Welcome to the Citizens JMP Life Science Conference. It's my pleasure to introduce Steven Kelly, CEO of Carisma. Steve, welcome, and thanks for being here.
Absolutely. Thank you. Thanks for having me, and in the process, I will be making some forward-looking statements. But I appreciate the opportunity to make them.
No, that's terrific. So I never know exactly who's in the audience, and I don't know who's listening to the webcast and how familiar they are with the Carisma story. So I always like to start off these Q& A's with, you know, a little maybe 2-5-minute overview of what Carisma's about.
Sure, absolutely. So Carisma is a cell therapy company. We are focused on a unique effector cell, the macrophage. And it has some unique properties. They are really—they're very industrious throughout the body. They have so many different roles, but we have this, the ability to engineer them, to direct them to exactly what we wanna do. Our sort of the beginning of the company was the ability to actually engineer these cells. They are resistant to traditional vectors, and we were able to solve how to actually put genetic material into the cells, and that was the beginning of the company. Today, fast-forward, six years, and we have a portfolio of products that are in three basic areas. The first is ex vivo oncology, and that is a HER2-directed program.
We have in vivo oncology, which is a partnership we have with Moderna, doing a similar thing, as the ex vivo program, but an off-the-shelf approach using LNP and mRNA. And then the third area is non-oncology, and sort of the highlight there is an application that we are looking at in fibrosis, specifically looking at liver fibrosis.
Great. So, I know recently you guys made a decision to focus on the monocyte moving forward.
Yeah.
Can you maybe take us through, you know, the rationale for that, and you know, kind of the benefit of it?
Yeah. Yeah, so ultimately, the effector cell is the macrophage. However, there's some challenges with that. Our first program was CT-0508, a CAR macrophage targeting HER2, and it really served its purposes. It demonstrated the feasibility of making engineered macrophages. It demonstrated the safety of administering these cells. It demonstrated some of the mechanistic properties, the ability to traffic, the ability to remodel the TME, the ability to drive an adaptive immune response. However, we saw two other things emerge. One, we appeared to be underdosing, and so we saw a lower number of cells, and we saw a sort of transient presence, so the persistence was low. The other thing that we saw was an exhausted T cell phenotype. So the former is why we switched to CT-0525. CT-0525 is a CAR monocyte.
It's typically what you see in the body is a CAR monocyte will leave peripheral blood and become tissue resident, and then it'll differentiate into a macrophage. We're engineering the monocytes rather, and then allowing that differentiation to occur in vivo. The advantages are multifold. One, we can make more cells, so we can make 10 billion cells versus, on average, 2 billion cells of macrophage. These cells traffic far better, not surprising, 'cause that's what monocytes are designed to do. So we see a 40-fold improvement in tumor localization, and thirdly, they stick around longer. So we think they're a healthier cell, and they're out of the body for their only one-day manufacturing process. And we see a 10-fold improvement in persistence, so overcoming those two things that we saw with the macrophage.
In total, a CAR monocyte approach, we think, has a 2,000-fold improvement in terms of therapeutic potential relative to the CAR macrophage approach.
Excellent. So, you know, it's always interesting to me, right? As you're kind of going through this, and when you make a slight pivot to something that's much better, the same sort of, you know, challenges kind of exist, right? So maybe you can talk a little bit about maybe what you see... You talked about the benefits, but maybe talk a little bit about the things that might keep you up at night, especially when talking about this class of therapy. 'Cause you guys—I mean, in my view, and correct me if I'm wrong, you're the pioneers in macrophages. I don't know of anyone else who's really doing it, but maybe you can comment on that as well.
Yeah, so we are the pioneers. We were the first to ever make an engineered macrophage and administer it to a patient, and I think we really are driving the sort of the frontier in tools and how to deploy these cells. So you're right, we make a change from a CAR macrophage, where we're seeing activity, to a CAR monocyte, which we think is going to be a definite step up. But the things that I think about are, you know, there's a couple of different categories of things that keep me up at night. I sleep pretty well, but generally, they're biologic, so we're stepping up from 2 billion cells to 10 billion cells. Is there going to be a safety issue?
Mm-hmm.
I mean, that's really what we're looking for. And then the question... We assume that they're going to traffic better and accumulate in tumor better and have a more robust effect and stick around longer. Is that actually going to be the case in humans? We see it in mice, and so we wanna question whether that happens in humans. And so that's really the sort of the proof of concept that we're- a monocyte is going to be superior. There's also execution risk. We are just like we were with the CAR macrophage, this is a first-in-man CAR monocyte study. And in doing so, we have, you know, clinical trials to run, sites to get up and running, patient enrollment.
The thing I think about a lot is that clinical development aspect, the execution, getting patients on study as quickly as possible, so we're getting data as soon as possible. You know, that's the thing I think about a lot.
Just, you know, sticking with this theme, you know, as we think about the phase I study-
Mm-hmm
... of CT-0525. How many patients do you plan on enrolling? You know, when do you think we might see these patients or see some data from the study? And then probably most importantly for us to know is kind of what are the metrics, the kind of metrics that you evaluate as you think about a go, no-go decision?
Sure. Yeah, I think the first thing that we wanna do is dose escalation, so we wanna rapidly get to that 10 billion cell point. Fortunately, all that we've learned so far with the macrophages is a relative... It's a very safe profile. We think you have a wide therapeutic range. So we think that that's going to be rapid. So 3 patients at 3 billion cells, 3 patients at 10 billion cells, and at that point, once you've established the safety of administering 10 billion cells, that gives us the ability to move forward and do two things. One, look at the combination with the T cell checkpoint inhibitor-
Sure
... which we think is going to be essential in late stage patients, overcoming that T cell exhaustion, and enabling the macrophages to work, or the monocytes to work the way we want. So that's that arm of the third cohort, it's still to be determined the numbers of patients we have, because I think the second part of your question is really important. What do we need to show to our scientists, or to clinicians, to patients, to investors, that says that a CAR- M approach in oncology makes sense? So safety, obviously, is important. I think we wanna see, once we get to the point where we're combining with a T cell checkpoint inhibitor, we're going to want to see objective response.
Before that, in the dose escalation phase, we wanna be able to show that we are localizing the tumor better than the macrophage. We're sticking around longer, having that long-term effect on expansion of T cell clones, et c. And so those are the sort of translational analysis at the outset, moving into objective clinical outcomes in the second phase.
So when I think about, you know, objective responses, right? There's always, like, a bogey number, if you will, right-
Right
... that we're trying to hit.
Right.
Same thing with duration.
Sure.
Right? Especially with cell therapies, I'm typically thinking you want a duration of at least six months.
Mm-hmm.
Now, that's in the T cell space.
Right.
Are both those kind of, you know, the bogey number, you know, the objective response, I'm always thinking around 30%. Are those reasonable sort of assumptions that even you think about, or is it slightly different?
Yeah
... you know, with macrophages?
No, I think that if you look at therapeutic options, just independent of what our modality is, I think that that's what you wanna see. You wanna see 25%-30% in a late stage patient, and you wanna see that kind of response. You wanna see disease control over a period of time. You know, on the one extreme, it's like two weeks, I think, when was it back when Erbitux was approved or something like that?
Mm.
But really, what people are looking for, for clinicians, payers are looking for, patients are looking for, is probably in that, you know, 4-6 months in a later stage patient. So we're thinking the same way, that we need to be able to demonstrate that. For arguably a complex therapy and likely an expensive therapy, it has to have some benefit in that later stage patient population that is significant.
Just as I kind of paint the picture for, or we paint the picture for investors, how do you see that, you know, that progression in terms of monotherapy, and then the combination with checkpoint, and ultimately when we'll see data?
Yeah. So we'll see monotherapy data by the end of the year.
Mm-hmm.
So I think that that will be the dose escalation phase, and so that we can administer this large number of cells safely. The next step would be the combination with a T cell checkpoint inhibitor.
Mm-hmm.
pembrolizumab is what we've used in the past. That date is probably a mid-2025 event. Our goal is to, by the second half of next year, to be able to define our cell dose, our regimen, so we think it's gonna be 10 billion CAR monocytes. The regimen likely will be the addition of pembrolizumab-
Yeah
... and a tumor type and a line of therapy. And where we're looking at now, half the patients we're treating are HER2-positive breast, the other are HER2-positive GI malignancies. And we'll have to pick one of them as our lead indication, and then likely where we see the line of therapy, it will be a post-HER2 line of therapy. There's a lot of patients now are being treated with Herceptin upfront, and then they go on to an Enhertu-based regimen. So we probably... Our goal is to slot in behind that.
So let's talk a little bit about, you know, how this fits into the landscape. So let's say everything goes the way that you are hoping that it goes-
Right
... if not better.
Yep.
The response rates are coming in, the duration is coming in. And let's narrow the field down to, let's say, HER2-positive breast, right?
Mm-hmm.
Where does something like 0525, you know, kind of fit in and ultimately, you know, where... I guess, where would you want it to be?
Sure. Yeah. No, it's a great question. I think that you, if you look at the current treatment there, typically it's a HERCEPTIN-based chemo regimen upfront. And increasingly, like I said, it's an ENHERTU-based regimen. The patients we're treating now, they're always looking for an option. So our... The average we've seen in our studies to date is sixth line, so we're... I mean, patients, nothing is curative at this point. Even in ENHERTU, which people are, have really grabbed onto, PFS is 18 months, I think. So there is a definite need. I think initially we probably have to slot in post both the, both of those in a third line setting. It all depends on what the outcome is.
If we're able to establish a robust adaptive immune response with durability, where we've had the body, you know, now start to re-engage the immune system, I think there's a chance to move it even earlier. So it really remains to be seen. If you look at a head-to-head comparison versus HERCEPTIN, for example, preclinically, we have a more robust anti-tumor effect. But we have to do the work, we have to generate the data to make that stepwise progression.
Got it. In terms of safety, you know, should we be thinking the macrophage is a complicated cell, right? It's antigen presenting, right? It activates various different arms of the immune system. But when we think about safety, you know, how should we be thinking about it, especially in terms of, especially when comparing it to something like a CAR T?
Sure.
Are you expecting something very similar, or will it be drastically different?
Right. Yeah, so the two things that we thought about initially were on-target, off-tumor toxicity. So you have this cell that goes and identifies an antigen, and in solid tumors, it's somewhat challenging. You wanna make sure you have an antigen that's primarily on cancers, and those are hard to come by. So there's 20 different tissues in the body that express HER2, so you wanna make sure that you have an engagement and a trigger of phagocytosis that is significantly higher, giving you that therapeutic window, significantly higher than natural presentation. So that's important. So that's the first thing we looked at: Are we having an issue with major organ system toxicity and is antigen dependent?
The second thing we look at, because you're administering this cell, are you going to see some of the adoptive cell therapy toxicities, looking at CRS, looking at ICANS? And fortunately, in our case, we saw grade 2 CRS. We saw no ICANS, and who knows if that will remain to be seen as we dose escalate with the 0525. The last thing we wanna look at is there's a definite localization of our cells to the liver. That's a common place where they become resident. And so you wanna look at liver enzymes, and are you having any liver toxicity? So we've been fortunate in the patients we've treated, 17 patients so far. We have not seen on-target, off-tumor toxicity.
We've seen no major organ system toxicity. We've seen grade 2 CRS, no ICANS, and no liver toxicity. So those are the things we watch for, and we'll have to continue to do so. And as we expand in the future past HER2, we'll have to look at, again, that on-target, off-tumor risk profile.
Yeah, perfect. Let's talk a little bit about the in vivo transduction-
Mm
... you know, platform that you have. We, we sat on a panel together at UPenn.
Yep.
And that was actually something that Saar Gill brought up, who's also a co-founder of Carisma.
Mm-hmm.
So it's nice to see you guys are tackling this as well. Talk to us a little bit about, you know, the in vivo transduction and, you know, how it maybe alleviates some of the current shortfalls.
Sure
... with cell therapy.
Well, everyone knows cell therapy is complex. And you know, there's a lot of people that have been trying to solve it, so an autologous approach, you have to engineer the cells. They're out of the body for a long period of time, and you know, 2 weeks, 4 weeks. And the longer they're out, the less effective they are. And they're expensive, and so people have been looking at allogeneic approaches. Sana, who you just had up here, was looking at an allo approach. The in vivo strategy is something very similar, using... There's 2 basic approaches, using viral integration or using LNP and mRNA technology. For us, we were looking primarily at mRNA and LNP, and we've forged a partnership with Moderna, obviously, leaders in the space.
The goal here is to take the same genetic material and deliver it in an LNP that is myeloid-tropic. The goal is to get that to the myeloid cells, where then you can have it expressed as a CAR. So we put the partnership in place. It's fully funded by Moderna. It is 12 targets over 5 years. There's $3 billion in milestone biobuck milestones. There's a royalty. And fortunately for us, we've seen so far a good proof of concept in mice, of course, where we're able to encapsulate a CAR or encapsulate the mRNA expressed in the CAR in an LNP. We're showing targeted delivery to only myeloid cells. We're showing CAR expression. And we're getting that it's...
mRNA, of course, is transient, so you're looking at a couple of weeks of expression, and you're seeing all the mechanisms that we wanted to show with our ex vivo approach, but we're showing it with this off-the-shelf approach. It's, it's pretty exciting.
And so Moderna, you know, you mentioned the biobuck deal. Clearly, they've... You know, you guys are the pioneers in the space, and so they picked you. So this will be something to clearly look out for. Is there any data, preclinical, you know, that might be coming out later this year that we should be focused on, or maybe something at ASGCT, the last weekend?
Yeah, so for the preclinical data on the in vivo, we presented that at SITC last November. Our next milestone there is a development candidate nomination and then a drive together towards IND. It's a handoff for us to Moderna, where they pick up manufacturing and clinical development, and so our goal is to, you know, be in the clinic as quickly as possible and generate that data. We did have data presented at ASGCT around liver fibrosis, and so I had some other data I can-
Yeah
... walk you through.
So actually, that was the last one that I wanted to chat about-
Yeah
... 'cause it was one of the three that you mentioned, fibrosis.
So we've put so much time into understanding macrophage biology, and understanding how to manipulate those cells to do things, and so we're looking at what's beyond solid tumors? And liver fibrosis is an area that we think makes a ton of sense. Macrophages, as I said, localized to liver, so we're going to see... Without tumor, we're gonna see macrophages getting into liver. We've seen some read-through to some work another company has done, and Stuart Forbes in Scotland has done work with an unengineered macrophage in advanced liver fibrosis, with a single infusion, is able to basically stop the progression of fibrosis. So pretty compelling data and meaningful. Our idea is to take that one step further. Can we genetically engineer these cells to be both anti-inflammatory and anti-fibrotic?
So not only are the cells going back to the liver and helping heal the liver, but they're also producing these factors. So we have some data we presented at ASGCT, where we took a macrophage and had it produce relaxin, which is an anti-fibrotic. It hasn't been used, because of extremely short half-life, so therapeutically, people have explored it, but there's no way to get it to have a therapeutic effect. With a macrophage that becomes tissue-resident, it'll produce. It's like a miniature factory, producing relaxin and having that anti-fibrotic properties. We've also engineered it to express IL-10, so an anti-inflammatory property. So we had 2 model systems we presented. One of them was a carbon tetrachloride model. It's a liver toxin.
It produces a fibrotic liver, and we did a treatment with... well, no treatment, unengineered macrophages, and engineered macrophages. And the unengineered macrophages had a 50% improvement, back towards normal. The engineered macrophages, 100%, back to normal. So it's, like that was a good, one-dose approach. The second model we did was a diet-induced model, where it creates fatty livers, and also fibrotic. We added not only diet-induced, we added carbon tet to that as well, so a very high hurdle. And in this case, again, we saw about a 20% improvement with unengineered, and about a 40% improvement with engineered macrophages. So it's an, it's a growth opportunity for us. We are optimizing what that construct looks like.
In this case, allo is probably the modality that we're thinking about as we turn it into a therapeutic. That's early data, but exciting as a new, the next growth opportunity for us.
So this is going to be allo. How, I guess, you know, what's the source here? So it's just donor, it's donor-derived?
Most likely, it'd be an iPSC.
Okay.
So we've done some work, o- o- over the years around iPSC-derived macrophages and monocytes, CAR macrophages, CAR monocytes. So while in cancer, it probably doesn't make a ton of sense because half the mechanism is antigen presentation. If you edit out MHC class I and II, you're not, you don't get antigen presentation. So for oncology, allo doesn't make a ton of sense. But in this case, it's a non-CAR-based approach, where we're just looking, producing little microfactories. It makes a ton of sense for us.
Gotcha. As we think about sort of the remainder of this year, 2024, the cash needs, the cash that you have, can you talk to us... Maybe just starting off with the cash, what is your cash position? As you think about these multiple programs, I mean, clearly, the in vivo transduction is partnered with Moderna. Are these other programs ones that, you know, you ultimately wanna bring forward on your own, or are you actively seeking partners? What's the best way to, to develop this going forward?
Yeah. So we just filed our Q last week, and so we had $55 million in cash. We have a cash runway into Q3 2025. We just went through a, you know, a focus and a reduction in force of the company to really crystallize exactly what we wanna accomplish, and those are the three, the three programs: CT-0525, the in vivo program, and the liver fibrosis program. In terms of how do we sort of monetize the company going forward, we'll deliver data on each one of those. We'll have data on CT-0525 by the end of the year. We're hoping... We're driving towards an IND with Moderna. On the in vivo program, we'll have a development candidate in early 2025.
So these are. We have very specific objectives of what we're trying to accomplish. In terms of funding the company, of course, we'll always look at equity funding and partnerships. We partnered with Moderna. That was a fantastic opportunity for us to not only take the technology to another area, but accelerate the development working with one of the leaders in the field. We would do the same thing on fibrosis, if it made sense. If we can accelerate our approach, and also, financially, it makes sense, it's something that we would partner. And even oncology, ex vivo oncology is something that we'd be open to.
So it all comes down to, is the incremental cash and the speed and acceleration of what you're able to do with a partner better? Does it make sense for us, versus, you know, additional equity financing?
Fair enough. I wanna go back, you know, to fibrosis real quick. When I think about fibrosis, I'm thinking about things like NASH.
Sure.
But, you know... You know, but when you're thinking about it, right... I think the diet-induced was probably a NASH model.
Yeah.
And so, but the different, that can't be the... I'm assuming that's not the only kind of-
Right
... fibrosis indication to go after.
Sure.
How big is this pie? I think, importantly, based on the data you're seeing, I'm sure you're comparing it to other, you know, therapeutics that are being developed-
Yep
... right? Or have been approved. How does it compare?
Sure. Well, we're in mice-
Yep
... so
Yep, 100%.
... the comparison is in mice. So you think, yeah, right, liver disease, there's 50,000 deaths in the U.S. due to liver disease. That's 1 every 10 minutes. And half of that is NASH, MASH-related. Half of it is alcohol or viral hepatitis, et c.. And so regardless, though, you're looking at a cirrhotic liver, scarring, fibrotic tissue, etc. . And so our models that I just described are more the NASH, MASH-based, but it's something that our scientists are also considering. Does this work for advanced, you know, advanced cirrhotic livers, and when patients reach the point where they're on transplant? So that is an area that we can explore. We presented data at ASGCT on lung fibrosis, so it's a different construct.
We had a TGF-beta construct, and we had activity there, so very similar, you know, complete resolution, so there's an area that we can explore. The macrophage biology is just amazing. Macrophages are everywhere in your body, and they're part of homeostasis. They're part of resolving disease, direct insults, and so we think about all the other places that we can deploy them. But right now, it's focus, get these three things, but I think there's a tremendous growth opportunity just building off of the discovery platform we have. In other fibrotic disease, we can look at neurodegeneration. We can look at autoimmune disease. There's a lot of places we could go.
Terrific. With that, I wanna thank you very much for coming.
Absolutely.