Caribou Biosciences, Inc. ($CRBU)

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.