Good. All right. Welcome again, everyone, to the second day of TD Cowen's 44th Annual Healthcare Conference. Thanks very much for being here. For this next session, it's a privilege to have a fireside chat with Immunocore. From Immunocore, I'd like to introduce Bahija Jallal, CEO, and Brian Di Donato, Chief Financial Officer and Head of Strategy. Bahija and Brian, thank you very much for being here.
Thank you for having us.
Before I get started, if you guys have questions throughout the fireside chat, feel free to raise your hand or chime in. Be happy to take them. So I'm going to do things a little differently this year and start with PRAME instead of KIMMTRAK. We'll get to KIMMTRAK. But with PRAME, you have several updates throughout the course of the year: melanoma Q2, and ovarian Q3, and lung in Q4. Obviously, during the second quarter earnings, you guys provided an update on the melanoma patients from ESMO, and we saw encouraging early durability in these very kind of late-stage patients. But maybe you could help set the stage for the Q2 update and what we will receive both as a monotherapy and combination.
Sure. First, thank you for having us. So we did say that we'll start melanoma-enrolled more patients faster because we were in the sights for melanoma. We did update in ESMO on the 20 patients or so that we had from ESMO data last year. So the data we will bring are new patients, if you will, from the expansion. We didn't say the number, but we'll have the durability and everything. This is the same data that we took to the FDA and to the investigators before starting the phase 3.
Okay. And then we'll also receive some combination data, I/O combination data that we obviously haven't seen yet.
Yes. So the combination data will be, again, just to manage expectations. It will not be a lot of patients, just as we're looking mostly for safety there. But we will bring that data as well.
Okay. That's clear. And then as we think about the additional data in monotherapy and melanoma, is it possible that these patients could be less heavily pretreated than the ones we saw at the original ESMO presentation?
No, not really. So in late lines, they are heavily pretreated. They are prior nivo, prior ipi, and the BRAF when it's available as well. So I think very heavily pretreated. So this is in the second line or in the late line, basically. And to really make the decision to go earlier, we know from our platform that the earlier you go, the better. And what we looked at and will be looking at, basically, is the clinical activity. So basically, in that late line, knowing that looking at the disease control, the PFS, and the stable disease and so on is really the level of the clinical activity and the number of patients that exhibit that clinical activity are very important ones to predict, basically, what the PFS would be and how you design your phase 3.
That's the kind of data that you will be looking at.
Okay. Even though you guys, with your past presentations, have not had a very significant dose response, we should expect all these to be at the recommended phase 2 dose?
So as you know, we will have in the phase 3 so this will be at mostly 160 microgram, basically, dose. But we are testing 2 doses from the, sorry, Optimus thank you, the Optimus project with the FDA.
Okay. All right. As you mentioned, PRISM-MEL-301 is kicking off this quarter, initial randomization, then a treatment phase. So I guess, what do you need to see in the first portion to decide between the 40 microgram or the 160 microgram dose?
Yeah. So this will be we'll be blinded to that. So the IDMC is the committee, basically, will be looking at safety and efficacy for 40 and 160. We'll be recommending then to us and to the FDA, basically, which one to drop. And we'll drop one and we'll continue.
Okay. And as we think about the ultimate readout, how long might it take to get that? And what do you think you need to achieve on progression-free survival to beat the control arm from a statistical perspective?
Yeah. So there are two things here. One is, I think, to the first question, it's hard to say. I will just say that we initiated the sites. And you really have a better idea once you start recruiting patients, right? So however, if we look at just what's in the field, for instance, Xarela and others, it takes approximately 3 years. So that's what we're counting on. I hope we will strive to be faster. But that's basically where we are. I think, as what I alluded to, we don't really discuss very much the design of the trial. But in a phase 3, you want to have at least design something around 0.75 on the PFS.
From what we are, what you expect, basically, from the clinical activity or the disease control, that you need to have at least a minimum of 30% of patients that are benefiting because that translates then into PFS in the phase 3.
Okay. Let's move to the ovarian update during the third quarter. How many patients could we get there from both the monotherapy and the combinations? Will that be more balanced relative to the melanoma update that you just described?
So we're not guiding on the patients. We're enrolling right now. So I can't really sincerely answer that question. I think we will have also some we will have combination therapy as well. Again, we made that decision to have the combos going at the same time. Sometimes, like in the melanoma, it's mixed patients, frankly, because we don't want to turn around patients because we're looking at the safety. So that by the time we decide, like in PRISM-MEL or other things, we don't have to do a safety run-in. So that's how I would look at the combination. But we'll have both. We'll present the monotherapy and the combination as well.
Okay. And I presume combination is like platinum chemo?
The platinum comes after. We have it in the program to come. Because we are in platinum resistance, we put the other chemos first. But we will do the platinum as well because that's important if you move earlier.
Platinum. Sounds good.
Yeah.
Okay. Do you think it makes sense to move earlier over time in ovarian, just like you guys are in melanoma?
Yeah. I hope so. Definitely. I think we have that possibility. But we have to start in the late lines, and then, depending on the data. So that's why we're doing the combo. And as you move into earlier lines where we know immunotherapy works better, you combine with the standards of care.
Sure. Are there any potential safety considerations as you think about combining with chemo?
Not so far. So we do believe that there is no overlapping toxicity. So that's what you really worry about, that you have overlapping toxicity. But it's not. And so far, our platform, we're lucky. I don't know if we have any wood. But it combines very well with the multiple agents. Yeah.
Got it. Okay. And I guess in the late line setting for ovarian, when you think about a bar that you would need to achieve to be excited in terms of response rate, is there anything you can say regarding that?
Yeah. So it's what I said before. I think what we learned from KIMMTRAK and knowing that PRAME is a little bit different but still has immunotherapy, in general, are very much focused on clinical activity because you look at in clinical activity, you're looking at the disease control with PR and stable disease. You're looking at the ctDNA. We want to capture as much as possible. That I don't believe is going to be just in the ORR or something like that. And we want the two dimensions that I talked about, seeing the level of clinical activity and the proportion of patients that exhibit that clinical activity, I think is much more predictive of what's the PFS you can have as you move into a larger trial. So we don't want to miss that.
I think if we learned anything from the immunotherapy and KIMMTRAK , it's really you don't want to miss that signal by just focusing on the RECIST response. There's more to that.
Yeah. That's for sure. I mean, I think you guys have the only oncology drug with a response rate below 10% and a very significant survival advantage, so. I guess if you guys do give us a spider plot, then you guys are going to want to basically be keeping those patients down or going sideways as long as possible.
Correct. That durability, I think, is really important. Yeah.
Okay. All right. Now, lung in Q4, I've learned now by the third update not to ask you about how many patients since you're still enrolling. But what should we expect from that update?
Yeah. So before I go there, I just want to close on what we just were talking about. So when you think about what we've seen, you have the PR. But you have the stable disease we're talking about. Sometimes you see patients with 29% reduction that behaves exactly like a PR with that kind of durability. That's really what you want to be capturing as well. Yeah. On the lung, we are signal searching there. We decided not to go with an all-comers, knowing how heterogeneous the lung is. We said that it took us a little bit longer to open the sites and everything for the lung. But we are recruiting right now. And so we believe by Q4, we can bring the data as well. We didn't say which subgroups. But you can imagine which subgroups we're talking about.
Yeah. The obvious ones. Yeah. So you guys did mention, though, that you do have a PRAME expression threshold. You haven't disclosed what threshold unless you'd like to do that today. But I think you guys are exploring multiple thresholds, right? And why do that for lung as opposed to other tumor types?
Yeah. So in lung, I think ovarian, the majority is express PRAME. So we're not going for that. I think in melanoma is the same thing. I think in lung, it's at least 40%, I think, of patients or so. So you had to go for at least understanding the threshold.
Yeah. About 70% of squamous express PRAME and about 50+% of adeno. Adeno, interestingly, is much more homogeneously expressed, whereas squamous is more heterogeneously expressed. So you have these dynamics. I don't think we have a hurdle, right? There's no bar for us. But we are segmenting them so we can see what the response is and the clinical benefit is in different categories. Got it. So is it fair to say that you guys are just as interested in squamous as non-squamous?
Absolutely. Yeah.
Okay.
We are signal searching the entire spectrum of lung.
Interesting. Okay. And again, just to be clear, we're going to get both monotherapy and combination data here.
Yeah.
Okay. But you guys led with the monotherapy before you did combo. So we should think about you guys getting more monotherapy data.
We always get more monotherapy. But we'll get also the chemotherapy at the same time. They're both open.
Okay. And just as we think about PD-L1 expression and TMB status, based on the data you've reported in the past, do you think either of those markers will have a significant impact on the ability to respond?
I really don't believe so because we saw from KIMMTRAK that the TMB didn't matter because it works in cutaneous melanoma with high TMB. But it works also in UV with very low TMB. So that's not the one criteria. And nor is the PD-L1, actually, high and low.
Okay. Any questions on PRAME before we go to KIMMTRAK unless you have anything else to add?
No. I think we had all the good questions.
Great. KIMMTRAK, the first approved TCR product, you guys have had an exceptional launch, $239 million in the second year, first full year. So what should we expect for KIMMTRAK growth throughout 2024? And what will be the primary growth drivers?
Yeah. So in the fourth quarter over third quarter, we grew 13% in the United States. Europe was roughly flat. We expect to continue to advance KIMMTRAK in the United States. It's now the first-line standard of care. And it's also primarily dosed in the community, which is excellent since immunotherapies start in the academic centers and then move to the community. But there's still health systems that we need to penetrate in the United States. So more growth, we think, to come in 2024 from the United States. Europe, we're continuing with sales growth as we have now reimbursement agreements with Spain, Canada, Australia. Those will be opening throughout the year. So growth in Europe, the reimbursement environment in Europe is much more challenging. So the price in Europe is a fraction of that of the United States.
From a net sales perspective, the U.S. is still going to be a big driver.
Can you just remind us how many patients are getting treated in the community now in the U.S.? I mean, obviously, I know some of them go to centers and get referred. But how widespread is that now?
I mean, it's a majority that is in the community. So really pleased with the uptake. Traditionally, ipilimumab was the standard of care for metastatic UVL, although not specifically a label for metastatic UVL. So that just requires education on our part to show the survival benefit. Our hazard ratio, as Tyler said in the phase 3, was 0.51 versus Investigator Choice, which 82% of the investigators chose Keytruda, so PD-1. So that just requires education over time. We're only our second year in the launch. So excited where we are. But more to come.
Yeah. Just to add, one insight we get from the market, which is always important to see for a drug, is we've seen going from academics to the community pretty early. And that usually is when you're comfortable with the safety. And we've seen that in the three-year survival that we published, you see there is no accumulation of toxicity or safety along the way. So if you're going to get CRS, you get it at the beginning. And then after that, that's really encouraging for the community. And now it's more looking at starting in the community, which is what Brian also talked about.
Okay. And I know I talk about the 99%-plus gross margin every quarter because it's wild. Never seen anything like it. And I guarantee that not everyone in the audience appreciates it because they're not updating a model every quarter like I am. But how are you getting, again, 99% gross margin? And will that continue? Because obviously, if you've got two $400 million products, one's 99% gross margin, the other one's 70%, you get a much higher multiple. And the one that's 99% gross margin is you think about valuation. So we'd love to.
So just for those that are new to the story, this is an off-the-shelf bispecific that is dosed in micrograms. So the targeting end of the bispecific that is targeting the tumor is picomolar affinity. So it's specific just for the tumor. So therefore, we're dosing, as Bahija mentioned, 40 micrograms for PRAME and 160 micrograms for PRAME. KIMMTRAK, our commercial products, dose at 68 micrograms. So incredibly low dose is efficacious. That's number one. Number two is it's microbial manufactured. So you can make a lot of it. And it goes a long way. So that's the cost-of-goods opportunity, very different than cell therapies or TILs, which are much, much, much greater.
Or even monoclonals because we're thinking in the hundreds versus the thousands or tens of thousands.
Even small molecule pills. Basically, everything else is a lot more manufactured. So as we think about PRAME, would you expect similar manufacturing and similar gross margins?
I would.
Yeah. Excellent. All right. So the TEBE-AM phase 2 top line.
Not to predict price on PRAME. But yeah.
Yeah. No formal guidance. But still amazing gross margins. And that's me talking, Tyler. So what should we expect from the TEBE-AM phase 2 update later in the year from the phase 2/3 study in Q4?
So the enrollment in that trial is going well. I think we're on track to bringing the data in the second half. What we will be looking at are two things. One is exploratory. That's the ctDNA. Then the trend in OS. The trial is powered for that to see the trend in OS. I think the decision to make there is basically, we have two arms. We have a KIMMTRAK arm and KIMMTRAK plus Pembro. Do we drop one and continue? Then the other one basically allows us to see if we are powering properly the phase three, underpowering or overpowering, so we can adjust. Hopefully, if we are successful, we'll be able to increase then the probability of success for the phase three.
Okay. I guess ctDNA is pretty straightforward, right? You'll look at difference in reductions there. A trend in OS, I think you talked about on the earnings call, survival being more mature in 2025.
Correct.
Could you file for approval on that potentially? Obviously, I know the data is going to mandate that. Then how do you think about filing versus NCCN compendium listing?
Yeah. So we'll always wait. I don't want to get ahead of myself with what the data tells us. And there is always, if you publish the data or present it or something, you can always file for the NCCN. Anything else, you have to have agreements with the FDA. And I think we are never shy to go to the FDA if we have good data. So we'll wait for the data to come.
Okay. If you didn't file for approval, but you've got a compendium listing based on a presentation, would that be covered broadly?
It should be because it's an approved drug already. The NCCN guidelines are yeah. It's.
In the United States?
Yeah.
We anticipate. Not Europe, obviously.
Okay. Yeah. They don't really pay for it anyway, so. I'm just kidding. They just pay less. So the ADAM Phase 3 trial in adjuvant uveal melanoma kicking off, perhaps you could highlight the data or the initial early proof of concept that encouraged you guys to do this trial?
Yeah. There are several points that really encouraged us to do the trial. We believe that has hopefully high probability of success. One is the fact that when we look at with KIMMTRAK, for instance, when we look at the phase 3 trial, for patients that have tumors less than 3 centimeters, the hazard ratio was 0.36, which is really amazing. That means the smaller the tumor, the better it will be. The other thing is we looked at when we have robust data in uveal with the ctDNA, for instance. We see a triple we see in the second-line trial that we have decrease of ctDNA in 60% or so of the patients. When we move into the first line, we triple the number of patients when there is a reduction of ctDNA.
So you can imagine if you're going less than 3 hardly detectable tumors that should work even better. So that's, I think, our assumptions going into the trial. These patients, basically, 50% of them will develop metastasis. And so hopefully, catching that up before they develop metastasis would be great.
Okay. And on that topic, I imagine for approval, you don't have to show anywhere near a 0.36 hazard ratio. But what do you think the bar might be for approval on RFS?
The patients, if I'm just getting my recollection, basically, they will remind me how they relapse, how long they relapse.
2-3 years is the mean for relapse. Could take as long as 10 years. However, the control arm here will be straight to follow-up. So it'll be a 1:1 randomized trial. So how those curves separate means we won't have to wait 5 years post-enrollment for the efficacy. Hopefully, it's a 4-year enrollment period. And then within 9-12 months after that, we have the curve that will predict whether KIMMTRAK, for a 6-month dosing period, can stop that micrometastasis to liver. And these patients can live a lot longer, hopefully.
Got it. So there will be defined interim looks where they could look at the curves.
Correct.
Correct.
All right.
But the ctDNA will be helping there.
In the last five minutes or so, maybe we'll move to some of the other pipeline, which is expanding rapidly. So PIWIL1 for colorectal or other GI tumors, new program that's entering the clinic. When could we see initial clinical data from this program? And why are you excited about it?
Yeah. So we're excited because it has a little bit of the characteristics of PRAME. It's a negative prognostic marker. It's expressed only in cancers. It's a CTA, actually. This is the cancer antigen, testis antigen. So it's another one. So far, I think we have not seen it anywhere else. We're excited about it because it really addresses the colon cancer. And colon cancer has been in the GI altogether. So hopefully, it's another one that has not been sensitive to checkpoint inhibitors. So it would be good to test it there. Just to remind everyone, we always start at MABLE, so at the very low dose because we don't do any tox studies in animals or anything. So we start at the low dose. But we incorporate the learning now to go faster. So we probably won't see data this year because it starts in Q2.
And then just going through the dose escalation, the observation, and so on. So probably by 2025, we'll have data.
Okay. That's helpful. Autoimmune disease is a very hot area right now. You guys, fortunately, are not another CD19 CAR-T. Maybe you could discuss about your strategy in autoimmune and how you're differentiated.
Yeah. So you say autoimmune, and I smile because I'm really excited about that area. We neglect how much it's 80-90 diseases and so on. And so what we wanted to do is to really come with very differentiated and we've been working on that for a while. So we've now shared with everyone now that we have a clinical candidate. And the idea here is the steroids really work. But they are a sledgehammer. So we have the expertise in research. We know exactly how we map that. That's how we got PWIL1 and everything. We have the research to look at peptides that are expressed only in a certain tissue. We did the same thing. We mapped, actually, the human body, if you will, with multiple organs and to look for peptides that are expressed only in pancreas or other things.
We know from our platform, we managed, actually, to make an agonist of PD-1 to basically turn off the T cells. What was really important for these, why we believe it's differentiated, is, on one hand, it's going to bind the tissue. But on the other hand, it brings PD-1 where it likes to function, which is in the synapses. And so we've seen a really nice inactivation of T cells. So the first program is in Type 1 diabetes because we have the preproinsulin that binds to the beta cells. And on the other side is the PD-1 then to turn off. And so we show preclinically that we can protect the beta cells and so on. And so now it's really a matter of doing that in the clinic. The second target is actually a universal target. We have not disclosed the target.
It's more for skin inflammation. Both of them are in GMP tox. The data that you said about the cell therapy with the CD19 at least puts the proof of concept. We believe that with us being also very targeted and the easiness off the shelf and the CMC, I think, makes a huge difference for patients that are more chronic, if you will.
Fantastic. So HIV data, second half of the year. What would the next maybe what you're hoping to see? And what would next steps for the program be?
It really depends on the data. But what we're looking for are two things. One is we're going after the reservoir. Nobody has done it before. The important thing is, are we touching that reservoir? Can we decrease the reservoir? That's the first set of data. That's on the first part of the trial that we're adding our drug. The second one is, if we decrease the reservoir, does it induce then a delay or a complete stop of viral rebound? These are two things that are very important because it depends then, depending on this data, the follow-up will be clearer.
Okay. Brian, cash, cash runway, you did a convert. That was basically free money, 2.5% converting at just under $95 per share, significant premium. But maybe you could talk about the runway that you expect based on the pro forma cash.
Yeah. With the convert, thanks, Tyler. We have about $800 million of cash. And what that gives us is flexibility to advance this portfolio. So we don't have to partner anything early, too early. We can find the right partners ultimately when the time is right or do it ourselves. So it gives us all that flexibility with this great clinical portfolio that we have. So the convert's a six-year instrument. So we're good. Last year, we were cash neutral for 2023, which is great. We'll see where we go for 2024.
It's 99% gross margins. All right. We're up on time. Maybe just to close, I'll ask you both what you believe is the most underappreciated aspect of the Immunocore story by investors.
So I truly don't believe that there is. I think there's just more things to talk about in the Immunocore. I think it's more if I reflect on what we are learning. So we are pioneer in this area. But that means the good part is that we know a lot. Then the other side is that we still have a lot to learn, right? And I think when it comes to what we learned from KIMMTRAK, we're learning that RECIST criteria was developed for chemotherapy. So it's continuous education on when you look at the signals here, really, you have to look at the entirety, right, what we talk about, the clinical activity, the disease control, that you don't miss the signal that's really important for how these drugs work. So that's, I think, it's continuous education to us and to everybody, frankly, how this immunotherapy works.
I'd say for me, it's because we're using. It's an off-the-shelf bispecific. And you're using your body's own immune system to attract T cells to the target and cancer to kill. And in the case of autoimmune, to repel. I think it's unappreciated that if you move earlier in the treatment paradigm, how effective this treatment can potentially be.
That's great. Thank you very much for the wonderful discussion.
Thank you.