Good morning, everyone, and thank you for joining us at the third day of the Needham Healthcare Conference. It is my pleasure to have with me this morning, Brian Di Donato, Chief Financial Officer, and David Berman, Chief Scientific Officer from Immunocore. As a reminder, any viewers who are watching through our conference portal are able to submit questions via the Ask a Question box below the video feed. And with that, I think a little bit of introduction is worth doing here. Maybe a good place to start is to describe for, for our audience, Immunocore's technological platform, and how is it similar and differentiated from other T cell engagers out there?
Hi, Gil. Thanks for inviting us today. I'm very happy to answer that question. So our platform is a T cell engager bispecific platform. One end grabs the T cell, that's pretty standard for all T cell engagers. What's unique about our platform is the targeting end, which we use a highly engineered T cell receptor, whereas most everyone else uses an antibody to target. And the reason that's important is that antibodies can only access cell surface proteins, which is about 10% of the proteome, whereas T cell receptors can access intracellular proteins, which is 90% of the proteome. And that's important because we believe most solid tumors, the specific targets are inside the cell and not on the outside.
And so, our lead program, KIMMTRAK, validated this hypothesis with a survival benefit, and now we're studying this outside of uveal melanoma with our PRAME program, and we can certainly talk about that some more.
So there are many companies out there, who are looking at cell-based therapy, you know, to T cell CAR Ts and even, even TCR CAR Ts. Where do you think a TCE, you know, a biologic, slots within that paradigm? Do you think cell-based therapy may be reserved for later lines?
So, there may, like all therapies, there may be room for both. Our platform is off-the-shelf, and the safety profile is very well. It's very predictable, with the key adverse event being mild or moderate cytokine release syndrome, usually on the first few days of dosing. So it's a very predictable safety profile, off-the-shelf, generally well-tolerated, with very low discontinuation. That's point number one. Point number two is we know that our platform can combine with just about any other standard of care out there that we've tested. And then the third aspect we've seen is that there's a very high element of disease control that we believe, as you move into earlier lines, also plays to its strength and should be even better.
So what we feel our platform is best suited for is moving into early stage, which also happens to be the largest indications, but early stage in combinations. I think with engineered cell therapies, which have shown interesting data and require the patient to be fit enough to wait for the T cell processing and receive chemotherapy conditioning, I think that those probably are better suited for a late line therapy.
So maybe a bit of a, you know, different example from the hematological oncology space, specifically in multiple myeloma. The argument has been made that you may wanna move CAR Ts in front of bispecifics just due to driving resistance. I know that solid tumor is a different space, but I'd love your input here.
Yeah. So the idea is that both cell therapies and off-the-shelf biologics require the target to be present, and so both of them can put pressure on the target. The differences I think that you're alluding to is that ours is, as an off-the-shelf, is administered weekly, so it's dosed until progression and beyond, whereas cell therapies are usually dosed once. However, even in those cell therapies that are dosed once, the cells presumably are still alive and present and still putting pressure on the tumor. So I think in both cases, there can be selective pressure put on for the loss of expression. We feel that part of the benefit of the durability that we've seen comes from the repeated dosing because we believe, or we hypothesize, that with each repeated dosing, we bring in fresh T cells.
So that way, you can replenish the T cells that are brought into the tumor with each dose, and we think that might play into the durability. So we see that actually as an advantage to repeated dosing, rather than a disadvantage.
And another kind of key point there, you know, the health of the T cells really matters. We're gonna get into that more, actually. Do you think that it is a specific issue with T cell engagers, or is this a broader observation?
Gil, I think it's a very insightful comment that you made. So we know from the literature, adoptive cell therapy, whether it's TILs or CAR T or TCR T, those T cells are engineered outside the body to make them highly immunologically fit, and that the better fitness T cell that you administer, the better the patient. So they exogenously make these immune-fit T cells. Of course, with an off-the-shelf biologic, we rely on the patient's immune fitness at baseline, and I think that this is emerging as a very important point, and it's something that we're going to be presenting on later this year. So I think let's come back to this, but I do think that this concept of T cell fitness is very important.
I think that there is literature out there, Gil, that shows that some tumors, for reasons we don't completely understand, can impact global immune fitness. So patients with prostate cancer can have a different immune fitness than patients with lung cancer, for example. I think more to come on that, and we'll be presenting more on that later this year.
I do wanna spend a significant portion of our time here, speaking to the PRAME readouts that are upcoming. Maybe to set the stage, to remind everyone, what is PRAME? Kind of how, you know, its expression across different tumor types?
Sure. So PRAME, gp100 as an example for KIMMTRAK is a lineage antigen, which is, it's expressed in melanocytes and in tumors derived from melanoma. So it's that lineage. PRAME belongs to a different class of targets, which is a cancer testis antigen. So this is a target that's presented during embryogenesis and in the testes, and then it's selectively expressed in tumors, but not in a normal adult tissues. So from that aspect, from a targeting aspect, PRAME is very exciting. It's highly expressed in lung cancer, melanoma, ovarian, and endometrial, which makes it intriguing for us to demonstrate that our platform works beyond uveal melanoma. So that's the general background of PRAME as a target.
Let's start with the first, you know, data readout, update actually, within the cadence, and this is, IMC-F106C.
Correct.
PRAME targeting in melanoma. Can you set the stage for what data was presented so far? How should we view this upcoming second quarter update?
Sure. So what we presented so far is seven cutaneous melanoma patients, one of whom was PRAME-negative, and six of whom were PRAME-positive. And what we showed is really striking disease control, which translates into progression-free survival in those original six PRAME-positive patients. Interestingly, the PRAME-negative patient was progressing, and I think this is a theme that we're gonna continue to see throughout our data presenting throughout the year, which is, A, the major effect of F106C is disease control, and, B, the PRAME-negative serves as an internal negative control that this truly is a treatment effect. The additional endpoints that we believe provide confidence that the disease control is drug-related, as opposed to you just enrolled good patients onto your trial, is that we see durable tumor reduction even in patients who still have stable disease.
That doesn't happen spontaneously, so it's clearly a drug treatment effect. And secondly, we see ctDNA molecular responses, which is something we've seen with KIMMTRAK and uveal, and we continue to see without our F106C program. Also, these molecular responses cannot happen without, they don't happen spontaneously. So these are the different elements which we've shown in our original data on seven patients, and we believe will continue to be carried through to provide confidence for the phase III trial.
We can spend a moment as an aside here on ctDNA. How is the regulatory agencies now looking at ctDNA? I mean, I know there's gonna be a debate during this weekend on multiple myeloma-on MRD in multiple myeloma as an endpoint. I'm just curious as to, is this evolving as a potential endpoint as well?
It's certainly evolving, at least, with the agencies, as far as I can tell, into an eligibility criteria. There are some studies in the adjuvant setting where you can enroll based on whether the patient has detectable ctDNA. I think it is still in the agency's mind interesting and exploratory, but they want to see more validation. For us, what we've seen with KIMMTRAK and uveal is in two large trials, we've seen almost the identical data, which is a large percentage of patients have ctDNA reduction, and that depth of reduction correlates with the long-term survival benefit, which is what you want to see. You don't want to just see a reduction that has no clinical endpoint meaning. So for us, we have confidence on KIMMTRAK and ctDNA in uveal.
We're increasing our confidence in cutaneous melanoma with KIMMTRAK, and I think we're beginning to see the early signs for PRAME, for F106C, that likewise, ctDNA can be used. For us right now, it's certainly used for decision-making and for confidence building. But to your question, Gil, I, I think from a regulatory endpoint, more probably still needs to be done.
Yeah, that makes sense. Maybe as a last point, though, for this specific readout, what does the company consider a win here?
For this, readouts in.
Yeah.
In second quarter?
Yep.
Yeah. So I think for us, you know, in general, for all of our programs, I think what we wanna show is, number one, does the drug have monotherapy activity? That's, I think, where we have to begin. If a drug doesn't have monotherapy activity, I think it's hard to understand how just combining it with a drug X, you're gonna actually have synergy. So number one, do we have monotherapy activity? And, we know we do in melanoma because we've shown that data before. I think the second thing in this heavily pretreated population that we're gonna show, a heavily pretreated cutaneous melanoma patient, is: Is there sufficient monotherapy activity to inform the phase III study that we've launched? Do we have sufficient evidence that this, IMC-F106C as a monotherapy, and thus in combination with a PD-1 in first line, could lead to a PFS benefit?
Can you draw that line to that level of confidence? And then third, can we show safety? Can you show that this can safely be combined with a PD-1? I think that's what we would consider success in this, data readout.
So phase III would serve as somewhat de-risking for the phase III, which.
Exactly.
I think about now. So the phase III design includes two doses. This is part of Project Optimus, and the decision to remove one arm, either the 40 or 160, would be predicated on both efficacy and safety. Will there be sufficient follow-up in this first interim to identify one or the other?
Yes, so we do think that there will be sufficient follow-up, in terms of de-risking from choosing the best dose. In parallel, we've also been backfilling the current phase I study at different dose levels, and I think the data we're accumulating there, plus this interim analysis on the first 90 patients, will provide confidence that we can select the correct dose to advance.
Will ctDNA measures play a part in this?
I think so, Gil. We can consider ctDNA as adjunctive, but I think for a decision where we're going to make, you know, where we have a large investment in phase III, we probably wanna tie the decision more closely to the primary endpoint of PFS. And ctDNA is still exploratory, so it will be adjunctive, but certainly, but I don't think will be the primary driver of the decision.
Okay. Maybe a broader question. So approval based on PFS is pretty typical in many of these indications. Is there any reason to believe you may also see survival benefit over what you would normally expect reflected just out of, you know, median PFS? That's given the difference in mode of activity, right?
Right.
I mean, oncology agent looks very different.
Yeah. No, what you're highlighting is, you're asking a question, based on the KIMMTRAK data, where we saw a statistically significant PFS, hazard ratio of 0.73, but the survival was striking at 0.51. So the survival benefit outstripped the PFS benefit. And the reason for that is because there were a high percentage of patients who had radiographic progression, in quotation marks, that was not really tumor growth. It was actually what we believe is probably necrosis. With IMC-F106C, I think we're seeing that there is more traditional disease control than with KIMMTRAK, so that increases the belief that PFS is the right endpoint here. However, we do certainly see some patients with, radiographic PD who are probably having benefit.
So there probably is some of that, pseudo-progression type effect, which does lend us the hypothesis that the survival still probably will be better than what you expect for a traditional, just based on traditional PFS.
Okay. Now moving to the ovarian cancer cohort, can you remind us of, you know, what kind of patients are being enrolled? Are we evaluating both platinum and, you know, platinum-responsive patients or on platinum-resistant?
So this initial phase I, especially the monotherapy, is in platinum resistance, so patients who are either refractory or have relapsed on platinum, and it is very heavily pretreated. The majority have had prior Bev, and the majority have had prior PARP. So it is a very heavily pretreated population.
Okay.
And we are also studying combinations as well as some monotherapy and combinations.
Do you expect to stratify results by PRAME expression?
So, for ovarian and melanoma, we're enrolling all comers, and then we're retrospectively analyzing PRAME expression. And so not prospectively stratifying, but retrospectively. And the reason is for ovarian, the PRAME prevalence is so high, so that's the reason we don't pre-screen for PRAME. Different for lung. We can talk about that later. And what we're seeing is that it's something consistent that we've seen with F-106C in melanoma, which is the benefit is in the PRAME positives, and then you have a minority of PRAME negatives where you don't see benefit. And that, I think, you know, feeds to the biological plausibility and reason to believe.
Yep. And kind of setting the bar here, you said, you know, platinum, proc, right? Platinum experience-
PARP, yeah.
patients. So around 20% ORR, what are we talking here, regarding moving forward?
So, You know, I just following, Gil, the standard drug principles I have to move forward. Is the drug active as a monotherapy? Well, we know it is because we've showed those PRs before. The second thing is, what percentage of patients are having clinical benefit, and what is the form of that clinical benefit in order to to move forward? And then, can you combine with chemotherapies? Because that, that also provides your your guidance with the next step. So I think what we're seeing across the entire platform is that this is a disease control drug. This is a drug where you have both stable disease, partial response, but within the stable disease, you have patients who are having tumor reduction.
I think we wanna have enough reason to believe that we have disease control that's really related to the drug and not just, you know, you enrolled good patients, and you're having stable disease. There has to be real reason to believe that it's treatment-related. Then we wanna see, can you combine with therapies in order to follow what we think is the right path for this platform, which is to move earlier?
Okay. Obviously, many investors are interested in non-small cell lung cancer. You said we were gonna talk about that. Results are guided for the fourth quarter. Company previously noted that it's taking a more selective approach on non-small cell lung cancer. Can you provide any additional detail? I know you said you would at some point.
Yeah. So I will provide a little bit of framing around this. Certainly, we're interested in lung, and lung is a T-cell sensitive tumor. We know that from the PD-1 field. We also know from the PD-1 field that the activity was greater in first line than it was in second line, it was greater when you combine. And then it was greater also in certain subsets, like PD-L1 high, as a monotherapy. It was not active in EGFR mutant and ALK mutant and tumors where there's low tumor mutational burden. So you have to look at that information in order to guide how we're developing PRAME. With IMC-F106C, we have decided to really focus on the tumor, on the patients, where we think we can see an initial signal before more broadly expanding into other groups.
That's the reason why we've, you know, we feel lung is a more heterogeneous population, and I can go into greater detail on that if you're interested.
Yes.
Yeah. So we have focused on enrolling the patients that we think are going to be most likely to respond. We're doing combinations to allow us to move earlier, and that just has taken more time. So we'll have that data maturing this year, and then we'll be presenting that data in fourth quarter.
So speaking to the heterogeneity here, a lot, most patients express PRAME. So is this PRAME heterogeneity, or as you mentioned, like other important biological.
Yeah. I mean, Gil, to me, there's like multiple levels of, and so maybe it's good for me to explain what I mean by that. First is the, first is the, there's the PRAME expression, right? Some patients express PRAME, and some don't. In adeno, it's about somewhere between 40%-45%, that's the largest type, are PRAME positive, the rest are PRAME negative. So we don't want to enroll those PRAME negative, because we won't see a signal. In squamous, it's higher. It's about 70% are PRAME positive. So that's that first level. There's that just patient heterogeneity and screening that has to take place.
The second is, I would say, there's population-level heterogeneity, which is we know that, as I alluded to, some patients are EGFR, ALK mutant, some patients are Adeno, some patients are squamous. So there's population-level heterogeneity, different subsets, and we want to try and enroll the subsets where we think our mechanism can work the best initially before we, more broadly expand. And then there's the third type of heterogeneity. There's been several publications of this recently, and that is the intra-patient, intra-tumoral heterogeneity that appears to be quite common, especially after checkpoints. And there was a very nice paper on this recently, which is after checkpoints, there was a lot of heterogeneity in lung cancer. You don't see that heterogeneity after EGFR or targeted therapy, and you see less of it after chemotherapy, although you do see some.
That may explain why some therapies in heavily pretreated lung cancer don't have the same degree of benefit that they do in earlier stage. Now, you need to see a signal first. You can't say, if the drug has zero activity in late line, you can't say that it's gonna have all of a sudden, you know, great activity in first line. But I think what you can say is if you see an initial signal in heavily pretreated lung, it's likely to be even better in first line. But that's the heterogeneity that I'm talking about.
Okay, that is very helpful and very interesting. So, moving on to endometrial cancer, it seems to have taken a bit of a backseat here. Can you provide any additional input on that?
Yeah. Endometrial is one that I'm, I'm still quite interested in because scientifically it makes the most sense. It is a tumor where there is very high PRAME expression. It is a tumor where checkpoints do work, although not as well as it does, for example, in other tumors, but it does tell us that it is a T cell, T cell-sensitive tumor. The reason it's taken a backseat is because we saw initial data in melanoma, we saw initial data in ovarian, and we saw those initial ctDNA reductions in lung cancer, and we just had to, you know, as a small company, we have to focus our clinical development group, and we also have to focus the sites and say, "Please enroll ovarian, please enroll lung." If you tell them to enroll everyone, it becomes a little challenging. So we will follow up on endometrial.
It's certainly something that I want to follow up on because of the reason to believe, and I hope we'll have some more endometrial data for next year to show.
And maybe a last one before I move to tebentafusp and melanoma. You know, you have a great gp100 engager, and it looks like you have a great PRAME engager. How about using them both?
Together, you mean, at the same time?
Yeah.
Yeah. So we are studying that, and I think, you know, history repeats itself, or it rhymes, as they say. And I think initially we thought you could just combine them together at full dose and, you know, it would be fine. I think we're repeating the experience we had with Ipi and Nivo, 15 years ago, which is, you have to figure out how to give these two drugs together in order to maximize the benefit. And so that is something we're continuing to work on. And so I think probably next year will be a time to roll out that data.
So moving to another key clinical readout that we're looking for, and that's using tebentafusp in melanoma. Can you remind our viewers, the type of data that we're expecting in the fourth quarter?
Yeah. I'm really excited about tebentafusp in cutaneous melanoma. All of the data that we saw in phase 1 with tebi alone were promising one-year survival of 75%. In second line, after PD-1s, in combination with checkpoints, we see a one-year survival of 75%. All of the other metrics, tumor reduction, disease control, all of those match what we see in uveal melanoma. They're both gp100-positive tumors, so that's the reason for my excitement to believe. In terms of the data, Gil, to your question that you asked, we have these three arms.
We're asking about which arm should we take forward, and we're asking about should we change the size of the trial in order to repower it based on what we see? So the data that we're gonna have later this year on this initial three arms is ctDNA, which will be mature, and then survival. And it's probably trends in survival at this early time point because the full survival will not be mature yet. But those are the two pieces of data we hope to have by the end of the year.
Can you walk us through potential scenarios out of this phase III?
Yeah. So scenario one would be to drop one of the KIMMTRAK arms. So for example, if the KIMMTRAK monotherapy has the exact same ctDNA reductions, the exact same trending OS than the KIMMTRAK plus pembro, we would drop the KIMMTRAK plus pembro, because what's the point of adding something on, increased toxicity, increased cost, if you don't need it? So that's one example. Can we drop one of the arms? The second thing is, we assumed what the treatment effect would be. It could be that this initial large phase , or phase II gives us a more refined estimate of what the treatment effect is, and so we can update the power. We could change the size of the phase III, based on what we see in the phase II.
Cool. And one question we get from investors, could a positive ctDNA signal and a trend in OS at this fourth quarter juncture allow for a compendium NCCN guideline listing? And would such listing support reimbursement?
Yeah, that's a great question, something we've been puzzling about, too. What's interesting is that this is the first trial that I'm aware of that is a randomized trial in you know double refractory cutaneous melanoma. Every other company out there, of course, is doing single-arm response rate trials in this population. So we do think this is unique because we are randomizing against a control arm. We'll be providing survival. I think the question in terms of compendium listing is: what level of evidence will they accept in order to put it onto the guidance? On one hand, it's we have the benefit the drug has already shown a survival benefit in a different type of melanoma, uveal, so that gives reason to believe.
But I think, I can't guess what the committee will do in terms of ctDNA. They might say that it's too preliminary. They might say, "Yes, we believe the ctDNA." The survival is a phase II survival. You know, it's not a phase III fully powered, but we're hoping that the mature survival will provide enough confidence to the NCCN guidance. But, of course, it remains up to them. And then I think for reimbursement, it depends on the level of NCCN guidance that they give, and I don't recall what those levels are, but it's the strength of the recommendation that will drive reimbursement in the U.S.
Well, taking together, you know, the fact that most of these studies are, as you said, single-arm, don't you think this kind of boils down to safety? I mean, if you have a trend in OS and the drug is safe.
You would, you would think so. And, you know, everything we've seen in our, in our cutaneous is that the safety is the same. So we're, we're, we're hoping that the NCCN committee can recognize that we are doing the right study, which is a randomized study. And I think it'll come down to the strength of the phase II data.
Brian, this might be for you here. So given the larger size of second-line cutaneous melanoma population, especially when compared to, you know, to the uveal, will Immunocore consider adjusting the price? Or, you know, this is still such a rare indication that it does matter.
Yeah, I think we need to see the data, Gil. The data will drive. We look at, you know, the benefit as we looked at the survival benefit with KIMMTRAK and metastatic uveal. Obviously, and then the patient population that will be using it. So I think we'll have to look at the, you know, competitive landscape in 2026, 2027, as we hopefully can enter the market and make that determination then. I think the decision's probably also different in the United States than Europe, as there's different dynamics in the reimbursement market in those, and so it'll be driven by the data.
Okay. And another one here. PRAME targeting post KIMMTRAK, you know, hasn't really panned out very well. But is there any reason to believe that this would be the same case in reverse, if you start with PRAME and then move to KIMMTRAK?
Yeah, I would say, Gil, although we didn't see any partial responses in the PRAME after KIMMTRAK, we did see quite remarkable disease control. We did see ctDNA responses, so I think the idea of sequential ImmTACs still needs to be validated or explored. We know the concept of sequential treatment of all mechanisms evolves, you know, with whether it's targeted therapy, even whether it's PD-1s. How do you handle sequential treatment? So those. I think with ImmTACs, it's still early. My hope is that F106C will have a positive trial in first line, KIMMTRAK will have a positive trial in second plus line, and I'm hoping that as we learn more, you can see that you can actually sequentially treat. But, of course, we need to prove that.
Okay. I don't want to neglect the commercial success of KIMMTRAK. So launch continues to go from strengths to strengths. Where do we expect additional growth to come from in 2024, given, you know, high penetration?
Yeah. The growth in vial sales will be in Europe, primarily in 2024. However, given the price differentials between the U.S. and Europe, I think the U.S. still is 72% of net sales for us, Gil. So we still have more to grow in the United States, and we're really focused on making sure that every patient has access to the survival benefit of KIMMTRAK versus traditional therapies used in this setting. So that's what we're focused on. I think we're still only two years into the launch, so in the United States, so more to come. KIMMTRAK is the first-line standard of care for HLA-A*02:01-positive metastatic uveal melanoma. It's about 50% of the population that's HLA-A*02:01 positive for uveal.
So yeah, still more to grow in the United States and globally. So excited about where this can go for patients.
Duration of therapy has also been a big driver for KIMMTRAK.
Yeah.
Do you expect the current figure, which is around 10 months now, to continue to increase over time?
Yeah, it's probably a little over 10 months now. I think we published the phase III follow-up, three-year follow-up, and it was great to see those survival curves stay separated and the survival benefit. The tail is significant, so I think just the math would show that the mean should increase the mean duration of treatment as you have patients staying on KIMMTRAK and surviving longer. That's what we'd expect over time.
Kind of focusing again on Europe, what has been your strategy to increase coverage?
So it's really just negotiating price per country. What's really nice about Europe, it's a homogeneous commercial launch. So Germany and France, within six months of launch, and actually, we had early access programs there. We were probably 80% penetrated within six months, which is really phenomenal and really pleased with the healthcare systems there, rolling out KIMMTRAK as a first-line standard of care. So that is happening in Spain. We now have reimbursement agreement. We just got another Nordic country recently, so that we continue to add reimbursement country by country. Some of those countries have had early access programs or have early access programs, which translates to commercial uptake faster. Some countries don't.
So, Australia is one that you are basically starting over with your commercial reimbursement, which we now have. So that's ongoing. So I think you should expect the next 12-18 months, we'll continue to add European countries and global countries as well. We still have not launched in Latin America, which is an opportunity as well. So we're focused on that as well.
Excellent. And, maybe, maybe as a final point there, can you remind our viewers how you reach such extremely high gross margins? That's a bit of a unique feature here.
So our KIMMTRAK bispecific, no, our current PRAME bispecific is a microbial manufacturing process. And the team has gotten very good at that manufacturing process. We've now manufactured five clinical candidates and one commercial candidate. So the microbial process is down to a science, no pun intended, and we've been able to. The other part is that because our bispecifics have such high affinity for the target, these are very low doses. So KIMMTRAK's dose is 68 mcg, not mg. So you don't need that much drug to have the efficacy survival benefit that we have. So it goes a long way. So that's the reason for the low margins.
Great. So, David, going back to you, I do want to spend some time on the new autoimmune disease programs 'cause they're fascinating. Can you provide some background on these recently announced programs, and specifically, the ability to accurately target specific tissues. I think that's kind of unusual.
Yeah, so before we talked about specifically targeting cancer and then activating the T cells only at the site of the tumor or infection, if it comes to HIV or HBV. Here, it's a roughly similar principle, which is, can we target a tissue that is under autoimmune attack, but instead of activating the immune system, can we turn it off? And the general concept is the current standards of care in autoimmune are these systemically administered drugs, which is a sledgehammer approach and can lead to systemic toxicities. And can we have a targeted immune suppression or immune modulation only in the tissue of interest? And so we use the T cell receptor to target the inflamed tissue, and the effector end is a PD-1 agonist.
So it does the opposite of pembrolizumab, which is it pushes the PD-1 brake, doesn't remove the PD-1 brake.
So actually, a specific question there, you know, driving basically exhaustion of T cells or PD-1 activation. Is that sufficient to kind of slow down type 1 diabetes? I mean, it, it's a compensatory mechanism, isn't it?
Hmm. So there's a couple pieces of evidence, I, Gil, I think, to address your question. The first is that there's publications from mouse models, and then data from the pembrolizumab and from the PD-1 world, showing that type one diabetes onset and progression is related to the PD-1 pathway. And so there is reason to believe that if you block the PD-1 pathway or if you ablate it, that you can exacerbate type one diabetes. So that's kind of an indirect reason to believe. Second is, we have shown in vitro, and we can't really do animal studies because our programs are human specific, but we've shown that we can specifically bind to the beta cells in a human pancreas slice ex vivo. So we can deliver the ImmTAAI to the beta cell.
Now, to come to your point is, what would be the therapeutic effect of targeting the beta cell, the beta cell? So we've done some interesting stuff. First, in several experiments, when we create type 1 diabetes, which is an autoreactive T cell recognizing a beta cell line, we can see that administering this bispecific will prevent the autoreactive T cell killing. So we can prevent the acute killing. And so the one idea there is this initial programs all have a half-life extension. There's going to be a long half-life, and so you can imagine subcutaneous dosing infrequently to prevent the continued attack.
But the second thing we've seen, this was kind of, I guess, somewhat unexpected, is we have done experiments where you repeatedly expose the T cells to the ImmTAAI, to the bispecific, in the presence of the beta cell, and then when you remove the bispecific and you wash it away, T cells that are exposed to this ImmTAAI remain suppressed even after the ImmTAAI is removed. And so this does lead us to believe that you can lead to a disease modification by chronically exhausting the T cells with repeated stimulation. So we think both approaches, having the bispecific there will prevent the killing, but then repeated PD-1 agonism will lead to exhaustion.
Okay. And you kind of touched on this, but you're designing some different pharmacokinetics, pharmacodynamics for your assets here. Sounded like maybe longer exposure versus oncology assets?
Yeah, So with the oncology programs, they're this, you know, somewhat small molecules, but half-life less than a day, but of course you see quite good activity and quite durable benefit. Here, it's a different profile because patients are not gonna come in for, you know, people with type 1 diabetes are not gonna come in weekly. So we knew that you needed to have infrequent dosing, ideally the option for subcutaneous, and so we built this half-life extension, which is an Fc fragment. And so we think this could be administered monthly or so to patients.
Now, this same half-life extension technology can also be applied to our cancer program, and so we have one half-life extension program for PRAME, which is gonna be submitted for health authority approval to enter the clinic, sometime this quarter. It's to test whether half-life extension adds anything to our platform.
Okay. And last but not least on this topic, very interesting target, a tissue-specific HLA-agnostic- dendritic cell targeting. When, when should we see more details on this? It's, it's still pretty under.
Yeah, it is. So the lead program is type 1 diabetes, that's HLA-A2 restricted, which is about half of all diabetes or type 1 diabetes patients. The second program is, as you mentioned, Gil, is to a skin target, and what's exciting here is that it's not HLA restricted, so it's a non-classical HLA. It's not HLA-A*02:01. And so we think that this program can have a disease-modifying effect in multiple different skin diseases. We are just in the midst of filing the IP on that, and once we have that all set, then we'll be able to publish on that. But it is a program that's really exciting, both in terms of the patient opportunity, but also it's our first non-HLA restricted approach.
Okay. Speaking to other assets in oncology that would be entering the clinic in 2024, including the prolonged half-life PRAME and PD-L1, how is the company prioritizing these assets?
Yeah, Brian, you wanna take that?
Yeah. So, our goal has been to get proof of concept in phase I's. The company is really good at running phase I's and manufacturing these molecules, as I mentioned. And then once we have proof of concept, it depends on the disease type, Gil, we will consider partnering. So in the case of HIV, and type 1 diabetes, we're looking for proof of concept in the phase I's, and then we would consider partnering those. For oncology, we're very comfortable in melanoma, obviously, with our uveal launch, and then we'll have to see where we go with ovarian and lung. Too early to tell. We'll evaluate those as we see the data.
Okay, really a last one for you, Brian. Post-financing, strong cash position, you have a program that brings in a lot of cash on a yearly basis. Can you remind us some of your assumptions around the runway?
Yeah, so when we did the convertible in January, we did a six-year convertible, and that was intentional, to fund us into 2030. As we just went through the portfolio, there'll be many opportunities for commercial opportunities and partnering opportunities before 2030, so that was our objective. So with a little over $800 million in cash currently, we feel like we can, we have latitude to optimize this portfolio, Gil, and really look at the highest probabilities of success and evaluate programs on an NPV basis individually. And we have no restrictions right now from a capital perspective.
All right. Very helpful, and we're at time. I wanna thank you both for attending today. It's been very helpful for us and investors.
Thanks for having us, Gil.
Thanks, Gil. Appreciate the questions.