Immunocore - Q2 2024
August 8, 2024
Transcript
Operator (participant)
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.
Clayton Robertson (Head of Investor Relations)
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 Bahija Jallal, 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 KIMMTRAK sales and additional growth opportunities for KIMMTRAK. David Berman, Immunocore's Head of R&D, 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. Bahija?
Bahija Jallal (CEO)
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 pinch hit for me. Brian, please.
Brian DiDonato (CFO and Head of Strategy)
Thank you, Bahija. 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 18-24 months. Today, we will provide updates on the first two of these pillars. First, we continue to maximize KIMMTRAK performance. We're pleased 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.
Ahu Demir (Managing Director)
We also continue to increase our global footprint with additional country launches, allowing us to bring KIMMTRAK to more patients around the world. To achieve our longer-term growth objectives for KIMMTRAK, we are simultaneously pursuing label expansion in both late-line cutaneous melanoma with the ongoing TEBE-AM trial, and also in adjuvant uveal melanoma with the soon-to-start ATOM trial. If successful, these two expansions may allow up to 6,000 patients to benefit from the survival benefit of KIMMTRAK. Moving to the second strategic pillar, our aim is to progress our nine clinical programs, all first-in-class, leading bispecific TCR therapies, while progressing our innovative research engine to identify additional novel targets and therapeutics. At ASCO, we presented phase I data of brenetafusp, our PRAME-targeted therapy in 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 KIMMTRAK's commercial performance. Ralph?
Ralph Torbay (Head of Commercial)
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 KIMMTRAK 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 III trial, the TEBE-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.
Ahu Demir (Managing Director)
I will now take you through the figures and financial performance in more detail. We delivered $75.3 million in net revenues with KIMMTRAK 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 KIMMTRAK, 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 U.S. through further market penetration and appropriately supporting duration of therapy, currently trending to 11+ months. This is exceptional and speaks to a different mechanism of action, with the benefit of KIMMTRAK extending beyond the typical RECIST response. Many patients with the best response of stable disease do well and remain on KIMMTRAK 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. KIMMTRAK has the potential to benefit patients beyond MUM and drive midterm growth through label expansion with the TEBE-AM study. Following a consultation with the FDA, we converted and accelerated our TEBE-AM 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 KIMMTRAK monotherapy arms, and second, by rolling the 120 patients already enrolled into the phase II, we accelerate the time to final analysis of the phase III 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 KIMMTRAK journey. In MUM, we're growing KIMMTRAK double-digit year-over-year as we increase our penetration in the US, support duration of therapy around the world, and launch new markets. Our two ongoing phase III registrational clinical trials position us to for continued growth in the mid- to long-term. With the TEBE-AM trial, we see the potential to extend the benefit of KIMMTRAK to up to 4,000 additional patients with second-line+ metastatic cutaneous melanoma. With the ATOM trial, we see this benefit expanded into the adjuvant uveal melanoma setting, where all the evidence with KIMMTRAK 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.
David Berman (Head of R&D)
Thank you, Ralph. I'm really pleased to update you on the strong progress we have made on our pipeline. 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 gonna focus on the two clinical stage programs with data readouts over the next 18 months, brenetafusp 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 pills for select patients.
Ahu Demir (Managing Director)
Our strategy is to demonstrate in the phase one trial in third-line patients that brenetafusp is active and well tolerated, and that this activity would support a PFS 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, brenetafusp 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 brenetafusp monotherapy than the combination of nivolumab plus relatlimab in a similar setting. Third, we see higher activity in brain-positive versus brain-negative. This provides biological plausibility as the brain-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 III in first-line. In our phase III first-line trial, we will combine two biologics, brenetafusp and nivolumab, each with monotherapy activity and with complementary mechanisms of action. Based on the phase I cross-trial comparison I just shared with you, we fully expect that brenetafusp 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 III 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 TEBE-AM in second-line that Ralph shared, we are really proud to be one of the few companies to have multiple phase III investments in cutaneous melanoma, both backed by strong data.
I will now turn to brenetafusp in 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 receptor alpha-positive tumors, antibody-drug conjugates. 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%-50%. In our phase one trial, we aim to demonstrate in the platinum-resistant setting that brenetafusp 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 from 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. Late-line 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 pretreated lung cancer, selected for FRα expression, and combinations with late-line chemotherapies enrolled without regard to selection for FRα 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. FRα is a promising target across multiple tumors, and brenetafusp is a first-in-class FRα ImmTAC. 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 brenetafusp and melanoma, and we'll follow the same thoughtful approach for brenetafusp in ovarian and lung. I will now close by updating on HIV.
HIV is currently managed by antiretroviral therapy, but when ART is 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 cure, 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.
First, 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 have enrolled 15 people living with HIV across three cohorts, the highest at 300 mcg. The 300 mcg 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 2025. I am very proud of our R&D team. We pioneered the world's first TCR therapeutic. We saw the value of KIMMTRAK early in phase I, and we followed that vision to bring a fantastic new medicine to metastatic uveal melanoma patients.
We saw that value for KIMMTRAK in cutaneous melanoma and the potential in adjuvant uveal, and these programs are underway. We see that value in brenetafusp, and we are excited to follow through on that vision as well. Brian, I'm going to hand back to you now.
Brian DiDonato (CFO and Head of Strategy)
Thank you, David. Earlier today, we released our financial results for the second quarter ended June 30, 2024. Please refer to the press release and our latest SEC filing on Form 10-Q for our full financial results. I'll now share some of the key highlights. In Q2, global KIMMTRAK 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. The 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.
Ahu Demir (Managing Director)
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 KIMMTRAK 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 30, or $770 million net of the planned $50 million loan repayment and an expected $40 million in European sales rebate payments, both expected in the second half of 2024. I'd like to congratulate the teams on continued KIMMTRAK 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 brenetafusp phase I late-line ovarian data at ESMO, and then in Q4, the initial phase I lung data at a medical conference.
Looking over the next four years, we expect numerous data readouts, including additional data from brenetafusp, our HIV phase I study, data from our three phase III trials with KIMMTRAK and brenetafusp, 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.
Operator (participant)
Thank you. We will now be conducting a question-and-answer session. If you would like to ask a question, please press star one on your telephone keypad. The confirmation tone will indicate your line is in the question queue. You may press star two 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.
Michael Yee (Senior Biotechnology Analyst)
Hey, guys. Thanks. Good morning. Congrats on great progress. We have two questions. On KIMMTRAK, 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?
Ahu Demir (Managing Director)
Is the study all blinded? What are you seeing there, and, what gives you that confidence to enroll more patients? Thank you.
Bahija Jallal (CEO)
Thank you, Michael. Brian or Ralph, for the first question, and David for the HIV, please.
Brian DiDonato (CFO and Head of Strategy)
Great. Ralph, why don't you take the European question?
Ralph Torbay (Head of Commercial)
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 reserve by $6.6, $6.7 million, sorry. 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.
Bahija Jallal (CEO)
David?
David Berman (Head of R&D)
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 mcg and we'll continue to dose higher. There's a couple of important first here that we're, 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.
Ahu Demir (Managing Director)
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.
Michael Yee (Senior Biotechnology Analyst)
... tantalizing. Thank you.
Operator (participant)
Thank you. Our next question is coming from the line of Jessica Fye with JPMorgan. Please proceed with your questions.
Speaker 20
Hey, this is Nick on for Jess. Thanks for taking our questions. First, on the brenetafusp ovarian update we should expect at ESMO, 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.
David Berman (Head of R&D)
Yeah. Uh-
Bahija Jallal (CEO)
David, go ahead.
David Berman (Head of R&D)
Yeah, happy to. So in terms of size, it's gonna be roughly the same number as the cutaneous melanoma data set 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 gonna be asking, so number one is, and these are the standard questions, you know, 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.
Ahu Demir (Managing Director)
In terms of the metrics or the benchmarks, I think you were asking, yes, so 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%-50%.
Speaker 20
Great. And then in addition to evaluating brenetafusp in 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?
Bahija Jallal (CEO)
Mohammed, do you want to take that?
Mohammed Dar (Chief Medical Officer)
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-resistant setting, but now, the study does allow us to move to earlier lines and combine with the therapies that are used in platinum sensitive, and those include Bev, and also will include platinum doublet.
Speaker 20
Great, thank you.
Operator (participant)
Thank you. Our next question comes from the line of Tyler Van Buren with TD Cowen. Please proceed with your question.
Tyler Van Buren (Managing Director and Senior Equity Research Analyst)
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 in platinum-resistant patients is low, but for the brenetafusp combo, chemo combo, specifically, isn't Elahere or mirvetuximab 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 front line with platinum-sensitive patients is high?
Bahija Jallal (CEO)
It's David and Mohammed.
David Berman (Head of R&D)
Yeah, so I'll address the first one, and then, Mohammed, you can talk about the platinum. So Tyler, the MIRV, it's good to see that there's a new medicine for these patients, and it's, you know, not, you know, this MIRV is a targeted chemotherapy. We know chemotherapies do work there. So, the key differences, I would say, Tyler, for us, is that the MIRV strategy is to, in the PR 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 mirvetuximab as well. Do you want to comment on the platinum sensitivity?
Mohammed Dar (Chief Medical Officer)
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, the platinum-based chemotherapies over the coming months and into next year.
Tyler Van Buren (Managing Director and Senior Equity Research Analyst)
Thank you.
Operator (participant)
Thank you. Our next question comes from the line of Eric Schmidt with Cantor Fitzgerald. Please proceed with your question.
Eric Schmidt (Biotechnology Analyst)
Well, thanks for taking my question. Maybe back to KIMMTRAK 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-over-year. You've spoken to more patients out there than you thought previously and longer duration, of course, than you had assumed. So 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 drug? Where is this gonna end?
Bahija Jallal (CEO)
I think to Eric, Ralph, you want to take that, and maybe, Brian, you can comment also at the end.
Ralph Torbay (Head of Commercial)
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.
Ahu Demir (Managing Director)
But really, I think where we get very much excited is when we think about the label expansions that are possible with the TEBE-AM study, which expects data in 2026, as I mentioned.
... from the ATOM study, a little bit further down the line, and, that also bring, would bring us into the adjuvant setting, bring the platform to the adjuvant setting. So I think there is still significant growth for KIMMTRAK, up to 6,000 patients potentially benefiting from it.
Bahija Jallal (CEO)
[audio distortion]
Brian DiDonato (CFO and Head of Strategy)
Yeah, the only thing I'd add, Eric, is that we're really pleased that given the survival benefit of KIMMTRAK, that the duration of therapy continues to extend, extend. The mean duration of therapy is now, you know, over 11 months, approaching 12 months, maybe plus. And as patients stay on longer and the tail is pronounced, as we see in the 3-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 KIMMTRAK. And as Ralph said, you know, 73% of net sales are coming from the United States. We'd expect that to continue going forward.
Eric Schmidt (Biotechnology Analyst)
Thank you.
Operator (participant)
Thank you. Our next question comes from the line of Michael Schmidt with Guggenheim. Please proceed with your question.
Michael Schmidt (Senior Biotech Analyst and Senior Managing Director)
Hey, guys. Thanks for taking my questions. I had another one for David, just, on the PRAME program again. Could you just provide us with the 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 and lung cancer? And what should expectations be for the scope of that data readout later this year? Thanks so much.
David Berman (Head of R&D)
Yeah. Yeah, thanks, Michael. So with lung, 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 actionable gene mutation-positive patients, because those are insensitive to checkpoint for instance. 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 PRAME positive because about half of the adenocarcinoma patients are PRAME negative, half are positive. And for the initial signal, of course, we want to make sure that the patients are PRAME positive.
Ahu Demir (Managing Director)
We have been doing this double screening, looking for the right patients. 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. 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 osimertinib combination. Mohammed, anything you want to add?
Mohammed Dar (Chief Medical Officer)
No. I guess we also will have chemo, platinum-based chemotherapy options that will come a little bit later after osimertinib and docetaxel.
Michael Schmidt (Senior Biotech Analyst and Senior Managing Director)
Great. Thank you.
Operator (participant)
Thank you. Our next question comes from the line of Jack Allen with Baird. Please proceed with your question.
Jack Allen (Senior Research Analyst)
Great. 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 PIWIL1 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 PRAME and have plans to submit the CTA for the PRAME A24 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?
Bahija Jallal (CEO)
Great. Thank you, Jack. Mohammed?
Mohammed Dar (Chief Medical Officer)
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 PIWIL1, 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, this is—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.
David Berman (Head of R&D)
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 KIMMTRAK and from brenetafusp. So the PIWIL1 study is now designed in colorectal cancer with all the best knowledge we have about where this platform is gonna work. Likewise, with the PRAME half-life extension, which is essentially the same molecule as brenetafusp, 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 PRAME half-life extension. So we see acceleration in our phase I trials, based on these learnings.
Jack Allen (Senior Research Analyst)
Got it. Thank you.
Operator (participant)
Thank you. Our next question comes from the line of Justin Zelin with BTIG. Please proceed with your question.
Justin Zelin (Director and Biotechnology Analyst)
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 your candidates. And any thoughts on a timeline for entering the clinic, these programs?
Bahija Jallal (CEO)
Yeah, 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.
Justin Zelin (Director and Biotechnology Analyst)
Great. Thanks for taking my question.
Operator (participant)
Thank you. Our next question comes from the line of Jonathan Chang with Leerink Securities. Please proceed with your question.
Jonathan Chang (Senior Research Analyst)
Hi, guys. Thanks for taking my questions. First question, how do you see the uveal 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, and how is this facilitating the commercial story? Thank you.
Bahija Jallal (CEO)
Great. I thank you so much for the great questions. So I'll start with David and maybe then Ralph, so you can comment more.
David Berman (Head of R&D)
Yeah, Jonathan, in terms of the landscape, I think there are two ways to look at it. First, in the metastatic setting, 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 ATOM 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.
Ahu Demir (Managing Director)
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?
Ralph Torbay (Head of Commercial)
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.
Ahu Demir (Managing Director)
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.
Jonathan Chang (Senior Research Analyst)
Understood.
Operator (participant)
Thank you. Our next question comes from the line of Peter Lawson with Barclays. Please proceed with your question.
Speaker 19
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-resistant setting? Or would the goal be to maybe try to go sort of directly into earlier lines of therapy in combination with chemo?
Bahija Jallal (CEO)
Thank you, Alex. David?
David Berman (Head of R&D)
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, get more platinum combinations and bevacizumab combinations in the platinum-sensitive. This is the dataset that we think will enable us to make the best decision on what the next study is, PROC or PSOC.
Speaker 19
Okay, great. And do we actually see any Bev combination patients in the 3Q update?
David Berman (Head of R&D)
No, there won't be any bevacizumab combinations in this update.
Speaker 19
Okay. Thank you.
Operator (participant)
Thank you. Our next question comes from the line of Ahu Demir with Ladenburg Thalmann. Please proceed with your questions.
Ahu Demir (Managing Director)
Good morning. Thank you for taking my questions. Two questions from us. First one is on the lung cancer program. When you present data, disclose data from it-
Bahija Jallal (CEO)
You cut off. If you could repeat your first question, please.
Ahu Demir (Managing Director)
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 one-
Bahija Jallal (CEO)
Okay, thank you.
Ahu Demir (Managing Director)
-after.
Bahija Jallal (CEO)
Thank you. Thank you, Ahu. I would say it's too early to say, but I'll give it to Mohammed to tell you.
Mohammed Dar (Chief Medical Officer)
Sure. Thanks, thanks for the, thanks for the question. In terms of lung cancer, as you know, David mentioned, it is obviously a more, it's a more heterogeneous, setting compared to, compared to melanoma, and we are still in the initial signal detection mode. But in terms of, in terms of patients, it will be, likely a smaller dataset 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, we are allowing regardless of PRAME status.
Ahu Demir (Managing Director)
... Mohammed, that's helpful. My second question is on the HIV program. You touched on the viral load and also the rebound rates. What would give you confidence to move forward from the MAD result? Would you be looking for? What data would you be looking and any two combinations for that program?
Bahija Jallal (CEO)
Yeah, David?
David Berman (Head of R&D)
Yeah, it's a really good question, Ahu, because of course, you know, we're pioneering this area here. No one's generated the data thresholds for what, 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, 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? 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 endpoint. But I think any insights we make here are going to be important for us.
Ahu Demir (Managing Director)
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.
Bahija Jallal (CEO)
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.
Ahu Demir (Managing Director)
Thank you much.
Operator (participant)
Thank you. Our next question comes from the line of Avantika Joshi with Mizuho. Please proceed with your question.
Avantika Joshi (Equity Research Associate)
Hi, this is Avantika on for Graig. I just had a question. Are you still looking at brenetafusp in tumors beyond melanoma, ovarian, and non-small cell?
David Berman (Head of R&D)
Yeah, you know, we certainly are, and there's, you know, strong scientific rationale. But as a team, I've asked them to focus, right? We're launching a global phase III 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 I 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.
Avantika Joshi (Equity Research Associate)
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.
Bahija Jallal (CEO)
Go ahead, Mohammed. I have to admit that I don't tend to retain the numbers, but go ahead.
Mohammed Dar (Chief Medical Officer)
Are those numbers referring to the half-life extended in the A24?
Avantika Joshi (Equity Research Associate)
Yeah, the half-life extended and the, the A24.
Bahija Jallal (CEO)
We would have to simplify them.
Mohammed Dar (Chief Medical Officer)
Yeah. Yeah.
Avantika Joshi (Equity Research Associate)
Sorry about that.
Mohammed Dar (Chief Medical Officer)
No, it's not an issue. As David mentioned earlier, we are certainly applying all of the learnings from our phase I to III PRAME program to those two programs. We know where PRAME is expressed, so yes, those three trials are designed flexibly, so we have multiple options in terms of the types of patients that we can enroll.
Avantika Joshi (Equity Research Associate)
Okay, thank you.
Operator (participant)
Thank you. Our next question comes from the line of Jeffrey Hung with Morgan Stanley. Please proceed with your question.
Speaker 21
Hello, this is Selena on for Jeff. Two questions here on PRAME. For the melanoma data, ctDNA 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 last, when might we expect an update from the endometrial cohort? Thank you.
David Berman (Head of R&D)
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 of that, called a molecular response. In our uveal melanoma data, that 0.5 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 ctDNA at, on the ovarian data at ESMO. But it does look like that 0.5 log reduction, I think, is a good log reduction. It is a good threshold for us, based on the data we have today.
Ahu Demir (Managing Director)
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.
Speaker 21
Thank you.
Operator (participant)
Thank you. Our next question comes from the line of Naureen Quibria with Capital One Securities. Please proceed with your question.
Naureen Quibria (Director and Senior Equity Research Analyst)
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 PRAME results that you, you'll be presenting at ESMO. You know, you've observed benefit with KIMMTRAK outside of RECIST 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?
David Berman (Head of R&D)
Yeah, it's a good question. I mean, we certainly saw this with uveal melanoma. There's even patients with, quote, radiographic increase in size that benefit, the survival benefit, but long-term survival. We saw a few patients of those with brenetafusp 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 ctDNA, which is a way to measure independent 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.
Ahu Demir (Managing Director)
Now, although we do see this TBP benefit, we see it very strikingly for KIMMTRAK. We feel that with brenetafusp, disease control rate is equally a very good metric to predict PFS. And in fact, my sense of the data is that although brenetafusp does have benefit in the TBP, it is more of a disease, it has more disease control than KIMMTRAK did. 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 brenetafusp. Mohammed, anything to add on that? No. Okay.
Naureen Quibria (Director and Senior Equity Research Analyst)
Okay, that's helpful. I guess sort of, sticking to the ovarian cancer topic, you know, what's the distribution of PRAME 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 the Elahere, you know, into this. Would there be any of those types of patients in the combo?
Mohammed Dar (Chief Medical Officer)
Sure. Naureen, 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%-90%. With regards to the folate receptor alpha, for Elahere, it's like, you know, between 35% and 40%. The exact overlap, I, 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%-40% for folate receptor and 80%-90% is the prevalence for PRAME and ovarian.
David Berman (Head of R&D)
I'll just add that what we've seen continually, we saw in melanoma, BRAF mutant, wild type, with the EGFR, 'cause we've looked at that, mutational status in 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 gonna 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.
Naureen Quibria (Director and Senior Equity Research Analyst)
Okay. Thanks so much. Thanks for taking my question.
Operator (participant)
Thank you. Our next question comes from the line of Rajan Sharma with Goldman Sachs. Please proceed with your question.
Rajan Sharma (Executive Director of Pharma and Biotech Equity Research)
Hi, thanks for taking my question. So, just coming back to KIMMTRAK 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?
Ahu Demir (Managing Director)
Just one follow-up on HIV, if I could. Where do you think the 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.
Bahija Jallal (CEO)
Great. Thank you, Rajan. I think, several questions. Maybe we'll start with the HIV, and then we'll go from there to, to commercial. Correct?
David Berman (Head of R&D)
Yeah. So with the HIV, I mean, if you remember, we showed at 15 mcg, we're already seeing target engagement because we saw IL-6. With our platform, you don't need to give a lot. With KIMMTRAK, it was in the 64-68 mcg dose we see a survival benefit. So, we don't know how high we can go. We're gonna go as high as needed, but we certainly know that, you know, 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 onto our trial. Our approach, once again, is not to replace the MIRV.
Ahu Demir (Managing Director)
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 mirvetuximab data.
Bahija Jallal (CEO)
And Ralph, 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, Ralph, please.
Ralph Torbay (Head of Commercial)
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 benefit, significant benefit to patients and, and society, that's how we price our, our further indication. To your question on the US, and to Bahija's point, we have not seen any downward pressure in the US so far. In fact, I expect that if the data is good in cutaneous, given that these are settings of high unmet need, and with, with small patient populations, that we would not have to erode the price significantly in the US. The other hand, in Europe, you have a good question in terms of price erosion, and I think it's too, too soon to tell.
Ahu Demir (Managing Director)
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, working with Europe.
Operator (participant)
Thank you. Our next question has come from the line of Ethan Markowski with Needham & Company. Please proceed with your question.
Ethan Markowski (Equity Research Associate)
... 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 a non-small cell lung cancer and ovarian. And then, for KIMMTRAK, 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.
Bahija Jallal (CEO)
Thank you, Ethan. Mohammed, you can take the first one, and then Ralph, maybe, on Europe.
Mohammed Dar (Chief Medical Officer)
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.
Bahija Jallal (CEO)
Ralph?
Ralph Torbay (Head of Commercial)
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. 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, it's the launch is driving the next level of growth.
Operator (participant)
Thank you. There are no further questions at this time. I'd like to hand the call back to Bahija Jallal for closing comments.
Bahija Jallal (CEO)
Thank you, operator. So once again, I just wanna thank you for your patience, first of all, and continued trust and commitment, and we now close the call. Thank you.
Operator (participant)
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.
