Caribou Biosciences, Inc. ($CRBU)

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.