Thank you so much. My name is Peter Lawson, and I'm one of the biotech analysts at Barclays. Welcome to Miami and Barclays Global Healthcare Conference. Really, it's a great pleasure to have up on stage with me, the CEO, Scott Wolchko, from Fate. If you have questions, I'm on Bloomberg. My associates are. You can always email us questions as well. But with that, I'd love to, you know, walk through some aspects of the story, the T cells in autoimmunity and B-cell lymphomas, et cetera. So first question would be around the T cell side in autoimmunity, and so I'm kind of curious there, the rationale for moving into autoimmunity-
Yep.
What differentiates you there in that space?
Sure, and thank you for having us. So, when we first started looking at the field of autoimmunity with respect, with respect to cell therapy, the history is that the field allogeneic stem cell transplant has been used successfully to cure patients of autoimmune diseases. And about, in 2022, there began to be exploration in using CAR T-cell therapy and applying that into autoimmunity. And what was remarkable is that out of a investigation in Germany, what was observed was using CAR T-cell therapy, specifically CD19 targeted CAR T-cells, that patients receiving those therapies were able to generate, receive an immune reset and drug-free remissions by depleting CD19 positive B cells, and that the reconstituting B-cell population was essentially curing people of their autoimmune diseases.
So we looked at that data that was emerging with autologous CAR T-cell therapy and thought about applying our platform, which is off-the-shelf iPS-derived CAR T-cells, towards the field of autoimmunity. Began to look at some of the clinical data that we were generating with, specifically our product candidate, FT819, which is an iPS-derived CD19 targeted CAR T-cell in the field of oncology. In that phase I study in oncology, we were seeing significant rapid B-cell depletion. We were seeing that the suppression of B cells was extending out at least through 30 days, and we were seeing certainly activity in the setting of oncology, where tumors that were sitting in secondary and tertiary tissues, we were able to reach them and clear tumors with FT819.
So based on the mechanisms that we were observing in oncology, we were super excited to bring FT819 into the field of autoimmunity. In the middle of 2023, we filed an IND to expand the clinical investigation of FT819 to patients with moderate to severe lupus nephritis. We're in a position now, after going through study start-up, where we've activated several different clinical sites for initiation of the study in autoimmunity and expect to enroll our first patient shortly in that study.
Got you. Are there particular patients in SLE go after, or how are physicians kind of talking about it and how they would think about positioning it?
So these are patients with moderate to severe disease, so significant disease burden. We are enrolling patients that both can have, both, kidney involvement as well as, lupus that affects other tissues. So these are patients with pretty significant disease, and patients will receive Cy/Flu conditioning, followed by the administration of our product, FT819.
Got you.
And the early markers that we will look for with respect to activity is look for B-cell depletion in the blood. Are we seeing significant rapid B-cell depletion in the blood? We'll also look at, obviously, these autoimmune diseases are characterized by aberrant production of autoantibodies, so we will be able to look at autoantibody reduction. And then ultimately, you can look at the reconstituting B-cell compartment, the health of that compartment, and whether patients have been, their disease burden has been significantly reduced.
Got you. Thank you. And then we expect to see data in the second half of this year?
Yeah. We've guided that we will be able to be in a position where we can discuss the first couple patients in this phase I study of FT819 in SLE in the second half of this year.
Okay, first couple of patients.
Yep.
And then from that, you think sort of patient narratives we're seeing in the second half, essentially?
Yes. Yes.
That's where we can kind of look through and see autoantibody reduction.
Yeah, absolutely. I think there's multiple different markers that we will be able to look at. You know, the kinetics of B-cell depletion, at least what's been observed in the autologous setting in the initial study, the kinetics of B-cell depletion are occurring very rapidly in the blood. The autoantibody productions are coming down significantly within the first month. The reconstitution of the B-cell compartment is occurring anywhere between the first, call it 45-90 days, and you'll be able to look at the B-cell compartment and understand whether that B-cell compartment that is being reconstituted is that of a naive phenotype that is not producing these aberrant antibodies.
Then ultimately, you're going to be able to do, in the first several months, you'll be able to do a disease, a formal disease assessment to understand the reduction in the severity of the disease and whether patients have achieved a drug-free remission.
Got you. When that would in no way serve as like a go, no-go decision? And at what point would we have enough data to say this is-
Well, I think in a small number of patients, that can serve as a go-no-go decision. I mean, patients with autoimmune diseases today, there really are no curative therapies. Patients are living on lifelong immunosuppressive therapies, are constantly dealing with the morbidity of their disease. What has been remarkable about this initial experience with CAR T-cell therapy is that these CAR T-cell therapies, while it's still early and it's a small number of patients, what's been seen in the initial patients coming out of the study in Germany is that patients appear to be cured of their diseases. They're achieving long-term, drug-free remissions, and that is quite remarkable based on the history of these patients and the lifelong therapy that they're on.
And so, I would say quite, you know, based on that type of data in a small number of patients can, in fact, be very informative with respect to go, no-go to accelerate development.
Gotcha. Perfect. Thank you. The fact that there's a conditioning regimen is required, does that change the dynamic of the patients that you're going to see?
Yeah, and so this is, I think, one of the challenges with autoimmunity that exists, right? So to date, what's been the therapeutic paradigm that has been used is that the autoimmunity patients have been treated like patients with cancer. So an oncology paradigm has been applied to these initial patients with autoimmunity, which essentially means these patients are undergoing apheresis. They're being taken off of immunosuppressive therapy. They're being admitted to hospitals. They're receiving intense chemotherapy conditioning, followed by the administration of the CAR T-cells. The paradigm works remarkably well in oncology, especially in hematological malignancies, and it's been exciting to see what's been achieved with autoimmunity using this paradigm. That said, the vast majority of patients, I think folks would agree, that should not be in a position where they're receiving intense chemotherapy conditioning.
And so moving away from Cy/Flu conditioning is, I, I believe, the ultimate solution in treating patients with autoimmunity. And so as we think about the field of cell therapy and the modality of cell therapy and its potential in autoimmunity, I think it's going to be incumbent on all of us as developers to come up with solutions and think about therapeutic paradigms and implement therapeutic paradigms that do not require Cy/Flu conditioning.
Gotcha.
In that manner, patients will not have to go to academic medical centers. They will not have to be hospitalized, and you can treat them more in the community where they're living and breathing today.
How, how close are we to getting away from Cy/Flu conditioning? And maybe you could walk through some of your approaches.
Yeah. So we're starting with first principles, so the initial proof of concept out of Germany is using Cy/Flu conditioning. Our initial clinical experience will use Cy/Flu conditioning. That said, as a company and as the fact that we're developing off-the-shelf cell therapy, we will begin to pioneer and expand our clinical footprint, I expect this year, to move away from Cy/Flu conditioning and looking at other regimens that are delivered as and used as standard of care in patients today. One of the elements of Cy/Flu is Cy/Flu does immunosuppress patients, and allows cell therapies to thrive when you deliver them. These patients are on immunosuppressive therapy, so there are other regimens that I believe can be used quite effectively, as a foundation for cell therapy use, and I think we will begin exploring those in 2024.
Great. Thank you. I'd love to move on to your iPSC CAR T-cell approach-
Yep
... in CLL and B-cell lymphomas.
Mm-hmm.
Just, I know there's data coming up-
Mm-hmm
... at, ASGCT. Kind of how much data should we expect?
Yeah. So at ASGCT, we're going to begin to highlight our platform, that is our CD19-targeted cell therapy platform and its application to autoimmunity. And so we have, as you've referred to, FT819, which is an iPS-derived CD19-targeted CAR T-cell. We also have, as part of our platform, iPSC-derived CD19-targeted NK cells. So we're uniquely positioned in that we're developing both NK cells as well as T cells in cancer and autoimmunity. And so at ASGCT in May, what we're going to do is we're going to highlight the translational data that we have generated in oncology with both our T cells and NK cells and discuss how that translational data that we've seen and the results that we've seen in oncology applies to autoimmunity.
Interesting.
So we can discuss, for instance, B-cell depletion is important, obviously, in autoimmunity. We can discuss what we're seeing with respect to B-cell depletion. One of the reasons it's believed that the cell therapy modality is able to generate these resets of immune system in autoimmunity is that the modality of the cells, they are able to leave the blood, they are able to traffic into secondary and tertiary tissue, and once they are homing in and infiltrating, they're able to kill resident bad acting B-cells. And so we'll be able to highlight the data of our programs with respect to their homing, trafficking, and infiltration and at least antitumor activity... and how that can apply to autoimmunity and the clearance of CD19 positive B cells in the sense of, in the context of autoimmunity.
Got you. Should we read that as the oncology program is taking a back seat, I guess?
No, no. I think, you know, some of the, some of the, the foundational elements that are relevant in oncology, you're, you're dealing with essentially whether the cell is a B cell expressing CD19 or a tumor cell expressing CD19. The target cell is of what is relevance here. And so whether we're talking about how we're thinking about oncology versus autoimmunity, ultimately the target cell is a CD19 positive cell, relevant in both diseases.
Okay. On the oncology side of things, what should we be looking for?
Yeah, on the oncology side of things, with FT819, we're dosing patients at what we consider to be the highest dose level that we're going to explore, 1 billion cells per dose. So we'll be providing an update. We've gone through dose escalation on the oncology side, starting at 90 million cells, up to 1 billion cells with FT819, and so we'll be able to discuss that data on the oncology side. For the most part, we've treated patients with very aggressive disease, and in many cases, the majority of our patients actually have already received autologous CAR T-cell therapy.
Okay. And is that regarded as a kind of a go, no-go decision for the 819 T-cell program?
In oncology, yes.
In oncology. Absolutely.
The data that we will look at, when we look at this highest dose level in oncology, will, I think, inform its future development in oncology.
Got you. And then you've got another go-no-go decision for FT522, so the NK cell.
Yeah. So FT522, we don't... I don't think we face a go, no-go decision this year with FT522. So FT522 is our program that is an NK cell that is CD19 targeted. That program, we are moving into autoimmunity in the middle of this year. We've committed to filing an IND to bring 522 into autoimmunity in the middle of this year. We have just initiated that study in oncology, in patients with B-cell lymphomas. And so very interesting study, and coming back to your point on Cy/Flu, that program specifically has been designed with functionality that we believe has the potential to alleviate the need for Cy/Flu conditioning. And so the 522 study has been designed with two different arms.
The first arm of that study, patients receive the traditional cy/Flu conditioning, followed by NK cell therapy. The second arm of that study, though, we are testing the hypothesis that you can deliver cell therapy, in this case, FT522, an NK cell, without cy/Flu conditioning. And that's because FT522 incorporates what we've called an alloimmune defense receptor. It's an edit into that program where that receptor, it's essentially a second CAR in that cell, that targets 4-1BB expressed on T cells. So FT522 becomes activated in the background of a, a functional immune system.
Gotcha. Thank you. And then I guess you've got a mid-2024 update around 576, so that's your BCMA-directed-
Yeah.
NK cell.
So also on the NK cell side, we are developing a BCMA-targeted CAR NK cell in multiple myeloma. We have progressed through dosing schedules. We've dosed patients at three times 1 billion cells. We saw activity at that dose level, and in consultation with our PIs, we decided to dose escalate that further to three times 2.5 billion cells. And so we're now enrolling patients at that dose level. Expect to have data later this year, which will inform a go, no-go decision on further development.
Okay. And so with that, we'd see, like, durability data as well?
I think we will certainly see, initial response and durability data at the 1 billion cell dose. At the 2.5 billion cell dose, I'd expect that the, certainly look, be able to look at response data and early durability data. It'll be less mature on the durability side.
Gotcha. Thank you. And then, sorry, I misspoke, but the NK cell 522, so your-
Yes
... CD19, does that data drive a go/no-go decision in the T cell CD19 in oncology?
No.
No.
No.
That's-
I mean, we think of each individual asset separately.
Gotcha. Okay. And the durability that we should see, so flipping back to the multiple myeloma-
Mm-hmm
- approach in NK cell, what kind of durability are physicians wanting to see with a product like this?
Yeah
- with competing CAR-Ts?
Very, very competitive market. I expect that there are going to be three autologous CAR T-cell therapies targeting BCMA that are approved. There are multiple monoclonal antibodies and T-cell engagers that are approved targeting BCMA, and so I think it's a highly competitive market. I think as we look at the landscape, for further development in multiple myeloma, you certainly have to look at, for instance, the therapeutic profile of, for instance, a T-cell engager, which is also an off-the-shelf therapy. And with T-cell engagers, you typically see CR rates in the 30%-40% range and overall response rates in the 60%-70% range with durability response that extends out beyond a year.
So that's the target, really, trying to-
Yeah.
-replace or-
Yeah.
-supplant-
Yeah
- T-cell engagers.
Or synergize with T-cell engagers, yes.
Interesting. Okay. So it's not the case that the... It's a crowded marketplace, so this is something you'll pull back on, and this is-
I think it's a crowded marketplace, yes. I mean, the good news is, in multiple myeloma, there are lots of options for patients that did not exist even three to five years ago. We have a platform company. We have multiple different therapeutic opportunities. We've not even discussed the solid tumor platform we have. And so, yes, we have a high bar in thinking about how we advance product candidates.
Gotcha. Maybe as a great segue, actually, if we transition over to the-
Mm-hmm
-solid tumor side of things. We've already seen a TIL approved.
Yep. Absolutely.
Things are transitioning.
Yeah
from heme to
Yep
solid tumors. Just your approach there, I guess, what is it predominantly around the Ono collaboration?
Yeah. So we've been developing a multiplexed engineered backbone for T cells. In attacking solid tumors, I think we would look at the space today in the sense that autologous CAR T cell therapy has been explored in solid tumors. I think the results to date with most autologous CAR T cell therapies, the efficacy has been modest as compared to, for instance, hematologic malignancies. And so one of the challenges that exists in solid tumors is, or actually there are severalfold. For instance, you're dealing with tumors that are not in the blood, not necessarily easily accessible. You're dealing with, and oftentimes, an immunosuppressive microenvironment. And so I think there's gonna. This will require a multifaceted mechanistic solution to fundamentally attack solid tumors. And our platform, an iPS-derived cell therapy platform, allows for multiplexed engineering.
And so you've referenced our first collaboration product with Ono, FT825. FT825 is a, is a cell therapy that has seven edits. We've created a seven-point edited cell therapy. We've initiated the clinical study with FT825, and it includes multiple pieces of synthetic biology that are specifically designed to enable cell therapies to thrive against solid tumors. For instance, homing is a challenge. We've engineered in a synthetic CXCR2 receptor, which can promote homing out of the blood into tissue. We've engineered in a TGF-beta redirector receptor, which takes that immunosuppressive signal in the microenvironment and actually activates the cell. The binding domain safety has been an issue in solid tumors.
The binding domain Ono has developed, it's cancer specific, and so we see activity against cells that are low expressers of HER2, and we see activity differentially against cancer cells versus healthy cells expressing HER2.
What's driving that differentiation of-
The binding, specifically the binding domain that's been incorporated into the product candidate, is unique and differentiated from other therapies that have been used to target HER2. So for instance, the binding domain that's been used most specifically in different sort of therapies, is that of trastuzumab, the Herceptin binding domain. We have a novel binding domain that Ono developed specifically that hits a different epitope.
Gotcha. Thank you. And then when could we see data for them?
Yeah, so we've initiated that study, beginning to dose patients, and so I do think we're in a position where, again, in the second half of this year, it's a, it's another milestone that I think the company can achieve and show initial proof of concept data.
Do you need, like, sign-off from Ono? How does that work?
Yeah, we'll work with Ono on that, but we've been pretty, pretty successful in working with Ono to highlight, certainly through preclinical development, the unique features and functionality of this product candidate. In SITC of 2022, as well as SITC of 2023, in November, those conferences, we were, we highlighted 825 historically with respect to its preclinical data and development.
Okay, so that's. It's something that's kind of... We often see partnerships where with big pharma and no data-
Mm-hmm
is really released until the end, but this is
Fate is the sponsor of the phase I portion of this study. So while this is a co-development and co-commercialization arrangement with Ono, Fate is responsible for conducting, or at least leading the conduct of the phase I portion of this study.
Gotcha. Thank you. And I'd love to just flip back to this kind of compare and contrast between FT522 versus FT819-
Mm-hmm
So the CD19 targeting therapies. Like, how would that change? How could you see those products being used in B-cell lymphoma? Is it a bake-off between the two?
I think they can be very different. Like, right now, FT819 is a product candidate that we're delivering with Cy/Flu, and we're delivering that and treating patients with the most aggressive forms of lymphoma, specifically, for instance, aggressive DLBCL. FT522, while it's an NK cell, the unique feature of FT522 is the ADR receptor, and it is potentially a product candidate that can move away from the requirement of Cy/Flu.
And if that is the case, if that does bear out, that FT522 is a product candidate that can thrive and be active absent Cy/Flu, I think FT522, I think FT522, as we think about whether it be autoimmunity or oncology, is a product candidate that can be used earlier in care and in combination with other therapies because it does not require... It potentially would not require Cy/Flu as part of its therapeutic treatment.
Gotcha. Do you think eventually that ADR construct is just gonna be ubiquitous in your platform?
It's. If ADR technology proves out, we already have built ADR technology into T cell lines. Yes. Yes.
That's great. Thank you so much for-
Thank you.
Top of the hour kind of thing.
Thank you so much!
Thank you so much. Pleasure.
Thank you.