Medivir AB (publ)

Thank you and welcome everyone to the Q4 conference call for Medivir. Let's get right into it. We'll touch on three different sort of topics today in today's call. First and foremost, we have made significant progress in quarter four of 2023. The FosTruxel and Vima study continues to progress very nicely with regards to patients staying on treatment, We are seeing improved benefit, and we had our first external data presented at ASCO GI conference just after New Year's. As we communicated in Q3, we have been focused on accelerating the FOSTRUX development program towards initiating a pivotal phase 2b with the aim of gaining accelerated approval. We believe that the data and the clinical benefit we're seeing with the data is strong and the unmet medical need in the second line HCC population is significant as there are no approved treatments beyond or after current standard of care in first line. And we have also with regards to acceleration activities taken strides with regards to CMC and also initiated our regulatory processes to get discussions with regulatory authorities on study design of the upcoming study, as well as initiated clinical preparations discussions with CROs. We'll talk, we'll give an update on the FosTrox Lenvima data today. The clinical benefit we are seeing continues to go from strength to strength. We have more than 40% of patients still in the study and data continues to improve and Pia will go through the details in a little bit. And finally, great news to see one of the outlicensed programs, the USP1 program, which was a preclinical program outlicensed to Tango Therapeutics. That now has a name, the molecule developed by Tango, TNG348, and they moved into the clinic with the first in human trial towards the end of December. So they moved into phase one, two, and Fredrik will give an overview of the program and what they are doing at the moment. So presenters today, apart from myself, our CMO, Pia, will go through the data. Fredrik Erberg, our CSO, as mentioned, will go through the T&G 348 program. And Magnus will touch on the financial highlights, of course. In terms of highlights during the last quarter or the last few months, first and foremost, The post-structural and VMAR program keeps improving. The magnitude of clinical benefit that we're seeing in this study is sort of outperforming what can be expected of standard of care in the second line HCC setting. We now have a time to progression that has increased to more than six months, which is sort of almost double what you have seen previously in second line HCC studies. And even more encouraging is that patients are staying on treatment longer than anticipated, as mentioned, more than 40%. And that's a number that we have sort of mentioned for a while. So it's been a while since we actually have seen any patient show tumor progression and leave the study. We also did a capital raise. In December and in January and and that enables us to sort of continue our acceleration activities as we move forward towards initiating a registration or face to be with accelerated approval intent. liver cancer is a challenging disease to treat and and we believe. But sort of having an organ specific targeted approach that we do have with with. Sorry, with false drugs is the key to improving clinical benefit for patients. If we look at the primary liver cancer and how it is is treated today in first line setting today, there is a standard of care and immune therapy combination that has shown improved benefit for patients. But even with that, there are still only 30% of patients that respond to treatment and the time to progression sort of across the first line studies with immunotherapy combinations is somewhere around sort of six and a half months. So still limitations in terms of what you can expect as a patient. If you move to second line, the situation gets sort of further worse. One, there are no approved treatments today. And when we look at the treatment guidelines and we speak with sort of global experts in the field, they all say the same thing. They recommend clinical trials as the first option, partly because the evidence for benefit in terms of what has been shown previously in second line is not sort of very good. In terms of those studies that has been done, we are seeing in second line somewhere along the lines of a 10% response rate and a time to progression of on average three and a half months. So when we look at our data, of course, that is what we need to sort of benchmark against in terms of what we need to improve on. A key strategy to improve treatment effect across cancer types over cancer patients is to try to, of course, deliver the drug as targeted as possible to the tumor. And if we look at that today, there are two ways or two approaches that that can be done. There is on the one hand, on the left-hand side, the antigen-specific targeting, or there is the organ-specific targeting. Antigen-specific is, of course, used by the antibody drug conjugates and is especially suitable for cancer types where there's a high expression of the target antigen selectively on tumor cells. That has been shown in a number of tumor types, and I think that maybe breast cancer and HER2 is the most sort of famous one or the one that most people know of. However, sort of it's still sort of for an antibody drug conjugate to be effective, sort of it does need high expression of the target antigen on tumor cells. And that is not the case across all tumor types. And liver cancer is perhaps the one that stands out the most with regards to being heterogeneous cancer without specific target antigen on tumor cells. So if we want to achieve a targeted delivery of the drug to the tumor cells, then we need to find a different way. And this is where the organ-specific targeting that we're utilizing with FosTrox is a different way of doing this to ensure that we can deliver the drugs as effectively as possible to where it needs to be while minimizing damage to the healthy cells. So we do believe that the approach that we're taking with FosTrox is the key to the improved clinical benefit that we're seeing in the ongoing Phase 1b, Phase 2a study. And with regards to what we are seeing in a bit more detail, I'll hand over to Pia to go through the data.

Thank you, Jens. Very nice introduction and also to explain what actually the mechanism of action is that we are utilizing in this study. And we recently presented data from the study that Jens mentioned at Ascogia in San Francisco. And here today, we will give a following update actually at a later time point here in February 14, so it's really, really fresh. The study, as you can see on this slide, just a reminder, I'm sure you have seen this before if you have listened to us, is still ongoing, and it was a dose escalation and dose expansion phase. It was in second-line liver cancer, and it was in the Post-Ox Plus combination with Benzema. So the study was finally enrolled with the 21 patients. And what is important to know here is that we had a generous inclusion criteria. Actually, 19% of the patients had two prior treatments and 67% of the patients had extrahepatic metastasis, meaning metastasis outside the liver. And we also allowed all grade of macrovascular invasion. And what I'm saying this is that it's a very bad prognostic sign if you have a complete macrovascular invasion, but these were allowed into our study. All the patients had tumor progression on prior treatment and Ticentric Avastin was used in 86% of the patients. We can go to the next slide. So the current data, again, they are from February, just fresh from the press. And with seeing this progressive disease on prior treatment, it was very encouraging to see that now 24% of the patients have an objective tumor response. And you can see that in the green bars to the right on this slide. And they needed to have, if you have an objective response rate, you need to have more than 30% reduction in the tumor size. But we could also see that 75% of the patients had an overall tumor shrinkage on Ostrox and Venema. We can go to the next slide. So how does this sort of relate to the longer term efficacy? And the improved response that we see in this study was reflected during follow-up. And we could see a durable clinical benefit. And most important here, an ability to stay on the treatment over time with, as Jens already said, that we have more than 40% of the patients still ongoing in the study. As said, again, overall response rate was 24%. And the disease control rate, and why we are mentioning this is that in liver cancer also disease control is actually seen as a response. So the disease control rates includes not only partial and complete response, but also disease control rate. And it was 81%. And now with the updated data, we have 6.3 months of time to progression currently. And I will just say, if you look at this, we must plot that two patients have been ongoing in the study for more than one year. And the patient with the shortest follow-up has now been treated for 5.5 months. You can see also here in the little pinkish text box at the end that, again, as Jens said, it is around 3.5 months when we look at the time to progression expected in the second line. And already now we can see 6.3 months. So we can go to the next slide. So we have actually shown this almost the same slide at our webcast from after ASCO. But we were really interested to understand sort of how does this time to progression of 6.3 months relate to what the patients have had on prior treatment? because that is often very prognostic or predictive of what you will see in the second line treatment. It is also important to know that if the patients haven't had any successful outcome or have optimal response on prior treatment, would they later respond on FOSTRX? And what we can see here, now we have 6.3 months, yeah, I've already said that, is that when we looked at prior treatment to the left here, It showed that there were no real correlation, and patients who had a short duration of prior treatment could actually have a longer benefit with FosTrux than Rheema. And again, interesting was to see that the median TTP here with prior treatment of 5.6 months was somewhat shorter. It is usually longer. And with this combination, we are, again, very encouraged about not only the response rate, but also the durability of the efficacy. Can we go to the next slide? So in order to have efficacy, it was more or less a prerequisite is that the patient actually can tolerate the treatment without seeing any compromising side effects. And in this study where we added FosTroc to Lenvima, we showed a really good safety and a tolerability profile, where there were no reports of any new unexpected safety events. And we have said this before, and it's still true, that the side effects related to FosTroc, they were mainly hematological, and they were temporary. which means that 70% of the patients could continue with the full dose without having any need for discontinuation or dose modification. Importantly here is obviously that the patient continued to tolerate Lenvima because we are adding FosDrux on top of Lenvima and we couldn't see any increase in dose modification or discontinuation on Lenvima either. compared to what you usually see when you have Lendvima as monotherapy. In short, the combination was tolerable, which was also shown in the previous slide, where the patient actually could stay on the treatment for a longer period of time. So we can go to the next slide. So the current result, which was just shown, showed superior efficacy compared to second line HEC. And if we look at all the parameters you usually look at when you compare efficacy, this is, of course, an indirect comparison with standard of care in second line HEC. We had an overall response rate of 24% where we are right now, and this should be compared with the 10% in second line HEC with current standard of care, a disease control rate of 81%, It is around 65% in standard of care. And here we have a 6.3 months of time to progression, which should be compared to 3.5 months. We can go to the next slide. This means that with this promising data, and I know that Jens already said this, but I will repeat it. We are now accelerating the next step in the development of post-trugs. And we are planning a randomized phase 2b study with a registrational intent. So the eligible patients will be a little bit more narrow, because they need to have received only one prior IO combination. And that is standard of care today. The randomization will be a 2 to 1, with FosTrox plus Levima versus Levima alone. And the primary endpoint is progression-free survival. To pressure test this study design, we actually took the possibility, since we were in San Francisco, we met with so many of the global experts to pressure test, is this the right way to go about a study? And the feedback we received was extremely positive, I must say. We had a strong support for the study, and it is because it is an underserved population. The guidelines recommend clinical trials. because there are no regulatory approved treatment and there is no consensus in how to treat this patient in the second line setting. Lenvima was absolutely considered as the best combination partner in second line and also very encouraging was that they expressed a keen interest in participating in the study. So what we need to do now is obviously that we need to confirm the study design in the ongoing FTA interactions as well. So with that, over to Jens.

I'll pick up on that just in terms of what is happening at the moment. What did we do in Q4 and what are we doing going forward? And then picking up on Pia's point on FDA, we can look on the bottom. From a regulatory perspective, we did have an initial FDA type D meeting where there were a couple of topics we needed to clarify with the FDA and got sort of positive response on. But the important, kind of the bigger meeting is what we then did call an FDA type C meeting. That is where we take our proposed study design, our proposed development program, and discuss in order to confirm with the FDA that this is an appropriate way to go. That process is now ongoing, and we will, of course, sort of communicate the outcomes of those discussions. In order to have US hospitals be part of the study, we need to open an ind a so-called investigation investigation a new drug and and that will also then happen sort of after the fda type c meeting so so that's sort of well underway and what happened maybe a bit earlier what we really needed to accelerate in q4 2023 as you see on the slide is to initiate um some development work on cmc side from a kind of formulation of drug substance, drug product, and that we did in Q4, and that's now ongoing with regards to preparing for the Phase IIb study start. And then on the clinical side of things, as Pia mentioned, engagement with KOL, investigators, and also engagement with our advisory council in terms of understanding appropriateness of study design and so forth. Again, we did that in 24, now we're taking the next step in terms of finding the best possible CRO partner with regards to executing the study. So the development of FosTrox is accelerating well in line with what we were planning and what we communicated sort of at the Q3 results. Maybe this is a bit early, but just for the sake of the argument, we are focusing on second line, as you see on the left. It is our fast-to-market opportunity because of the significant unmet need. But as a locally or organ-specific targeted drug, there is clearly opportunity to look beyond second line And that we are getting the feedback from in from our experts that sort of we should be looking towards first line setting as well and adding it on top of the combination alternatives in first line, so we are looking ahead. and we do see significant sort of future development opportunities beyond the second line setting but you also need to start somewhere second line is a significant unmet need highly underserved population and it's a it is a significant value opportunity as well so that is our sort of fast to market lead indication So with that, we'll move into as there's been sort of exciting news in other parts of the pipeline with regards to the partnering programs, specifically T&D 348. We will sort of touch a little bit on that. And as you see here, we do have postdocs as our in-house program that we focus our efforts to. The outlicensed programs are run by our partners without sort of further investments from our side. and the most exciting piece of news in q4 was the one community by tango so just to provide a little bit of of of an intro to what tng348 is and what they are doing at the moment frederick

Thank you Jan. So as Tango is making good progress in this project, we think it would be a good idea to describe a little bit more about what USP1 inhibitor does. So USP1 or ubiquitin specific protease one cleaves off ubiquitin molecules from target proteins. And one key target protein is PCNA, which is a protein involved both in DNA replication but also in DNA repair. So it needs to be mono-ubiquitinated to start with and then this molecule needs to be cleaved off in order for the DNA repair process to proceed. So what TNG348 does is inhibit the USP1 protease activity so it doesn't cleave off ubiquitin. This means that PCNA will accumulate several polyubiquitinated molecules and this will lead to cessation of the DNA repair and degradation of PCNA. And as you may know, cancer cells are often reliant on a few DNA repair mechanisms because they usually have mutations in several repair mechanisms. And such a mechanism is mutations in BRCA1 or 2, BRCA1 or 2. And these mutant cells are essentially very sensitive. They rely on this PCNA-driven translation synthesis. So they are very sensitive to inhibition of USP1. So there's a good scientific rationale, but also, as we see in the next slide, uh solid preclinical data demonstrating that mutant or cancers with mutant bcr a1 or two for that matter genes are sensitive to inhibition with tng348 so these these are our graphs showing tumor growth uh patient derived xenografts so tumor cells from patients with breast cancer or pancreatic cancer transplanted to mice. And these mice are then treated with the drugs indicated here. So it's shown that also as a single agent, TNG348 does inhibit mutant cancer cells or the tumor growth in these mice. But also you can enhance that activity by inhibiting another important enzyme in DNA repair, namely the PARP enzyme by PARP inhibitors. So there's a good rationale both for single agent and combination studies with TNG348 together with PARP inhibitors. So if we move to the next slide, as Tango announced early January, They had dosed their first patient in the clinical study with TNG348. So they are in the dose escalation phase right now, where they are trying testing two arms, TNG348 as a single agent, or in combination with Olaparib, which is a PARP inhibitor. And their clinical development plan is then to move into specifically then BRCA mutated breast or ovarian cancer with single agent. And also the combination in these two indications, including also pancreas and prostate cancer. And as you see on the right hand side, this is because the mutation or frequency of BRCA genes or other genes involved in homologous recombination are relatively high in ovarian, breast, prostate, and pancreatic cancers. So we are really happy that they are moving this rapidly forward, and this is really what you want to see when you out-license a program, a very good progress in their clinical development.

move the program along with sort of very nice speeds and communicating sort of strong enthusiasm for this. PARP inhibitors have now been sort of well established as standard of care in BRCA mutant cancers, sort of as blockbuster options. So adding benefit on top of the PARP inhibitor would have a significant value upside for a USP1 inhibitor. So we look forward to reporting sort of future progress of T&T 348.

With that, financial, Magnus? Magnus Eriksson Thank you, Jens. Next slide, please. We can see the financial summary for the quarter four for the financial year 2023, and all numbers are in . From a financial viewpoint, 44 was according to our plan from a cost perspective and turnover 44 amounts to 4.4 which relates to the royalty income for Seclear and also the milestone income related to Tango. Those are the first patients as we have mentioned right now. Year to date turnover is higher and it almost relates to the milestone income. Other external expenses are higher compared to last year in the quarter and relates to the cost for the ongoing combination study. Year to date is in line with last year. Personnel costs are higher and relate foremost to more employees compared to last year and year end accruals. The operating loss for quarter four was 21, which is in line with our estimations for the year. The cash position At the end of the year, it's 169, and we received the right issue proceeds in December, but we have paid most of the transaction costs related. We paid that in January this year. And also, as Jens has mentioned, we carried out the directed issue to Hallberg Management, which we received in January this year. And according to our current plan and assumptions, the cash run rate will be into Q1 2025. And with this, I will hand back to Jan.

So before Q&A, just sort of a summary of things before we open up the call. So we continue to strongly believe that the combination of FosTrox together with Enviva has the potential to transform second-line primary liver cancer or HCC. We are seeing that the smart organ-specific approach with FosTrux that selectively kills liver cancer cells while sparing healthy cells is showing encouraging clinical benefit. The data keeps getting stronger and stronger as patients stay on treatment longer than expected, further improving or outperforming what can be expected of standard of care in this second-line setting. uh the fast to market opportunity in second line is sort of spi so communicated previously it is highly underserved and it is a high value population where there is significant value upside also beyond that indication as we move forward so with that we stop there and we move to q a

If you wish to ask a question, please dial pound key 5 on your telephone keypad to enter the queue. If you wish to withdraw your question, please dial pound key 6 on your telephone keypad. The next question comes from Richard Romanious from Red Eye. Please go ahead.

Hello, good afternoon. I have a couple of questions in different areas. Let's start with the ORR. Is the numbers you presented confirmed objective response rates?

The objective response rate ORR? I should have added that in most of the cases it's actually confirmed and to be honest I haven't looked at the data where it is not confirmed so I will have to come back to you for that. It was not the primary endpoint and that is the reason that we have added objective response rate and not overall response rate.

Okay but the overall impression is quite good. Could you say anything about median overall survival? Do you have any predictions for that? Or when could you report?

So the median overall survival, in this study, the patients were treated until they progressed. And after that, we had a follow-up for six months for overall survival. So as you can understand, if the patients did not die during the six months, we will not have the opportunity to report that overall survival so and that is the reason why we need to move forward into a new trial where we have randomization it's not only for the landima comparison it's also to have really conclusive data but we will have time to progression on progression sort of progression free survival we are reporting time to progression due to the fact that in progression free survival you all also count in the overall survival And yeah, one more thing I need to say here, and that is that in the studies, I mean, there are not many studies with LEMVIMA monotherapy, but in the studies where we have looked, the progression-free survival and time to progression has been very similar due to the fact that they progress this early. So that's why these two parameters or endpoints are relatively comparable in HEC.

Yeah, right. And I was thinking about the responses you were talking about at the GI ESCO conference you were at and the strong support. And it's interesting that a clinical trial is recommended for Phase II Shouldn't that play to your advantage? I mean, that would suggest you could recruit patients really fast in a phase two trial. I'd also like to ask, what do you think about academic support? I guess you're not interested in getting such a trial sponsored, even if you could. What kind of academic support could you get for such a trial? Yeah.

Yeah, if I start with the recruitment, you are absolutely correct. So we could see that already in the trial that's ongoing now, the phase 1b and 2a. It was a fast recruitment, it was a huge interest because they cannot access LENVIMA. LENVIMA is approved in the first line setting and it's not regulatory approved in the second line setting, which means that we hope still, since there is nothing regulatory approved in the second line setting, to be able to recruit really, really quickly in this study. that is the reason why we are ramping up all the preparation activities to be able to open this study as soon as possible that was the first one the academic support sort of we have the academic support and we realized that very very strongly since we talked with a global expert from the us from asia and from europe when it comes to consortium if that is what you are Obviously, we are going to look into that more in detail when we do our feasibility to see if there is, for example, any research consortium, particularly in the US, that might be interesting to participate. But we need to have it as a company-sponsored trial. We cannot have it as an academic trial because then it will be very difficult to have the correct monitoring and everything that is required for regulatory approval.

Okay, thanks. I had the question about business development for Jens. You have, although sample is small, but results convincing. You also have the right regulatory pathway and you have the right market. Could you discuss which of these points you think is most important because we've seen in the last year that large pharmaceutical companies, they don't seem to be that interested in early stage assets. But if this is a pivotal trial, then that makes it a late stage asset. How does that affect interest?

Yeah, I think that it is a fair statement. Larger pharmaceutical companies, they can afford to sort of wait somewhat. I sort of move, sort of wait for late stage. We are now moving to the late stage. One of the key elements, as Pia commented on previously, is the regulatory path. That is why we have emphasized our focus and prioritized moving to regulatory interactions, specifically focused on FDA, with regards to generating clarity on study design, and primary endpoints, size of patient population, et cetera, because we do anticipate that is going to be a critical element of any partnering discussions. And we focused on the U.S. because we know that sort of a majority of other regulatory agencies will look to the FDA and they will sort of follow how FDA guides. So always difficult to sort of make an assessment of what parameters are most important. I think it's important to conclude that the clinical benefit we are seeing is going to be sort of the first thing you look at. If there isn't a convincing clinical benefit, if we're not seeing as we're adding anything on top of current standard of care, Clearly, that will deter people from being interested, but as we move towards pivotal stage, yes, as much clarity as possible on regulatory path and feedback from regulatory authorities will also be important. And as mentioned earlier, that process is ongoing and is well underway, and it was encouraging quite encouraging that the feedback from the leading global experts we met at asco gi was quite um not looking for the right word some stemming uh was quite uh conclusive and and they all communicated the same message i.e in in terms of supporting the approach we're taking with the proposed to be studied

Okay, thanks. Some final financial questions, if you bear with me. So for Magnus, first of all, about working capital, you had a quite, as you say, positive effect on cash flow in this quarter. That is, you burnt quite a little, but you have a negative working capital. Would that affect That should reverse in the common quarters, right?

Yes, thank you for the question. Yes, that's the first statement. As I said, all the transaction costs that related to the right issue, they were paid in January, and then there were some accruals at the year end that will be paid in Q1 as well. So you are correct, Richard.

Final question. I wanted to ask about the milestone structure for the TANGO agreement. since you got paid roughly around 4 million for start phase one, would it be correct to assume then that it's very back heavy?

I mean, we have not disclosed the terms of the agreement, but like I say, the figure that we mentioned for the miles on payment, that's kind of accurate that you say. We have not disclosed that, but that will be shown in the annual report that we show later on, so. So it's around that figure, I would say.

And yes, it is a relatively, there are going into details because we haven't disclosed, but it is a relatively back heavy sort of standard sort of licensing agreement, especially sort of considering that it was outlicensed as a preclinical program.

Okay, great. Thanks. You've answered all my questions.

Thank you.

The next question comes from Joe Pantginnis from HC Wainwright. Please go ahead.

Taking the question. Two questions, please. First, for the responders in the study, can you disclose any color about whether any of those were the dose reduction patients? And second question is, going into the Type C meeting, can you disclose sort of what your rate-limiting steps or ongoing discussion points are with regard to the final study design. Thanks a lot.

Thank you for the question. And yes, there were some of those patients who actually are responding who those reduced. Just talk about sort of what Fostrox is. Fostrox is this targeted drug to the liver where it is released. So it's really dependent on the liver function, the enzymes in the liver and the liver functions of the patient. which means that it's difficult to understand the tolerance for one specific patient. So that's why it's important that we have a dose that is on as high level as possible. And you need to expect some of the dose reduction. So yes, it was. That was a long answer. Sorry, now I forgot the next question. The regulatory, yes. So what we are waiting for is really to have the interaction with the FDA to finalize the study design. We have done what we can do until now with trying to sort of structure primary endpoint and all the steps and so on. But of course, if there is something that they have opinions of we need to to be designing part of it but i would now i'm really saying that but i and this study design has resonated very well with the majority of all the experts that we have been talking to so um let's hope for the best and and i think that the the added color joe i mean some of the i mean the the the assumption of clinical benefit

and that we are making sort of the six months PFS versus four months and whether that's clinically relevant, et cetera. Those are some of the design points that sort of we have seen as key with regards. And we think that the FDA will view as key as well. And that's where, as Pia concluded, we've been encouraged by the feedback from the experts agreeing with some of the assumptions that we've made.

Okay, thank you.

The next question comes from Klaas Palin from Carnegie. Please go ahead.

Hi there and thanks for the quick questions and just a question about to clarify this type C meeting, do you expect this to be finalized in the first half of 2024? Yes, that's correct. Perfect. And also about your IND that you are intending to open up in the US. Do you expect you need to do some sort of a bridging study before being able to recruit patients, American patients, into the pivotal study?

No, we don't need to have a bridging study, but we need to have the IND in place. That is what we need. So there's no need to have any additional US patients before you go and open the IND. And the IND will be open. on the randomized Phase II study. That's why we need to sort of have the FDA feedback first.

Okay. Great. Thank you.

Thank you.

The next question comes from Jason McCarthy from Maxim Group. Please go ahead.

Hi, team. Thanks for taking the questions. Can you just go back to the Phase I, II? study and walk us through what the median follow-up time has been. I know the TTP, 6.3 months. And with that, how far out are you going to continue to monitor these patients?

So that's a very good question. And we are actually planning to start closing the study this year. And the reason for that is that it is heavy work for the institutions and also for the patients to be controlled this regularly because we have CT scans and MRI every six weeks. You can only imagine. So that is one thing. And the other thing is that even if we have 40% of the patients still in the study, we see the safety data as long in HEC second line population. and also the efficacy data that we can get from this study is starting to be really, really mature. So our focus need to be to start the randomized phase 2B study now, and that's why we are planning to close out this study this year.

Got it. And I know it's a little bit down the road, but considering first-line HCC therapy, what's the expectation of improving or potentially improving response rates in first line if T-centric or checkpoints with a TKI, they're already being used, right? Or would you have to use kind of that combination for a comparator arm versus your own combination with a TKI?

So we are talking about the first line here, and it's very interesting, and I'm sure that you're aware that there are quite a lot ongoing where you add something on top of centric LHC. But since we also need to have more data with this combination, so we haven't decided since we are focusing on the second line now, but that need to be established first, the tolerability.

J. But I think i'll say the following that the feedback from the advisory Council when we discuss with them Okay, what sort of path do we have forward. J. They are relatively sort of clear in there in in their advice to us that yes let's move with speed in second line, because the unmet need is clearly there and and sort of we're lacking options but. we also get the same strong message that you should start exploring first line as soon as possible because there is as we concluded to earlier that there's there's still only 30 response rate and the pfs is relatively short in second line any first line as well and the guidance is to we should explore uh adding four strokes on top of sort of either Ticentric Avastin or another immune therapy combination. So they see a triple combination as the logical sort of next step, rather than necessarily sort of taking Fostroxil and Vima and competing with Ticentric Avastin. So triple combination is kind of where they would be steering us to go as a first-line option.

And I will only add to that, the reason why they do that is also that it is a completely different mechanism of action and it has been very tolerable. And if you have three different drugs in a very frail patient population, the tolerability is going to be key. So I think we will have to come back on more details on that.

Or can I elaborate even further? No, no. We also do see that the landscape will probably shift a bit with regards to the the data we're seeing the centric of us in has shown in. In the adjuvant setting and we've seen with the Emerald study in terms of sort of treatments that have immune therapy combinations being used earlier. So it is not unlikely that as they are used in earlier settings, when patients progress and you come into today's first line advanced setting, then a combination like Fos-Troxel and Vima, which will be tested in second line and hopefully approved, might actually be moved up to first line just because the immune therapy combinations are being used in earlier setting. But again, that's something that the future will need to hold. At this stage, we focus on showing the benefit of FosTrux Plus Levima in order to get to market as quickly as possible, because that's going to provide the greatest benefits for HCC patients.

Got it. Last question, just briefly. What is the current cost per patient in the ongoing trial? And do you expect similar costs per patient for a US-based study, where you're going to have about 210 patients for the phase to be?

Can I respond?

You can respond. I think it's going to be difficult to respond.

So I mean, the cost per patient. it's an estimation and it is so dependent on where you are right now. We have been in Spain, South Korea, in the UK. It's completely different if you go to the US, for example. So the cost is going to increase for these sites, obviously. So that's why it's going to be difficult. But somewhere between one and two million per patient, maybe?

In SEC.

In SEC, sorry. 100,000 to two. Thank you.

Yeah, that scared us for a second. And it's difficult to compare with the current study because current study, as Pia alluded to, they are required to do CT scans. They are required to do MRI scans. So again, costs for the study is going to also be dependent on examinations done and what are we asking them to do, what will the FDA require us to do, et cetera. But yeah.

Got it. Thank you all.

There are no more questions at this time, so I hand the conference back to the speakers for any closing comments.

Thank you all for dialing in. I'll just go back to this one. Again, as we have hopefully conveyed, we are quite excited by what we are seeing in the ongoing study. Patients are staying longer on treatment. Yes, that on the one hand generates additional costs for the study, but most importantly, it generates additional benefit for patients. And it makes us even more confident in moving the program ahead with as much speed as we possibly can. We truly believe that there is an opportunity to get first to market and change how second line HCC patients are are being treated. It is highly underserved. It is a high value population. So with that, thank you for dialing in and look forward to sharing additional updates as we move forward.