A senior biotechnology analyst at Jefferies, and I'm happy to introduce members of the team from Immunocore up on stage. I would love the opportunity for Bahija to sort of give us an introduction to where Immunocore stands today. 2024 was a bit of a volatile period, and you put out a bunch of data earlier this year on PRAME for solid tumors in melanoma, and Wall Street sort of reacted negatively. But yet you continue forward aggressively, and other companies continue to also interrogate PRAME, Immatics, somewhere around the conference as well. I would love for you to tell us about what we learned in 2024 on PRAME, why you're confident in that, and where we're going forward for 2025.
Okay. Good morning.
Tell us why you're excited about PRAME, because the market seems to be unclear?
Yeah, so thank you for having us. Obviously, this is real fun to be here with the first very long question. Okay, so 2024 was really for us, as we saw it, as still an exciting year and an execution year, I would call it, right? So we still have KIMMTRAK with high revenue and quarter-on-quarter growth, and that continues. There's 10 quarters of growth that continue, so we're very, very happy with that. I think that allows us actually to really focus on the R&D. You know, we put data, so we have also why we're excited. If you think about, you know, this is a company that has three Phase III's right now ongoing, so it's really about execution and bringing that. So now, you know, if I focus on PRAME to answer your question, you know, we brought the data in cutaneous melanoma.
We absolutely believe that PRAME is a validated target. We showed data there, and we know from everything we've done that we have to move earlier, and that's with all the reasons to believe from the monotherapy activity, the disease control, and so on. We moved into the Phase III. The Phase III is enrolling right now, and so we'll see the data, and I think that was the right thing to do. We confirmed in ovarian with the ovarian data that we have monotherapy activity in ovarian. Ovarian is more complex, as you know, and we now can.
For members of the audience, remind me about 13% ORR in second-line melanoma.
Yes, in second-line melanoma, yes, but the DCR was in the 50s, right? So, 56 or something like that, so it is a different way, as we are learning from KIMMTRAK and the platform of looking at what really matters for the platform, so we have the next steps for ovarian, and we showed that data, and, you know, again, I think as we're learning, you know, we are pioneers in this area, so we are continuing to learn and apply this learning. We are also moving earlier in ovarian for the PROC, so the platinum-resistant and platinum-sensitive, so we know moving earlier is always good. We also learned, I think this time, that our platform can combine with a lot of things and combines very well.
Have to go PD-1.
Exactly. And chemotherapy. So as we get into ovarian, this is what we're doing, and that's exactly what we're doing now. And then finally, you know, we said in Q3, looking at, we're continuing to explore in non-small cell lung cancer being very heterogeneous. You know, we're opening more cohorts, and we're going even earlier. So I can.
So look, I think the takeaway is the data earlier this year at ASCO continues to show promising results where Wall Street may historically, you and I have both been doing this a long time, historically looks at ORR, says, "Oh my gosh, it's not 20%, 25%, 30%, 35%. Not clear. It's not a no-brainer to me." But the overall disease control rate, tumor shrinkage, ctDNA in a heavily pretreated second-line population monotherapy should look even more promising in combination with PD-1 moving to healthier patients in first line. And that has a total opportunity to hit on PFS and survival. It will take time, but we need to run that study, and we'll see it in time. So where are you in the Phase III? Tell us about that one at the time.
So it is a global Phase III, so that means we opened sites everywhere. So now we are randomizing all over the world, so we will have a better, you know, view on the enrollment and how long it will take and stuff like that in the beginning of next year.
Okay, but traditionally it could take up to two years to enroll?
Yeah, something like that. Two to three years.
Two to three years. Okay. And I, you know, said that sounds like a lot, but other first-line melanoma studies have also taken that.
Yes, absolutely. Yeah.
Okay. So that readout will take a couple of years, but could look promising. Was there any learnings from the other company that supports, yes, they're also showing activity with their bispecific, I believe that was like last week, and/or this week, and/or their TCR that they had, CAR TCR, that also shows activity? You would just say it's consistent, it's once again validating that there's activity. Do you think you're better?
Yeah, it's very hard to make comparisons, and I would not comment on that other than to say that it really validates PRAME as a target. I think that's, you know, the data that was released, in my opinion, is still preliminary, so I will hold my, but we're happy with the data we have.
In addition to the melanoma, remind us we'll get a lung cancer update as well in 2025, Phase II, keep our expectations low, and also ovarian, you're also running that as well. So incremental updates across lung and ovarian next year as well.
Yeah, so what we said is that every time we have enough data, especially when we are looking at the early phases, if you will, when we have enough data that we can interpret and we can say what's the next step, then we'll bring it, and that's exactly where we are for ovarian and for lung.
In addition to that, but in my opinion, a high focus on super value creation if the Phase III works is the fact that KIMMTRAK is a hugely important part of your franchise. I mean, I know I didn't start there, but KIMMTRAK continues to do well commercially, and I think is going to run towards almost a $300 million type run rate in just uveal melanoma.
Correct.
That you also have promising data in cutaneous melanoma, and that's also in a Phase III. So tell us about that study, what data you've seen, because you have a second asset that works differently, but is also in a Phase III in cutaneous melanoma.
Great. So if you allow me, you know, KIMMTRAK, just to show my enthusiasm for this molecule and what we're really learning, and it's the stories from the patients, right? We have patients. We just met a patient that is alive now seven years later with very low ORR. I'm just going to make that. I think it's doing fantastically in the market because it's helping patients. And so we have, to your point, in year to date is $226 million, and we will be going beyond the 300. So year to date, and that's 10 quarters growth on growth since launch. So it's been really.
Consistent steady growth. You have been beating numbers there.
Exactly, and that's, you know, not only the impact on the patients, it's that duration of treatment that's continuing to grow. We still see incremental growth in the U.S., obviously, because we are 65% penetrated with that. So we see still some growth to be had in the duration of treatment because we are in the community. And something that's really good about this platform is the safety, so we see how it translates into the market is the fact that 40%-50% now are starting in the community, which really speaks to the safety and efficacy.
Look, initially people thought this was like $200 million-$250 million global. If I may give you credit, the drug is available in countless countries worldwide, including in the U.K., where you're negotiating.
Negotiating, we're almost there.
We're still negotiating with the U.K.
We're almost there.
We're almost there. Minister of Health was here yesterday, but we're working on that, but widely available in countless countries, and the point about why business continues to grow is duration of therapy because people continue to have great benefit and people are staying on the drug longer.
Yes, absolutely, and then we continue to launch, like just this year, we launched in 11 countries, and I think just really commitment to patients there. So, to your point.
So cutaneous melanoma could be a huge upside and drive a lot more use. What do we have there?
Yeah, that's basically if we are successful, that's doubles or triples the market there. So we have, you know, the reasons to believe is what this was based on a Phase 1B, 60 patients in combination in cutaneous melanoma, where we saw one year overall survival of 75%-76% compared to 55%. That's the TEBE-AM that we call TEBE-AM. It's basically enrolling really well. We should be finishing enrollment. So this is, as I said, when we get to 2025, this is very close. So we'll finish enrollment the first half of 2026, and we should be having data second half of 2026, and hopefully if we are successful, launch in 2027. So that's getting really close. And that will, we go from a population right now is a thousand patients to somewhere between 2,000 to 4,000 patients.
Right, for second-line cutaneous melanoma.
Second line, exactly.
So that could double, triple, or quadruple the opportunity for a different melanoma indication.
Exactly. And you asked about the two assets. So we have KIMMTRAK in the late line, and PRAME is actually in first line in combination with nivo.
Right, right, exactly. So PRAME is first-line melanoma in combination with PD-1, and also this is in second line here for a different drug, KIMMTRAK, but also in combination.
So it's tested KIMMTRAK by itself, KIMMTRAK with Pembro, and then the control. So we're really addressing does Pembro add anything or not, so we will see.
Okay. So that will complete, you're enrolling that as well. You're in all these geographies enrolling across every melanoma center. But that is something that would complete enrollment first half 2026, you said?
Yes.
Data in second half 2026. Okay. So 2025 is very much an execution year on those. Now, appreciating that KIMMTRAK continues to grow, you're going after more community centers, you've got more reimbursement in more countries, and you're executing enrollment across PRAME and KIMMTRAK across all these melanoma indications. There's also other opportunities for your platform. Tell us a little bit about that because there's also some HIV data, and you're also looking at other autoimmune indications.
Correct. So I'll take the autoimmune, and I have the expert in HIV to talk about the HIV. So it's really the excitement and why I came to the company is always the science and the fact that this platform is so modular. And what we're trying to do, and one thing that we showed with KIMMTRAK is that we're not going just incremental. It has to be transformative. And we're doing the same thing. We're trying to address the same thing in autoimmune is to go very much organ-specific down modulation of the immune system, right? And so the first proof of concept we're doing there is type 1 diabetes. So what we're taking is a PD-1 agonist. We have a preproinsulin, which binds in the beta cells in the pancreas, so very specific to pancreas, because that's what happens is T cells kill the beta cells.
And we're trying to come with an agonist to PD-1, but have that very, very much specific. So all the preclinical, we satisfied everything. We see really great data there, and we are very much now looking into going into IND in 2025.
So what is the construct of the drug?
So the construct is you bind to the beta cells, the pancreas with the preproinsulin. So the TCR, the peptide with HLA is to the preproinsulin that's specifically expressed in pancreas. And then you come with the agonist of PD-1 to basically switch off the T cells. That's what it is and stop them from killing the beta cells.
Got it.
This is just the beginning, right? We can, this is the type 1 diabetes, but there are more.
You're activating the antagonist or blocking the break. You're activating to stop the T cells from attacking those specific beta cells in the pancreas.
Exactly.
Got it.
So if that works, you can imagine the opportunity is huge because you can go after any T-cell-driven diseases and also, you know, B-cell ones that we can do.
Why not kind of prove it first with an easier indication where you could more immediately shut down the immune system and see effects, which are more traditional autoimmune indications, you know, derm, other rheumatologic indications, because in very short time frames, you can clearly see if your drug is safe and well tolerated and is working because the rash is going to go away, you know, the inflammation is going to go away.
Yeah.
Diabetes is very tough.
Yeah. Yeah, you know, but we're warriors. I think we believe in the science and we can do that. We have a second target we actually talked about in 2024. We were putting the patents together, but we will be talking about it in January in derm.
Where are you with that construct for the type 1 diabetes?
We should have IND, so the CMC, the GLP CMC is going. So we should have, or GMP, sorry, we'll have the IND towards the end of the year, 2025.
Okay. Yeah. But since we do have the HIV expert you set up here, tell us about the Phase I HIV study. Tell us what you're trying to do because this is some super novel. Again, going back to you guys are looking for game-changing stuff. You are trying to basically seek a functional cure in HIV so that patients can come off of standard antiretroviral therapy. Gilead in the other room doing $20 billion of HIV business, but you think you can add on to that and induce functional cures. Tell us how you're going to do that. You are in the Phase I and you were seeing biological activity. So we're intrigued.
Good morning and thanks for having me and thanks for the question, so we went into this indication exactly as you said. We want to change the paradigm of standard of care, which is lifelong medication, and what we're aspiring to do is have a finite period of treatment using our technology, which will enable people with HIV to at some point discontinue their antiretroviral medication, so that's our aspiration, but keep in mind two things. One, we're four decades into the pandemic and treatment has improved enormously, but people with HIV are committed to lifelong therapy, and two, we're taking a platform that's been developed for oncology where people have limited treatment options to an indication where people are now pretty healthy and have a normal life expectancy, so those considerations have really guided our development plan.
As you recall, we started very cautiously with a single ascending dose study, going very slowly from a very conservative starting dose just to demonstrate safety and demonstrate activity that you might expect based on the platform. T-cell engagement, evidence of cytokine production. To impact the disease, we believe we need multiple doses and we started the multiple dose study, I think last year. You know, we've continued to enroll into that study and demonstrating tolerability, safety, and demonstrating activity that we would expect based on our learnings from oncology.
So to put that into context for everyone because they're not as familiar. What is the construct? What is the drug binding to to then bring in the T cells? What is the construct?
Yeah, so the construct is very similar to the oncology construct. So you have a T-cell receptor that's very super sticky, high affinity. It binds to a peptide HLA. Instead of this being a cancer peptide, this is a peptide from an HIV protein that's very abundant and very conserved across HIV strains. That's on the surface of cells that are containing HIV virus in them. And then the other end is same as tebentafusp, an anti-CD3 that recruits T cells to come and kill that HIV-infected cell.
Right. So this is an antigen peptide on the surface of HIV cells.
Exactly. Cells that actually hide somewhere. So that's basically, I think, as Lucy said, we have patients that while they're very well served today, they cannot stop their medication because once they stop, you have the viral load that goes up. And so there is what we call the reservoir, and that's exactly what we're after. So small number of cells.
It's. I got to remind me of my metrics, but like less than 10 copies per mL or something very small.
One in a million T cells, helper T cells in the blood.
Yes. Now in the Phase I, right, we're trying to get rid of that last reservoir and have the immune system come in, clear that last little bit, and if we can do that, either the immune system is now in full control of it or it's basically gone, so you could get off standard Biktarvy antiretroviral therapy, which is basically just stopping the replication of that small amount, so in the Phase I, it was promising first on safety because this is bringing in T cells in basically a healthy person, and you saw what in that Phase I? Markers of what?
So as you said, we see safety. We see people tolerate the medication, and we see cytokines. And we are looking at a number of other viral specific markers to suggest that we are touching that reservoir. So that's work that's ongoing, and we'll be sharing data on that next year.
I agree. Safety is critically important because you're inducing the immune system here on a very small amount of HIV in basically a healthy person. This is not a cancer person. So then we've gone to a dose escalation Phase I cohort where you describe it. You're on taking patients who are on basically Biktarvy, if I may say, for 13 weeks. You're going to add this drug on top of it. It is weekly, weekly for 13 weeks, 12 weeks on top of the Biktarvy, and then you're going to basically cold turkey take everybody off these drugs and follow them for X amount of time, I think 12 weeks.
There are specified criteria for following. So we follow them. We measure the viral load every week. We measure the T-cell count every week.
Sure. And you want to see that in these patients. How many? How many patients?
Again, we're kind of following a standard sort of early dose finding study paradigm where we'll enroll a small number of patients, minimum four. We can expand those cohorts to more than that, driven by questions around safety, tolerability, and what we see.
Have you disclosed how many cohorts you've gone up?
Yeah, we did. We actually said, you know, we had five patients per cohort, and we went up to 300 microgram. We see very clean, and we see biological activity. And then after that.
300.
300 was the top, and then we're going higher now.
So can I do some math? Five times how many cohorts? Five times three, 15 patients.
Yeah.
Thank you. 15 patients, five cohorts, dose escalation. The reason why I want to say is because, A, it's safe. You've gone up to five different cohorts.
Exactly.
B, we have 15 patients. That's not a totally tiny amount. C, has it been fully enrolled?
We're continuing to enroll.
We continue to enroll, yeah.
When we take these patients off therapy, we want to see that a certain percent, help me out, are not going to have viral rebound over a defined period of follow-up. Wall Street analyst and person who covers Gilead says, people traditionally rebound when you come off Biktarvy. In four to eight weeks, most people are going to see viral rebound. Now, Gilead.
Even faster than that.
What's that?
Even faster than that.
Even faster than that. Now, Gilead says to me, you can have some rare outliers, so I want to be cautious. But we want to see multiple, multiple, multiple patients, not just one, not have viral rebound in over four to eight weeks. Can we agree on that?
Yeah, absolutely. So I think, you know, but there are two things we are doing in this trial. One is addressing the question that has not been addressed yet. Can we touch that reservoir? And then the second question is, touching that reservoir, how much do you have to bring it completely down? Do you get delay or reduction of the viral load?
Are we talking about low levels? Like, obviously, they have low levels, but we're taking them to undetectable by assay or what are we talking about? That's one endpoint. Can we take a tiny reservoir and take it to undetectable?
As Brian just says, you know, we're looking to have an impact on the reservoir. That hasn't been shown with immunotherapy consistently so far, despite decades of people trying that. So we're looking at a number of things. One is actually measuring that reservoir and seeing how much we can reduce it and how consistently across patients in the study.
By undetectable, is that like a basis?
It's not so simple as that because a reservoir is not homogeneous. So a lot of it is cells that have got dead end virus. And there are complicated ways to discriminate the dead end from the stuff that we care about. So all of that has to be factored in, and those are not straightforward to ascertain. So we need to ascertain all that information.
Most of Wall Street just knows the term undetectable. So I'm trying to keep it kind of cheap and simple for people. When it's complicated, then people don't say, well, it's complicated. I don't know what do I do with that?
The undetectable refers to what you measure in the blood as a kind of diagnostic standard.
What I say is basically, do we have an impact on the reservoir? Do we bring it all the way down? And what that means on the viral rebound? That's the correlation we're going to be looking at, right? Because when we did the antiretroviral plus our construct, that's 12 weeks. It could be longer. It could be that's where we started. So I think first quarter of 2025.
First quarter of 2025. Thank you very much. Look forward to the updates. Congrats on the success and looking forward to catching up. Thank you guys very much.
Thanks a lot.