Okay, good afternoon everyone, and welcome to the Cantor Healthcare Conference. This is the very last fireside chat of the day. Of course, we've got a bunch of great topical panels afterwards, so I hope you can stick around for those. And those of you who are still here with us, we've got a near full room, you will be well rewarded, I promise, with a great presentation and chat from Immunocore. We have with us the company's Chief Executive Officer, Bahija Jallal, as well as the company's Head of R&D, David Berman. David, Bahija, thank you so much for being here today, and I'm joined up on stage by my colleague, Imogen Mansfield. Bahija, maybe just start with a high level for those who might be a little bit less familiar with Immunocore. What's the sort of 64,000 sq ft view of where you are today?
Sure. Well, first of all, thank you for having us. You know, if I describe Immunocore in three points, we pioneered the soluble T-cell receptor bispecific with the first ever approval in solid tumor. Because, and thanks to the fact that the technology is modular, we have a very deep pipeline, but also diversified pipeline that spans oncology, infectious disease, and autoimmune diseases, and I'm really excited about that one. And then the third one is, we had a very successful launch with our first product, KIMMTRAK. And thanks to that, and also a very disciplined, you know, disciplined spend, we have a very strong balance sheet that's allowing us now to finance the pipeline.
You wanna just give us a quick snapshot of that balance sheet?
$800 million.
Thank you. So the case for investment in Immunocore, we were talking before the chat about the debate on the stock today. I'm a stock guy. You've been spending all your day with investors today. What do you think is not being fully understood or appreciated about the company?
Let me tell you what the value that I see in the company that hopefully will be visible to everybody. If we take just the flagship product, KIMMTRAK, just for the first half of the year, we announced $146 million. That's 34%-37% year-on-year growth on $146 million net sales. And we don't stop there, so there is still growth to be had in KIMMTRAK, and we can talk about that. But as we go into the midterm and long term, there is also that we have two phase IIIs. One that started already, that's the TEBE-AM, that could add in cutaneous melanoma, that could add another 4,000 patients.
The adjuvant trial, that's at least 1,200 or 1,500 patients, that can really take us from 1000 patients now to, if we are successful, to almost 6000 patients. So just on KIMMTRAK alone. With that, we have, you know, more innovation coming. So we have PRAME, we have PIWIL PRAME. We showed now the first phase III in cutaneous melanoma first line, and then we are looking into ovarian and other indications. P just accepted now by the CTA accepted, so we are about to start the dose escalation in colon cancer. And this is just, again, oncology. Of course, we have outside of oncology that will be also very, very exciting. So, for me, that's, you know, a lot of value to be had.
Okay. You mentioned the KIMMTRAK run rate approaching $300 million on an annualized basis. Where do you think we are in the penetration curve for that drug? How much growth is left?
So, you know, when we think about the penetration and we, you know, think about the U.S., we have around 65% penetration right now. However, you know, we do see still more growth in the U.S., and definitely, the majority of the growth will come from the U.S. As we go outside of the U.S., as you know, Europe has its first of all, is country-by-country negotiations on the price, and the price is not the same. So our approach there, while we know it's gonna be incremental, but we're bringing this medicine to patients through more launches in Europe and outside of Europe. So we have nine, just this year, we launched in nine countries already, and we continue that way. So that's... And the penetration in some of the countries or in Europe are pretty really high, like, Germany is in 80%-90% already.
But one of the big drivers of growth that we've seen over the last couple of years is duration on therapy.
Yes.
This has exceeded probably almost anyone's expectations. We're about, I think, 12 months on average or so, duration of therapy-
Yeah, eleven months.
Eleven months-
Yeah
G rowing. Well, is there ever a reason to come off this drug? David, when you talk to folks in a real-world practice setting, are they very reluctant for a number of reasons to take patients off? What's happening?
You know, when we speak to the doctors who treat in the commercial setting, they say that their patients have radiographic progression, but they're actually feeling better. And sometimes they'll treat these small lesions and continue them on therapy. Interestingly, and we can talk about it later, we're seeing the same phenomenon even in ovarian cancer. So we can talk about what we're seeing there also.
With Brenni.
With Brenni.
Yeah, Brenni.
You know, in the ovarian phase, data we just showed, 64% of patients who had progression were treated beyond their progression on average about two months. So there's something very interesting with this platform that we're continuing to learn about.
We'd love to talk about that.
Yeah.
So with... Sorry, go ahead.
. No, I was just going to add, because you've been in this field for a long time, usually the duration of treatment is less when you get into the market versus in the clinical trials, which is very well controlled. We're seeing the opposite here, and I think that speaks volume for the product.
So patients are progressing, they're staying on the drug. Is there a theoretical limit to where the duration could end up being?
We don't know yet. I think it's, you know, so eleven months so far, which surpasses what we've seen in the clinical trials, and so we don't know. We had the three-year survival. We have anecdotes, of course. We have patients that came that were on treatment for seven years, six years. This is a disease that usually they die after 12 months, so we'll see. I think this year, the 2025 , we'll have a five-year survival as well.
Okay. And, KIMMTRAK, TEBE, is also in a pivotal study. I think your next pivotal readout will likely be the TEBE-AM study, second line, cutaneous melanoma. First, David, maybe just remind us on this design, you made the decision to-
Mm-hmm
M ove directly into the phase III stage of that study, earlier this year.
Yeah. So the trial is a randomized phase III, three arms: KIMMTRAK, KIMMTRAK plus Pembro, and then investigator choice. So investigators can choose to do whatever they want. The primary endpoint is overall survival, which plays to the KIMMTRAK strength. And as you pointed out, we recently did convert this from a phase II, III seamless into a phase III.
Where is your confidence or optimism in a successful phase III result coming from?
So we had two phase I KIMMTRAK trials. We had KIMMTRAK monotherapy in the early days before anti-PD-1s were broadly available, and there, the one-year survival was 75%, so pretty much what you see with PD-1s. Then we had this about 60 patients of KIMMTRAK plus checkpoints in a PD-1 relapse refractory setting, and interestingly, the one-year survival was 75%. Historically, it's about 55% in that population. So we had two independent data sets, which give us confidence. I would say also, when I look at the KIMMTRAK cutaneous melanoma data, the response rate is low, like we see in uveal, but every metric that we saw for KIMMTRAK in uveal, I see those same metrics in cutaneous, and that's why I have a pretty high conviction.
Those metrics being specifically. Okay.
So we see durable tumor reduction. We see patients who have progressive, "progressive radiographic disease," but have very long-term survival. So you can line them up metric by metric, and I think we're seeing the same thing with uveal that we see in cutaneous. And-
In that context, have you been able to biopsy data or patients who, post-mortem data for patients to look at whether that, pseudoprogression is in fact necrotic tissue and... Or if it's-
Yeah, we have had some imaging-
Anecdotes.
We've had anecdotes of those-
Yeah
At time of progression, and there, interestingly, is evidence of necrosis and macrophages, and we don't understand why the tumor doesn't resorb it. But clearly, you know, this is a novel platform, so we certainly need to investigate that more.
Another drug that you already mentioned seems to be acting by a similar novel mechanism in a maybe unconventional way is Brenni. Maybe before we get too deep into how these drugs are working, just remind us of the Brenni data that we saw in melanoma at ASCO, and-
Sure
... the stock reaction to that wasn't so positive. So potentially, you could address what investors are not seeing.
Sure. So number one, we see single agent monotherapy activity in heavily pretreated cutaneous melanoma. That's something that can't be said for a lot of biologics. The response rate was 11%, so modest, but interestingly, the response rate for ipilimumab in a post PD-1 setting is also 11%. We also saw benefit in patients with stable disease who had durable tumor reduction, an additional 17% of patients. And the reason I call that out is because in our KIMMTRAK uveal data, patients who have stable disease and tumor reduction have the exact same clinical outcome as patients with PR. In other words, the depth of response doesn't seem to matter. We saw about one out of every three patients have a ctDNA molecular response, and having a molecular response correlated with longer PFS and survival.
Those were clear evidence to me that somewhere between, you know, 28%-35% of patients are having clear monotherapy activity. Second is we looked at disease control rate because we know that's a good predictor of PFS, and our DCR rate was about 56% for brenetafusp monotherapy. When we put that into context, we looked at RELATIVITY-020, which is NIVO plus LAG-3, so a combination. That DCR rate was 40%. Finally, we presented data on T cell fitness, which shows that as you move into earlier lines, our activity should improve because the T cell fitness of the patient. So as we head into PRISM-MEL, I think there are three multipliers that we anchor on, and I've mentioned them. Just to repeat, the DCR for our monotherapy is better than NIVO plus LAG-3 in an apples to apples.
Number two, we should expect greater activity as we move to first line, and then finally, in the first line setting, we are now adding two active agents together with different mechanisms of action, NIVO and Brenni.
So what you've just described between either TEBE or Brenni, KIMMTRAK or your PRAME molecule, is kinda turning the cancer drug development platform almost on its head, right? I mean, this is a very unconventional thing that's happening, where we're seeing patients seemingly do better, whether or not they have deep responses or stable disease. We're seeing patients even who progress, seemingly live longer. You've proven that with-
Mm-hmm
With TEBE. What's going on? What's your best guess or explanation for how your drug is acting in a, again, very unconventional, unprecedented way, which has pros and cons, right?
Yeah. So the general phenotype is certainly one of disease control, and we've coined this term a "closed umbrella spider plot" to really capture what it is that's going on. Now, we do have evidence of cytolytic activity, because we do see durable PRs. I've already mentioned we see durable tumor reductions, we see ctDNA molecular responses, we see necrosis, as I talked about with the imaging. So there is evidence that there is killing going on, but there also may be evidence of something else going on that we don't understand. And radiographically, when we speak to radiologists, they say it could be a picture of necrosis, it could be a picture of inflammation, it could be a picture of vascular hemorrhage that's occurring. So clearly, more needs to be done to understand what exactly is happening.
You think that phenomenon is going to be applicable to the broader field of bispecific T-cell engagers? Any evidence of that elsewhere?
There's clear evidence in other therapies. You know, we saw that with ipilimumab, that the RECIST response underestimated the benefit. It's also seen with Avastin, interestingly, sorafenib, so we see that also maybe a little bit with the VEGF inhibitors. I think right now, the field of bispecifics and solid tumors is still early, right? There's only now two approved bispecifics, so I think more to come as more data comes out.
I mean, this is both a blessing and a curse. This, you're laughing because I know you deal with this all day, Racha.
Mm-hmm.
Feel free to jump in. I mean, how do you allocate resources when you see many unconventional signs of activity that don't necessarily show up immediately in a RECIST response?
Yeah, I think the, you know, ultimately, you have, as I was saying to somebody today, we are, you know, we're going for the long, long-term gain, right? Or the long-term run, because here, ultimately, what matters is the OS, right? So we did have drugs that were good on ORR and stuff like that, but didn't have the OS benefit. Ultimately, you want the patients to have that survival. We made that decision the first time, yeah, I think, when we joined the company to go to phase III with the very low ORR, where, you know, because we saw signs that it's really underestimating the impact, and when you talk to investigators, they tell you that. Now, I think what we know is that, to your point, being first or being ahead is good and challenging. You know, good because you're ahead-
Yes
And then, it's challenging because you have to produce all the data, all the questions that we have, and we are very much scientifically minded, and that's exactly what we're gonna do. I think, you know, when I see a drug, I've been in the drug development for 30 years, to not age myself, but 30 years. But to see something that's working even better in the markets than in clinical trials and prolonging life, you know, we owe it, I think, to patients and everything to continue.
David, the more data you see on this phenomenon between Brenni and TEBE-
Mm-hmm
The more similar, or are there differences that you would point out between the two?
So there's certainly similarities, but there's a major difference, and we presented that data this weekend at ESMO, which is in our T-cell fitness oral presentation, we showed the discovery of T-cell fitness in KIMMTRAK about 132 uveal melanoma patients. And then we showed replication in 22 uveal melanoma patients treated with brenetafusp. And actually, if you look at the demographics of the two populations, the uveal melanoma Brenni was a little bit worse off, more heavily pretreated, and about a quarter actually had prior to brenetafusp. But other than that, general. Now, if you look at the T-cell fitness predicted benefit in both, so that's fine. But if you look at the outcomes on Brenni, all of the outcomes indicated more disease control. The PFS was actually much longer for Brenni in uveal melanoma than it was for KIMMTRAK.
The survival actually was much longer. The disease control was better. The responses were better. So it's another evidence that Brenni is more of a PFS disease control drug than KIMMTRAK in an apples-to-apples population.
You ascribe that to antigen? What do you would to what?
I don't think we understand it really well. I think we have the most data from the clinic right now, and trying to answer the question: Is it antigen? You know, the level of the antigen, you know, the homogeneity of expression and so on-
Yeah
... but we really don't know.
But it certainly makes you-
Not yet
... feel good about your investment in Brenni.
Yeah, it's-
And-
It's clear, yes.
We are all in on Brenni?
Absolutely, yeah.
We are going to do a pivotal study in PRISM-MEL, as we'll talk about in a moment. In ovarian, we're going to develop Brenni to the fullest as well. Have we made that decision?
will be based on data, so I think the data will tell us. I think the first, you know, what David presented with the team at ESMO is telling us is definitely, you know, and not just us, the KOLs and everything, there is activity there. There is activity to look at more in the PROC and PSOC as well. So I think we will expand, increase our reasons to believe, and then if the data warrants it, we'll move into phase III.
How are we feeling about Brenni outside of melanoma and ovarian at this stage?
So go ahead.
Yeah, so, we've showed the Brenni melanoma ovarian. The next tumor that's being mostly enrolled is the lung cancer cohort. Now, lung cancer is a more heterogeneous disease, and I would say that the patients we're getting on are very heavily pretreated, very aggressive tumors that are coming on the trial. So we've generated some data, as we've said we would, and we're continuing to enroll a few more, some more patients, and we're discussing this data with the key experts from the key lung cancer experts on the trial to see if there's a complete story to present, and so once we finish those discussions, we can update on the next steps in the fourth quarter.
You want to get to
In the PRAME-positive patients, for lung, do you see any differences in the homogeneity of expression or copy number compared to...?
So the major difference, imaging that we see in lung is 90%+ of melanoma are PRAME positive, and it tends to be homogeneous. In lung, I'd say about 70% of squamous are positive and about 40% of adeno. Interestingly, the expression of PRAME is, you know, reasonable in terms of homogeneity. It's not very sparse. I don't think it's rate limiting. I think the challenge for us in lung cancer is it's the patient's aggressiveness and the heterogeneity, the intralesional heterogeneity of the patients. And interestingly, the T cell fitness of the lung cancer cohort is among the lowest out of all of the tumors we've looked at to date. So I think third line lung cancer is just a very tough place to study immunotherapies in general.
So I know we want to talk about the recent update in ovarian and get your take on what you showed at ESMO. But maybe before we move too fast, too far into the secondary indications, the PRISM-MEL study, David, just quickly remind us of that design timeline.
Sure
... and its milestones to look forward to.
The PRISM-MEL is a two-arm study. It's NIVO plus Brenni versus NIVO or NIVO plus LAG-3. We expect that the majority of patients are going to be NIVO monotherapy, with the minority being NIVO plus LAG-3. Primary endpoint is PFS, secondary endpoint is survival, and the trial is enrolling now, and we expect to complete the trial in 2027.
How competitive is recruitment in this indication, frontline melanoma?
You know, there are a couple trials. Some of them are closing out, so we're actually entering a good space now, and we are in the period of site activation, which is always the hardest part. It's like the take-off part of a clinical trial, and so we're in that place now, but we are planning to go global in terms of our footprint.
Okay. And then, the ESMO data that we saw over the weekend, why don't you give us your-
Yeah
... conclusions there?
Yeah, so, we're really happy to see monotherapy activity. That's always the first step I'd want to see in drug development. You need to have evidence of monotherapy activity. Here we saw a follow-up of those original two patients with PRs that were very durable, extending past one year, and both of them on treatment for eighteen plus months. So very impressive durability. In terms of the overall phenotype, it was very similar to what we saw with melanoma, with disease control. Though this closed umbrella spider plot. We saw treatment beyond progression, as I mentioned, about 64% of patients. About one in three had a ctDNA molecular response, so very impressive that we're seeing ctDNA molecular response across the platform as a good marker, independent of radiographic assessment.
We then also looked at chemotherapy combinations, and here we see quite interesting data that the disease control rate is much higher. Now, it's only 13 patients, but the DCR is higher than we would expect. The response rate was in the low twentieth percentile, where it should be single digit, and about 80% ctDNA molecular response, and getting a molecular response in our platform always correlates with PFS and overall survival, and then we saw the same phenomenon with T cell fitness, suggesting that earlier lines, we're going to see even increased activity. The final point I'll add is, aside from the data, which we are quite pleased to see, this was also another step for our platform.
We've combined with PD-1s before, but this is the first time ever that we've combined with chemotherapy, so it just increased confidence our platform can be combined with almost anything.
About the ovarian landscape and ... How are you thinking about progressing this?
Yeah, and ovarian is certainly more complicated, perhaps even more than melanoma is to date. So for us, the next steps is to get more chemotherapy combinations in the PROC. We see an interesting signal. We want to see if we can have a path forward in a randomized trial with a PFS endpoint with these chemotherapies. The other step in parallel is in the platinum sensitive setting, to do a bevacizumab combination and to do a platinum combination, primarily for safety. And those two data points, the PSOC, bevacizumab combination, the PROC chemotherapy combination, will inform, our next step, our next trial.
I guess they're all still ongoing, when we'll get more of an idea of what the plan is there.
I think next year.
Mm-hmm.
Yeah, I think 2025 will be...
Beyond ovarian and lung and melanoma, which we now talked about for Brenni, is there any other opportunity that's even on your radar screen?
We have said, endometrial is on our radar screen. That's a tumor where I scientifically believe this platform and PRAME should work because it has the highest PRAME expression. So that's another place we want to continue to look at. And then there's less frequent tumors, not rare ones, but less frequent tumors where PRAME is positive. But I think ovarian, lung, and melanoma are probably the lead three right now.
You've got the half-life extended PRAME. What are your latest thoughts on whether that's going to be a good or maybe not good thing?
Yeah. So first of all, the HLE, so the PRAME HLE, is the CTA was accepted, so we are right now into, you know, opening sites and starting the dose escalation. You know, when we went into the HLE, it was really mostly for convenience. We don't, we don't know if it has any impact on the efficacy or not, and for a simple reason. When we look at KIMMTRAK, that has the shortest half-life and it has a ratio of 0.51. So we'll know with the PRAME, but at least for the convenience and as we're thinking combination with chemotherapy and with PD-1s and things like that, it will be good to have. So that's what the trial will tell us.
But the way we're looking at it, so we'll have all the information from the PRAME that's ahead, and if we need to switch, we'll switch.
All the data we're generating on Brenni is applicable to the half-life-
Yeah
because it's roughly the same molecule, except with an Fc extension.
Okay. Okay, let's talk about HIV. I know this is something you want to talk about, David. We had a little discussion in the foyer outside on this, and it is one of your next milestones in terms of development updates. So I think in the early part of next year, you're going to give us some potentially proof of concept data from a phase I study. Novel biology, certainly very scientifically interesting. Maybe just review what you hope to show and why investors should care.
Yeah, and the reason we talked about it outside was 'cause it's scientifically so interesting. You know, can... This is a disease where there's never been evidence of a functional cure. So it's just, it's open question: Can you actually do something? So, currently, the current treatments obviously are daily antiretrovirals, and I know there are other therapies that are intended to be less frequent dosing. That's kind of where the field is now. The question is: Can patients stop taking any of their therapies? And so our trial is designed to ask that question. We have two parts of the trial. The first is, during the treatment phase, we're looking at the viral reservoir, so these HIV positive CD4 T cells. Can you actually reduce that reservoir with a bispecific? No one's ever done this before with any therapy, so can that be done?
And then the next step is, when we stop the antiretroviral and the bispecific, and then monitor for viral rebound, can you delay or alter viral rebound here? Once again, no one's actually been able to show this. So we believe that doing something on either of these tells us that HIV can be an immunotherapy, an immunotherapy sensitive disease, and we can build on that. So any initial finding here, to me, to me personally, is a major breakthrough, and it just opens the door for further work?
So what type of delay would convince you that, wow, this is... we're onto something here-
Yeah
We've got to hold?
Right. So there was an academic Bill and Melinda Gates working group that looked at what a target product profile would be that would be considered a success commercially. So it's mostly doctors from around the world. The minimum case is off therapy completely for two years, with viral levels below transmission, which is 200 copies per ml. That's the bare minimum. The base case would be off all antiretrovirals for three years, with levels that are undetectable, viral levels, and then, of course, the upside would be yours, off therapy with undetectable. So that's kind of the commercial TPP. For us, as I was saying, is any initial evidence that we can get viral control for our HIV line, you know, ideally through week 12, which is how the study is designed, would be an important initial step.
And then what would the next steps be, should you be able to achieve just that?
So the next step would be a randomized phase two. Now, there are some patients, always these super controllers. When you stop therapy, they can super control those. It's usually less than 1% of patients, so you would have to do a randomized control, and there are some recent examples. The RIO trial had about 72 patients, placebo-controlled, randomized phase two.
Just to give an idea, today, if you're not the super controller and you stop the ART, it takes two to three weeks.
Two weeks, yeah.
... to get the rebound.
Yeah. So 80%, 90%
Yeah
Yeah, 80% will relapse within two... You'll see the virus within two weeks, and 98%, by eight weeks, they. They're back on their medication.
Okay.
I guess the patients that rebound, some of them then come back down again after a short rebound, I think. Is that? Are you kind of interested in what duration would you be interested in virus control?
The trial right now is set up for a 12-week, because that's the standard when you go in with a novel therapy, and then if you see something after, at 12 weeks, you can always amend the trial to extend it, but you're initially going in with a 12-week ATI, analytical treatment interruption.
Bahija, David, we could keep going all afternoon, but we need to let you go, and we are out of time. So thank you so much for coming.