Caribou Biosciences, Inc. (CRBU) Earnings Call Transcript & Summary

Good morning, ladies and gentlemen. I'm delighted to introduce the President and CEO of Caribou Biosciences, Rachel Haurwitz.

Good morning, everyone. Thank you very much to the JPMorgan team for the opportunity to present today. My name is Rachel Haurwitz, and I'm the President and CEO of Caribou Bio. Before we dive in, of course, I'll acknowledge this presentation includes forward-looking information, and I encourage you to look at our SEC filings for additional information. Caribou is at the forefront of allogeneic cell therapies, and we believe that an off-the-shelf strategy is critical to bring the power of cell therapies to larger and larger patient populations across both oncology and autoimmune diseases. At the heart of our clinical stage assets is our next-generation CRISPR technology, the chRDNA technology that results in far more specific genome editing than first-generation CRISPR-Cas9, allowing us to really unlock the broader potential of off-the-shelf CAR T-cell therapies. Today, we are advancing 4 clinical programs and expect multiple milestones across the platform in 2025, including 2 clinical data readouts in the first half of this year. We ended Q3 with $281 million cash on hand, a strong balance sheet resourcing our operating plan into the second half of 2026. I believe we are poised at the beginning of a very exciting opportunity to bring cell therapies, as I mentioned, to larger and larger patient populations through the readily available off-the-shelf nature of an allogeneic CAR T-cell strategy. We fundamentally believe the future of cell therapies has to be off the shelf to overcome so many of the challenges inherent in an end of one bespoke strategy of auto CAR Ts, including, of course, access, speed and scale. If you look, for example, in the second-line DLBCL setting here in the United States, only 2 out of every 10 patients gets access to an auto CAR. So you can readily see how an off-the-shelf approach could bring cell therapy to a much larger fraction of these patients. Allo CAR Ts are readily available in our ongoing ANTLER Phase I clinical trial, patients on average begin lymphodepletion only 2 days after completing eligibility, which is obviously dramatically faster than the auto setting, where patients typically wait weeks, if not months, for their product. And finally, we can bring significant scale with an allo CAR T platform. Already today, our manufacturing process for CB-010 results in enough cells for more than 300 doses from just one manufacturing run, which, of course, compares quite significantly to the NF1 nature of an auto CAR T. Our clinical stage pipeline today is composed of 4 Phase I studies across hematologic malignancies and autoimmune diseases. CB-010 is an allogeneic anti-CD19 CAR T cell therapy that we are developing both in oncology and autoimmune diseases. In the oncology setting, we're primarily focused on second-line large B-cell lymphoma, and we have committed to a key data readout in the first half of this year. If we see the signal we are looking for, that would lead us to a go decision to then initiate a pivotal study in the second-line setting by the end of this calendar year. We are also now excited to share that we have initiated the GALLOP Phase I study to additionally develop CB-010 in the lupus setting, and I look forward to sharing some of the details of this program with you today. Our second asset, CB-011, is an off-the-shelf CAR T-cell therapy targeting BCMA for multiple myeloma. We have also committed to a data readout from this program in the first half of this year, following a disclosure towards the end of last year that we've begun seeing encouraging efficacy. We have committed to a readout of at least 15 patients at active dose levels in the first half of this year, including, for example, information on MRD negativity rates in these data. And last but certainly not least, we are advancing CB-012, an off-the-shelf CAR T-cell therapy targeting CLL-1 for relapsed or refractory AML. This is obviously an incredibly challenging disease and a patient population we hope to be able to serve with an off-the-shelf strategy. We've made significant progress rapidly with this program. We only dosed our first patient in Q1 of last year. And recently, we've shared we've successfully concluded dosing at dose level 3, no DLTs and are enrolling patients at dose level 4. As I mentioned a few minutes ago, underpinning our entire clinical portfolio is our chRDNA genome editing technology. It allows us to address many aspects of biology to enhance the potential activity of our cells through a variety of armoring strategies such as a PD-1 knockout, immune cloaking or the combination of the two. The chRDNA technology platform allows us to deploy multiplex genome editing at high efficiency while maintaining genomic integrity to bring these kinds of cell therapies to larger patient populations. To the best of our knowledge, we are the first to use the PD-1 knockout strategy in an allogeneic CAR T-cell therapy with our CB-010 program and now again with our CB-012 program as well. I'd like to start by digging first into the CB-010 program, which is being advanced both in oncology and in autoimmune. In the oncology setting, we're largely focused on second-line large B-cell lymphoma patients. And I'd like to come back to that patient population for just a moment, 80% of second-line DLBCL patients in the United States are not accessing auto CAR Ts today. And we know that an allogeneic strategy holds the potential to bring cell therapies to a much more meaningful fraction of this patient population. We also already know based on our ongoing clinical work that CB-010 can drive durable complete remissions in some of these patients. In fact, the very first patient ever dosed with CB-010 remains in complete response almost, I should say, more than 3 years since receiving just a single dose of CB-010. At this point in time, we've now dosed more than 65 patients in the ANTLER study and continue to see a generally well-tolerated safety profile. And we're very excited about how quickly we can deliver this cell therapy to patients in our ANTLER study. In ANTLER, we're actively enrolling 2 cohorts today. Cohort 1 is 20 second-line LBCL patients. And the objective for this cohort is to hopefully confirm the signal that we shared at ASCO in the middle of last year. What we saw at ASCO last year is that patients who receive a dose of CB-010, where the patient and the donor share at least 4 HLA alleles, that's 4 out of 12. Those patients thus far have demonstrated outcomes that appear to be on par with the autologous CAR T-cell therapies. That is our objective. Our goal for CB-010 is to develop an off-the-shelf CAR T that can be on par with the outcomes of the auto CAR Ts. So the objective for this new 20-patient cohort is to intentionally provide each of these patients that kind of product, where we set the threshold of at least 4 HLA alleles matched between patient and donor in order to enrich our data set and build our better understanding of the role HLA matching plays in driving these outcomes. That means in our data update in the first half of this year, we'll have a little more than 30 patients who've been dosed following that strategy, with a range of follow-ups for these new 20 patients between 3 and 6 months, and of course, for the historical patients, even more time than that. We will use these data measured against what we understand to be the outcomes of the auto CAR Ts to drive our go/no-go decision for a pivotal study in the second-line LBCL setting. And if these data hit their mark, we intend to initiate that study by the end of this year. These data also motivated us to open for the first time ever last year, a new cohort for patients who've had prior CD19 targeted therapies and relapsed. We understand this is a rapidly growing patient population. And so we're enrolling up to 10 patients in this early proof-of-concept cohort to get an understanding of whether CB-010 could benefit these patients as well, and we plan to read out these initial data in the first half of this year too. I'd like to spend a few minutes sharing some of the key data that we initially disclosed at ASCO last year. They underpin our enthusiasm for the program and really explain why we are focused on this 20-patient cohort and driving the HLA matching strategy forward today. What I'm showing you here is a look at some of the patients who've been on study the longest. These were the first 16 patients enrolled in ANTLER in the dose escalation portion of the study. And I think most importantly, what we can see is that CB-010 holds the potential to drive quite durable outcomes. And in fact, multiple of these patients had been in CR for at least 2 years following just a single dose of CB-010. What we shared last year is that after exploring multiple doses, we landed on a recommended Phase II dose of 80 million CAR-T cells and very encouraging evidence, as I mentioned, that those patients who, by chance, received a dose of CB-010, where they and the donor share at least for HLA alleles, experience outcomes that appear to be on par with the auto CAR Ts and in particular, in that data set, a median progression-free survival of more than 14 months. Importantly, CB-010 has generated -- has demonstrated a generally well-tolerated safety profile. What we're focused on here are some of the key AEs, including CRS, infections and ICANS. And as you can see, when comparing against some of the auto CAR Ts, we see rates that are on par with, if not perhaps slightly better than the historical comparable data in the auto CAR T setting. Here are some of the key efficacy data that really drove our understanding of the role partial HLA matching can play in driving outcomes that have the potential to be on par with autologous CAR T-cell therapies. What you see here on the left-hand side of the slide is progression-free survival data for all 46 patients included in the data cut at ASCO last year, broken out by the relative level of HLA matching between the patient and the donor. Now keep in mind, all of this was by chance. And what we see is that patients in the gray line had fewer than 2 matches, the dark blue line, 2 to 3 or the light blue line, 4 or more. Very similar analysis on the right-hand side of the slide, where we've focused on the 40 patients within that cohort who had various forms of large B-cell lymphoma specifically. And again, very similar story, where increasing modestly the level of matching increases outcomes for these patients. Now as I've shared, our objective is to develop an allo CAR T that could be on par with the auto CAR Ts. So if we then take these blue lines and compare them against the historical data for ZUMA-7, this is the study where Yescarta was approved in the second-line setting, we're very encouraged by this. Now I readily acknowledge cross-trial comparisons are quite challenging, and there are a number of caveats to keep in mind here. However, I do think this provides an important context and understanding to see the relative comparability of the PFS across these 2 studies. Now at the time, we also recognize that these data were early. This is an 11-patient cohort and patients who by chance received this type of therapy. And so we made the decision at the time that we are continuing to execute on to create this new 20-patient cohort that we are enrolling now and intentionally providing patients this kind of partially HLA matched product in order to increase the end from the 11 patients you see here to at least 31 patients who will be part of the readout in the first half of this year. Now importantly, the PK data really support our efficacy observations. So what you're looking at here on the right-hand side of the slide is an analysis of PK, again, broken out in a very similar way by relative level of matching. And I think what you can see quite profoundly is that patients who received a product with fewer than 2 matches on average, experience quite negatively impacted PK relative to the other PK profiles. Said another way, PK expansion is on average lower and persistence is lower. Now this makes a lot of sense, right? We are not inventing a new wheel here in terms of biology. We're really leaning on decades of experience in transplant biology, demonstrating how important the role of HLA matching can be in terms of driving sufficient persistence of a product. Now I will highlight this is very different from, say, stem cell transplant, where you typically are aiming for a 12 out of 12 match. This is a much more modest match. We're looking at 4 HLA alleles here being enough to really move the needle to result in outcomes that were demonstrated last year to be on par with the autologous CAR T-cell therapies. So to wrap up on the oncology front for CB-010, we're very encouraged by the 2 cohorts we're enrolling today, continuing to execute, and we plan to share data from both the 20-patient second-line LBCL cohort as well as the new CD19 relapse cohort in the first half of this year. Thanks to the fact that we have RMAT designation for this program, we're able to continue in a dialogue with the FDA about next steps. And as I mentioned, if we hit our objective of continuing to be able to confirm that CB-010 can drive outcomes that are on par with the auto CAR Ts, our goal is to initiate a pivotal study in the second-line setting by the end of this year. Now all of these data, the encouraging safety and efficacy we've seen in oncology also motivated us to bring CB-010 into the lupus setting. This is obviously a much larger patient population. In the United States, there are 320,000 patients alone with lupus nephritis. And I believe that this is a patient population that can only truly be served at scale with an off-the-shelf strategy. Now I say that for a few reasons. In part, it's simply a numbers game. And this is why we're glad already our manufacturing process today results in enough cells for more than 300 doses from just a single batch. But I think even more importantly than that, we have to think about the patient experience. For a lupus patient to receive an auto CAR T, they, of course, first have to go under apheresis, removal of their T cells for manufacturing of the product. Well, to prepare them for that, they have to be washed out of their lupus meds for a period of time. And these, of course, are severe patients who are typically on a number of maintenance meds to keep their disease somewhat in check. So they have to go through a washout period, undergo apheresis, and then they have this weird limbo time in between apheresis and receiving their product, where depending on the circumstances, they may or may not be able to go back into some of those meds. If they do, they have to get washed out yet again ahead of receiving their CAR-T product. And I believe this will be untenable for a meaningful fraction of lupus patients. So obviously, in the allo setting, you take a lot of that straight off the table because, of course, these patients are not undergoing apheresis and you simply have to focus on preparing them for receipt of their CAR T-cell product. Now all of the data that I just shared with you from an oncology perspective clearly helped motivate our enthusiasm for bringing CB-010 to lupus. There's one additional piece of data I'd like to share with you that was critical to that decision as well. And that's, of course, the B-cell aplasia data that we have collected in the ongoing ANTLER study. So these are, again, data that we shared at ASCO last year. And what we're able to see is quite profound deep B-cell aplasia. On average, our oncology patients following just a single dose of CB-010 see about 114 days of B-cell aplasia. And in fact, it takes almost 270 days until their B cells are back to baseline. Now importantly, this is a strong contrast to their T cells and natural killer cells, which rebound rapidly and are back to baseline within about 3 weeks post dosing. This profile, the combination of these is very important. On the one hand, of course, we know we need to drive deep B-cell aplasia to hopefully achieve the kind of profound immune reset that's been shown in a small number of publications recently. But simultaneously, we need to have confidence that these patients otherwise can reconstitute a functioning immune system. And so seeing the Ts and NKs bounce back very quickly is quite important. Now to put this time line in context, I just showed you we see B-cell aplasia on average of 114 days in the oncology trial. Dr. Georg Schett and his colleagues have reported 112 days of B-cell aplasia in their data. So we think our experience in the oncology setting helps to derisk and really bring confidence to our ability to hopefully deliver good outcomes for patients with lupus using CB-010. So we were very pleased to be able to share recently that we have initiated the GALLOP Phase I study for patients in lupus. Pun intended, we are able to hit the ground running, thanks to the fact that we're able to leverage so much of the work that we are doing in the oncology setting. For example, this is not a dose-finding study. We are able to directly take the RP2D from oncology, 80 million cells and use it here with these patients. We will also be able to enroll 2 patient cohorts in parallel, lupus nephritis as well as extrarenal lupus. And we're very excited to provide updates as this program progresses. I'd like to shift gears now to CB-011. This is our allogeneic CAR T-cell therapy targeting BCMA for the treatment of multiple myeloma. Myeloma is obviously also another very large patient population. And when we speak with physicians to ask them how they benchmark success for an allo CAR T, what we hear back uniformly is that the benchmark for success is set by the bispecifics. This is the other approach that is broadly and readily available off the shelf for this larger patient population. And what they tell us is that they hope an allo CAR T could achieve on par efficacy with a bispecific, let's call that 60% to 70% overall response rate with an expectation that the one-and-done nature of an allo CAR T could really overcome some of the significant treatment burdens associated with the repeat dosing necessary for the bispecifics and the prolonged high infection risk that comes from that strategy as well. Our CB-011 program benefits from our immune-cloaking strategy. So this is where we knock out all HLA Class I endogenous alleles and then further engineer the cells so that they only present HLA-E on their surface. Our goal is to slow down immune-mediated rejection in order to ensure that we get sufficient antitumor activity. When we began this trial, we started with, of course, a traditional 3+3 dose escalation design and what I'll call a standard lymphodepletion protocol that included 300 milligrams per meter squared of cyclophosphamide. We evaluated 3 different dose levels, 50 million, 150 million and 450 million CAR T cells with no DLTs. At that point in time, we decided to modestly deepen the lymphodepletion from 300 cy to 500 cy. Following that, we have been very encouraged by the initial efficacy that we have observed, and we're taking advantage of the flexibility of our clinical protocol that allows us to simultaneously enroll additional patients at active dose levels while we continue to dose escalate. And so today, we are enrolling patients both in Cohort 3B as well as Cohort 4. And it's patients from these cohorts and additional patients who will form the foundation of the data set that we intend to share in the first half of this year. As I mentioned a few minutes ago, we're committing to at least 15 patients at active dose levels, given the timing of this trial, we know some of these patients will already be at the 6-month mark by the time we're able to share data. Others will be at 28 days or 3 months post their single dose of CB-011. We know durability is very important in this space. We also know depth of response is critical. And so we will ensure that as part of our data update, we are able to share information on MRD negativity rates for these patients. And again, we've committed to sharing those data in the first half of this year. Finally, I'd like to highlight CB-012. This is our third allogeneic CAR T cell therapy that we are developing for patients with AML. This is obviously an incredibly challenging disease and one for which there are no approved autologous CAR T-cell therapies. We chose the target of CLL-1 because it's highly expressed on AML tumor cells, but not expressed on healthy hematopoietic stem cells. And we think that's a very important discrimination so that this therapy long term doesn't have to be a bridge to transplant, but holds the potential to have disease-modifying activity on its own. In this particular program, we're taking advantage of both the PD-1 knockout strategy and the immune-cloaking strategy together. So this is a 5-edited product. And I think it speaks to really the strength of the chRDNA technology that we can carry out 3 gene knockouts, 2 gene insertions at high enough efficiency while maintaining genomic integrity to bring this product to patients. We dosed our first patient in the first quarter of last year and continue to make rapid progress in this program. We recently disclosed that we have successfully concluded dosing at dose level 3, no DLTs to date in the program, and we're actively enrolling patients at dose level 4. Stay tuned as we continue to make progress with this program as well. And finally, I'd like to wrap up by highlighting what a catalyst-rich 2025 we have in front of us and in particular, the 2 key data readouts that we'll be sharing in the first half of this year. For CB-010, we'll be looking at the 20-patient cohort and the historical HLA matched patients in order to inform our go/no-go decision. If we meet our objective with those data, our intent is to initiate a pivotal study in second-line LBCL by the end of this year. Additionally, we've committed to our first data readout from CB-011 in the first half of this year in at least 15 patients in active dose levels. With that, I'll just have to say a huge thank you to the team for the incredible work last year and all the work they do on behalf of patients and our enthusiasm and excitement for the year to come. Thank you all very much for your time and attention, and I'd be happy to take your questions.

Thank you very much, Rachel. If anyone on the floor has any questions, please raise your hand. But we've got a few that have come in online. So Rachel, what is your view on the current state of the CAR T-cell therapy field? How does allogeneic CAR T cell therapy fit into the treatment landscape given what is currently approved for patients?

Yes, great question. I think if we start with lymphoma, the data for the auto CAR Ts are extraordinary, right? What these therapies can achieve for patients is truly remarkable. And yet only 20% of second-line DLBCL patients are accessing auto CAR Ts, and so I think it really speaks volumes to the fundamental challenges associated with delivering an end of one bespoke therapy in this kind of oncology patient setting. So we see that as a tremendous opportunity, right? If we are able to meet our objectives with CB-010 and develop an allo CAR T that is on par with the auto CAR Ts, it means we have the potential commercially to compete not only for the 20% of patients who are getting cell therapies today, but to hopefully make meaningful inroads on the 80% of patients who are not. My understanding is in myeloma, the significance of that problem is even larger. What we heard folks on a recent Gilead call say is that only about 10% of myeloma patients are accessing CAR T-cell therapies, I think setting up even more significant unmet need in terms of the long-term potential for these cell therapies for those patients.

Thank you. So another question here is that many peers are shifting exclusively to immunology. Caribou still has oncology programs ongoing. So what's your strategy?