Caribou Biosciences Aktie

Welcome to our next fireside chat. I'm Robert Burns, Managing Director and senior biotech analyst at H.C. Wainwright. And I'm joined by Rachel Haurwitz, the CEO of Caribou. Rachel, thank you for joining us today.

Rob, thanks so much for having me. Really appreciate it.

Before we just dive in. So from a high-level perspective, for those who may be unfamiliar with Caribou, can you provide an overview of the company and its pipeline?

Absolutely. Caribou is a CRISPR genome-editing company solely focused on leveraging our technology platform to develop allogeneic, off-the-shelf CAR-T cell therapies for patients with hematologic malignancies. We're advancing 2 clinical-stage programs, and I hope, Rob, we get the chance to discuss both of them in detail today. The lead program is vispa-cel. It's an off-the-shelf CAR-T targeting CD19 for non-Hodgkin lymphoma.

This program is done with Phase I. It's pivotal-ready. And so excitingly, it has demonstrated in Phase I data that look just like the published data for the auto CAR-Ts. And we think this unlocks a tremendous opportunity to bring the benefit of cell therapy to a much broader swath of patients that can benefit from the NF1 bespoke, complicated process of autologous CAR-T cell therapies. Second in the pipeline is CB-011.

This is our allo CAR-T targeting BCMA for multiple myeloma. This program is in the middle of Phase I. We've shared some really encouraging Phase I dose-escalation data so far, demonstrating responses that actually far exceed our benchmark for success. We were hoping for at least bispecific-like response rates, as that's really the only other asset class that's readily available off-the-shelf for these patients.

But we've actually, thus far, seen response rates that are approaching those of the auto CAR-Ts. And in data we recently shared at EHA, we've been able to demonstrate just how durable these responses can be in late-line, heavily pretreated patients. We're actively enrolling patients in dose expansion, and we've committed to sharing initial dose-expansion data by the end of this year.

So before we get to your pipeline, can you please discuss the advantages of the chRDNA platform relative to other gene-editing tools? And how you've used that platform in designing vispa-cel and CB-011?

Yes. Thank you for the question. I think the chRDNA technology is our key to success. The advantage of the chRDNA platform relative to other CRISPR technologies is its specificity. Through engineering new guides that are part DNA and part RNA, instead of just all-RNA, we've been able to improve editing specificity by several orders of magnitude. And therefore, what this has unlocked for us for our clinical pipeline is the ability to address areas of biology that have been well understood, but have not been acted on for a long period of time.

So if you look at our approach to allo CAR-Ts, it's really quite different from a lot of the companies who are a little earlier to us -- earlier than us to the clinic, most of whom are no longer in this space because their programs did not achieve auto-CAR-T-like outcomes for patients. If you think back several years, Rob, and I know you'll remember this, most of those early players were largely doing the same thing, taking a healthy donor T cell, getting it to express a CAR through one means or another, removing the T-cell receptor, and called that a product.

And our team looked at that and just sort of scratched our heads because we know that these allo-cells are foreign to the patient's immune system. And therefore, they're going to be rejected a lot more rapidly than your average auto-CAR. And we felt we need to use our genome editing to address that. In our myeloma program, we do that quite literally. We actually deploy a multi-edit strategy for immune cloaking to try to slow down immune-mediated rejection to buy additional time for additional antitumor activity. And I think that's working. That program has PK, has persistence of the CAR-T cells. That's about twice as long as our uncloaked program.

And I think it's been key to the success that we've seen in multiple myeloma so far. With vispa-cel in lymphoma, we actually went in an orthogonal direction. We're not trying to impact how long the CAR-T cells persist. They're around about a month. We're instead trying to enhance their potency. And we do that by knocking out PD-1. We obviously did not invent the importance of PD-1 in CAR-T or even T-cell biology, but we're the first to do that with an allogeneic CAR-T.

And of course, the idea is to take the brakes off the CAR-T cells to really drive a better anti-cancer activity during that window of time where the cells are present. So all the biology I just walked you through, Rob, we didn't invent it, but we are the first to have an editing technology that actually allows us to address all of these with high efficiency and high specificity, and that's what really sets our programs apart.

I completely understand. And it clearly has an advantage for you guys relative to other competitors, but coming out of ASCO and EHA, I wanted to get your thoughts on the second-line LBCL opportunity and how it might evolve over time, given the data that we saw for rapid autologous cell both the CD20 bispecifics and the FrontMIND trial. And also when we factor in ZUMA-23 and the ALPHA3 interim data that we saw earlier this year?

Yes. Great and robust question. I'll try to tackle it a couple of different ways. Maybe I'll start with what is happening in the second-line setting today. So today, there are about 12,000 patients treated annually in the U.S. with second-line large B-cell lymphoma. And I think no one would argue that the gold standard, top choice is an autologous CAR-T cell therapy. And yet only 25% of those 12,000 patients actually get an auto CAR-T.

And it's not because there's some close trade-off with another asset class that's almost as good and maybe has some other advantages. There's a huge gap in outcomes relative to anything else. It's really driven by 2 key challenges that prevent so many of those patients from getting an auto CAR-T. The first challenge is urgency of need. A meaningful fraction of these patients have a quite significant and rapidly progressing disease. They simply cannot wait the couple of months, or 3 months it takes to go through the referral patterns, apheresis, bridging therapy while their product is manufactured and finally get their dose. They need something now.

The second is geography. The majority of these patients are cared for in the community setting, and yet it's really only the top-tier academic sites that are able to deliver auto CAR-T cell therapy. And for a number of very understandable reasons, a meaningful fraction of patients cannot afford to pick up and move and take a caretaker with them to a large city to be close to one of these academic sites long enough to get a dose. And so you asked a great question about the many evolving elements of the landscape.

And yes, there's some very interesting work being done both in the second line and in the frontline setting. But none of them, other than what we're trying to do with vispa-cel really address either of those 2 key issues with respect to getting a CAR-T cell therapy with potentially curative intent to a larger fraction of patients. Vispa-cel, of course, has the tremendous benefit of being off-the-shelf. It is readily available. So that long timeline, we can just collapse down to 0 using vispa-cel.

And I actually mean 0. Even in our Phase I study, we had some patients conclude their eligibility paperwork and begin lymphodepletion on the same day. Even some of these faster auto CAR-T manufacturing timelines don't really chip away at those much longer timelines. If you think about the bulk of the time being the blocking and tackling of referral patterns, waiting to schedule an apheresis slot, there's still a lot of QC that happens even if the manufacturing itself is faster. So it cuts down the timeline, but not enough to bridge the gap for most of these patients.

And as we think about some of the front-line studies that you've highlighted, whether it's, say, an auto CAR-T for very specific high-risk patients or the allo CAR-T strategy that Allogene has, these are serving a very different segment of the patient population than the one we expect to serve. So we don't see a lot of impact on vispa-cel opportunity from those areas of development.

So since you presented updated data from the ANTLER trial, can you walk us through what was incrementally new and how it might differentiate vispa-cel relative to the FDA-approved, CD19-targeted CAR-Ts?

Yes, great question. We were so excited that the vispa-cel abstract was picked for an oral presentation at EHA just a couple of weeks ago. What we were able to share, very excitingly, is more of the same. We were able to continue to demonstrate that vispa-cel drives auto CAR-T-like outcomes for patients. This data set is now sufficiently mature with a median follow-up of about 16 months, to measure a median PFS of 17.1 months -- it's actually numerically longer than the published data for the auto CAR-Ts 14.8 and 14.9 months.

Now, ours is a smaller data set. We'll put an error bar on it. I'm happy to say those are the same. And that's incredibly exciting, right? That is the very high bar we set for ourselves many years ago when we initially developed this program. We wanted to develop an allo-CAR-T for lymphoma that could drive outcomes just like the auto CAR-Ts. And these data continue to demonstrate that vispa-cel fits that challenge. Now importantly, Rob, part of what we could share as well is continued update on the safety side. This is a really key piece of the puzzle.

As you know, there are important differences in the safety profiles for the 2 commercially available auto CAR-Ts. And those differences result in real-world outcomes that matter. One of those 2 products, axi-cel, is typically delivered inpatient as a result of the AE profile and the care model necessary to keep an eye on those patients compared to liso-cel, which has very low rates of Grade 3 ICANS or Grade 3 CRS, and patients typically receive liso-cel outpatient. The safety data that we have for vispa-cel look extremely similar to liso-cel, very low rates of Grade 3 CRS or neurotox. And it gives us a lot of confidence for our ability to deliver vispa-cel outpatient and in the community setting.

That's definitely a differentiating factor relative to the FDA-approved CAR-Ts. And one of the things that we saw at EHA as well, was real-world analysis comparing the CD19 CAR-Ts versus the CD20-targeted bispecifics. And the CAR-Ts obviously won out generally. But we also saw the Phase III data from the SUNMO trial, which was evaluating mosunetuzumab plus POLIVY. And when I looked at that data set, we saw a relatively comparable mPFS and complete response rate with only a 0.7% Grade 3 CRS. So, how do you think about that data set in the second-line setting, especially now that the FDA is -- or that Roche has filed its sBLA for that combo?

Yes, it's a great observation and a great question, and I'll maybe address it in 2 separate ways. One is thematically. One of the key themes we constantly hear from KOLs is how they think about the trade-off between the asset class of CAR-Ts versus the asset class of antibody-based drugs, specifically in lymphoma. And what we uniformly hear from our friends in the field is that they will pick a CAR-T every day of the week in front of an antibody-based therapy. And when we say great for us, but why? Their answer is CAR-Ts have continued to demonstrate curative potential for this patient population, whereas they are not convinced that the antibody-based drugs have true curative intent.

And so that's a really important trade-off, especially if you're thinking then about CD19 specifically as a target and how you make trade-offs there, but also generally regardless of the target. We're hearing a lot about that. Now, specifically for the Mosun-Pola data, one of the interesting things that's happening in the field is that frontline utilization of polatuzumab is continuing to increase. And so, the fraction of second-line patients who are naive to polatuzumab is actually going down. And so, I think there will be some interesting questions specifically about this regimen and who might be able to benefit given the increasing utilization of polatuzumab in the frontline setting.

I completely agree with you there. Do you think that there might be a shift with the market penetration of POLIVY now that the frontline trial has read out?

Yes. It's a great question. I mean, certainly, what we're hearing both from our friends at community sites as well as academic sites is that polatuzumab is here to stay in the frontline setting, and I think we should expect to continue to see greater utilization of it.

Okay. One of the things that I also noticed was that there was a meta-analysis that compared the efficacy of CD19 CAR-Ts as a single target versus the dual-targeted ones, CD19/CD20 or CD19/CD22. And generally, the dual-targeted ones won out from an efficacy perspective, although it wasn't stat sig. And when we look at the competitive landscape, we're seeing several of these agents being advanced in the clinic. How are you thinking about that competitive threat with the dual-targeted agents?

Yes. It's a really important question, and I'll step back for a moment and highlight how we think about the development of vispa-cel because it's really differentiated from all of the auto CAR-Ts. Our strategy for the Phase III pivotal that we're planning, and we've recently achieved alignment on with the FDA, is to focus explicitly on a patient population who is not getting auto CAR-T, either because they're medically ineligible or they're facing access challenges, and these patients are also not eligible for auto transplant. So, we're really focused on, if you look at the commercial data, the 75% of patients who are not getting auto CAR-T.

So the dual-targeted assets that you've highlighted, the way I think about them is they're all competing for the same 25% of patients who can actually get to an academic site and wait long enough to get an auto CAR-T. I think it's super scientifically interesting to think about the role of dual targeting versus single targeting. I agree with you. It's interesting. Let's continue to watch the field. But it doesn't solve the fundamental reasons why patients are not getting auto CAR-T. It's not a lack of efficacy. It's a lack of access. It's a lack of being able to wait and vispa-cel addresses those in a way that the dual auto-CARs cannot.

So shifting back to the SUNMO trial then. Obviously, that trial was performed in ASCT-ineligible patients. And I believe the hazard ratio for PFS was 0.38, which is pretty significant. So when we think about the ANTLER-3 trial, how are you thinking about the powering and what you need to demonstrate from a survival perspective to be competitive with that agent?

Yes, that's a great question. So, I'll first highlight how the study itself is designed. So, the study is designed, as I mentioned a moment ago, to focus on explicitly the patient population that's not getting auto CAR-T and not getting auto transplant. It, therefore, allows us to design and run a randomized, controlled trial where the control arm is receiving the grab bag of immunochemotherapy regimens that patients get in real life today in second-line when they're not getting an auto CAR. So, we're leveraging 4 different options for the investigators' choices, to contain polatuzumab for the ones who don't get pola in the front line.

And then to the conversation we had just a moment ago, 2 of them don't contain polatuzumab. So, the total list is Pola-BR, Pola-R-GemOx, R-GemOx, and Tafa-Len. And as you look at that cohort of approaches, median PFS is something like 4.5 months for these regimens. Compare that against the 17.1 months we've seen for vispa-cel, and I think that should get anyone excited. But perhaps even more importantly than just where does the curve cross the midline, it's what is the actual shape of the curve.

And if you look at the vispa-cel efficacy data, you see an auto CAR-T-like plateau, right? You see more than 40% of patients maintaining these incredibly long, durable responses, which is so exciting to see. Whereas with these other regimens, it is just a drift back down to baseline. The only question is exactly how fast it gets there. And so with the 20-patient population, we believe we have powered this such that we have quite a bit of power to detect success in almost any scenario.

So why don't you shift gears now to CB-011. Can you update the investors as to what you presented there and how it stacks up against the BCMA or the GPRC5D, and what have you?

Yes. Great question. So obviously, there's a lot going on for patients in multiple myeloma. And it's also such a humbling disease to think about how many different lines of therapy these patients chew through and how complicated these combinations can get. So, we're really excited about the role that CB-011, as an off-the-shelf CAR-T, could play in being a one-and-done therapy that could provide patients a treatment-free interval that is really valuable in the landscape of drugs for these patients.

So, specifically with respect to the data that we've shared and most recently at EHA, again, we were so thrilled that this abstract was also accepted for an oral presentation. We've been able to tell a pretty robust story from our Phase I dose escalation dataset. So we've enrolled 48 patients in dose escalation. Through that, we were able to evaluate 2 different lymphodepletion regimens, multiple cell therapy doses. And at the end of last year, we had disclosed which dose we had chosen as a recommended dose for expansion, a single dose of 450 million CAR-T cells.

At the end of last year, as part of that initial data update, we were able to share we already had a dozen BCMA-naive patients enrolled in that RDE cohort, and we were able to share efficacy data on that cohort. And that's where the theme came from that I mentioned a few minutes ago of being able to see almost auto CAR-T-like response rates in these patients where we were hoping to at least meet the benchmark of bispecific-like responses. Now, just recently at EHA, we were able to provide an update with several additional months of follow-up on those same 12 BCMA-naive patients. And the story only gets better.

As a result of further deepening of our response, we're now up to an 83% CR/sCR rate, 92% overall response rate. And I think most importantly, really encouraging evidence of durability. Half of those patients remained in response at 15 months in counting. And if you think about this late-line, heavily pretreated patient population, that is a remarkable outcome. Now, what we've also started doing since then is enrolling patients in dose expansion, I should say, since the disclosure at the end of last year. We've been busy working on that this year. And our dose expansion work continues to focus on BCMA-naive patients, and it is also including BCMA-exposed patients.

We know that the utilization of BCMA-targeted assets is only increasing and getting earlier and earlier in the myeloma treatment landscape. And so as we think forward in the not-too-distant future, we believe the vast majority of late-line myeloma patients will have had at least one, if not multiple BCMA-targeted therapy. So, we're really eager to see what role CB-011 can play in providing benefit for those patients. So, the one other thing we were able to tuck into that EHA data disclosure was a single-patient case study from a patient who had prior BCMA-targeted therapy and then came on to CaMMouflage, our Phase I study.

This patient is a perfect example of how humbling multiple myeloma is. He had 8 prior lines of therapy. He actually achieved a CR following frontline therapy and then never again achieved complete remission following any one of the additional lines of therapy, including CARVYKTI, he had a dose of cilta-cel to which he achieved a VGPR. He ended up on CaMMouflage for his ninth line of therapy. And remarkably, at day 28, he was already in complete remission. And as of the data cutoff for the EHA presentation, he was out a little past 3 months still in CR. So, early evidence of the benefit CB-011 can bring those patients, too.

I must say that's quite impressive given his ninth line of prior lines of therapy, and he already got cilta-cel as well. When we think about the excitement of competitive landscape in multiple myeloma, how are you thinking about the go/no-go signal for CB-011 in dose expansion for both the BCMA-naive and BCMA-exposed patients?

Yes. I'll start with BCMA-exposed. I think that's probably the best near-term opportunity for CB-011 to really compete in the broader competitive landscape. And as I mentioned a few minutes ago, we expect that this late-line patient population will be heavily BCMA-pretreated. And as you know, as the field continues to demonstrate, it is really hard to find efficacious agents for patients who've had one, let alone multiple prior BCMA-targeted therapies. And so we think this is where CB-011 has a really unique role to play because whether it's an auto CAR, a bispecific, or an in vivo CAR, all of those approaches necessitate the patient's own T-cells to do the heavy lifting.

And it's why this chronic utilization of these different assets results in dramatic worsening of the T-cell compartment and worse and worse efficacy in later and later lines of therapy. CB-011 is completely different, right? It is built on healthy donor T-cells. And therefore, we are able to just completely bypass the patient's immune system. We don't need it to do the heavy lifting. We can provide the healthy donor T-cells. And so perhaps even for that one patient case study that we've shared already, perhaps that's part of the reason why he's able to experience a complete remission now in such a late line of therapy.

That completely makes sense from a scientific perspective. When we think about the data that's coming at the end of this year for dose-expansion, how should we be thinking about that dataset?

Yes, great question. So, it will be both dose-expansion in BCMA-naive and dose-expansion in BCMA-exposed. I think both of those stories stand on their own as we think about the potential to serve both kinds of patients. And so, we're excited to leverage those data to make some of our initial go/no-go decisions around the best place for future development of CB-011. I'll also highlight, Rob, this program recently received RMAT designation from the FDA. And so, that will facilitate our ability to more proactively engage with the FDA and get some of their feedback as we think about development next steps. And we expect to have a first engagement with them ahead of this data disclosure.

Okay. Sounds good. Well, we -- obviously, there's been a lot of enthusiasm with regard to the in vivo CAR-T space, and we saw data from Legend's in vivo CD19/CD20 targeted agent, LB2501 and Eli Lilly's KLN-1010. So, where do you think that those that modality will sort of fit into the treatment paradigm of hematological malignancies. And where does allogeneic therapies sort of slot in then?

Yes. Great question. Obviously, it is extremely early days in, in vivo land. That dataset that you just referenced, I think, had 12 patients, 6 of whom were in the cohort where they saw some efficacy with very short follow-up. So certainly, I think intriguing, we'll be keeping an eye on it. I know many others will. Especially with vispa-cel, we have a dramatic time advantage, right? We have a pivotal-ready program and can see line of sight to potential commercial utilization of vispa-cel on the other side of an approval.

Zooming out for a moment and not just thinking about the blocking and tackling of time, we see this incredible value of healthy donor T-cells to do the anti-cancer activity, whether it's in myeloma for the reasons we talked about a few minutes ago or in lymphoma. And so, we're really excited about an allo strategy really being beneficial to these broader patient populations. I'll also highlight, Rob, obviously, one of the key challenges for auto is just how expensive it is, right? Cost of goods sold and the time associated with it is very costly to the health care system and have created some significant challenges as we think about the businesses that are being built with these programs. Vispa-cel and CB-011 are, again, completely different.

And I joke with my team sometimes I wish we could call our therapy something other than cell therapy because they're just so different. With vispa-cel, for example, we anticipate cost of goods sold at launch to be 96% lower than the auto CAR-Ts. I mean, it's a cheap biologic at that point. And so if you think about some of the numbers that are being quoted for the COGS of in vivo CAR-Ts, they're actually the same, if not a little more expensive than what we anticipate for vispa-cel. So, we really feel like vispa-cel is the best of both worlds.

So how are you thinking about potential pricing of vispa-cel then, given the lower COGS that you guys have?

Important question. I think I'll have to say probably a bit premature for us to comment specifically on pricing. However, what I can say is that COGS profile gives us tremendous flexibility as we think about our pricing strategy for these different patient populations.

Okay. Last question for me. Can you remind us what your end 1Q '26 cash was? And what sort of catalysts can we expect other than the CB-011 update by the end of this year?

Yes, great question. So we last reported almost $120 million on the balance sheet, and that funds our current runway into the second half of 2027. That gives us the ability to do the dose expansion work that we've been discussing for CB-011. And as we've highlighted, get to that initial dose expansion data disclosure by the end of this year. It also allows us to invest in the critical start-up activities to get ready for the ANTLER-3 vispa-cel Phase III study.

Awesome. Well, I really appreciate your time, Rachel. Thank you for joining us today.

Thanks, Rob.

Welcome Rachel Haurwitz, the CEO of Caribou Biosciences. Thanks so much for joining us today, Rachel.

Thanks for having us.

And for those who are new to the story, maybe give a 1-minute intro to the company.

Absolutely. Caribou is a CRISPR genome editing company at its core, and we're leveraging our proprietary home invented CRISPR platform to develop off-the-shelf CAR-T cell therapies for patients with hematologic malignancies. We're advancing 2 programs at this point, vispa-cel for non-Hodgkin lymphoma and CB-011 for multiple myeloma.

I know we'll have a chance to dig into both. Maybe to quickly set the stage, I'll highlight that vispa-cel is now a pivotal-ready program. We have successfully concluded a Phase I study for vispa-cel, demonstrating that vispa-cel drives outcomes that are on par with autologous CAR-T cell therapies, which is extremely exciting to see, and we can talk about the plans for that pivotal study that we believe gives us a uniquely high likelihood of technical success in Phase III.

CB-011 is cooking along in Phase I. We shared first-ever clinical data from that program last year, where, again, we're really excited about the clinical activity. We are seeing response rates that far exceed our benchmark of the bispecific antibodies, actually really approaching auto CAR T-like response rates. And we're actively enrolling patients in dose expansion, and we'll be sharing dose expansion data later this year.

Got it. Yes, it's a great overview and set up for the company. And you mentioned the pivotal study and announced alignment with the FDA on the pivotal ANTLER-3 study last month. Can you talk about the key points of alignment? And are there still moving parts with stratifications, interim analyses and crossover plans?

Yes. So this is a randomized controlled trial that we're planning for this pivotal Phase III program. And we're focused on a really important patient population. We are focused on what I call the have-nots, the patients who don't get auto CAR-T and don't get auto stem cell transplant. They actually represent the majority of patients in the second-line setting. Actually, if you look at the commercial data today, 75% of second-line large B-cell lymphoma patients do not get auto CAR-T, which is the undisputed gold standard therapeutic approach for these patients.

So this is by far the lion's share of patients who are not benefiting from these profoundly important potentially curative cell therapies. So by focusing on this patient population, we're able to run a study where the control arm will receive one of multiple different investigator choice control regimens that are chemoimmunotherapy regimens. They do not have demonstrated curative potential. In fact, median PFS for that basket of approach is about 4.5 months. And if you look at the PFS curve, either from trial data or real-world data with these different regimens, it just drifts back down to baseline. The only question is exactly how quickly it gets there.

And that's, of course, compared to vispa-cel, which has demonstrated these incredible long-term responses just like the auto CAR-Ts and where we see a really important plateau in the PFS curve exactly as you would expect for such an active cell therapy program. So we've aligned with the agency on these moving pieces. And importantly, the agency has explicitly endorsed our ability to enroll 2 different kinds of patients in this study. One is those who are medically ineligible for auto CAR-T, which really boils down to can't wait for therapy and need something urgently now.

And the second is the patients who might otherwise be medically eligible but are unable to access for all the real-world challenges that we can appreciate, they can't pick up and move to MD Anderson or some other big center, and they don't have a caretaker who they can take with them during that time to help oversee their care. So we're really excited that vispa-cel has the potential to benefit both of these patient populations. We're excited to enroll both of these patient populations in the study. And of course, on the other side of a successful trial and following a future approval, we would anticipate the ability to promote to both of these patient populations, which we think is very encouraging.

Got it. Yes, that's a helpful setup for the Phase III. And for these 2 patient populations, how readily identifiable are they? And maybe talk about differences in the United States and ex-U.S.

Yes. Here in the U.S., they make up the lion's share of the second-line setting. So we think they're pretty easy to find. And we think we'll find them both at top-tier academic institutes, which is where we did most of our Phase I work. But we'll also find them at sophisticated community hospitals. That's actually a really important part of our trial strategy is to leverage not only top-tier academic sites, but to also take the study to some of these sophisticated community hospitals that are today routinely delivering bispecific antibodies to their patients that can't and won't be able to deliver autologous CAR-T cell therapy.

So we think that's a really nice sweet spot. To your point, Maury, we do expect this to be a global study. So as we think about the ex U.S. footprint, we're also specifically focusing on countries that have a similar kind of 2-tier challenge-ridden system, where there are some sites or some ways that some patients have access to autologous CAR-Ts and then some patients who don't for both of these different kinds of reasons. We'll also be collecting data for each patient when they come on study, how do they end up there? Is it because they're medically ineligible? Or is it because they face access challenges and really digging into the discrete details that support either of those decisions.

Got it. Makes sense. And for these patients that have the access challenges and just with the logistics of getting treatment and the urgency to treat, how do you plan to address these challenges and potentially turn them into opportunities?

Yes. They absolutely define the opportunity for a program like vispa-cel. I really like the way you phrased that question. The 2 key reasons why 75% of second-line patients don't get commercial auto CAR-T today are, one, urgent need of therapy; or two, the access challenges that we just talked about. So vispa-cel, we believe, is uniquely well positioned in the second-line setting to address both of these. We'll take timing first. With an auto CAR-T, especially if you're a patient being treated in the community, there are 8 to 12-plus weeks of time to go through the referral patterns, actually end up at the site, apheresis bridging therapy to finally get your dose.

With vispa-cel sitting in the freezer as we speak today, there is truly no wait time necessary. Even in our Phase I study, we had some patients go from finishing all the eligibility paperwork to beginning lymphodepletion on the very same day. So truly no wait. We've demonstrated that already and look forward to leveraging that going forward. The second piece, of course, is the ability to bring vispa-cel into the community closer to where these patients are. We think this trial will be an important initial footprint as we think about what a future commercial rollout could look like.

Got it. Okay. And the comparator arm in the study, it's investigator's choice standard of care immunochemotherapy. How are you thinking about control arm performance variability across sites and geographies?

We certainly recognize that which of these different regimens, and we think there will be 4 that physicians can choose from. The utilization of them might vary a bit by geography, maybe community site versus academic site in the United States or certain countries or regions ex U.S. But the real-world performance of all of them are actually extremely similar. They're all in that kind of plus or minus 4.5 months of median PFS. So even though there will be different utilization in different geographies, we actually don't expect the outcomes to vary dramatically for these different patients.

I will highlight part of our strategy for this control arm is to both include regimens that have polatuzumab and ones that lack it, recognizing that the utilization of polatuzumab is heterogeneous in the frontline setting. And so this approach allows us to capture both patients who've had pola in frontline and those who have not. Importantly, especially as we think about enrollment in the United States, we've also gotten the green light from the FDA to leverage crossover. So if a patient is on the control arm and experiences progressive disease, they're then eligible to cross over to receive a dose of vispa-cel.

Got it. So that should help with enrollment having that incorporated. Okay. Anything else about the study design that you want to highlight?

Maybe I'll just quickly say it's a 250-patient study, and the primary endpoint will be progression-free survival. And just to explain that in a bit more detail, it's not a landmark PFS. There's not a magic date in the calendar that we've circled. It's really event-driven, which is why we have such high confidence in the very high likelihood of technical success for vispa-cel over these other agents that, again, have no demonstrated curative potential for this patient population.

Yes. Makes sense. And at EHA next week, you're going to present longer follow-up from the ANTLER Phase I study. What should investors watch for in the data set to help derisk the ANTLER-3 execution?

Yes. I'd say success equals more of the same, right? What we've shown historically is data that is really indistinguishable from the autologous CAR-T cell therapies both in terms of overall response rate and complete response rate as well as how durable these responses can be. So more of the same would be, I think, very encouraging and would certainly be success in our minds. And keep in mind, we're running a study where the control arm has a median PFS of 4.5 months. And so we think this continues to set us up for a very high likelihood of success.

Got it. And with auto CAR-Ts, we see about 14.8, 14.9 months median PFS. What do you think about these benchmarks? And are they attainable for vispa-cel?

Yes, it's a great question. If you look at the real-world data, the median PFS can sometimes shift around a little bit just based on where exactly that line crosses 50%. But if you look at all of the commercial auto CAR-Ts across both the pivotal data sets and real-world data that has been published more recently, they are indistinguishable in that they are all resulting in these profound plateaus in the PFS curve where somewhere between 40% and 50% of patients experience these very long-term outcomes. I believe we've already shown that is what vispa-cel can do and continue to believe it is an attainable goal for this program.

Got it. And is there any signal that vispa-cel relapse patients track differently versus the auto CAR-Ts?

I think it's actually quite similar. If we look at our data and if people are interested in looking at some of the swimmer plots, I'll point them to the swimmer plots in our current corporate deck. If you look at individual patients, if a patient is in response 3 months post dosing, the likelihood that they maintain that response is extraordinarily high.

Now the discrete timing differences between some of the auto CAR-T studies and ours are important to note for all of those studies, day 0 is the date of randomization. It takes usually at least 30 days to get your dose. So those early months don't line up perfectly. But when you control for that, you largely see the same things with the auto CARs, too, that the patients who are not going to have long-term remissions relapse fairly quickly and you get to that really stable plateau by about 6 months.

Got it. Yes, makes sense. And for the second-line LBCL landscape, it's evolving rapidly. How do you think about impact from bispecifics getting second-line approvals? Will they compress your addressable market or reinforce the 75% second-line patients don't get auto CAR-Ts?

Yes, it's a great question. I'll maybe start with the auto CAR-T piece and say, a few years ago, there clearly were manufacturing limitations. There just were not enough slots and not all the patients who wanted or could get auto CAR-T got to it. That is not the case anymore. The players in that space have made extraordinary investments in CMC and yet the numbers are largely stabilizing at about 25% of patients. And so I think that is reflecting the ceiling driven by these real-world challenges of just how urgently most patients need therapy and the access challenges to boot.

The bispecifics, none of them have been approved, not for lack of data or trying at this point. And yet the real-world answer is today, they are one of the market-leading drugs in the second-line setting because there is so little for patients if they're not getting an auto CAR-T. So I actually don't think a future approval of a bispecific dramatically changes the equation.

What I will share is with the market research that we've done with a profile matching vispa-cel, we've seen significant enthusiasm, both from physicians who actively treat patients with auto CAR-Ts today as well as physicians who don't and have to refer their patients into top-tier academic sites to get that dose. And so even though you see pretty different bispecific utilization between those 2 populations, we're seeing very similar enthusiasm for the potential to use a one-and-done cell therapy like vispa-cel that's off the shelf by both of those groups of physicians.

Yes. Yes, it makes sense. And what are your thoughts on Allogene read-through with cema-cel where they showed 58.3% MRD clearance in frontline consolidation versus 16.7% observation. If eventually commercialize, does that change the second-line patient mix with fewer frontline MRD-positive patients relapsing in second line?

Yes. I think if Allogene is wildly successful with cema-cel, the impact to vispa-cel's potential is actually extremely minimal. And I think that's because our teams are focusing on very different patient populations. They are taking a strategy, as I understand it, that's largely focused on patients who have a good response to frontline therapy and are MRD positive, whereas we are focused on the folks in the second-line setting who have full-blown disease and the vast majority of whom were actually primary refractory patients. So the Venn diagram between the patients they could serve and the patients we could serve is extremely little overlap. And I think that's good for patients, right? We're taking orthogonal approaches for how an off-the-shelf could benefit patients with lymphoma.

Got it. Yes, it makes sense. And so basically, minimal overlap there. And with ZUMA-7 and Transform enabling auto CAR-T in the second line, do you expect penetration to move materially above 25%? Or will the typical constraints from manufacturing and access limit potential?

I think the real-world numbers are bearing out the answer to that question. They've been hovering around that kind of 20% to 25% for a few years now. And so I think we should expect it to be range bound for the foreseeable future. A huge fraction of that is just driven by how urgently a patient needs therapy and that you just -- you can't address that without something that isn't off the shelf.

Yes. Yes, makes sense. And what are your internal estimates for vispa-cel market share in the second-line LBCL settings?

Yes. I don't think we've shared publicly the quantitative answer to that. So I'll give the qualitative answer, which is that market research that I described has given us the confidence that vispa-cel has the potential to be the market-leading drug in the second-line setting with a profile matching what we've already seen clinically in the Phase I study.

Got it. And how do you think about pricing at this point?

Obviously, premature to comment explicitly on pricing. But what I will highlight is how vispa-cel really stands on its own from a CMC supply perspective. So it is nothing like an autologous CAR-T cell therapy. It is highly scaled. In fact, our process today is commercial ready. Each batch gives us enough cells for 200 to 300 doses. And we anticipate cost of goods sold at launch to be 96% lower than the auto CAR-Ts. So to answer your question, that gives us tremendous flexibility as we think about an appropriate pricing strategy for this product while giving plenty of wiggle room to actually build a true business that our colleagues outside of cell therapy might recognize within the drug industry.

Yes. Yes, it makes sense. And from like a specific benchmark in the space, I guess, is there something that comes to mind then or no comment?

I mean I think it's fair to say we've gotten feedback from many stakeholders who would have no problem with pricing on parity to auto CAR-Ts. And I think that's in part reflective of just how costly for the health care system it is to deliver an auto CAR-T. It's not just the sticker price of the cell therapy. We've gotten feedback on numbers north of that and numbers south of that, which I think really feeds into what I said a moment ago around flexibility. We see tremendous flexibility for pricing strategy.

Got it. Makes sense. And for CB-011, you're going to present longer follow-up data from the Phase I CaMMouflage trial at EHA next week. What should investors watch for as a kind of a home run data set there?

Yes, great question. So I'll anchor it with what did we share last year, which was our first ever look at CB-011 clinical data. So at the end of last year, we shared data on all 48 patients enrolled in dose escalation. We did quite a bit of heavy lifting with that study. We evaluated 2 different lymphodepletion regimens, multiple cell therapy doses, landed on one of those 2 LD regimens as a go-forward strategy and selected 450 million CAR-T cells as the recommended dose for expansion. At that time, we already had 12 BCMA-naive patients enrolled in that recommended dose for expansion cohort. And what we saw at the time, and I highlighted a few minutes ago, was response rates far exceeding our benchmark for success.

So our hope based on KOL feedback, was to see responses at least on par with the bispecifics. That's the only other readily off-the-shelf available product or asset class available to these patients who urgently need therapy. And what KOLs have always told us is they'd love to have an allo-CAR that kind of looks and smells like a bispecific because then the patients benefit from a one-and-done treatment followed by a treatment-free period of time compared to the repeat dosing of the bispecifics and in particular, the repeat infection challenges that they face. So what we actually saw with that cohort was response rates north of 90%, approaching auto CAR-T like response rate, 75% complete response rate.

And I think the open question at the time was great responses, how durable are they going to be? So I think it's an important part of the story that we'll be able to tell next week as we now have many additional months of follow-up on these patients, and we can better understand how durable these responses are. In terms of benchmarks for success, as we talk to KOLs and think about these late-line high-risk relapsed/refractory multiple myeloma patients, they'd like to see a median PFS somewhere in that 12- to 15-month range. So that's part of how we'll be judging success for the program.

Got it. Okay. So 12 to 15 months median PFS is kind of the benchmark there. And for the 12 patients where you had median approximately 5 prior lines, how confident are you that in a larger dose expansion data set, you can replicate...

I mean that's the question, right? And that's why we do the work. So we're actively enrolling patients in dose expansion now. And I'll actually highlight, we're enrolling 2 separate cohorts in expansion. We're continuing to grow that BCMA-naive data set, but we are also enrolling patients who've had prior BCMA exposure. Certainly, as you look at the evolving landscape in multiple myeloma, the fraction of patients who will be exposed to BCMA in early-line therapies is only increasing. So we're very interested in understanding the benefit that CB-011 could bring to those patients as well.

Got it. Okay. And what are the time lines for that cohort?

Enrolling now, and we've committed to sharing initial dose expansion data by the end of this year.

Got it. Okay. And for CB-011, you've got RMAT designation, got that earlier this year. What's your current thinking on pivotal trial design and projected time line for start? And have you had discussions with the FDA for earlier line development?

Yes. So we were so excited for CB-011 to get RMAT earlier this year. That obviously will facilitate our ability to start engaging with the agency more proactively. So I'm hoping we will have had our first FDA interaction by the time we get to sharing some of these dose expansion data by the end of the year to help frame how the data drives some of these critical next step decisions for the program.

To answer your question, I think there are a lot of different options as we think about future development for CB-011. Some of them might be aiming first for quite large patient populations where it might necessitate a decent amount of capital and/or partner to run such a large study. And others that might be quite focused, especially as we think about later-line patients who are post BCMA, maybe patients with extramedullary disease, where we've actually seen some really encouraging activity with CB-011 and most of the other CAR-Ts don't. So I think we'll have some choices to make about different approaches, some of which may be faster and more capital efficient than others.

Got it. Makes sense. And for the BCMA space, it's viewed as kind of a crowded environment. How is CB-011 positioned within this market? And how do you see that shifting over the next 3 to 5 years with emergence of new therapies?

Yes. I'll share what we hear from the physicians who've so eagerly enrolled patients on this study. I think the value of an off-the-shelf one-and-done agent in this setting is incredibly high. Multiple myeloma patients typically are chronically on something and then something else and then 3 of something and then 4 of something for the rest of their lives, right? And so the impact to them as a human being is quite profound for constantly being on these different regimens that come with all different kinds of AEs. And so I think the value of a one-and-done asset that gives them a treatment-free period of life is super valuable.

And then as we think specifically about CB-011 versus some of these other potential strategies for a one-and-done, CB-011 leverages healthy donor T cells. We are not asking the patient's immune system to do the heavy lifting. It's part of why we're enrolling post-BCMA patients in our study right now because we think that CB-011 could have a role to play with these healthy donor T cells to drive outcomes in patients who may not otherwise benefit from an auto CAR T or a bispecific because their own T cells are too chewed up at that point in time.

Yes. Yes, it makes sense. So clearly differentiated, and it's probably something that's underappreciated with the allo approach. And on the BD front, you've got enough cash to derisk the story, but not to fully fund the pivotal trial for CB-010. What are some of the highest priority strategy options here as it relates to financing or potentially partnering vispa-cel or CB-011?

Yes. I think it's a pretty high likelihood that partnership plays a role in the future of vispa-cel and/or CB-011. And those are the kinds of time lines that my team and I have the least control over, right? So we're certainly interested in what additional opportunities partnership could unlock, but not banking on that as the only future for either of these programs.

So specifically for vispa-cel, as we think about the capital necessary, you're right, capital on our balance sheet today, we are leveraging to do some of the initial start-up, get sites ready, supply, et cetera to fully fund the study, we've shared publicly, we will need to raise additional capital to do that. I think we're being super thoughtful about the different ways we could do that, anything from, of course, the equity capital markets through to nondilutive structured financing opportunities as well.

Got it. Makes sense. And going back to the ANTLER-3 study, so you mentioned 250 patients. How long do you think it would take to run that study? Any more perspective on time lines there?

Yes, that's a fair question. I think we expect from initiating the study to data to be 2-ish years. It's a pretty rapid study to execute on and deliver data.

Got it. And that's because of the PFS numbers that you're working with there.

Correct. Correct.

Yes. Okay. So maybe just in closing out, if you just want to highlight key catalysts ahead that investors should be focused on. We've got the EHA data next week, which we'll be looking out for that. Anything else you want to mention?

Yes, absolutely. Come to Stockholm. We'll see you there twice. Two podium presentations, one for vispa-cel, one for CB-011, really excited to see both of those stories shared in that context. And then for CB-011, we have also guided to dose expansion data by the end of this year. So certainly, stay tuned as that program continues to progress.

Great. Thanks, Rachel, and thanks for joining us today.

Thank you, Maury.

Welcome to our H.C. Wainwright BioConnect Conference. I'm Robert Burns, Senior Biotech Analyst and Managing Director at H.C. Wainwright. And I'm joined by Tina Albertson, the CMO of Caribou; and Sri Ryali, the CFO of Caribou. Thank you for joining us today.

Thanks for having us.

So why don't we start from a broad high-level overview of the company. For those who may be unfamiliar with Caribou, talk to us a little bit about your tech as well as your pipeline.

Great. Thank you. So Caribou is advancing 2 allogeneic CAR-T cell programs. Our first one is vispa-cel. This is an allogeneic CAR-T cell. It's targeting CD19 in large B-cell lymphoma. And our second one is CB-011. This is our allo CAR-T targeting BCMA in multiple myeloma. Caribou has a next-generation CRISPR-Cas based technology that really has built on the original technology such that it's much more specific and has a lot less off-target editing. And what this allows us to do is multi-genic editing while maintaining the integrity of the cells.

This allows us to armor cells. And then for vispa-cel, that means we have knocked out PD-1, which is the checkpoint pathway that's very important in lymphoma biology. With CB-011, we've taken another tactic where we have armored the cells where we've knocked out HLA-1 and really immune cloaked the cells in myeloma in order to have longer persistence of the cells. And what this means for our lead program, vispa-cel, is that these cells have more antitumor activity for the time that they're around.

We see these cells persistent for about 30 days. So during those 30 days, we get deep durable responses due to the increased antitumor activity of that product. As I mentioned already for CB-011 in myeloma, we've taken the tactic of trying to improve the persistence of those cells. We see about twice the amount of persistence in that program. So we think that the immune cloaking is working in CB-011.

Before we actually dive into the pipeline, I sort of want to talk about the CAR-T landscape in general because there obviously have been a lot of recent developments and new tech that's sort of moving its way into the field. And in particular, there's been a lot of enthusiasm around in vivo CAR-T. How are you thinking about this development within the cell therapy landscape from a competition standpoint? And where exactly does allogeneic CAR-T sort of fit into the treatment paradigm if in vivo CAR-T actually has legs to it?

So if we think about where we're at today, auto CAR-T are clearly the gold standard for second-line large B-cell lymphoma right now, but 75% of patients can't access it or they can't wait for it. So they're either medically ineligible or they can't access due to geography or other financial constraints. So there's 75% of the patients that need something faster or that can come closer to them out in the community. And for allogeneic off-the-shelf CAR-T cells like vispa-cel, this is a sector that we feel like we can really be a market leader and give these long durable potentially curative agents to more patients.

And so the other benefit of allogeneic CAR-T cells is they are from donor healthy T cells. And we've learned through treating over 140 patients at Caribou that young donor T cells matter a lot for durability. Both auto CAR-T and in vivo rely on the patient's T cells. So we think there will always be a place for allogeneic CAR-T cells, especially in these patients that are -- have T cells that are neither not enough in number or not as functional.

And so in vivo is very early on. We already see that there's some safety signals that are coming out. There's a lot of engineering and things that they're going to have to figure out over the next 5 to 10 years. And I think for allo, we're ready to go. We're headed into pivotal trial, hopefully this year with vispa-cel. So we think that allo is well poised really to really increase the number of patients that these potentially curative agents.

Yes. So why don't we focus on vispa-cel for the time being, also known as CB-010. I know you presented data late last year with regard to vispa-cel. Talk to me a little bit about those results that you saw. And how does this data set stack up against some of the comparators here?

Yes. So late last year, we submitted -- we presented and disclosed clinical data on both our programs for vispa-cel. In particular, it was really the first time with a meaningful data set. So 35 patients that had gotten vispa-cel made from young donor that was partially matched at HLA modestly 2 out of 12 alleles. And we showed efficacy and safety on par with auto CAR-T, which a lot of folks never thought we'd see with allogeneic CAR-T cells. So we saw a plateau in our PFS curve with a 12-month PFS of 53%, very high ORRs and complete remission rates that rival the auto CAR-T.

In fact, they look identical with a safety profile that's the best of the auto CAR-T, much like liso-cel or Breyanzi, where we know that, that product can be given in community centers because of the low rates of Grade 3 CRS and neurotoxicity. So we're really excited about having an off-the-shelf agent that looks just like auto CAR-T, but you can take it out of the freezer when you need it and not have to manufacture and patients won't have to wait 8 to 12 weeks.

Yes. I know you're using a partial HLA matching strategy. Talk to me a little bit about the percentage of patients that you can actually treat with that HLA matching and with regard to your cell banks.

So actually, it takes a very modest number of lots to match 99-plus percent of patients at 2 plus. So at the time of launch of trial, we model that it will take maybe 10 lots to match 99% or more of the patients at 2 plus. We'll use a best match strategy. So this will all happen in the background that patients won't be waiting for or ever not be given a dose of vispa-cel.

These are -- this will be done where we'll have these 10-plus lots in the freezer. And when they're signing up for the trial or ultimately in the commercial setting, it will be a simple blood test. And as they get started with their lymphodepletion, we will have algorithms that will figure out what the best matched lot is and send them a dose of that in time to infuse.

Okay. So there won't be a sort of lag time here.

No, there's no lag. And in fact, in our clinical trials currently, we've had patients that have reached eligibility and started lymphodepletion on the same day because we can then ship the drug while they're getting their lymphodepletion because there's no risk for manufacturing, right? You don't have the site, doesn't have to wait to have the dose on site to know that, that patient is going to get CAR-T.

Yes. So I know at the upcoming EHA meeting, we're going to be seeing some updated data from ANTLER. A lot of excitement around this data set. So help frame investor expectations with regard to what they can expect to see and sort of what should be the takeaways once that data is revealed?

I think for ANTLER, it's likely going to be more of the same. This is more months of follow-up on the same patient population. It really is just cementing the data that we have already as we move into pivotal trial, and we'll probably talk about this later. But when we think about comparing this to noncurative agents such as the standard of care for these kind of patients, what it will do is set us up for the conversation on the chance of technical success as we move forward in the pivotal.

Yes. Obviously, within the pivotal trial, you're going to be going after the second-line setting. Now I know a competitor just dropped some interim futility data not too long ago. So I'm curious to get your thoughts as to how you see -- and that was in the frontline setting. So I'm curious to get your thoughts as to how you see that second-line opportunity sort of evolving as we look at that trial as well as ZUMA-23.

Yes, it's a great question. And we've done a bit of market research and talking to folks to try to understand what impact that might have on a second-line population that can't access auto CAR-T or ineligible for auto transplant. And it's actually a very modest impact even on their highest success. And part of the reason is most of the patients that get into second line have never had a response to first line. So they're not in remission with an MRD-positive result. They actually still have active disease. Those are not patients that are going on to cema-cel after onto that trial.

And so those are patients that would go immediately to second-line therapy, and those are the patients that we would enroll trial. Similarly, with ZUMA-23, these are very high-risk patient population, randomizing against R-CHOP. We're waiting for data on those. Getting something like axi-cel into the frontline setting into the community is going to be very challenging for all the reasons of access, but also the safety profile of that product. So I think safe to say, we think there will be a meaningful unmet need in second line for a long time.

So I do know that there is a CD19-targeted ADC that's being combined with a CD20 bispecific in the second line setting. I want to get your thoughts as to how you see that regimen sort of stacking up against vispa-cel because it potentially also could be deployed in the community setting. So I want to get your thoughts there. And I'm pretty sure you know which regimen I'm talking about.

Yes, it's a great question. So both ADCs and bispecifics are agents that you give at infinitum until they progress. So these are weekly, monthly infusions that aren't curative. And so any of the -- right now, bispecifics are being used off-label second-line large B-cell lymphoma. Some have had some failures in regulatory trials in second line. And so we know that's an uphill battle for some of these agents that aren't curative in second line. So vispa-cel just has this wonderful space where we are one and done off-the-shelf potentially curative agent that will look very favorable against a regimen that's weekly to monthly infusions for a year or more.

Yes. I know that you recently reached alignment with the FDA with regard to the pivotal trial of vispa-cel. Talk to me a little bit about that trial design and when you expect that trial to actually start?

So recently, we've been -- we have RMAT for vispa-cel. So we have been discussing with the agency over the last several years, different options for what vispa-cel pivotal trial might look like. We came to alignment with them earlier this year on exactly what we disclosed in the fall, which is a Phase III study in patients who can't access or wait for auto CAR-T and also are not eligible for auto transplant, which is the only other curative agent available for these patients.

And so that means that we can run a randomized controlled trial against agents that are not curative. The median PFS in the literature for these regimens in high-risk patients is about 4.5 months. That means for 250 patients randomized 1:1 with a single dose of vispa-cel, we have a very high chance of technical success with the plateau that we see on our PFS curve. We have alignment on our control arm regimens.

Two of those are polatuzumab containing regimens in case they don't get that in the front line, either combined with BR or R-GemOx and then [indiscernible] and R-GemOx for those patients that have gotten polatuzumab in the front line. And so we see a lot of excitement in both the academic and the community sites for this study. We are already engaging with those sites. We plan to have sites in both of the community where they can't access, but also in the academic centers that have auto CAR-T, that's where we enrolled our 1 study for patients who can't wait.

When we think about those 2 control arms, obviously, those 2 regimens have different efficacy profiles, right? So I'm curious to get your thoughts as to what is the market share that Pola is attaining in the frontline setting, just so we can sort of figure out what the sort of breakdown between those 2 control arm regimens is going to be, just so we can sort of gauge or try to predict what the control arm is going to generate holistically.

We're estimating about 20%, 25% or pretty equal usage of all of our control regimens in our control arm and partly because we will -- this will be a global study. In the U.S., polatuzumab is probably used in about 30% of frontline patients, but that differs on type of different sites, different patients. So we expect both in the U.S. and globally that this will differ between sites and patients. But overall, there should be equal. As we've done our feasibility, that's why we are having 4 regimens, there's a desire to have kind of options for these patients because each patient in front of them might need something different.

Okay. Why don't we shift gears now to CB-010. Can you remind us about the data that we saw for that agent late last year? And how it stacks up against some of the BCMA-targeted bispecifics and CAR-Ts because obviously, that's a very burgeoning field. That's very crowded.

Yes. So CB-011, as I mentioned before, is our BCMA allo CAR that's immune cloaked. We disclosed data on 48 patients from our Phase I study last November, where we disclosed that we picked a recommended dose for expansion. That's 450 million cells. And in the 12 patients treated at that regimen who had not seen BCMA targeted therapies before, we saw very high rates of response and complete remission with 91% of those patients achieving an MRD-negative state, which for myeloma is one of the most important endpoints.

We are currently expanding that cohort in expansion. We've also disclosed that we're starting to treat patients who've previously had BCMA agents before since that's one of the largest growing sectors of unmet need. And we know that some of the failure mechanisms for auto CAR-T and even bispecifics that target BCMA are due to the patient's own T cells. So we think the allogeneic BCMA-targeted cells may have a benefit for those patients.

Okay. Considering that extensive landscape of BCMA-targeted agents in multiple myeloma, while also acknowledging that for dose expansion, you're going to be looking at both BCMA naive and BCMA exposed. So I'm curious to get your thoughts as you think about those 2 subpopulations, what do you view as the go/no-go signal to move forward with CB-010 in each of those populations?

I think right now, we're getting our numbers higher in both of those populations. We do still think the bispecifics are our benchmark for both of those populations. In BCMA naive patients, we have exceeded that bar, which is why we're continuing to expand. We just got RMAT for CB-011 and so we look forward to talking to the agency about opportunities, both in BCMA-naive and BCMA-exposed patients. The exposed patients, there's not a lot available for them. So the bar will be lower. What exactly is that bar, I think, is yet to be determined. And so we'll wait. We're anxiously awaiting those data in the future.

Okay. So what sort of expectation should investors hold? Because I know initial dose expansion data is coming later this year. How should investors be thinking about that data release?

So I think at EHA, what we have disclosed is we will have follow-up on our dose escalation patients, so the same patients that we talked about in the fall. The expansion patients will probably be later in the year, but we're having a robust enrollment. This is an agent, again, also at sites that have auto CAR-T and bispecifics and there's still an unmet need for an off-the-shelf one-and-done agent. So I think we're really excited to continue to enroll expansion and share those data later this year.

Okay. Well, last question for me, and this is directed at you, Sri. Can you remind us what your cash on hand was as of end 1Q? And what sort of operational runway that provides?

Yes. We ended Q1 with about $120 million, just under $120 million in total cash, and we've guided that, that funds the company into the second half of 2027. What that gets us is the expansion cohort for CB-011 that Tina has been talking about, that's fully funded off our balance sheet. We're also able to initiate some of the critical start-up activities for the vispa-cel pivotal trial, ANTLER-3, but we'll need to fully fund the ANTLER-3 study through data readout.

Okay. That's really all the questions I had. Are there any questions from the room? All right. Well, thank you for joining us today. I really look forward to all the data that's going to be coming out from Caribou this year.

Thanks for having us.

Thank you.

All right. Let's get going. Thanks for joining this session with Caribou Biosciences. My name is Alec Stranahan. I cover SMiD Biotech at Bank of America. And I'm pleased to welcome Rachel Haurwitz, President and CEO of Caribou. Thanks for being here, Rachel.

Thanks so much for having us today, Alec.

Yes. Great. Looking forward to the discussion. But maybe just for the benefit of the audience, those that have either not looked at Caribou for a little while or haven't seen the latest update, maybe you can give a high-level overview of what the company is doing and for the recent data that we've seen.

Absolutely. Thank you. So Caribou is advancing two off-the-shelf CAR-T cell therapies. Vispa-cel targets CD19 for lymphoma and CB-011 targets BCMA for multiple myeloma. Each of these programs, we shared actually quite significant clinical updates towards the end of last year. And in both cases, we are seeing Phase I data that give us the confidence that each of these programs has best-in-class potential.

And I think what really unlocks unique outcomes for these patients is how we use our CRISPR technology platform. So we have our own proprietary next-generation CRISPR technology. We call it the chRDNA technology and its unique attribute is that it drives editing outcomes that are orders of magnitude more specific than first-generation CRISPR/Cas9.

And so we've leveraged that to edit to armor our cell therapies in ways that we believe are unique in the competitive landscape and that we think are really critical to unlocking the kinds of high response rates and durable outcomes that we've seen with both programs. And we're really excited that actually both programs have abstracts that were accepted at EHA for oral presentations next month, which will give us a chance for both of them to provide really, we think, important data updates.

Great. Yes. Well, we can definitely unpack sort of what we're looking forward to at EHA. But maybe at a higher level, you mentioned the chRDNA platform. You've also got some kind of unique edits that you're incorporating PD-1 knockout, for example. So maybe you can just talk through kind of like the rationale for that approach and how it's armoring or, I guess, camouflaging here.

Yes. Yes. If you wanted to clock back a few years, we were certainly not alone in our vision that off-the-shelf has to be the strategy to bring cell therapy to much larger patient populations. But we were really differentiated in how we set about doing that. Most of our peers move forward with roughly the same construct, healthy donor T cells, you get rid of the T cell receptor, so you don't cause graft-versus-host disease and you get the cells to express a CAR, and they called that a product.

And we looked at that and just sort of scratched our heads. We couldn't quite square that circle because we know these healthy donor cells are foreign to the patient's immune system, and they're therefore, going to be more rapidly rejected than auto CAR-T. You have to do something to bridge that biology. With CB-011, our myeloma program, we're actually directly trying to address that. We use an immune cloaking strategy. It's a multi-edit approach to try to slow down that immune-mediated rejection to buy additional time for additional antitumor activity.

We've seen the PK for that product, the persistence for that product is about twice that of uncloaked cell therapies. And so we think that's working, and we think that's really a key part of the differentiated clinical outcomes that we've seen so far. With vispa-cel, in lymphoma, we've taken an orthogonal strategy and said, we don't necessarily need to tweak how long the CAR-T cells are there if we can drive better antitumor activity while present.

And so that really drove us to the PD-1 knockout strategy. The intent, of course, is to take the brakes off the CAR-T cells so that during that window of time, about 30 days while they're present, they pack as much antitumor punch as possible. And we think it's that PD-1 knockout that is helping vispa-cel drive outcomes that are on par with autologous CAR-T cell therapies.

And it feels like we have the first gen, which is the ex vivo CAR-Ts. You've got allogeneic like what you guys are doing. Now we have in vivo CAR-Ts, which are kind of unproven earlier stage, but it's kind of -- each one has its own lane, it feels like, but maybe allogeneic is the sweet spot. Maybe you can just talk from a technological perspective, the differentiation and sort of the benefits that allogeneic affords.

Yes, absolutely. And I'll build with what do we see in the commercial landscape today, which is obviously exclusively auto CAR-Ts. And in spite of the extraordinary clinical and real-world data that have cemented auto CAR-Ts as the gold standard for second-line large B-cell lymphoma patients, only about 25% of patients get auto CAR-Ts. So we're actually really excited that we've achieved alignment with the FDA on a Phase III pivotal design to directly hit that head on by developing vispa-cel for patients who are not getting auto CAR-T and are not getting auto transplant.

And we see significant opportunity to address that unmet need and build a really compelling future commercial case for vispa-cel by doing so. I think the key differentiator for vispa-cel , again, with the backdrop of today's commercial reality is twofold. The majority of those 75% of patients who don't get auto CAR-Ts don't get them for one of two reasons. Either their disease has already progressed too far or is progressing too rapidly to wait, right?

The reality of these NF1 therapies is it takes 8 or 12 weeks from the idea of getting an auto CAR to actually getting your dose and a huge fraction of patients simply cannot wait. And the other key driver is geography. Most of these patients are cared for in the community, but it's really only the top-tier academic sites that offer auto CAR-Ts, and there are a lot of real-world reasons why many of these patients cannot pick up and move to go, let's say, to MD Anderson to get their dose.

And so we believe vispa-cel is really well situated to address each of these issues, specifically as we think about the unmet need that is exactly the patient population we're solving for in our Phase III study. And as we think about geography, because of the efficacy and the safety profile we've seen with vispa-cel so far, we know it can be delivered in the community. And so actually, our Phase III study intends to leverage both sophisticated community hospitals alongside, of course, top-tier academic institutes. Your point is well taken.

The field in the technology space continues to evolve. And so what role might in vivo CAR-T play in the future? I'll say probably first and foremost, it's early days. We've seen some safety signals emerge already in that space. There's probably a decent amount of engineering that it's going to take to get either the LNP mRNA or lentiviral platforms to function and function safely for a large enough patient population.

But what I'll highlight is whether it's auto CAR or in vivo CAR in both of those settings, it's the patient's own T cells that need to do the heavy lifting, whereas with allo CAR-Ts, we don't ask anything of the patient's T cells. We are leveraging healthy donor T cells that have been armored, be it through PD-1 knockout or otherwise to really boost their antitumor potential. And so we think in both of these landscapes, allo CAR-Ts have a really important role to play for these patients.

Right. And we can definitely talk about the manufacturing advances that you guys have made. But maybe just double-clicking on the Phase III design since this was a recent update. You've aligned with the agency, second-line LBCL patients who are ineligible for auto CAR and transplant. I guess can you maybe talk us through the design regarding the endpoints, the comparators, sort of the patient groups, crossover.

Yes. We are really excited to have achieved alignment with the FDA on this study and believe that the study design gives us incredibly high likelihood of technical success. So as I mentioned a moment ago, we're really focused on what I call the have-nots, the more than 50% of patients who can't get auto CAR-T and are not getting auto transplant. So by focusing on this patient population and running a randomized controlled trial, the control arm regimens, therefore, are chemoimmunotherapy regimens that don't have curative intent.

And so we think that setup gives us incredibly high likelihood for technical success. So we are planning for a 250 patient population, 1:1 randomization. And in the control arm, physicians will have a choice amongst four different regimens. Two of them contain polatuzumab, so Pola-BR and Pola-R-GemOx, two of them don't because we know some patients will see Pola in the frontline setting, so R-GemOx or [indiscernible]. And as you look at all of those regimens, either clinical trial data or real-world data, all of them have PFS curves that just kind of drift back down to baseline.

The only question is exactly how fast they do that. And looking across all of them, the median PFS is like 4.5 months. Now compare that to the Phase I data from vispa-cel, where at our update at the end of last year, we saw this incredible plateau in the PFS curve, just like you see with the auto CARs, where somewhere between 40% and 50% of patients are achieving these very durable outcomes.

We have not yet reached median PFS or 12-month progression-free survival was about 53%. And so we really like that setup. We also know that potentially accessing a cell therapy for patients who otherwise, by definition, have no access to cell therapy is a really important part for recruiting patients to the study.

So we plan to have crossover so that if a patient experiences a progression event on the control arm, they can cross over and get a dose of vispa-cel. So the primary endpoint will be progression-free survival. Now it's event-driven, not a landmark analysis. And so again, zooming out, we really like the setup and how high the likelihood of technical success is.

Okay. Could you maybe -- that's a really great overview. Maybe just going one level deeper around what drove the 250 number in terms of powering, how is the study blinded given that there's a crossover component?

Yes. It is not possible to blind this because it's pretty obvious to everyone involved, whether you're getting a few days of lymphodepletion and a single dose of a cell therapy or repeat cycles of, say, Polivy or one of these other regimens.

So it is not possible to blind the study like this. In terms of the size of the study, we've looked at a number of different scenarios as we think about the performance of vispa-cel and the performance of the control arm. We've modeled endlessly, as you might imagine, at this point and have high confidence the 250-patient population gives us quite high power in a huge fraction of these scenarios to detect success.

Okay. Great. And I guess maybe we can talk about the November update just as kind of setting the stage for what we expect in the pivotal. You showed efficacy and durability that was actually on par with autologous CAR-T. And some of the conversations I was having after was like at this level of activity, why don't we just compare it against the auto CARs? I appreciate the unmet need and kind of the driver, and it might actually be faster to read out given the study or the setting you chose. But maybe you can just talk to the efficacy that you're seeing there and how that should hopefully translate to the pivotal?

Yes, your headline is exactly correct, sort of copy paste the auto CAR-Ts, whether you're looking at overall response rate, complete response rate or how durable these responses are. Really interestingly, what we saw in our Phase I data set is that if a patient achieves a response by the month 3 efficacy analysis, the likelihood that they remain in response is incredibly high.

There were very few patients who relapsed post 3 months. And so we're really excited next month at EHA to share an update that will be many additional months of follow-up, looking at these patients to get an even better picture of how durable some of these outcomes can be.

Okay. And obviously, the longest duration patient in the study, I think, is out to 3 years, and they're still in response.

As of that update, that's correct. Actually, the very first patient we ever treated who wasn't a second-line large B-cell lymphoma patient, so he doesn't fit in that cohort that we've been focused on. He's been in complete response for more than 4.5 years at this point.

Wow. And that's obviously auto CAR or better type of activity.

Exactly.

Maybe you could elaborate a little bit more on the EHA presentation. You've got an oral there that's in a couple of weeks. What do you hope to sort of gain from -- in terms of incremental on the follow-up? And how do you think you'll be able to position that data set to help recruit investigators for the pivotal?

Yes, it's a great question. And look, keep in mind, the way we've been thinking about developing vispa-cel is we want to see auto CAR-T like outcomes. And now we're planning for a pivotal study where the control arm is chemoimmunotherapy regimens with no curative potential and pretty rapid progression-free survival kinetics. And so we love the setup for this study, as I mentioned a few minutes ago.

And what we expect to see based on our historic data is what I'll call more of the same, continued evidence of how durable the responses are with vispa-cel following just a single dose. And so we think whether it's last year's PFS curve or what we might be able to put out later this year, any of those data sets are going to be incredibly attractive to this patient population because they don't have access to anything curative potential.

I think part of one of your earlier questions, Alec, was maybe getting at why not think about a head-to-head study against auto CAR-T. You might imagine, we thought about a lot of different development paths for vispa-cel and actually discussed many of them with the agency. There is a potential path forward to run a head-to-head study. You wouldn't need to show superiority.

You would simply need to demonstrate noninferiority. That's also a fairly large and therefore, fairly expensive and long study to run. And we saw such an opportunity to serve the lion's share of the second-line setting who is not getting auto CAR-T today with our study design in a way that is addressing unmet need right on the nose and is more capital efficient and time efficient.

I should say, based on the payer research that we've done and the KOL interactions that we've had to date, we expect on the other side of an approval that vispa-cel will be more broadly used than just the patients who would most appropriately fit the pivotal study.

Payers, for example, have shared with us an expectation that it'd be a fairly simple physician attestation to say patients is not going to get auto CAR-T, patients is not going to get auto transplant and they're off to the races with vispa-cel.

And that could be as simple as the patient can't or won't travel. They can't wait for the auto to be produced -- just simple things like that.

Exactly.

Okay. I guess when we think about logistics for enrolling the pivotal, is patient selection based on the criteria we mentioned easy to implement? What sort of training have you had to -- or are you putting in place for your investigators?

Yes, that's a great question. So we certainly want to collect the data on why any individual patient is being enrolled in the study. And in particular, is it because they are deemed medically ineligible? And if so, why versus are they access challenge, the real-world constraints, be they financial, geographic or insurance based.

I'll gloss over the medically ineligible criteria by saying they all sum up to can't wait, right? There's something about their disease biology that means it is not appropriate for them to sit around for 8 to 12 weeks. To wait for a dose of CAR-T, they need something now.

And so we are getting tremendous enthusiasm from sites both here in the U.S. and ex U.S. We expect this to be a global study to drive rapid enrollment. People are super excited about having something that looks and smells like an auto CAR-T, but is readily available off the shelf.

Okay. And we'll talk about the manufacturing next, but maybe one more question on kind of the site -- the complexion of the sites that you expect will open on the clinical study. Are these larger academic centers that have maybe already established their auto CAR infrastructure? Or is it the vast majority of the country where these capabilities haven't been built out, but there's a strong desire to have a cell therapy option.

Yes and yes. So we're aiming for, let's call it, a 50-50 mix here in the U.S. between top-tier academic institutes that have ready access to auto CAR-Ts as well as these sophisticated community hospitals who, for a variety of reasons, are unable to stand up auto CAR-T practices, but are using bispecifics today.

And I highlight that because the care approach necessary to serve patients with a bispecific is exactly what you need for an allo CAR-T, right? It's the same AEs. It's the same monitoring. It's very similar SOPs. And in many ways, it's actually easier for these sites to deliver an allo CAR because it's a single dose compared with the bispecifics where it's repeat dosing, and therefore, you have these very prolonged periods of time where those bispecific patients need to be monitored for AEs and in particular, address the infection challenges that they face over a long period of time.

Okay. That makes sense. And maybe talking about the ease of manufacturing. This is something you guys have obviously been optimizing over the past several years. COGS seem very low, a fraction of the price of an auto, obviously, which is quite expensive and laborious to make.

So it's more like a drug than a cell therapy like your analogy with the bispecifics. I guess how does the cost structure change the commercial case? And maybe if you could just add a point on kind of how you're positioning the antigen makeup within the batches for patients?

Yes, absolutely. Look, the supply strategy for vispa-cel makes it incredibly compelling commercial case for this program. This is not the very expensive end of one bespoke strategy that people are used to when they think of cell therapy. To your point, this truly looks like a drug that anyone here at the Bank of America conference would recognize in their businesses.

We anticipate cost of goods sold at launch to be 96% lower than the auto CAR-Ts. And so it creates just tremendous opportunity as we think about building that business. You highlighted kind of a key piece of our biological strategy here, which is based on a learning that we've come to over the past few years that very modest HLA matching between patient and donor helps drive these auto CAR-T-like outcomes.

So very quickly, there are two different classes of HLA, 12 different alleles total. And we found that matching any 2 out of the 12 helps drive those auto CAR-T-like outcomes. And so we can solve for this on the supply side without restricting patient access to vispa-cel.

For example, here in the U.S., based on our modeling, we only need about 10 different lots from 10 different donors to be able to serve 99% of lymphoma patients with a 2-plus match product. And actually, to get that long tail into the 2-plus category, our average match in the U.S. will be something like 7 alleles.

That's great. So definitely scalable, way more scalable than auto.

Yes, tremendously so.

I want to shift gears and talk about CB-011. This is your anti-BCMA allogeneic CAR-T for multiple myeloma, slightly different complexion in terms of what you would be comparing yourself against maybe more bispecific heavy in multiple myeloma. You also have an oral presentation for this asset at EHA. But maybe you could just speak to what you're seeing in the dose escalation and sort of what we'll be expecting at the conference?

Yes, absolutely. And I'll start with the benchmark for success, which is exactly as you highlighted, the bispecifics, right? For years, as we talk to myeloma physicians, they uniformly point us to the bispecifics and say they'd love to see an allo CAR-T that could at least drive responses on par with the bispecifics because then they pick that one and done every day of the week over the repeat treatment burden and the long-term infection challenge that bispecific patients face.

So that was really the goalpost that we had in mind as we've been developing this program for a few years. So at the end of last year, as you well know, Alec, we shared our first ever update, which was a pretty needy update. It was all 48 patients enrolled in dose escalation. One of the many decisions we made based on those data was the recommended dose for expansion, which is a single dose of 450 million CAR-T cells. And we had already enrolled 12 BCMA naive patients in that cohort in the recommended dose for expansion cohort.

And the response rates that we saw there far exceed those of the bispecifics and are actually approaching auto CAR-T-like outcomes. And so we're really excited to leverage some of the podium time at EHA next month to share an update on those patients. And we'll be really focused on the fact that many months have passed by. This will be a much longer follow-up on those patients because, of course, not only is response rate and depth of response important. And by the way, 91% of those patients achieved MRD-negativity that's really exciting, but also the duration of response.

And so we know this data set will allow us to tell that story.

We're also busy with that program. I'll say we are actively enrolling patients in dose expansion. We've committed to sharing dose expansion data by the end of this year. And though our update at the end of last year really focused on that BCMA naive cohort, we're now really trying to think about both sides of the BCMA equation.

We're continuing to enroll BCMA naive patients to continue building that data set. We're also enrolling post-BCMA patients. We know that's a large and rapidly growing patient population here in the U.S., and we're eager to understand what benefit CB-011 can provide for those patients.

Great. And maybe looking past EHA to the second half update from the dose expansion. I guess what would you want to see here to give you conviction that this is truly best-in-class? And at what point would you maybe approach the FDA to talk about a further study or even past the pivotal?

Yes, it's a great question. By building data sets in both BCMA naive and BCMA exposed patients, we're really maximizing optionality as we think about the future development path for CB-011. I think these dose expansion data will be a key piece of the puzzle for making decisions about how to prioritize our resources as we continue developing the program.

And we were so excited that just recently, the FDA granted RMAT designation to this program. So it actually gives us the opportunity to engage earlier and more proactively with the agency. So we expect to engage with them later this year. And ideally, we'd be in a position where we're not only providing that dose expansion data update, but also providing some guidance that we're hearing from the FDA about how to leverage these data learnings for next steps for the development of the program.

Okay. Great. Is there an expectation from the dose escalation or maybe a bar in terms of activity that you're driving towards? And what's sort of the regulatory precedents for what a registrational endpoint looks like?

Yes, great question. So maybe starting with that dose escalation data set, what KOLs have told us for years is look like a bispecific. So what does that mean? The bispecifics have overall response rates in the kind of 60% to 70% range. We're well north of that with what we've seen so far. And then how about PFS? And what we've largely heard from KOLs is they'd love to see median PFS somewhere in that 12- to 15-month range.

So I think that's an important benchmark for those BCMA-naive patients. Probably stay tuned as we think about how best to articulate the goalpost for post-BCMA patients. Those are obviously even higher unmet need in higher-risk patients. And so we think there's a lot of opportunity for a healthy donor T cell product for those patients.

In terms of the pivotal path, like I said, I think there's a lot of optionality as we think about the development strategy. I almost worry we're a little bit kid in a candy store right now with where you could go with CB-011 kind of on one end of the spectrum would be an initial strategy into a fairly large patient population, running a traditional randomized controlled trial and thinking about how best to sequence that versus there might be some pretty straightforward capital-efficient, faster paths that even could be a single-arm trial, for example, in some of these post-BCMA patients or other well-defined patient populations where we think CB-011 could have a lot of benefit.

Okay. And just thinking about the cadence of enrollment for the BCMA naive versus the BCMA exposed. Are you seeing any difference in terms of the enrollment rate from either of those populations? Just thinking about the information that we will gain from the expansion.

Yes, that's a great question. I'd say our expectation is to be able to read out a bigger data set on BCMA naive than where we left at the end of last year with our dose escalation and to have enough patients in the post-BCMA cohort to say something meaningful about that, too, right?

We'll be leveraging those data to help drive those decisions. Will it be the exact same numbers between those two cohorts? Time will tell. But I think enough patients to drive these learnings and decisions is our objective, and I think we're on path to do that.

Okay. And just thinking about what you want to keep for yourselves versus potentially partner out, especially thinking about larger like a head-to-head study against bispecifics and multiple myeloma, for example. Do you have like a preference within the pipeline for what you want to kind of -- or what you feel like is reasonable for you to push forward on your own versus what you think you can maybe drive the most value through a partnership?

Yes. I'll tell you what's on my whiteboard, but I'll readily acknowledge it takes two to tango, right? And so there might be very different opportunities that present themselves in the future to us. But our objective right now is to develop vispa-cel on our own.

We believe we can be the company that pushes vispa-cel across the finish line from a regulatory perspective and could launch vispa-cel here in the United States. To your point, as we think about multiple myeloma, we feel that is a disease area that is really ripe for partnership as we think about simply how large the unmet need is and how significant the commercial opportunity is.

Okay. And I guess your guided cash runway, I think, is second half '27, which carries you through the start of the pivotal for CB-010. How do you sort of see that runway or the optionality within the pipeline to extend that?

Yes. So our balance sheet today fully funds the CB-011 dose expansion work that we were just talking about. So really excited to get to those data later this year. And it funds our ability to kind of get started, do some of the important start-up work for the ANTLER-3 pivotal trial. It does not fully fund the company through the readout for that study. So we will need to raise additional capital to do that work.

Okay. And definitely having the RMAT for CB-011, like even having that feedback from the regulator in hand, like I imagine that's valuable to your partnership discussion?

Absolutely.

As well. Maybe just in the last minute or so, just so we've got a nice checklist for what to be looking for from Caribou over the next 12 months, if you could run down like the updated catalyst calendar for you guys, that would be great.

Yes, absolutely. Look, come and see us in Stockholm. We're excited to see both vispa-cel and CB-011 on the podium at EHA next month. And then with respect to CB-011, as we've been talking about, we've also guided to dose expansion data by the end of this year. So I think a rich series of data updates for both programs.

Okay. Do you think we'll be getting updates on manufacturing to or like nonclinical updates to be looking at it for?

Yes, that's a great question. We've also taken some time already this year to tell the translational story behind both of our programs. We think there's a lot that we've learned that continues to really support why we've seen such differentiated clinical outcomes driven by kind of the unique edits and the biology of our healthy donor allogeneic CAR-T cells.

From a manufacturing perspective, we are fully scaled. We are at a commercial scale for vispa-cel already. And so really excited that we're there, sort of check box on that one and leveraging that for manufacturing for a pivotal study as well.

Okay. Great. Well, I think with that, we're out of time. So we'll have to leave it there. But thank you, Rachel, for the great conversation, and thanks, everyone, for attending.

Thanks, Alec.

Thank you.

Hopefully, the audio is coming through clear. I'm hosting the Caribou Biosciences team this morning. I've got Tina and Sri. And how are you guys doing? And how is Miami treating you?

Good. It's nice to be in the sunshine. Thank you.

Thanks for having us.

Well, a pleasure. Before we go diving into Q&A, let's have a quick update on where we are on data throughout this year for the pipeline. And then separately, we'll start chatting events, funding strategy, et cetera. But let's sort of get a sense let's reset the table in terms of catalysts for the year.

Sure. As you know, we put out clinical data in November for both vispa-cel and for CB-011. And this year, it's another busy year for Caribou. We're going to have additional follow-up from the vispa-cel data set in 2026. like we had a medical meeting. We initiated dose expansion for CB-011 late last year. We'll have both follow-up from the dose escalation data we put out in November as well as additional data from dose expansion that we just initiated. So look for those in 2026.

Okay. Let's talk a little bit about -- no problem. A little bit of technical staff. Let's talk a little bit about how you think about financing strategy and how that aligns with execution time lines, pivotal design, et cetera, which I guess is a question for you, Tina.

Let me start, yes, with the plans for the pivotal trial. Right now, we are in discussions with the FDA to finalize the design on a Phase III randomized controlled trial with vispa-cel against standard of care in second-line large B-cell lymphoma in patients that aren't eligible for transplant or auto CAR-T cells. And so this allows us to do a randomized controlled trial of about 250 patients with the PFS endpoint. And we are in final discussions around the statistical design of the patient and the control arm. And so that will be coming in the first half of this year.

And then I'm going to hand it over to Sri about how that will lead to our financing efforts that will be required to run that trial.

Yes. So as Tina noted, those discussions are ongoing. And really to initiate the pivotal trial, there are 2 things that have to happen. One is conclusion of the discussions with the FDA on the pivotal trial design and then securing sufficient capital to fully fund the study through data readout. Now we don't have to have all that capital on our balance sheet the day we start the study, but we need to have line of sight to that capital to say we're fully funded through data readout.

And we expect that after we have concluded our discussions with the FDA, that would enable us to have those discussions with potential investors and funders of the trial. Now we're thinking about funding across multiple different options. Equity capital markets are certainly one source of that, but also looking at potential business development and other, I'd say, more structured types of financings, nondilutive sources of capital as well. We want to be very thoughtful about how we fully fund this program.

Let's talk a little bit about some of those partnership BD nondilutive sort of approaches. How do you think about where we are in terms of market demand for partnerships and assets like this as the company is now on the other side of Pfizer's negotiation right of negotiation. How do we think about where demand is for these assets? And who would be the right partner? Like what profile of the company? I'm not asking you to name a name and restrict everybody.

I think a couple of things. One, the time line for business development is something that not fully within our control, certainly. So as we think about how we fund the clinical trial, certainly, that is an option, but it's not, I'd say, the base case to fund our pivotal trial just because of the timing component of it, it takes significant amount of time from not just Caribou, but also potential partner on the other side.

And on types of partners, I'd say there are a couple of different classes. One are groups that are in cell therapy today that believe in the technology have made investment there and understand what we're doing with allogeneic cell therapy and the potential access benefits. And then there are other pharma companies that aren't in the space that we offer significant advantages with vispa-cel that look very different from traditional cell therapy.

We've talked to you before about cost of goods being one of those, right? So vispa-cel cost of goods are anticipated to be 96% lower than auto CAR-Ts. That looks more like a drug or something you can build a business around. And there are companies out there that have not gotten into cell therapy out of concerns about the economics there where a drug like vispa-cel could make much more sense given those dynamics.

So let's talk about the economics of this business. I think one of the challenges that cell therapy has faced, both fundamentally in the physical world, but also in sentiment in the minds of investors are concerns around cash generation, margin profile, distribution, timing, combination of issues that all add up to how quickly can this business become an attractive business. Talk about how that has evolved in your conversations and also a little bit where you are in terms of moving out of the most challenging segments of that business model out towards community, out towards outpatient, et cetera.

You want to talk about that part?

Sure. Let me talk about the specific -- the clinical part first. What we've been able to do with an off-the-shelf allo CAR-T cell is get immediately a cell therapy to patients. And this can -- this is needed at academic centers as well as community centers. So we're doing our ANTLER trial at academic centers. So we're enrolling patients that can't wait for auto CAR-T cells or they don't have enough their own T cells to make an autologous product. So the demand is there.

There are patients that cannot wait or cannot access auto CAR-T, and we think it's about 75% to 80% of patients. And a lot of those patients are being referred into these academic centers, but then can't wait the 2 to 3 months it requires. And even if those academic centers have something immediately available, what we know from our ANTLER trial and what we hear from other sites that we're talking to is then they'd have something immediately available. That patient wouldn't have to wait those -- or those 4, 8, 12 weeks to get their autologous CAR-T cells.

And so once something like this is out in the market, we think there's a lot of demand, both at the academic centers for the patients that are getting referred. But of course, we're also talking with these sophisticated community centers that haven't yet invested in the infrastructure needed for CAR-T cells because of the complexity of the manufacturing of auto. And so when they hear we have something that we can just ship on demand and they can start lymphodepletion and infuse immediately, that's something, as Sri mentioned, they're used to doing. They have infusion centers. They have the hospitals that can care for these patients if they have toxicities.

And so a lot of these centers, many of them who are taking up bispecifics already are ready to start thinking about taking on an allogeneic CAR-T cell. And so those are really the 2 sectors clinically that will allow us to get to more patients at the academic centers who already are comfortable with CAR-T cells and these sophisticated community centers that are now getting more and more comfortable with bispecifics, cytokine release syndrome and are ready to have a one-and-done allogeneic CAR-T cell in their armamentarium.

So I want to touch base on the complementary side of that, which is the product side. And where -- what you guys have disclosed and how we should think about building on a donor base, what an appropriate donor base would look like here globally, et cetera, to supply the broad universe of all possible patients. And operationally, what that looks like in terms of accumulating an adequate supply for any hypothetical future launch?

It's a great question. And right now, as we prepare for pivotal trial, we think we need about 10 lots. So 10 different donors, 10 lots to get enough doses to match all of our patients, 250 patients in the trial at 2 or more HLA match with an average match of 7. And we think that this would supply the U.S. population. So we get -- we can get 200 to 300 doses per lot. So this is thousands of doses that will be ready for the pivotal trial. There's only 9,000 probably patients in second-line large B-cell lymphoma. So you can imagine we don't need many more lots for launching into that indication in the U.S.

We're already starting to look at HLA diversity and what we would need in the freezer to supply anyone on-demand in other regions. We think it would just take other lots supplementing our diversity in the freezer to go outside of the United States. And we're just starting those efforts, especially as we're starting to think about the global clinical trial, but also, as you mentioned, out into the land of possible.

We think with one manufacture -- well, we know with one manufacturing suite in the United States, we can generate 9,000 doses a year. And as I mentioned, that would supply the U.S. for a whole year if we had 100% of patients being treated. So you can imagine we can scale as we would need to, both for the U.S. in different indications as well as ex U.S. with very small footprint.

Just to know that one suite I talked about is only 500 square feet. It's at a U.S. CDMO and the process we have today is commercial ready. So we're going to have batches ready to go when we start the pivotal trial for a process that we believe is already commercial ready.

And let's talk a little bit about moving back to the pivotal trial. Obviously, one of the questions is what's the right site selection. We've seen site selection and investigator experience be really important in terms of execution of trials. This has been -- I think the most extreme example of that was Allogene. I'm dating myself not 4 years ago, with an off-trial administration of drug, which obviously create challenges there.

I think we're all around for that, not mean to name check anybody. But obviously, how do you think about site selection U.S. and globally and what the right patient population is to reflect the most commercially viable label and the extent to which that patient population in the pivotal translates into label discussions, which in this case is a little more delicate because you've got a standard of care that exists. This isn't a blue ocean with no approved therapies.

In second-line large B-cell lymphoma, patients who are not eligible for autologous CAR-T cells and are not transplant eligible, there's actually not a standard of care, which is why we are negotiating with the agency a control arm of immunochemotherapy possibilities, things like Pola-BR and other immunochemotherapy. Because these patients can't access the standard of care, as you mentioned, and as I already mentioned when we were talking about access eventually to this drug, even for the clinical trial, our big academic centers have these patients that aren't transplant eligible and can't wait or can't either socially or medically can't wait the months it takes to auto CAR-T.

So we will have U.S. academic centers enrolling our pivotal trial, but we also have the opportunity to expand out into these sophisticated centers that are, as I mentioned, doing bispecifics. And so we, as Caribou, will be evaluating each of these sophisticated community sites to make sure they have all of the things required for infusions, toxicity management, getting all the algorithms in place really as a way of showing we can do this on launch as well. So our pivotal trial will be the chance we get to expand out into the community centers, find the physician groups that are willing to have the CAR-T cell teams that will be required with the support of the hospitals behind them to run the trial.

And then, of course, clinical trial requires a lot of other infrastructure that's not required for CAR-T cells. So it will be a subset then of what's eventually going to be able of these community centers that could do it in a commercial setting. So that's the United States.

When we think globally, the autologous CAR-T ineligible and transplant ineligible population, we need to go to countries that also have an aspect of access challenges. So these have to be countries that have autologous CAR-T cells so that they'll be relevant to the United States and the FDA when those data are reviewed. And so we're looking at countries that have access to auto CAR-T. Therefore, these sites also have experience with cell therapies. They have the systems in place, but they can't get them to all their patients and also are looking for an off-the-shelf readily available CAR-T.

And in the U.S., a lot of the community sites, Tina talked about that we're targeting are administering bispecifics today. So they're equipped to deal with a lot of the toxicity events that arise from this class of therapies.

So you've talked about standard of care and access. And in the real world, the existence of a standard of care and being able to access therapy collapse to the same thing from a patient perspective. If you can't get the care, it's clearly not standard. That hasn't always been the view of the agency. And obviously, decisions around control arms have become contentious, I may make a politic statement. Where -- what is the state of your conversations with the FDA around the extent to which a control arm should be standard of care as defined by best possible data in sort of a photonic sense, capital P or standard of care being determined by what's accessible to patients in the real world financially and based upon distribution systems? Like how does -- how is the agency defined what they call standard of care in the context that will eventually be a registrational review?

It's a great question, though, we're continuing to have those conversations, things like Pola-BR are on the list of things that they're willing to accept as a control arm. I can't necessarily speak to where we're going to end up finally, but we're confident that immunochemotherapy will be the standard general type of therapy in the control arm. And clearly, these patients are auto CAR-T ineligible. So those -- that standard of care will not be required for the control arm.

And let's talk a little bit about your state of your discussion with the agency. Obviously, there have been -- and this is a conversation I've had with, I think, now 15 different companies over the course of less than a day. Let's talk about how your conversations have changed or not changed at the agency? How much stability have you had in terms of counterparties in your particular review process? And have you seen any changes in terms of capacity resources, et cetera? Obviously, the agency has gone through a volatile period of a couple of years.

So vispa-cel has RMAT. So we have had regular access and frequent access to the FDA over the last couple of years as we've discussed paths forward. Our team has been quite stable, our review team. It does take a very official process to talk about every issue, which is why I think it takes all these cycles of interactions that perhaps takes longer now than it used to. But we have had very, very productive interactions with the agency and are continuing to have very productive and we're confident that we will soon get to those final discussions for the pivotal trial.

And can you remind me on the time line for the discussions and the venue which we should expect to hear feedback from you guys?

Yes. We haven't put out specific guidance on timing other than to say our goal is to initiate the pivotal trial later this year. And in order for that to happen, we need to come to conclusion with the FDA here before that.

I'm going to hop off this topic. So obviously, the company has generated some internal data in myeloma. You've looked at autoimmune applications, et cetera. Talk about opportunity set to monetize that data that's in-house and to find a new home for that data either internally dependent upon financing resources, but also externally to allow that data to find itself -- to find a place to monetize and move forward to benefit patients. Like how do you think about the value of those resources and where that data -- that data set that's in-house can go?

I think CB-011 is a great example. We put out data in November on a robust data set of 48 patients worth of data that have been treated at different dose levels, including 12 at a recommended dose for expansion, very strong initial data. The next phase there was an expansion cohort, which we have the resources to run and have initiated and expect that data later this year. And in parallel to that, we're looking to have our first discussions with the FDA on the regulatory path for CB-011.

So the combination of longer follow-up from the data we put out last year plus additional patients where we're looking at both prior BCMA exposed and BCMA naive patients and the regulatory piece could all come together and potentially lend itself well to partnering discussions.

Do you want to comment on autoimmune?

Yes. With vispa-cel, I mean, I think we're even more excited than we were before on the activity of vispa-cel and its opportunity in autoimmune. Obviously, right now, we do not have an active program in autoimmune, but we still do have an active IND. So as we get that program moving forward, I think we would be very interested either internally or with an external party to go back into autoimmune since we know CD19 CAR-T cells can really benefit patients in that situation.

It sounds like that's something that you would -- you see primarily as a partnerable asset rather than something you move it internally? Or am I -- is that the wrong way to think about it?

As I mentioned, we have an open IND. I think as we look at life cycle management of vispa-cel, we're going to start weighing those opportunities. I think it's a big opportunity, obviously. And so as we think about our resources and where we allocate them, I think we will very seriously be thinking about what the next steps would be when we have the capital to do so.

Perfect. And I don't want to gloss over CB-011 that you brought up. I just slid right past, so apology there. Let's talk a little bit about that data and to clarify to what extent Caribou has control over that asset completely or if there are any information -- are there any residual information rights that are retained by Pfizer within the constraints of what you guys have disclosed, obviously?

Yes, we have control over that asset. Pfizer sort of a friend at the table. They have information rights where we share updates on the program and a right of first negotiation, which expires later this year. So that is a program that's wholly owned by Caribou.

Great. So we've talked a little bit about the CB-011 corporate structure. We've talked about the sort of the ANTLER study, pivotal, et cetera. Let's zoom forward to on the other side of pivotal data and sort of how to commercialize an asset like this globally. Obviously, we've talked about the U.S. opportunity. I presume that when you look out globally that you will need local manufacturing facilities elsewhere because you may need a little bit of a donor mix depending on the population by country? I know we talked about this earlier. Is it reasonable to assume that that's something that will land with an in-country partner in places like Japan, Europe, et cetera?

I think we would need depots there for supply for ready access when the patient is ready in some of these regions, we would probably want to supply depot. I think the actual manufacturing, we haven't talked a lot about this. So -- but when we get to that situation, as Sri mentioned, it's a very small footprint in our CDMO that can generate thousands and thousands of doses. So I imagine we would scale locally in the U.S. and then just ship our supply elsewhere.

As I mentioned, it doesn't take very many donors to diversify the HLA. So it might be that we need a handful of patients of different HLA diversity to fill in gaps that would help us go globally into certain regions. And so I imagine we would supply those -- we would generate those ourselves and have supply depots, that's future speed.

And then on the commercialization piece, we see ourselves as being able to commercialize vispa-cel in the U.S., but you're right, ex U.S., I think the path there will go through partners. And then on myeloma. Myeloma is a much bigger commercial opportunity, as you know, which is why we think that's right for partnership as well. And -- but I think if we're on the other side of pivotal data and we've got options for ex U.S. partners, but looking at myeloma, that opens the door for some of your prior questions on other indications or the life cycle management.

That makes sense to me. And I think I want to touch on something that I continue to get questions from investors. I guess, an accent to the last question, which is not just the local manufacturing and how to think about the depot dynamic. But how much HLA variability is there globally in terms of what you would need for a product to treat patient populations in places like China, Japan, et cetera, that have a different ethnicity mix. Does that translate to the HLA matching dynamic needing to be a different product or simply a subtly tweaked manufacturing process? Will CB-010 be the same product in different geographies? Or can it be? I guess, is the underlying question.

It's a great question. I think we're starting to evaluate that HLA diversity. As we talk about -- talk to the regulators in those countries, I think we may get that answer and that would probably need to do further evaluation. As we mentioned, the COGS here are quite low. So the ability to have another 10 batches for different regions is something that's quite achievable. So I do believe this would likely be the same product despite different regions. But again, we would have to talk with the regulators about that in the future.

Great. That makes sense to me. And I think we've hit on the key points. Obviously, we're running out of time here. Thank you so much. I'm looking forward to seeing more of this data and moving forward to pivotal.

So are we. Thank you for having us.

Thank you, Mani.

Thanks, guys.

All right. I thank everybody for joining us. We've got Tina and Rachel here from Caribou with us this morning. Thank you so much for coming down to Miami for the conference.

Thanks for having us.

Thank you.

Awesome. Let's -- obviously, we've got 2 main programs to talk about. We'll try and get through everything I want to get through in 20 minutes. I think I sent you a list of questions that would easily take us an hour. But let's start with CD19 with vispa-cel. Walk us through the recent update. What are you most proud of? And how does it set you up as we head to the future?

Yes. I'll hit a few highlights, and then I'll pass it to Tina for some of the key clinical details. I mean, look, we've been evaluating vispa-cel in the clinic for about 4.5 years now. And the clinical update that we provided last month allowed us to really plant a flag and say, we've got an allo, what looks like an auto. It's remarkable. I think it's fair to say that a lot of people, yourself included, were really skeptical whether an allo ever could look like an auto and recognize the potential of if you could accomplish that, what you could do for patients. And we've done that, and that's incredibly exciting. And Tina, I'll let you talk about what that looks like and maybe where we're headed next as well.

Great. So last month, we were really able to show after treating 84 patients that in a subset of patients that are treated with young donor, partially HLA-matched vispa-cel that we see overall response rates, complete response rates and duration of response that are nearly identical to auto CAR-T. And as Rachel mentioned, with an off-the-shelf CAR-T cell, this really can change outcomes for patients since 75% of large cell B-cell lymphoma patients do not get auto CAR-T.

And so as we look at the data from these patients, we also see a safety profile with very low rates of cytokine release syndrome, very low rates of high-grade neurotoxicity, low rates of severe infections and what this means is a safety profile that's very much when you look at the auto CAR-T like liso-cel, which is the better tolerated product, which we know can be given in community centers and as an outpatient, but has really hit a wall due to logistics on getting out into the community centers to patients that need it. And so our strategy moving forward with outcomes -- efficacy outcomes like auto CAR-T, safety like liso-cel, it's really getting vispa-cel out into sophisticated community centers where patients choose not to go into the academic centers to get auto CAR-T.

And so our path forward with the FDA has been discussions around an auto CAR-T ineligible and an auto transplant ineligible population. And what this means, historically, in trials, when we look at who's done this before, the auto CAR-T ineligible patient population includes patients that have challenges with geography, insurance, manufacturing challenges in addition to patients that can't wait. Their disease is too aggressive. They can't make it the amount of time that it takes to refer or manufacture for auto CAR-T. And so when you look at this patient population that can't get a transplant or can't get auto CAR-T, it leaves you with a patient population that does not have curative options.

And so our plan moving forward is to do a pivotal trial in this dual ineligible population randomized against immunochemotherapy truly does not have curative intent. And so this will allow us to do approximately 250-patient randomized controlled trial with a PFS endpoint that really has a high rate of -- or high chance of technical success because as we showed in our data, we have this nice plateau, much like the auto CAR-T when we look at our durability of outcomes and responses where patients after they get 3 months -- 3 to 6 months out after vispa-cel, there's really a very, very low rate of relapse, whereas immunochemotherapy patients continue to relapse over time.

So we have a randomized controlled trial opportunity against a noncurative agent that we're really excited should result in a high chance of technical success and really be able to get this off-the-shelf allo CAR-T to more patients.

Excellent. All right. Well, lots to unpack in there. Let's start with the beginning maybe. Rachel, you mentioned you've been working on this for 4 years, 5 years. Tina, you mentioned the qualifications on the allo nature of the product, young donor cells, partially HLA match. Obviously, it took you a little bit to find this. So can we talk about how you've been able to succeed or maybe I should say, Rachel, to match auto data where previous allos have had a lot of trouble. What's driving the delta there? And how important was the -- all of those qualifications that we just talked about compared to some that [ think ] were fundamental to the platform?

I think there are key parts of the story, but they're not the only elements of the story. I also think the construct itself is differentiated in unique ways that I believe are really important to the clinical success we've seen. In particular, we use our CRISPR technology, what we call the chRDNA technology to knock out PD-1 from the vispa-cel T cells. This is intended to prevent premature CAR-T cell exhaustion. We did this because we know these allo CAR-Ts are going to be rejected by the patient's immune system.

Our PK data indicate they persist for about 30 days. So you want them to have as much antitumor punch as possible during those 30 days, and we think that's a key part to the success. The other key part is exactly what you've highlighted, these critical clinical learnings. We've built a database of more than 140 patients, we've treated with multiple different allo CAR-Ts across our different studies. We have one of the largest allo CAR-T clinical data sets, and it's led us understand these different factors and how to put them together along with the differentiated construct to see auto CAR T-like outcomes.

Excellent. Let's -- since you mentioned the PD-1 knockout, that's something that I've been very curious about. Obviously, in preclinical data, you can see that it has effects on T-cell exhaustion on T-cell efficacy, especially at longer time points. It's hard to pick these signals out in a clinical population. Obviously, there's so much else going on. Is it possible to assign a proportion of your effect to that? How big an impact is it really having in a patient with a complicated disease course?

That's a fair question with no possible direct answer. I can point to some of our historic mouse preclinical data because that is where we can run some of these pure experiments where we could make vispa-cel of 2 flavors, right, vispa-cel as we know it, and vispa-cel without PD-1 knocked out and could deliver equivalent doses to mice with equivalent significant tumor burden and just watch and see what happens. And what was really interesting is in the early days, both animal cohorts had very similar responses. It appeared via imaging that their tumors were just completely eradicated.

But then over time, the 2 cohorts bifurcated dramatically. The cohort that had been treated with the PD-1 expressing version of vispa-cel, their tumors rebounded and they all had recurrent cancer. In contrast, the ones that actually got vispa-cel as we know it, the majority never saw their tumors return. The PK was the same. There was no difference in PK between the 2. But it tells you that there was a key difference in the underlying biology, which we think was vispa-cel driving better initial tumor debulking that was actually driving these longer-term outcomes. We have no way to run that experiment in humans, but Tina, would love to hear how you think about this.

Yes. I think the only thing I'll add is when you look at outcomes of auto CAR-T, patients who have lymphoma that express PD-L1, they don't do as well as those -- which is part of the reason we genetically engineered vispa-cel in this way. So not only is there kind of an inherent T-cell activation pathway that makes it more potent, but in certain patients, even more -- that's even more necessary.

Maybe then let's turn to the Phase III design. There's a couple of things that we should definitely touch on here. First and foremost, what's required to get a competitive label in this CAR ineligible population? It seems like the barrier here is relatively low. But dovetailing with what you said earlier, Tina, how can you ensure that, that ineligible label truly captures patients who are medically eligible but don't pursue treatment for other reasons and especially the breadth of other reasons that are holding people back?

Yes. It's a great question, and it really gets to there's a regulatory discussion around defining a population that the regulators will allow us to treat and test in a trial and then what happens in the real world. We anticipate with this trial that the label will simply be auto CAR-T ineligible and auto transplant ineligible. We have had initial discussions with the payers. And for a physician ordering vispa-cel, it's likely going to be a check box. Yes, they're auto CAR-T ineligible. Yes, they're CAR-T -- transplant ineligible. For -- depending on what's in the label will have our inclusion criteria.

We do anticipate, as I mentioned, that geography, insurance, other manufacturing challenges, which are more logistical will be a large part of the definition of auto CAR-T ineligible. So right now, we don't see any barriers. And in fact, when we talk to the providers out in these sophisticated community centers that are struggling to get their patients to go to academic centers, this is the kind of agent they want for patients that -- by that definition.

And certainly, they want to be able to treat the patients themselves.

Absolutely.

So can we talk then about those sophisticated centers and about the bulk of the population, which is being treated in these regional centers. What proportion of the 70% or 80% of patients that are not getting CAR-T are ineligible for each of these various reasons?

It's a great question. I think people are just starting to dig into those. I think at ASH, we'll hear actually some nice presentations around the access challenge. And so I don't have all of that granularity yet. I think in a week, I might be able to answer your question a little bit better, but we're...

We'll be back in a week.

Collaborating with some of these folks. But I think it is a large percentage of patients. When we talk to these sophisticated community docs, I say half their patients just refuse to travel. They want them to go get a curative option, and they're stuck giving them our chemo. And so if we can get them access, which they believe they can give, they have sophisticated hospitals with ICUs, infectious disease docs, neurology docs and a group of colleagues that are willing to be the care team 24/7 for the first week or 2 of these patients, and they're committed to doing that for their patients.

And Jon, I should say, as we look at both academic sites and the community, we think about half of the second-line setting are patients who are dual ineligible, ineligible for both transplant and auto CAR-T. So we're talking about a very meaningful fraction of the second-line setting that could be appropriate for the study.

Makes sense. And expanding beyond that, that would be appropriate for the study. But if you get a label that says dual ineligible, then the implication here is that there are a fair number of patients who are going to show -- who might not show up in the study, but who would show up in the commercial...

Correct. And I think who right off the bat would be obvious potential beneficiaries of vispa-cel. I'll also point to what's happening in the real world in the second-line setting. So as Tina mentioned, only about 25% of patients get auto CAR-Ts, but that is the gold standard. So what's happening with the other 75%? Actually, a pretty good fraction are getting bi-specific antibodies which, by the way, are not approved in the second-line setting, but I think demonstrate that physicians are being creative in using discretion to bring the best agents they can for the patients who are not benefiting from cell therapy. So said another way, those same physicians are telling us they think there would be important physician discretion in the utilization of vispa-cel in the future as well.

Excellent. Let's move to the BCMA program, CB-011. You've always framed myeloma as being a competition -- allo product being in competition with bispecifics. I think I've always pushed back against that with you. But given the data set that we've seen, how are you thinking now about competitiveness versus an auto CAR product?

Not changing the goalposts. We still think the bispecifics are the goalpost as the base case for a compelling product opportunity, right? And it's really built on an understanding of this very large myeloma patient population and the fact that access there is actually even worse than access in myeloma -- in lymphoma. Only about 10% of myeloma patients are getting auto CAR-Ts. So yes, we think CB-011 could do a lot to broaden that footprint, and that's obviously a key piece of the story. But what we continue to hear from physicians is they love to see an allo CAR-T that's got efficacy at least as good as the bispecifics. By the way, they're not complaining that it's more. And they see so much value in that one and done off-the-shelf over the very high treatment burden associated with the bispecifics.

Yes. We certainly heard that from all the docs that we've spoken to, the treatment-free interval, lack of long duration infection risk is a huge driver. But in that context, all of the auto CAR-T players are doing their level best to make inroads into community centers as well. If established and emerging auto CAR players are successful in that, how does it change the bar?

I think if you look at lymphoma, which is a space where the auto CAR-Ts are a few years ahead in terms of their development and maturity, those players have invested dramatically in trying to move into the community and very little has happened, right? There are a lot of really fundamental barriers to having the sophisticated care model necessary in the community setting. And so sitting here today, I think there are single-digit numbers of community sites that offer these kinds of auto CAR-T cell therapies, and that's after many years of trying. So I think it's probably a low likelihood that, that changes dramatically anytime soon. And so as I think about the future of CB-011, maybe there's a role for it to play in the community setting, too, as we think about tackling that severe access challenge.

As we head into more cohorts from this study next year, what are the key metrics that you're looking forward to sharing with us?

So we will be expanding 450 million cell cohort out to approximately 30 patients. And so what that will give us is just a better estimate of our overall response rate, the deepness of remission, so complete remission stringent CR and of course, what's most important for myeloma, the MRD negativity rate. And so this will give us just more confidence in the data. It will also give us longer follow-up of these 12 patients that we reported on. And so we should get into that couple of year for some of the patients and over a year for all of the patients. And when we look at outcomes such as bispecifics that we're comparing to really is these median PFS is up in the 15-month range that we really need to show.

I mean you say over a year for all the patients in the cohort and...

In the current cohort, correct. And then early data, so these next 18, let's say, what we will have is depth of response, MRD negativity and then for the 12 that we have right now, longer follow-up.

But we shouldn't be expecting proper PFS studies for quite a while given the length of durability for some of these cohort for an auto CAR.

For this cohort, correct. We do have at a number of different dose levels, long-term responders that I think we will -- this is a Phase I study. So we'll have to translate what the MRD negativity and depth of response means for longer-term outcomes because we will likely be making development decisions on these data and talking to the FDA about next steps this coming year as well.

Okay. Now especially in myeloma, I want to make sure we talk about some of the other emerging competitors in the allo space. There are other allo CAR products and in vivo CAR products that seem to be rapidly advancing here. How should we think about the setup there and the potential competition?

I think for auto CAR-T, I think they are fighting for the same 10%, 15% of patients. So we don't necessarily think of them as our competitor. I think in vivo CAR, they are handfuls of patients right now. They have a long road ahead of them and especially with safety and regulatory path, it's uncertain how that's going to move forward. It's certainly exciting technology, but it's years behind allo CAR-T at this point.

And maybe I'll just add. I think allo CAR-T has really interesting kind of in the middle positioning. So both auto CAR-T and in vivo necessitate the cancer patients' T cells to do the heavy lifting. That works great for some. It works terribly for others. And so regardless of those 2 platforms, I think there will continue to be a role for allo CAR-T, especially for those patients who need the healthy donor T cell product to have an anticancer response.

That makes sense. In our last few seconds, we'll talk a little bit about commercial readiness. Can you walk us through logistics of an allo product, but your product, in particular, cost to produce, the cost or challenge of getting partial HLA matching and all of those logistics concerns that we've mentioned being a driver of access challenges for the auto product.

Yes. Look, this is one of the most exciting parts of the vispa-cel story, right? Auto CAR-Ts are inherently an end of one bespoke one-off for each patient. For vispa-cel, it's a drug. We manufacture it. We stockpile it in the freezer. It is immediately available the moment the patient needs it. In fact, we've had patients confirm eligibility and start treatment the very same day. We already have a commercial-ready scale process. It gives us enough cells for 200 to 300 doses per batch. And to do our HLA matching, we only need about 10 batches in the freezer at the start of our pivotal to do 2-plus matching for 98% of patients. And by the way, that's COGS that should be 96% lower than the auto CAR-Ts at launch. Very exciting.

Awesome. All right. Well, well out of time. But thank you so much, Rachel and Tina, for joining us, and I hope you have a wonderful conference.

Thanks, Jon.

Thank you.