Welcome to our next Fireside Chat. I'm Robert Burns, Managing Director and Senior Biotech Analyst at H.C. Wainwright, and I'm joined today by Rachel Haurwitz, the CEO of Caribou. Rachel, thank you for joining us today.
Thanks so much for having me. Appreciate it.
Why don't we start off by taking a sort of 10,000-foot view of the cell therapy space? I sort of want to get your view on what the current state of CAR-T cell therapy is in the overall field, and how does allogeneic CAR-T fit into the treatment landscape, given the approved autologous CAR-T cell therapies, as well as the bispecifics that are available for patients?
Yeah, that's a fantastic place to start today. Thank you. I mean, looking broadly, on the one hand, we can see from the pivotal studies and the real-world evidence that's emerging from the clinic just how impactful CAR-T cell therapies can be for patients. Of course, these are specifically autologous CAR-T cell therapies that are approved in both lymphoma and myeloma. The outcomes are quite profound. Yet, their application in the real world is still so limited. Only about 20% of second-line lymphoma patients are getting auto CARs. Only about 10% of myeloma patients are getting auto CARs. I suppose that makes sense when you think about just how challenging the infrastructure and the nature is for an N-of-1 bespoke manufacturing process, one therapy for one patient. It's really hard to imagine how that scales to a much broader patient population.
Where we think allo has a role to play is, of course, tackling exactly that. As we think about scale and access, we believe that allogeneic CAR-T cell therapies have a really important role to play, right? They are readily available off the shelf, the idea being that they can be available to a much broader patient population across these diseases. Of course, to say nothing of some of the coming areas of therapeutic application for cell therapy, such as autoimmune, where, of course, you're thinking about very large patient populations. Again, it's very easy to imagine how an off-the-shelf strategy could scale appropriately for that kind of patient population, too.
It's very important that you mentioned immunology and autoimmune disorders. Obviously, we've seen a massive shift for a lot of your peers where they're shifting exclusively into the autoimmune space. Caribou seems to be one of the few who still has those oncology programs ongoing. Can you talk a little bit more about your strategy there?
Data, right? We will always follow the data. With CB-010, we've shared as recently as ASCO in the middle of last year that we continue to see the potential in the data that CB-010 can drive the kinds of outcomes that are on par with autologous CAR-T cell therapies, and that is our objective for CB-010. For those listening who are not familiar with our pipeline, CB-010 is an off-the-shelf CAR-T cell therapy targeting CD19. Yes, it is one of the few remaining in the allogeneic setting continuing to be developed in oncology, and it's driven by our continued enthusiasm for the data and the potential of this program. That said, what we've seen in oncology, we think, really motivates our enthusiasm for evaluating CB-010 in lupus as well.
We now have an open phase I study called the GALLOP study to evaluate CB-010 in lupus. Of course, the safety and the efficacy that we've seen in oncology are quite encouraging as we think about its potential in lupus. We also have quite robust B-cell aplasia data from the oncology setting that demonstrates quite deep and durable B-cell aplasia on par with what Dr. Georg Schett has shared from his lupus patients, again, really motivating our decision to develop CB-010 in lupus as well.
You mentioned the data that you generated for CB-010 that was presented at ASCO 2024. Obviously, one of the takeaways was you're seeing a greater efficacy profile in those patients who have four or greater HLA matches. Maybe you could sort of give a little bit of background for individuals who might not be as familiar with that data set as you and I are.
Yeah, absolutely. If you really just think broadly about transplant biology, stem cell transplant, almost any other kind of transplant, of course, for decades, it's been understood that HLA matching between the donor and the patient is critical for good outcomes for the recipient of the donation. Obviously, in, for example, the blood stem cell setting, hematopoietic stem cell transplant, you probably need 12 out of 12 alleles matched, maybe 10 out of 12 at certain sites given their protocols. The importance of HLA matching has been incredibly well established for decades. It's an area that was, I'll say, of scientific intrigue to our team in the early days as we started to think about developing allogeneic CAR-T cell therapies and the role that HLA matching might play in outcomes for these patients. It's something our team has been keeping an eye on for years.
By ASCO of last year, we finally had a large enough, rich enough data set to really look at this and ask whether partial HLA matching between the patient and the T cell donor might impact outcomes. As you highlighted, the answer is yes. What we shared at ASCO last year is that those patients who by chance received a dose where the patient and the donor share at least four HLA alleles, again, modest match, right, four out of 12, those patients are experiencing on average better progression-free survival and PFS that appears to have the potential to be on par with auto CAR-Ts. We are doubling down on that strategy right now, continuing to enroll patients today where we are intentionally providing that kind of product.
Yeah. I know that you're currently enrolling 20 patients in that second-line LBCL in the ANTLER trial. What do you need to see from that data set, that upcoming data set, to advance that program into a pivotal phase three trial? Will you have additional discussions with the FDA prior to doing so?
Yeah, we want to see more of the same, right? Our fundamental objective for this program is an off-the-shelf CAR-T that has the potential to rival auto CARs. What we shared at ASCO, of course, was a retrospective analysis where by chance some patients had received a partially matched dose and some had not. We were able to look at those data and observe this important phenomenon. This 20-patient cohort is what I'll call a confirmatory cohort, right? The goal is to intentionally provide this kind of four-plus matched, best-matched style of product to these patients. Our hope is to see very similar outcomes, again, evidence that CB-010 could potentially be on par with the auto CARs. Yes, we are excited that CB-010 has RMAT designation from the FDA.
That facilitates our ability to have continued and ongoing discussions with the agency about the best next steps for the future development of this program.
When we think about obviously scaling up your CB-010, not only for the autoimmune indications, but for this potential pivotal trial, can you talk about your manufacturing process there? Will you have to really scale up not only for the pivotal trial, but for the autoimmune indications, which we're going to talk about in a few short moments?
Yeah, that work is already done. Today, our process, one manufacturing run, results in enough cells for more than 200 doses. We feel we are in good shape for where the process stands today.
Okay. One last question with regard to LBCL. Obviously, we know that we know about the ongoing Z UMA-23 trial, obviously the Allogene program in the frontline setting. I wanted to get your thoughts as to how you see that evolving treatment paradigm if CD19-targeted CARs move into that frontline setting.
Yeah, all of these are important pieces of the puzzle, right? As we think about Z UMA-23 and some of the other work being done, that's, of course, focused on patients with certain kinds of high-risk characteristics. We're not looking at the all-comer population getting auto CAR-T as their first line of therapy. I think R-CHOP or some flavor of that will remain the standard of care probably for the foreseeable future. It is exciting to see the auto CARs have potential for certain high-risk patients in first line. Maybe an allo CAR has a role to play there someday, too. Certainly, as we think about the bulk of those lymphoma patients, they will get R-CHOP or something like it. Some will be cured by that, which is incredibly exciting. Many won't. They will be relapsed or even primary refractory patients who are in need of something.
We believe that second-line relapsed refractory population will remain a significant unmet need for the foreseeable future. We believe that's a really important place for an allo CAR -T to be. It's the patient population that we're focused on for our development today.
Okay. Thank you for that background there. One of the things I sort of wanted to touch on here as well, obviously shifting to the autoimmune space, obviously there's a lot of different players that are going after autoimmune, in particular lupus. We saw some data sets at ACR 2024 with regard to the Bristol-Myers agent. Obviously, we saw some CD19 bispecifics. I wanted to get your thoughts as to where you see differentiation for CB-010 relative to all of those other approaches, and particularly in the context of all the data that we've seen to date.
Yeah, as we think about that patient population, lupus or likely other autoimmune diseases as well, I'm a fundamental believer that off-the-shelf is the only cell therapy strategy that's really going to fly for that patient population. I say that for really two fundamental reasons. One is just thinking about scale and access, right? Already in lymphoma, we see only about 20% of patients getting these auto CARs. Lupus or any of these other autoimmune diseases, these are much, much larger patient populations. Scale and access will be that much more difficult, and off-the-shelf will be even more impactful, I think, in that setting. The other reason really has to do with the patient experience in the autoimmune disease space.
If you're, for example, a lupus patient and you want to receive a dose of auto CAR-T, of course, first you have to undergo leukapheresis, apheresis to have your T cells removed for future manufacturing. To undergo apheresis, you actually have to get washed out of your lupus meds. You undergo apheresis. You have this weird limbo period. Do you go back on your maintenance meds? Do you stay off them? You then get prepared to receive your cell dose. It's a long period of time. If you actually look at some of the discrete data from the case series that have been published, you can see that some patients have really significant flares right before they receive their cell therapy.
I would hazard a guess that's because they had to go off their maintenance meds for a period of time because of all these logistics. By contrast, of course, a patient who gets an allo CAR-T, they're not undergoing apheresis. There isn't this prolonged period of trying to figure out how to navigate a medicine-free or medicine-low environment. They simply have to be prepared to receive their cell therapy dose. We think that mindset and that strategy will be really important for, again, this broader patient population.
Okay. When do you think that we'll actually start to see data for CB-010 from the GALLOP trial?
Yeah, great question. We have not guided to it yet. We shared last month that we had initiated the study. Stay tuned as we're working to bring additional sites on study and we'll start collecting data.
Okay. How is the trial going so far? How receptive are the sites to evaluating CB-010 in lupus patients?
Yeah, I'll say high enthusiasm for an off-the-shelf strategy writ large and high enthusiasm specifically for CB-010. I think it comes back to your point a few minutes ago. There's really encouraging evidence on the oncology side from CB-010. I think that helps to set the stage and de-risk CB-010's potential in lupus. In particular, we can point to the B-cell aplasia data that we're collecting on the lymphoma patients, where we see on average about 114 days of B-cell aplasia, which is exactly on par with what Dr. Schett has shared for his lupus patients. In fact, it takes almost 270 days for our oncology patients to have B-cell levels back to baseline. I think that really demonstrates the kind of profile that rheumatologists expect. Now, of course, some of the logistics, the blocking and tackling, this looks different from oncology, right?
To get a cell therapy study up and running at a hospital in, say, lymphoma or myeloma, you need your one champion in Heme/Onc. They have access to the resources writ large, right? That is going to be the beds where the patients are going to be inpatient. They have the clinical research staff. They have the expertise to manage and deliver cell therapy care. It is a little different in the autoimmune setting, right? Often these rheumatologists or nephrologists, they do not have access to any of those resources. They are building relationships within their own institutions or sometimes even across institutions with people in the Heme/Onc space to make sure that they have really the full package to be able to appropriately enroll and treat lupus patients.
Awesome. I'm very eager to see that initial data set for CB-010. Considering the time restrictions that we have today, why don't we shift gears to CB-011, which is your BCMA-targeted CAR in relapsed refractory multiple myeloma. Obviously, there's a ton of different BCMA-targeted agents with regard to ADCs, bispecifics, cell therapy. I wanted to get a sense just from a broad high-level overview, where do you see differentiation for 011 relative to those approved therapies, in particular the Legend data?
Yeah, great question. I think we have to be humble in drug development for a number of reasons. One of the key questions we've been asking KOLs for years is, where would an allogeneic CAR-T fit in your decision-making and in the treatment landscape for multiple myeloma? Stating the obvious, CAR-T has quite compelling efficacy. What we hear uniformly is that there's such tremendous interest in a readily available off-the-shelf cell therapy and that KOLs would think of that, would benchmark it against bispecifics because that's the only other readily available off-the-shelf approach. What we've been told is they'd love to see an off-the-shelf CAR-T that could be on par with the bispecifics from an efficacy perspective.
They have baked in an assumption that there's some other attributes that are really quite compelling, specifically the one-and-done nature of a CAR-T versus the bispecifics that obviously you have to be on for quite some time. Also, because you're on the bispecifics for so long, the prolonged profound infection risk can be quite challenging. There is an expectation that an allo CAR-T could be better from that perspective as well.
Yeah, no, I certainly get you from that perspective. One of the other things I'm sort of curious about, obviously, there's a bunch of other targets that are coming post-BCMA. I sort of want to get your thoughts as to, do you see any potential for combinability with, let's say, the GPRC5D-targeted agents? How do you view that evolving treatment paradigm from a combinatorial perspective sort of working out?
Yeah, it's a fantastic question. I think it's a really interesting emerging space. Every target is different. The reason for target selection probably varies disease by disease and target by target. One of the interesting things about BCMA is it doesn't go away. In the vast majority of patients who respond and then relapse after a BCMA-targeted asset, their tumor is still BCMA positive. I think the field has been able to focus on even thinking about multiple rounds of distinct modalities, each of which targeting BCMA that can still have important efficacy in these patients. What I will highlight is a lot of the work that's been done historically looking at an antibody-based asset first and a CAR-T second or vice versa, what's the right way to do it?
All of those have been bispecifics, which rely on the patient's own T cells, or auto CAR-Ts, which rely on the patient's own T cells. We have yet an orthogonal angle here of a donor healthy T cell population targeted against this particular antigen. That said, there could absolutely be potential for additional targets in this space. I'd say personally, I'm quite intrigued by thinking about where a dual CAR could be appropriate, either in the oncology or the autoimmune setting.
Since we're going to see data from that ongoing CaMMouflage Phase I trial in the first half of this year, can you help frame the expectations around the size of the data set? What's the sort of duration of follow-up that we can expect to see here?
Yes, absolutely. We shared towards the end of last year that we're starting to see quite encouraging efficacy with this program. We have committed that the first update in the first half of this year will have at least 15 patients from efficacious dose levels. It will be a range of follow-ups. We will have a few who are at the six-month mark or beyond, some at the three-month mark, and some who will have just experienced their first efficacy assessment at day 28. We know that duration of response is important. Those sentinel patients out longer will be an important piece of the story. We also know that in multiple myeloma, depth of response as measured by MRD negativity is a critical prognostic indicator. We will also be sharing MRD negativity rates for this data set.
Awesome. I really look forward to that data set. Shifting on to your next asset, CB-012 in relapsed refractory AML, obviously, a lot of people aren't as familiar with that CLL-1 target as they are with BCMA or CD19. Can you talk about the rationale for that target there? Given the heterogeneity of AML, how do you see that sort of treatment paradigm working out from a target perspective?
Yeah, really important question, right? Target selection in AML is super challenging. Our objective was to identify a target that is highly expressed on AML tumor cells, but not expressed on healthy hematopoietic stem cells. We think that discrimination is important because if you have an active cell therapy, you do not want to simultaneously blow up the heme compartment and necessitate a bridge to transplant. Really, our big long-term objective for this program is to have an asset that could have disease-modifying activity on its own and not always have to be a bridge to transplant. We got really excited about some work that was done at Memorial Sloan Kettering on this antigen, CLL-1, that has exactly that profile. It is expressed on the vast majority of AML tumors. It is expressed on leukemic stem cells, but not healthy HSCs.
In fact, one of the groups there had developed fully human binders that target CLL-1. We've exclusively in-licensed those and used one of them to build the CAR for this program.
Given that we're running up on time, why don't we talk a little bit about your capital allocation here? You've got a cash runway into the second half of 2026. How are you thinking about your capital allocation? What should investors be thinking about as we move forward over the next six to 12 months?
Yeah, absolutely. We have a strong balance sheet that gives us the ability to execute and deliver on critical catalysts really across the pipeline. As you've highlighted, we have two data readouts in the first half of this year alone. On CB-010, we'll be reading out on that 20-patient cohort and making a go, no-go decision into phase three based on those data. With CB-011, sharing what we've only editorialized so far as encouraging efficacy, we'll be sharing those data in the first half of this year too. Obviously, these resources allow us to continue making significant progress on CB-012 as well as moving into lupus with CB-010 as we are now. Very encouraged by all of the things that we can accomplish with the resources we have on hand today.
I certainly look forward to all the data set that Caribou is going to be generating over the next six to 12 months. Rachel, thank you for being here today.
Thank you. Really appreciate it.