Immunocore Holdings plc

Welcome to the Immunocore conference call and webcast. At this time, all participants are in a listen-only mode. A question and answer session will follow the formal presentation. If anyone should require operator assistance during the conference, please press star zero on your telephone keypad. As a reminder, this conference is being recorded. I would now like to turn the call over to Clayton Robertson, Head of Investor Relations. Thank you. You may begin.

Good morning and good afternoon. Thank you for joining us on our Q2 and first half 2024 earnings call today. During today's call, we'll make some forward-looking statements which are qualified by our safe harbor provision under the Private Securities Litigation Reform Act of 1995. Please note that actual results can vary materially from those indicated by these forward-looking statements, including those discussed in our filings with the SEC. On today's call, I'm joined by Baheja Jalal, CEO of Immunocore, and Brian DiDonato, CFO and Head of Strategy, who will share a strategy update. Ralph Torbay, Head of Commercial, will review our first half ChemTrack sales and additional growth opportunities for ChemTrack. David Berman, Immunocore's Head of RD, will provide some pipeline updates. including near-term readouts in oncology and infectious diseases. Brian will also provide highlights on our financial results reported this morning. Adhija.

Thank you, Clay. As you may be able to hear, I'm losing my voice and I have pharyngitis. So to be able to answer your questions at the end, I will ask Brian to pitch it for me. Brian, please.

Thank you, Adhija. We hope you feel better. We are pleased to share with you an update on Immunocore through the first half of 2024. We've achieved excellent commercial results while advancing our T-cell engager platform in three therapeutic areas. We appreciate your continued support in advancing our mission of delivering innovative and life-changing medicines to patients. Earlier this year, we outlined our three strategic pillars and our areas of focus for the next 18 to 24 months. Today, we will provide updates on the first two of these pillars. First, we continue to maximize ChemTrack performance. We continue to report continued sequential revenue growth for the quarter and significant year-over-year growth for the first half of 2024. This growth is driven by strong U.S. performance. We expanded our customer base and increased market penetration and reported longer duration of therapy. We also continue to increase our global footprint with additional country launches, allowing us to bring ChemTrack to more patients around the world. To achieve our longer-term growth objectives for ChemTrack, we are simultaneously pursuing label expansion in both late-line cutaneous melanoma with the ongoing TEBI-AM trial and also in adjuvant uveal melanoma with the soon-to-start ADAM trial. If successful, these two expansions may allow up to 6,000 patients to benefit from the survival benefit of KimTrack. Moving to the second strategic pillar, our aim is to progress our nine clinical programs, all first in class, leading by specific TCR therapies, while progressing our innovative research engine to identify additional novel targets and therapeutics. At ASCO, we presented phase one data of Bredentifos, our PRAME-targeted therapy, and previously treated cutaneous melanoma patients, which drove the decision to start the Phase III Registrational Trial in first-line cutaneous melanoma patients. Next month at ESMO, we will present late-line ovarian cancer data, and in Q4, we're planning to present late-line data in lung cancer at a medical conference. We're also excited about the potential of our platform to treat infectious diseases. As you recall, our objective is to deliver a functional cure for people living with HIV, and we expect to present the MAD data from our HIV trial early next year. I'll now ask the team to share additional details. First, Ralph will discuss Chemtrax's commercial performance. Ralph?

Thank you, Brian, and hello, everyone.

We've had a strong first half in 2024, delivering $146 million in net sales, which represents a 34% increase compared to the same period last year. I'm proud of our cross-functional team's achievements and commitment as we expanded our reach to more patients. We've now launched ChemTrack in 19 countries, including nine new launches since the beginning of the year. In the context of a challenging reimbursement environment in Europe, we have made good progress with access. signing two additional reimbursement agreements in Poland and Sweden, which are expected to launch in the fourth quarter. In Q2, we also announced the acceleration of our Phase 3 trial, the TEBI-AM study, in advanced cutaneous melanoma. This is an important part of our growth strategy beyond MUM, and we are very pleased with this progress. I will now take you through the figures and financial performance in more detail. We delivered 75.3 million in net revenues with ChemTrack in the second quarter, which is an increase of 7% compared to the first quarter. Net revenue growth was driven primarily by the US, where we saw an 11% growth compared to the first quarter. This growth comes from our continued focus on the community and increasing duration of therapy. We estimate we now have around 65% market share in the US and believe there continues to be opportunity for further growth. In terms of penetration since launch, over 500 unique sites in the US have treated patients with ChemTrack, most in the community. To continue expanding our reach, we're constantly innovating and recently rolled out our AI-enabled patient finding tool. This has allowed us to find more patients in lower density community centers while keeping our field force footprint unchanged. Our goal is to continue growing the US through further market penetration, and appropriately supporting duration of therapy, currently trending to 11 plus months. This is exceptional and speaks to a different mechanism of action with the benefit of ChemTrack extending beyond the typical resist response. Many patients with the best response of stable disease do well and remain on ChemTrack years later, contributing to the growing duration of therapy we observe. Shifting gears to Europe, demand flattened in Q2, and revenues declined net of 6.7 million increase in rebate reserves. The access environment remains very challenging across Europe, and we expect incremental demand growth in the second half of the year to come from the launches in Poland and Sweden. I'm pleased with our team's effort to reach more patients globally with MUM, driving near-term growth. ChemTrack has the potential to benefit patients beyond MUM, and drive midterm growth through label expansion with the TEB-EAM study. Following a consultation with the FDA, we converted and accelerated our TEB-EAM study into a Phase III Registrational Trial in Second Line Plus Advanced Cutaneous Melanoma. This is exciting and helps us in two ways. First, to robustly test the PD-1 combination and chemtrapped monotherapy arms, and second, By rolling the 120 patients already enrolled into the phase two, we accelerate the time to final analysis of the phase three by up to 12 months. We now expect to complete the enrollment in the first half of 2026 and potentially see data in the second half, noting, of course, the event-driven nature of the endpoint. Today, we're only at the beginning of the ChemTrack journey. In MUM, we're growing ChemTrack double digit year over year, As we increase our penetration in the U.S., support duration of therapy around the world, and launch new markets. Our two ongoing phase three registrational clinical trials position us for continued growth in the mid to long term. With the TBAM trial, we see the potential to extend the benefit of Chemtrak to up to 4,000 additional patients with second line plus metastatic cutaneous melanoma. With the ATOM trial, we see this benefit expanded into the adjuvant uveal melanoma setting where all the evidence with ChemTrack points to our platform being potentially transformative. If successful, we could help up to 6,000 patients across all three indications live longer and better lives. I'm very excited about our future, and to tell you more, I'll hand over to David.

Thank you, Ralph.

I'm really pleased to update you on the strong progress we've made on our pipelines. I'm proud of our R&D team. We have hit all our development milestones in progressing nine clinical programs, including three phase three trials, starting three new phase ones, and expanding to three therapeutic areas. Today, I'm going to focus on the two clinical stage programs with data readouts over the next 18 months, Bernadifus and HIV. Let's recall our strategy in cutaneous melanoma and the data supporting the phase three trial. The most common therapies used globally are anti-PD-1, either as monotherapy or in checkpoint combination, and BRAF therapy for BRAF mutation-positive patients. Once patients progress on these available therapies, the only options are clinical trials and TILs for select patients. Our strategy is to demonstrate in the Phase I trial in third-line patients that Benetafest is active and well-tolerated and that this activity would support a TFS endpoint. in a phase three trial in first line. Here's a summary of the key data from the phase one trial we presented at ASCO. First, BRENI has monotherapy activity, something not commonly seen for other biologics in heavily pretreated melanoma. Second, the disease control rate, which is a surrogate of progression-free survival, is higher for BRENDIFUS monotherapy than the combination of nivolumab plus rilatilamide, in a similar setting. Third, we see higher activity in PRAME positive versus PRAME negative. This provides biological plausibility as the PRAME negative subset behaves as an internal negative control. And finally, the systemic T cell fitness data indicates we expect an even higher disease control rate and longer PFS in first line. These data supported our decision to move to phase three in first line. In our phase three first-line trial, we will combine two biologics, brenetafest and nivolumab, each with monotherapy activity and with complementary mechanisms of action. Based on the phase one cross-trial comparison I just shared with you, we fully expect that brenetafest plus nivolumab in the first-line setting will be superior to both nivolumab alone and nivolumab plus relatlimab. We are pleased to announce that the phase three PRISM MEL 301 study has started, and we are focused on activating more sites globally. With the PRISM MEL 301 in first line I just shared, and with the TEBI AM in second line that Ralph shared, we are really proud to be one of the few companies to have multiple phase three investments in cutaneous melanoma, both backed by strong data.

I will now turn to brunetifuscin ovarian cancer.

Women with ovarian carcinoma are cycled through platinum regimens, shown in the blue, until they become resistant or refractory, shown in the green, at which point they receive non-platinum chemotherapies or for the folate alpha receptor positive tumors antibody drug conjugate. Unlike melanoma, ovarian cancer has historically not been sensitive to immunotherapy. In heavily pretreated platinum resistance, which is the population in our phase one trial, the outlook is poor with non-platinum chemotherapies having response rates less than 10% and disease control rates between 40 to 50%. In our phase one trial, we aim to demonstrate in the platinum resistance setting that brunetifus is clinically active and can be combined with non-platinum chemo. This will be the subject of our ESMO poster next month. We have learned for our platform that clinical benefit manifests as disease control, that activity is even higher in earlier lines, and that combinability with standards of care may enable at least additive activity. In addition, unlike melanoma, ovarian cancer is more complex with two distinct disease segments that are treated very differently, which requires us to study more combinations. Therefore, our next step in ovarian is twofold. First, in the heavily pretreated platinum resistant disease, we will expand our patient data set of combinations with non-platinum chemotherapy. And second, in the earlier line platinum sensitive disease setting, we will test the combinations with Bevacizumab and with platinum chemotherapy. Let's now turn to lung cancer. Lately, lung cancer is a heterogeneous disease, with patients generally having rapid progression. With lung, we're still in the signal detection phase. Later this year, we plan to share monotherapy in heavily pre-treated lung cancer, selected for frame expression, and combinations with the late-line chemotherapies enrolled without regard to selection for PRAME expression. The next steps are additional combinations with osimertinib in the EGFR mutant patients and with docetaxel. This will then be followed by first-line platinum combinations. PRAME is a promising target across multiple tumors, and bernetafusp is a first-in-class PRAME impact. When you pioneer a novel platform, you have to be ready to look, to learn, and to adjust. And in fact, frankly, this is the exciting part of drug development. We did this for brunetifusp and melanoma, and we'll follow the same thoughtful approach for brunetifusp in ovarian and lung.

I will now close by updating on HIV.

HIV is currently managed by antiretroviral therapy. But when ARTIF stopped, the virus rebounds on average within two weeks. By week eight, after treatment interruption, 98% of people will have a viral load of at least 200 copies per mL. This is the threshold commonly used to denote risk for viral transmission. The next frontier in HIV treatment is functional care, where the goal is to reduce or eliminate the viral reservoir which would then delay or prevent viral rebound. To date, no therapy has convincingly demonstrated either of these endpoints. This is the goal of our 113V program called STRIVE. The MAD portion of the STRIVE study is ongoing. We are treating with 113V plus ART for 12 weeks and then stopping both therapies. The objectives of this study are twofold. Determine whether we can reduce the viral RNA reservoir during the treatment phase. And second, whether we can delay viral rebound or alter the kinetics of viral rebound after treatment interruption. As of June, we enrolled 15 people living with HIV across three cohorts, the highest at 300 micrograms. The 300 microgram dose is biologically active. The next step is to enroll more people living with HIV to better characterize the activity and to explore higher doses. This will move the data release into the first quarter of 25. I'm very proud of our R&D team. We pioneered the world's first TCR therapeutic. We saw the value of Chemtrakt early in phase one. and we followed that vision to bring a fantastic new medicine to metastatic UVL melanoma patients. We saw that value for chemtrax and cutaneous melanoma and the potential in adjuvant UVL, and these programs are underway. We see that value in brenadocresp, and we are excited to follow through on that vision as well. Brian, I'm going to hand back to you now.

Thank you, David. Earlier today, we released our financial results for the second quarter ended June 30th, 2024. Please refer to the press release and our latest SEC filing on form 10Q for our full financial results. I'll now share some of the key highlights. In Q2, global ChemTrack unit sales and net sales have both continued to grow sequentially, even with the challenging reimbursement environment in Europe. Net revenue grew to 75.3 million in Q2, from 70.3 million in Q1, a 7% increase driven primarily by the 11% growth in the United States. The U.S. has consistently contributed over 70% of global net sales. In Q2, we increased rebate reserves by 6.7 million in Europe as we continue to make best estimate revenue recognition assumptions and associated accruals. For the remainder of 2024, we anticipate global unit sales will continue to grow on a sequential basis. as we continue to expect solid demand in the U.S. market and new country contributions from non-U.S. markets. While both SG&A and R&D expenses declined sequentially this quarter, they have increased 31% in the first half over the same period in 2023. We expect R&D expenses to marginally increase in the second half compared to the first half as clinical development for late-stage PRAME and ChemTrack Phase III programs continue to accelerate. In aggregate, our net loss for the first half of $36.1 million, or $0.72 a share, was roughly unchanged from 2023, given our increase in sales revenue. As you can see on this slide, our net cash and marketable securities position increased to $860 million as of June 30th. For $770 million, net of the plan $50 million loan repayment and an expected $40 million in European sales rebate payments, both expected in the second half of 24. I'd like to congratulate the teams on continued Chemtrax sales growth as we reach progressively more patients globally. This cash flow enables us to accelerate the broader portfolio while delivering transformative outcomes to patients. For the remainder of 2024, we will be presenting the Bernantifus phase one late line ovarian data at ESMO, and then in Q4, the initial phase one lung data at a medical conference. Looking over the next four years, we expect numerous data readouts, including additional data from Bernantifus, our HIV phase one study, data from our three phase three trials with ChemTrack and Bernantifus, and data from several new trial starts across our three therapeutic areas. With a strong balance sheet, a robust and diversified portfolio, our talented and dedicated teams, and a clear and compelling vision for the future, We are confident we can continue to deliver significantly for patients and shareholders. Thank you. We will now take questions.

Thank you. We will now be conducting a question and answer session. If you would like to ask a question, please press star 1 on your telephone keypad. The confirmation tone will indicate your line is in the question queue. You may press star 2 to remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. One moment, please, while we poll for your questions. Our first question comes from the line of Michael Yee with Jefferies. Please proceed with your questions.

Hey, guys. Thanks. Good morning. Congrats on great progress. We have two questions. On ChemTrack, I know you made a few comments about the challenges about reimbursement in Europe. Can you just help us understand in the second quarter there what the reserve was for? Was that a specific country? And what does that mean for the go forward third and fourth quarters? Do we go back to adjusting for that? And was that a one-time reserve? So help us understand the second quarter and then third and fourth quarter adjustments. And then on the pipeline, I thought you made a very, very interesting comment about HIV. Can you just expand on that a little bit? You're saying you're enrolling more patients at a higher dose and it's biologically active. Have you been looking at the prior doses? Is the study all blinded? What are you seeing there? And what gives you that confidence to enroll more patients? Thank you.

Thank you, Michael. Ryan or Ralph for the first question and David for the HIV, please.

Great. Ralph, why don't you take it? Sounds good.

Thank you. Thank you, Michael, for the question. So, look, we've had successes with reimbursement as proven by the nine launches that we've had so far in this first half of the year. We increased the estimated reserves by 6.7 million. This should be a one-time thing based on the latest assumptions that we have on the negotiations. Now, in terms of looking forward, I would caution you against just adding the 6.7 because The erosion is both backward-looking and forward-looking, and it's mainly on our negotiations with France and Germany.

Michael, so with the HIV program, we're in the dose escalation phase of the multiple ascending dose, and as mentioned, we've gotten up to 300 micrograms and will continue to dose higher. There's a couple of important first year that we're looking at. This is the first time we've taken our platform into a setting with such a low peptide target density and where we have such a low, in fact, you know, cell target density. And so it was an important question for us to ask, can we actually see anything? And then, of course, there's never been a functional cure. There's never been a therapy that can reduce the reservoir or delay the rebound. So these are all really important firsts. And we do see evidence of biological activity during the MAD portion, but it's still early and there are only a few patients per cohort. And so we think it's prudent to get some more patients in that cohort and also to continue to go higher. We will discuss more of what biological activity means as we approach the full data release, which will be in the first quarter of next year.

Thank you.

Thank you. Our next question is coming from the line of Jessica Fai with JPMorgan. Please proceed with your questions.

Hey, this is Nick on for Jess. Thanks for taking your questions. First, on the brenio-ovarian update, we should expect adesmo. Can you just help set the stage for how many patients worth of data we should expect, kind of the split between mono and combo, though I believe you stated should be more combo? And maybe add some more detail around what you see as promising data that supports continued evaluation here in the setting based on some of those benchmarks you provided?

Yeah. Yeah, happy to. So in terms of size, it's going to be roughly the same number as the cutaneous melanoma dataset at ASCO. It will be mostly monotherapy, but in contrast to the ASCO melanoma, we will have more combinations because there's more chemotherapy options to test here. So we'll be mostly mono with combination as well. In terms of the questions that we're going to be asking, Number one is, these are the standard questions I've been asking throughout my drug development career in the States. Is there monotherapy activity? Can you combine with the intended registrational partner if you plan to do a combination? And can you have confidence that the drug activity can meet whatever registrational endpoint? So those are the types of questions we're asking in order to progress. In terms of the metrics or the benchmarks I think you were asking, yes. There aren't a lot of good benchmarks in this heavily pretreated platinum-resistant setting. There are a few published chemotherapy trials. And so the chemotherapy benchmarks there, the response rates are in the single digits, and the disease control rate is about 40 to 50%.

Great. And then in addition to evaluating the platinum-resistant ovarian cancer patients, you noted some evaluation in the platinum sensitive setting as well. So, you know, can you provide a little more detail on the progress there and when we kind of expect an update from that data set?

Mohamed, do you want to take that?

Sure, happy to do that. So, as David mentioned, obviously, you know, ovarian is more, you know, more heterogeneous and complex than melanoma. So, we've been exploring mostly in the platinum resistance setting, but now the study does allow us to move to earlier lines and combine with therapies that are used in sensitive, and those include Bev, and also will include platinum doublet.

Great, thank you.

Thank you. Our next question comes from the line of Tyler Van Buren with TD Cowen. Please proceed with your question.

Hey, guys. Good morning. Thanks very much for the presentation. I have a couple follow-ups on the ovarian update at ESMO. So, I understand that the bar for beating non-platinum chemo and platinum-resistant patients is low, but for the Brenny combo, chemo combo specifically, isn't Elihir or Mervituximab data the bar? And then the second question is, if you can combine with non-platinum chemo with good safety, do you believe that the likelihood of combining with platinum chemo in the frontline with platinum-sensitive patients is high?

David and Mohamed.

Yeah, so I'll address the first one, and then, Mohamed, you can talk about the... So, Tyler... The MRVA, it's good to see that there's a new medicine for these patients, and it's, you know, not, you know, this MRVA is a targeted chemotherapy. We know chemotherapies do work there. So the key differences, I would say, Tyler, for us is that the MRVA strategy in the PROC setting is to replace chemotherapy. Our strategy is to add on to chemotherapy, not to replace chemotherapy. And so our approach is going to be an add-on to chemotherapy. And of course, eventually, there also could be an add-on to Mervetaximab as well. Do you want to comment on the platinum sensitivity?

Sure. Happy to do that. So I would say, Tyler, you know, this is early days. This is the first time we're actually combining our platform with chemotherapy and we're learning. But so far, you know, the expectations that we should be able to combine and the plan is to then move from the non-platinum-based chemotherapies to the platinum-based chemotherapies over the coming months and into next year.

Thank you.

Thank you. Our next question comes from the line of Eric Schmidt with Cantor Fitzgerald. Please proceed with your question.

Well, thanks for taking my question. Maybe back to Tim Trak for a moment. It sounds like you've crossed the $300 million annualized run rate for the first time. You've grown now for several quarters at 30% or more year on year. You've spoken to more patients out there than you thought previously and longer duration, of course, than you would assume. I guess the question is, what's the ceiling for this drug in the current uveal melanoma indication? Do you think it's a 500, 600, 700 million-odd drug? Where's this going to end?

Thank you, Eric. Ralph, do you want to take that? And maybe, Brian, you can comment also at the end.

Happy to. Thank you, Eric, for the question. So, look, we're very proud of the growth that we've had. A lot of it has been driven, as we've stated, by the U.S., growth where we're 65% penetrated. It's important to keep in mind two aspects. One is the reimbursement landscape in Europe is such, and the challenges are such, that we expect really minor to very incremental growth coming from Europe moving forward. So a lot of the growth will be driven by the U.S. A lot of the incremental growth will be driven by the U.S. That's for MUM. But really, I think where we get very much excited is when we think about the label expansions that are possible with the TEB-AEM study, which expects data in 2026, as I mentioned. And from the ATOM study, a little bit further down the line, that also would bring us into the adjuvant setting, bring the platform to the adjuvant setting. So I think there is still significant growth for ChemTrack, up to 6,000 patients potentially benefiting from it.

Yeah, the only thing I'd add, Eric, is that we're really pleased that given the survival benefit of ChemTrack that the duration of therapy continues to extend. The mean duration of therapy is now over 11 months, approaching 12 months, maybe plus. And as patients stay on longer and the tail is pronounced, as we see in the three-year survival follow-up, it's still unclear how long the duration of therapy can extend. So that's one of the upside potentials in ChemTrack. And as Ralph said, 73% of net sales are coming from the United States. We'd expect that to continue going forward.

Thank you.

Thank you. Our next question comes from the line of Michael Schmidt with Guggenheim. Please proceed with your question.

Hey, guys. Thanks for taking my questions. I have another one for David. It's just on the PRAME program again. Could you just provide us with your updated views on the opportunity in the lung cancer indication? Are there any particular patient subsets and focus for the development strategy? Are you enriching certain patients into this cohort? Any particular genotypes perhaps that might benefit most from PRAME in lung cancer? And what should expectations be for the scope of that data readout later this year? Thanks so much.

Yeah, thanks, Michael. So with Lyme, of course, you know, it's a lot more heterogeneous disease on multiple levels than ovarian and melanoma. And so we have been very interested in looking at those key subsets in order to first see the initial signal before we expand. So, you know, one example of a key subset, of course, are are actionable gene mutation positive patients because those are insensitive to checkpoints. And so that would make an interesting place for us to look. But there are other potential subsets as well. We have initially for the monotherapy, as I talked about in the presentation, we focused on enrolling pre-positive because about half of the adenocarcinoma patients are pre-negative, half are positive. And for the initial signal, of course, we want to make sure that the patients are praying positive. And so we have been doing this double screening, looking for the right patients. And so the monotherapy data later this year will be smaller probably than what we're seeing for ovarian and for melanoma, but it's a little too soon to guide to the numbers of that. The combinations, of course, is where we're also interested because that's where we believe our platform is going to work best in terms of combination. So it will be a monotherapy, and it will be a mostly chemotherapy combination initially. As I talked about, Michael, going into next year, we expect to move into earlier lines with a docetaxel combination and with the Ocimertinib combination. Mohamed, anything you want to add?

No. I guess we also will have platinum-based chemotherapy options.

That will come a little bit later after Ocimertinib. Thank you.

Thank you. Our next question comes from the line of Jack Allen with Baird. Please proceed with your question.

Thanks so much for taking the question and congratulations on the progress. I wanted to ask a little bit about the earlier stage pipeline. I know the pill will program recently cleared CTA and is expected to enter the clinic in the second half of this year. And you also submitted the CTA for the Half-Life Extended PREEM and have plans to submit the CTA for the PREEM 824 program. I guess my question here is when can we start to see the pipeline kind of build out and see clinical data from some of these earlier assets?

Great. Thank you, Jack. Mohamed?

Yeah, thanks for the question, Jack. So you're absolutely right. We're quite excited about the progress we're making with the early-stage pipeline. So for P-WILL, following submission, we're now in the stage of activating sites. And then hopefully we'll be able to meet our target of enrolling the first patient before the end of the year. With HLE, we've made the submission. So it's, you know, we're waiting for health authority feedback. And with A24, we remain on track for making the health authority submissions by the end of the year. In terms of data, I mean, these are first in human trials, right? So we need to get the trials open and start accruing. So it's too early to guide to when we would expect data from these trials.

If I could just add one other point, Jack, is Mohammed's team has really baked in important learnings that we've made from our entire platform, from ChemTrack and from Bernadiphus. So the P-WOL study is now designed in colorectal cancer with all the best knowledge we have about where this platform is going to work. Likewise, with the PRAME Half-Life Extension, which is essentially the same molecule as Bernadiphus, but with an FC Half-Life Extended. all of the wall of data we're building in terms of combinations and translational insights are directly applicable to the trained pathways extension. So we see acceleration in our phase one trials based on these learnings.

Got it. Thank you.

Thank you. Our next question comes from the line of Justin Zelen with BTIG. Please proceed with your question.

Thanks for taking the question and congrats on the progress. I think I'll ask a question about the autoimmune disease programs. It looks like you're kicking off CMC manufacturing here for candidates. Any thoughts on a timeline for entering the clinic on these programs?

Thank you, Justin. You know, we're hoping by next year. So the CMC is going well and, you know, we take it from there. But, yeah, we're excited about that program as well.

Great. Thanks for taking my question.

Thank you. Our next question comes from the line of Jonathan Chang with Learing Securities. Please proceed with your question.

Hi, guys. Thanks for taking my questions. First question, how do you see the UVO melanoma competitive landscape potentially evolving in the future? What gives you confidence in the ability to continue and potentially expand the successful commercial story in the event of potential new entrants? And second question, I guess just out of curiosity for the lower tech people like myself, can you provide more color on the AI-enabled patient finder and how is this facilitating the commercial story? Thank you.

Great. Thank you so much for the great questions. I'll start with David and maybe then Naval so you can comment more.

Yeah, Jonathan, in terms of the landscape, I think there are two ways to look at it. First, in the metastatic setting, we, in the HLA-A2 positive, of course, we now have the three-year survival benefit. It's a global standard of care. And so we're continuing to build on that. We know that in the HLA-A2 negative, there are studies going on. And by the way, it's great to see options, but that registrational study is in the HLA-A2 negative setting. In terms of the adjuvant, we have the ADAM trial, which is a well-designed standard relapse-free survival endpoint. It's the standard endpoint used globally for full approval. So this is a trial that we believe will give us a full approval label with high confidence in the adjuvant setting. We are aware that there's competition in the neoadjuvant setting, and I think it's too early for us to comment in terms of that. Ralph, do you want to talk about the AI?

Sure. Thank you, David. So we're very excited about this tool, actually, because when you recall, we were discussing initially how our approach to addressing the market, particularly in the U.S., we talked about the fact that there's a higher density at academic accounts. And then after that, it tails off with very low density in the community. And one of the challenges is how do you address that low density, those patients that pop up, you know, once a year or once every other year? And really, now that AI has gotten to the place where some of the predictive models have become very good, we're leveraging that ability to predict based on historical data where the patients and when the patients might pop in in some of the different practices. And that's enabled us to find patients and send reps on a just-in-time basis, which allowed us to basically keep our rep footprint the same.

Understood. Thank you.

Our next question comes from the line of Peter Lawson with Sparkplace. Please proceed with your question.

Hey, good morning. This is Alex on for Peter. Thank you for taking our questions. Just had two on the ovarian update. So assuming data is supportive, would you pursue a monotherapy or chemo combination approval in the platinum resistance setting, or would the goal be to maybe try to go sort of directly into earlier lines of therapy in combination with chemo?

Thank you, Alex. David?

Yeah. So, Alex, I think it's important to understand, you know, to remind about our, what insights we've made. First of all, our platform works really well with disease control. It works very well, you know, it increases activity in earlier lines. And we think it works best in combinations. In ovarian cancer, which is different from cutaneous, there's these two major disease segments and, of course, multiple different combinations. So, we have to generate the data before we decide on what the next step is. So, the immediate next steps are more chemotherapy combinations in the platinum-resistant setting. And then, as we talked about, more platinum combinations and bevacizumab combinations in the platinum-sensitive. This is the data set that we think will enable us to make the best decision on what the next study is, P-ROC or P-SUS.

Okay, great. And do we actually see any Bev combination patients in the 3Q update?

No, there won't be any Bevacizumab combinations in this update. Okay. Thank you.

Thank you. Our next question comes from the line of Ahud Demir with Lattenberg Thalmann. Please proceed with your questions.

Good morning. Thank you for taking my questions. Two questions from us. First one is on the lung cancer program.

When you present data, how do you disclose data from it? You cut off if you could repeat your first question, please.

I was asking how many patients disclosure that you would have from the lung cancer, and what percentage would have monotherapy versus combination? And I have another question after that.

Thank you.

Thank you, Ahu. I would say it's too early to say, but I'll give it to Mohamed to tell you.

Sure, thanks. Thanks for the question. In terms of lung cancer, as David mentioned, it is obviously a more heterogeneous setting compared to melanoma, and we are still in the initial signal detection mode. But in terms of patients, it will be likely a smaller data set than melanoma and ovarian. And we will likely have more combo patients than mono patients for the reason David mentioned, that for monotherapy, we have to select for PRAME. And with combo, we are allowing regardless of PRAME status.

That's helpful. My second question is on the HIV program. You touched on the viral load and also the rebound rate. Would it give you confidence to move forward from the MAPS? Would you be looking for, what data would you be looking for and any combinations for that progress?

Yeah, it's a really good question, because, of course, we're pioneering this area here. No one's generated the data thresholds for what um you know what's required to move forward i would say at this stage any evidence of activity that is definitely related to you know antiviral um would be really intriguing to us because no one's been able to show that so we're looking at can you reduce the viral reservoir and can you delay or alter the rebound kinetics um anything i think here would be interesting for us to continue of course at the end of the day it's going to have to be an antiviral delay and rebound that is going to be the end point. But I think any insights we make here are going to be important for us. So immediate next steps are for us to generate more data and to get to higher doses because we only have a few patients per cohort.

Yeah, and I would just add one thing. I think you talked about combination. Just remind you that we do it, the first part is on top of the antiretroviral.

Okay, thank you so much. Thank you. Our next question comes from the line of Avantika Joshi with Mizuho. Please proceed with your question.

Hi, this is Avantika for Greg. I just had a question. Are you still looking at brunetifus in tumors beyond melanoma, ovarian, and non-small cell?

Yeah, we certainly are, and there's strong scientific rationale. But as As a team, I've asked them to focus, right? We're launching a global phase three cutaneous melanoma. We are committed to following up on the signals in ovarian and to look for signals in lung. And we've certainly had the sites focus on those as well. We do have ongoing phase one exploration in other tumors, but we've had to focus. And so we are certainly interested and continue to be interested in other tumors like endometrial.

And one more question was, for the earlier stage assets for P115C, and T119C, are you initially running basket studies or are you focusing on specific tumors? Thank you.

Go ahead, Mohamed. I have to admit that I don't retain the numbers, but go ahead.

Are those numbers referring to the half-life extended and the A24?

Yeah, the half-life extended and the A24.

We would have to simplify them. Sorry about that.

It's not an issue. As David mentioned earlier, we are certainly applying all of the learnings from our F1 to succeed frame program to those two programs. We know where frame is expressed. So, yes, those trials are designed flexibly, so we have multiple options in terms of the types of patients that we can enroll.

Okay, thank you.

Thank you. Our next question comes from the line of Jeffrey Hung with Morgan Stanley. Please proceed with your question.

Hello. This is Selena on for Jeff. I have two questions here on frame. For the melanoma data, CT DNA responders were defined as 0.5 log reduction. Do you expect the threshold for meaningful correlation to longer survival to be similar across indications like in ovarian and lung? And the second question was, when might we expect an update from the endometrial cohort? Thank you.

Yeah, I'm happy to take both of those. So, you know, ctDNA response criteria are still in their early stages. Externally, companies have looked in lung cancer, for example, at a 0.5 log reduction. So there's precedence to that called a molecular response. In our cutaneous melanoma data, that .5 log reduction did seem to be a good threshold cutoff for correlating with survival. We saw the same correlation in cutaneous melanoma, and we'll share that data on the ovarian data at ESMO. But it does look like that .5 log reduction, I think, is a good log reduction, is a good threshold for us. based on the data we have today. In terms of the endometrial timeline, I think it's a little too soon to guide because, as I mentioned, we've asked the team to focus on ovarian lung and cutaneous melanoma.

We've asked the sites to focus on that as well, too. Thank you.

Thank you. Our next question comes from the line of Noreen Kibria with Capital One Securities. Please proceed with your question.

Hi. Good morning. Congrats on all the progress. I guess my first question sort of follows up on the last one. It's in terms of, you know, the PREEM results that you'll be presenting at ESMO. You know, you've observed benefit with ChemTrack outside of rhesus response, right? So can you remind us how you're tracking response rates under estimates? You know, should we just focus on the disease control rates or, you know, you mentioned that there'll be ctDNA. Is there anything else?

Yeah, it's a good question. I mean, we certainly saw this with uveal melanoma. There's even patients with radiographic increase in size that benefit the survival benefit, but long-term survival. We saw a few patients of those with rennetifast in the cutaneous melanoma. We will, I think, continue to see that in the ovarian and the lung as well. I think the way that we're looking at how do you measure benefit, of course, is cpDNA, which is is a way to measure independence of radiographic, but also looking at treatment beyond progression. Because this is where the investigator sees the patient having a radiographic increase in size, but they feel the patient's benefiting. So we saw this early, this treatment beyond progression was a good initial indicator. Now, although we do see this TB benefit, we see it very strikingly for chemtrax, we feel that with brunetifus, disease control rate is and equally is a very good metric to predict PFS. And in fact, my sense of the data is that although brunetifos does have benefit in the TB, it is more of a disease, it has more disease control than chemtractive. But I think at the end of the day, of course, survival will be the ultimate endpoint. I do feel PFS is still a good endpoint for brunetifos. Mohamed, anything to add on that? No? Okay.

Okay, that's helpful. And I guess sort of sticking to the ovarian cancer topic, you know, what's the distribution of prane compared to folate receptor? Is there like an overlap there? I guess I'm just trying to gauge, you know, if you expect to see any patients coming off of St. Eliher, you know, into this, would there be any of those types of patients in the combo?

Sure. Noreen, happy to address that. So for PRAME per se, it's very similar to, in ovarian, it's very similar to melanoma. It's around, you know, 80 to 90%. With the rest of the folate receptor alpha for LHR, it's like, you know, between 35 and 40%. The exact overlap, you know, I don't think we have that data, but, you know, there's probably some overlap, but you can derive sort of 30 to 40% for folate receptor and 80 to 90% is the prevalence for premium ovarian.

I'll just add that what we've seen continually, we saw in melanoma, BRAF mutant, wild type, and with the EGFR, because we've looked at that, mutational status in the lung, that we see PRAME expression independent of whether there's a mutation or not. And so, although, as Mohammed said, we don't have the exact overlap with folate receptor alpha, I suspect 90% of folate receptor alpha positive are going to be positive for PRAME, and I suspect 90% of folate receptor alpha negative are going to be. I suspect that, but we just don't have that data right now.

Okay. Thanks so much. Thanks for taking my question.

Thank you. Our next question comes from the line of Rajan Sharma with Goldman Sachs. Please proceed with your question.

Hi, thanks for taking my question. So I'm just coming back to ChemTrack Dynamics, and I just wanted to get your thoughts on how you see pricing evolving in the long term. So I think it was slide 10 where you laid out the increased patient opportunity with the additional indications. But just given the extent of that potential volume uplift, do you expect there to be some pressure on price both in the U.S. and in Europe? And I guess related to your comments on Europe, if there is kind of downward pressure on price with these additional indications, do you think that a European launch would be viable for those? And then just to follow up, and sorry if I missed it, but in ovarian cancer, do you expect to include folate receptor alpha positive patients in that trial as well? And then just one follow-up on HIV, if I could. Where do you think dose could go? So I think at the minute you said 300 is the upper level. Related to that, how high do you think you can dose? Thank you.

Great. Thank you, Rajan. I think several questions. Maybe we'll start with the HIV. And then we go from there to commercial, correct?

Yeah, so with the HIV, I mean, if you remember, we showed at 15 micrograms, we're already seeing target engagement because we saw IL-6. With our platform, you don't need to give a lot. With ChemTrack, it was in the 64, 68 microgram dose we see of survival benefit. We don't know how high we can go. We're going to go as high as needed, but we certainly know that you don't need to go up to milligram doses with our platform. In terms of the folate receptor alpha, we don't exclude prior folate receptor alpha. In fact, we have had a few patients who had prior ADC enroll on for our trial. Our approach, once again, is not to replace the MRVA. It's not to go head-to-head, which is why it's to add on to chemotherapy. And so it's independent of the market data.

And Rafi, can you comment on the reimbursement, just to reiterate here? I don't think we have any issues in the US, but it's mostly the EU. Go ahead, Rafi, please.

Sure, happy to. So first of all, our pricing strategy really depends on the benefit that we see from the data, right? So if it brings significant benefit to patients and society, that's how we price our further indication. To your question on the U.S. and to Bahia's point, we have not seen any downward pressure in the U.S. so far. In fact, I expect that if the data is good and cutaneous, given that these are settings of high unmet needs, and with small patient populations, that we would not have to erode the price significantly in the U.S. On the other hand, in Europe, you have a good question in terms of price erosion, and I think it's too soon to tell. We need data for us to decide whether we'll be launching in Europe or not, although it is a very tough market access environment. Frankly, one of the toughest I've seen through all my years of working with Europe.

Thank you. Our next questions come from the line of Ethan Markowski with Needham and Company.

Please proceed with your questions.

Yeah, hi. This is Ethan on for Gil. Thank you for taking our questions. I think most of them have been answered thus far, but just wondering, so I know endometrial is not one of the focus indications for PRAME, but wondering if you plan on going into a similar strategy there where moving maybe combination in earlier lines, like you're planning to do in non-small cell lung cancer and ovarian. And then for ChemTrack, you talked about the difficult reimbursement in Europe. Will growth there really be mostly driven by just adding additional countries, or do you think that those dynamics are likely to change over time? Thank you.

Thank you, Ethan. Mohamed, you can take the first one, and then Ralph, maybe, on Europe.

Thanks, Ethan, for the question. I think, you know, as David mentioned, the focus has been on ovarian, you know, melanoma and lung for now. So the endometrial data that we're generating is really in monotherapy with some of the chemotherapies that are used in late line. And, you know, right now we don't have current plans to explore endometrial and early lines until we actually generate data in the late lines to guide.

Sure. So there is, in fact, a very tough environment in Europe, as we've been discussing. However, we've had a lot of successes when it comes to reimbursement. So we've had nine launches in the first half of the year. And we expect some of that marginal growth will come from further additional launches because we're currently in negotiations with several countries. In addition to that, I mean, obviously, we're very well penetrated. The team has been doing a great job in Europe. So, really, the launch is driving the next level of growth.

Thank you. There are no further questions at this time.

I'd like to hand the call back to Bahija Jalal for closing comments.

Thank you, operators. So once again, I just want to thank you for your patience, first of all, and continued trust and commitment. And we now close the call. Thank you.

Thank you. This does conclude today's teleconference. We appreciate your participation. You may disconnect your lines at this time. Enjoy the rest of your day.