All right. Thank you, everybody, for joining us. We have 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 two 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. Let's start with CD19, with Vispa-cel. Walk us through the recent update. What are you most proud of, and how does this set you up as we head into the future?
Yeah, 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 four and a half 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 that 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. We've done that, and that's incredibly exciting. Tina, I'll let you talk about what that looks like and maybe where we're headed next as well.
Great. 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, we see overall response rates, complete response rates, and duration of response that are nearly identical to auto CAR-T. 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.
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. What this means is a safety profile that's very much, when you look at the auto CAR-T, like Lysosel, 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.
Our strategy moving forward with efficacy outcomes like auto CAR-T, safety like Lysosel, is really getting Vispa-cel out into sophisticated community centers where patients choose not to go into the academic centers to get auto CAR-T. Our path forward with the FDA has been discussions around an auto CAR-T ineligible and an auto transplant ineligible population. 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. 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. Our plan moving forward is to do a pivotal trial in this dual ineligible population randomized against immunochemotherapy. It truly does not have curative intent. This will allow us to do approximately 250 patient randomized control trial with a PFS endpoint that really has a 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 three to six months out after Vispa-cel, there's really a very, very low rate of relapse, whereas in immunochemotherapy, patients continue to relapse over time. We have a randomized control trial opportunity against a non-curative 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 auto CAR-T to more patients.
Excellent. All right. Lots to unpack in there. Let's start a little at the beginning, maybe. Rachel, you mentioned you've been working on this for four years, five years. Tina, you mentioned the qualifications on the allo nature of the product, young donor cells, partially HLA-matched. Obviously, it took you a little bit to find this. 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 all of those qualifications that we just talked about compared to something more fundamental to the platform?
I think they're 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 allogeneic CAR-Ts are going to be rejected by the patient's immune system. Our PK data indicate they persist for about 30 days.
You want them to have as much anti-tumor 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 allogeneic CAR-Ts across our different studies. We have one of the largest allogeneic CAR-T clinical data sets, and it's let us understand these different factors and how to put them together along with the differentiated construct to see autologous CAR-T-like outcomes.
Excellent. Since you mentioned the PD-1 knockout, excuse me, 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 two 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. 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.
Over time, the two 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 two. 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.
Yeah, 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-1, they don't do as well as those, which is part of the reason we genetically engineered Vispa-cel in this way. Not only is there kind of an inherent T cell activation pathway that makes it more potent, but in certain patients, 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-T ineligible population? It seems like the barrier here is relatively low. 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?
Yeah, 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. For a physician ordering Vispa-cel, it's likely going to be a checkbox. Yes, they're auto CAR-T ineligible.
Yes, they're transplant ineligible. Depending on what the label will have are 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. Right now, we don't see any barriers. 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.
Most certainly, they want to be able to treat the patients themselves.
Absolutely.
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. 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.
We'll pack it up. We'll be back in a week.
Collaborating with some of these folks. I think it is a large percentage of patients when we talk to these sophisticated community docs, they 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. 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 two of these patients. They are committed to doing that for their patients.
John, 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 for both transplant and auto CAR-T. We are talking about a very meaningful fraction of the second-line setting who could be appropriate for this study.
Makes sense. Expanding beyond that, that would be appropriate for the study. 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 or who would show up in the commercial study.
Correct. 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. As Tina mentioned, only about 25% of patients get auto CAR-Ts, but that is the gold standard. What's happening with the other 75%? Actually, a pretty good fraction are getting bispecific antibodies, which, by the way, are not approved in the second-line setting, but I think demonstrate that physicians are being creative and using discretion to bring the best agents they can for the patients who are not benefiting from cell therapy. 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. Given the data set that we've seen, how are you thinking now about competitiveness versus an auto CAR-T product?
Yeah, not changing the goalposts. We still think the bispecifics are the goalpost as the base case for a compelling product opportunity, right? It's really built on an understanding of this very large myeloma patient population. 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.
Yes, we think CB-011 could do a lot to broaden that footprint, and that's obviously a key piece of the story. What we continue to hear from physicians is they'd 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. They see so much value in that one-and-done off-the-shelf over the very high treatment burden associated with the bispecifics.
Yeah, we've 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. 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-T 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.
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. I think it's probably low likelihood that that changes dramatically anytime soon. 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?
We will be expanding the 450 million cell cohort out to approximately 30 patients. What that will give us is just a better estimate of our overall response rate, the deepness of remission, so complete remission, stringency, and of course, what's most important for myeloma, the MRD negativity rate. 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. We should get into that couple of years for some of the patients and over a year for all of the patients. When we look at outcomes such as biospecifics that we're comparing to, it really is these median PFSs 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.
In the current cohort.
In the current cohort.
Correct. 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.
We should not be expecting proper PFS values for quite a while given the length of durability for some of these.
For this cohort.
For auto CAR-T.
Correct. We do have at a number of different dose levels long-term responders that I think we will this is a phase one 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.
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-T products and in vivo CAR-T 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 do not necessarily think of them as our competitor. I think in vivo CAR-T, they are handfuls of patients right now. They have a long road ahead of them, and especially with safety and regulatory path, it is uncertain how that is going to move forward. It is certainly exciting technology, but it is years behind allo CAR-T at this point.
Maybe I'll just add, I think allo CAR-T has really interesting kind of in-the-middle positioning. Both auto CAR-T and in vivo necessitate the cancer patient's T cells to do the heavy lifting. That works great for some. It works terribly for others. Regardless of those two 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 anti-cancer response.
That makes sense. In our last few seconds, we talked a little bit about commercial readiness. Can you walk us through the 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?
Yeah, 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 200-300 doses per batch. To do our HLA matching, we only need about 10 batches in the freezer at the start of our pivotal to do 2+ matching for 98% of patients. By the way, that's COGS. It should be 96% lower than the auto CAR-Ts at launch. Very exciting.
Awesome. All right, we are out of time. Thank you so much, Rachel and Tina, for joining us. Hope you have a wonderful conference.
Thanks, John.
Thank you.