trial design. Now, this program benefits from RMAT designation, and that means we do not have to wait for an end of phase I meeting to start discussing next steps. It means we are actually able to go proactively to the agency. Additionally, I will highlight these data actually allow us to think about multiple potential pivotal trial designs. We are in the midst of actually multiple discussions with the agency about a few of these potential options, and we look forward to sharing potential next steps in that disclosure in the back half of this year.
Just out of curiosity, with the recent leadership changes at the FDA, has any personal changes been in the interactions you had so far?
I would say our interactions continue to be normal course, and we're engaging with the same project teams we've historically worked with.
That's good to hear. Okay. What will you be proposing for the pivotal study design? Anything you can comment on, the size, scope, duration, control arm?
Yeah, great question. Not 1 that I can answer yet. I'll say stay tuned as we are discussing multiple different potential paths with the agency right now.
Just to ask a little bit more, how practical is it to run a superiority study as opposed to simply a non-inferiority study?
That's a really interesting question. I suppose it depends on what is the control arm, whether you're thinking about non-inferiority or superiority. Certainly, in terms of our own benchmark for success, the way we think about the bar to beat for CB-010 is maybe better phrased as the bar to match, right? Our goal is for CB-010 to be on par with autologous CAR-T cell therapies. We think that drives the largest opportunity therefore for this patient population, which would allow us to serve not only the patients who can never, will never access auto CAR-T, but also the patients who could choose auto CAR-T based on either their disease state or the geography in which they're being treated.
Got it. Stepping back a bit, did FDA set a threshold for the partial HLA matching correlation? Like, is there a correlation between the improved outcomes, and do you think like 4 is enough, or would you be aiming for more?
Yeah, great question. Thus far, our thresholds have been driven by our own data analytics and then sharing that information with the agency. They have not, for example, analyzed the data and given us any minimum or maximum thresholds. Certainly, this is something we are continuing to analyze as our data set grows, right? We've now dosed north of 70 patients in the ANTLER study, and that allows us to have, I think, a large enough database to start to understand some of these differences. We look forward to sharing that information in the back half of the year as well.
For the safety database, could there be a particular threshold level like you need to enroll?
Great question. I certainly expect as we think about a future potential launch and commercialization ahead of that, we would certainly need a large enough safety database. We've obviously done quite a lot of work in phase I. I think that helps a lot, and that's factored into some of our thinking for a potential pivotal trial as well.
Got it. Fast forward, what is your expectation for the start of the study and BLA filing, which people care about, I guess?
Yeah, great question. Stay tuned. Certainly, as we get to a point where we're sharing these data and the pivotal trial design, we expect to be able to provide a lot more granular details about the timing for that work as well. Obviously, I think it's fair to say we'd like to move as expeditiously as possible.
Got it. For a potential pivotal trial, is your manufacturing process scaled sufficiently? What do you have to do? How about the HLA matching model work?
It is scaled sufficiently. Already today, our process, one manufacturing run, results in enough cells for 200-300 doses. We think that's not only sufficient for our pivotal study, we think that's sufficient for commercialization. An important question also about having sufficient diversity of supply to drive appropriate partial HLA matching. Our analyses suggest that we would need about 13 batches from 13 distinct donors to provide a 4-plus match to more, let's call it 90% of patients who we could enroll in the pivotal study. We believe we are in good shape from a CMC perspective to meet these objectives.
Great. How do you feel in the competitive landscape with Allogene and then CRISPR programs? Where do you see room to differentiate on safety and efficacy?
Yeah, great question. I'd say as we think about the competitive landscape, really the top of the list for us, of course, remains the autologous CAR-T cell therapies and ensuring that we're really keeping that in mind as our bar to meet in terms of the efficacy profile that we desire for this particular program. We're really the only group who's in advanced development in second line large B-cell lymphoma. There's no 1 ahead of us in this patient population. Very excited about our relative positioning in the competitive landscape today.
There has been more discussion on in vivo CAR-Ts now in the clinic and likely to have a unique set of positive and negative trade-offs. How do you view the in vivo approach and how the entire CAR-T space will evolve?
Yeah, early days. I think there's a lot to learn for the field. I would certainly say 1 of the things that I'm intrigued about is learning about the importance of lymphodepletion for driving CAR-T activity. I think a lot of people think about lymphodepletion as clearing the way, physically creating space for CAR-T cells to expand and proliferate. No doubt that's true and important, but I actually think that's only a piece of the puzzle and that actually the pro-inflammatory microenvironment that is caused or driven by lymphodepletion is also really critical in the biology of CAR-T cells expanding and proliferating. Maybe one other piece of the puzzle is just thinking about the health of the T cell. 1 of the things we get to do with allogeneic CAR-Ts, of course, is rely on healthy donors.
There are many oncology patients, many lymphoma patients in particular, whose T cells are not in the best shape. I think we're in a unique position to be able to offer a healthy donor T cell to really form the foundation of the cell therapy. Of course, it's readily available. In our phase I study right now, on average, patients conclude eligibility and begin lymphodepletion in two days' time. It's incredibly readily available in practice.
Got it. Switching gears to the CB-011 program for the relapsed/refractory multiple myeloma. For the dose escalation data update from the CaMMouflage study, what do you hope to see and what is the bar?
Yeah, so this program is a little bit newer into the clinic than CB-010. We started it with obviously a traditional 3 plus 3 dose escalation design and what I'll call a fairly low lymphodepletion. If you look at the commercial autologous CAR-Ts, there's kind of a range of cyclophosphamide that is used ahead of the commercial CARs, typically somewhere between 300-500 mg per meter squared of Cy. We started with 300. We went through three levels of dose escalation, 50 million, 150 million, 450 million CAR-T cells, no DLTs. Also, we weren't fully seeing the efficacy profile that we were hoping to achieve. Maybe I'll sidestep for a moment and say our goal here is to develop an allogeneic CAR-T that looks like the efficacy of the bispecifics as the base benchmark.
We think that there are some real potential advantages for a one-and-done over chronic dosing as you think about long-term infection risk, et cetera. We were not seeing that profile. We decided to deepen the lymphodepletion from 300 to 500 psi. That is really driven by work across the field that has demonstrated that depth of lymphodepletion is critical for driving appropriate CAR-T proliferation and cytotoxicity. Now that we have moved from 300 to 500, we have seen quite encouraging efficacy. Our protocol allows us to actually do quite a bit simultaneously. As we clear 1 dose from a safety perspective, we can start enrolling at a new dose and continue to backfill. It has allowed us to explore 4 different dose levels with the deeper lymphodepletion.
What we've committed to in terms of the readout for the back half of this year, which will be the first time we're ever actually putting out data for this program, is a minimum of 25 patients who've received the deeper LD across these different dose levels. All of those patients will at least be 3 months post-dosing. Some of them will obviously be quite significantly past 3 months. We will be using these data to inform the decisions about the next steps for the program. In particular, our protocol allows us to expand at 1 or even potentially multiple dose levels. We will be able to share what the plan will be for dose expansion going forward.
Twenty-five patients is quite meaningful, but then you have multiple doses and varying lymphodepletion regimens. With these variables in play, what are the expectations, especially on the MRD negativity aspect?
Yeah, important question. I will highlight all 25 of those patients will be at the deeper LD. There are actually additional patients at the original LD, which I'm not counting against the 25 that we've committed to. We think that there will be enough patients at the critical cohorts to drive some of these key decisions. However, Farzan, you've highlighted a really critical element of developing a myeloma asset, which is of course reading out MRD negativity. We will be providing MRD negativity rates as part of the data update. We understand that's a really important metric for describing kind of initial depth of response and also being potentially prognostic for duration of response.
Makes sense. Will you have, is the data set enough to have conversation with the regulators for a registration path this year?
That's a great question. I would say it's enough to start the conversation, but I'm not sure that it would be enough to conclude the conversation.
Got it. You mentioned about the 300-500 cyclophosphamide doses, but you're keeping the fludarabine level the same. Could that also help to increase the persistence and the cell expansion?
It's a fair question, probably with infinite resources and infinite time. That's a question we could ask in the clinic, but we have neither of those. We have maintained a pretty standard dose of fludarabine across all of these patients, and we do not currently see that as a variable that would need to be tweaked in the future.
Makes sense. And then competitively, how is it different from the other approved therapies for the myeloma relapsed/refractory setting?
Right, great question. Obviously, this is a very different disease from lymphoma as we think about the repertoire of assets that patients need. Typically, it is not a disease that is thought of as having curative potential. You see patients chew through line after line after line of therapy and often ever more kind of complicated combinations of therapies as well. Of course, some of the more recent data from the autologous CAR-Ts are, I think, very modestly starting to change that viewpoint and demonstrating that at least for certain patients, maybe some of these cell therapies do in fact have curative potential. I think that's really exciting to see, obviously, even some of the data just recently shared at ASCO underpinning some of those observations and hypotheses.
As we look at this space, we hear a lot from KOLs about how valuable it is to access cell therapies for their patients. Yet, when you look commercially at the data, we know it's only about 10% of patients who have access to the commercial autologous CAR-Ts. We see a lot of opportunity for an allogeneic CAR-T. Maybe I can point to our experience with our study and how quickly we've been able to enroll patients over time as an example of that. If you look at ct.gov, we're running this study at all the top-tier academic sites that have ready access to autologous CAR-Ts. Yet, every time we've opened a new cohort on this study, we've been able to enroll it pretty rapidly. I think that's really a demonstration of the significant unmet need and therefore the significant opportunity.
Got it. This has been a great conversation. To wrap up, what is your cash runway guidance? How are you currently thinking about the capital allocation going forward over the next 6 to 12 months?
Yeah, important question. Earlier this quarter, we disclosed some really important decisions that we made to prioritize our efforts onto the 2 programs that we've spent all of our time discussing today. We actually discontinued 2 other phase I studies and we discontinued preclinical research. With these changes to our business and enhanced focus, our resources today, we have about $212 million on the balance sheet, take us into the second half of 2027. That allows us to carry out all the work that we just talked about, as well as some of the work at risk to get ready for next steps, such as a potential pivotal for CB-010 or to get ready for dose expansion for CB-011.
Great. Thank you so much, Rachel.
Thank you, Farzan.