Medivir AB (publ)

the Medivir Q3 report. Today is a very exciting day. In addition to sharing the great progress in continued momentum in the ongoing Fostrox program. It is with great enthusiasm.

We look forward to providing an in-depth update on the promising signals of clinical benefit we're seeing with the Fostrox-Linvima combination in primary liver cancer. And we will also touch what that means for our plans as we move ahead. Before we go into the details, as always, important information and this in detail you will find when we post the presentation on our website. My name is Jens Lindberg and I am the CEO of Medivir. Today I am joined by our Chief Medical Officer Pia Baumann and our CFO Magnus Kristensen. Our Chief Scientific Officer Fredrik Öberg is also here with us for the Q&A session towards the end. But most importantly, we are joined by Dr. Jeff Evans from Glasgow, Scotland, who is principal investigator in the ongoing Fostrox Lendvima study. Jeff is joining us via link today from Scotland, where he is working clinically today, and he will be putting the Fostrox Lendvima data into clinical context. But before we go into the details of the data we're seeing in the study, a brief update on the overall Q3 results for Medivir. So, Magnus.

Thank you, Jens. I will briefly comment on the Q3 report from a financial viewpoint. All the numbers you see are a million SEK.

Most importantly, the result in cash flow in Q3 Q3 were in line with our estimate. No big surprises. The turnover for Q3 relates to royalty income from Seclair. It is similar to last year in line with our expectations. Other external expenses are higher compared to last year in the quarter and relates to clinical costs for ongoing combination study. This is a positive sign as patients from a benefit in long from the foster accommodation and currently more than 50% of the patients in the phase 2a are still on treatment. The cash position at the end of Q3 is approximately 61. And as previously communicated, current cash run rate is into Q2 2024 with the current assumptions. We are... evaluating different financing alternatives and we make the assessment supported by the positive data in the ongoing combination study that we have good conditions to carry out the financing for the group, continue operation and continue the development of the FOSDUX program. And with this I will hand over back to Jens. Thank you Magnus. Before we dive into FOSDUX update A quick note on the pipeline. We do have a broad pipeline of partnering programs, and they have experienced nice progress in the past 12 months.

And I would specifically like to outline that for two of the programs, one being TNG348 with Tango Therapeutics and the other one being MET-X with Infex Therapeutics, we are very much looking forward to seeing both of these programs stemming from the Medivir Research Program to move into the clinic in the first half of 2024. But as mentioned today in the beginning of the webcast, we will focus completely today on the very encouraging progress we're seeing with Fostrox and the plans ahead. The main agenda topics today. First, Pia will kick off the session with a much more detailed and comprehensive data update than we have previously shared. This includes a deeper dive into the Fostrox Lendvima data and a benchmark against what could be expected for Lendvima alone. One of the key reasons for this update is that a clear majority of the patients have now had at least 12 weeks follow-up, and the longest patient has been on treatment for 14 months. So that means that for second-line HCC, the data is becoming much more mature, and it allows us to evaluate and draw conclusions about the potential benefit to a larger degree.

After PIA, Dr. Evans will put the data into context as he talks about how the HCC treatment landscape has evolved and how he sees it evolving moving forward, including where and how phosphorus has the potential to provide clinical benefit. And then finally, we will outline what this means for our plans going forward and the commercial opportunity for FOSTRUX before we close with the Q&A. As mentioned, we will share a much more detailed update than we have done before. Hopefully not too detailed. But if you want to keep it simple, there are three key takeaway messages to remember from this session. First, the combination of structural envema is showing improved clinical benefit. for patients across endpoints without compromising on safety and tolerability. This we can see even though more than 50% of patients are still on treatment and data will continue to mature, or further. Number two, the key focus ahead is continued development in second-line HCC, the great clinical benefit we are seeing in combination with Lendvima, in combination combination with the significant unmet medical need, there is a second line, opens the path for accelerated approval intent as early as 2027. And then finally, there are no approved treatments in sector.

Second line HCC today after sort of current standard of care. And Fostrox Linvima is at the forefront of second line development with a very clear opportunity to be the first treatment in the market with a significant unmet need and estimated at $2.5 billion annually. It is a great opportunity for Fostrox to lead the way and make a meaningful difference to HCC patients in need of new treatment options. And with that, I will hand over to Pia to go through in much more detail why we are so optimistic and energized about FosTrox and its potential in HCC. Pia?

Thank you, Jens. And I look forward to providing a more in-depth update of the clinical data from the ongoing, as we said, FosTrux plus Lenvima study. In addition, I would like to put our data into context and compare it with the Lenvima monotherapy study data. And these data are in second line HSE, as Lenvima is still the current standard of care in second line. But first, a very short background of HCC.

So, HCC is a heavily underdeserved disease where patients diagnosed in early stages are actually the only ones that have hope for really long-term survival. Unfortunately, around 80% of the patients are diagnosed in more advanced stages, where you see an overall survival of around 20%. The cause of HSC is cirrhosis in the liver, which damages the liver function and reduces the ability to tolerate medical treatment. It is therefore important that for new treatments to be successful in HEC, they should not further harm the liver. So, despite recent advances in systemic therapies, only one third of patients respond to best available combination. And that is in first line. And the need for new treatment option remain high. So in 2020, the combination of Tricentric and Avastin was approved. And the treatment paradigm in HTC changed very rapidly. This treatment is now used in the majority of the first-line patients. And as a result of this change, there are no systemic treatments approved, as Jan said, in the second-line setting. Guidelines have since been recommended clinical trial in second line and when a clinical trial cannot be offered, Lenvima is the preferred treatment. Despite the lack actually of clinical data and regular trial approval, current treatment algorithm also shows that

Traditional chemotherapy has no real role in HCC and that is primarily due to systemic side effects challenges that is preventing to have the dosing that is needed to provide clinical benefit. There is a high need for treatment that targets the tumour in the liver as well, are tolerable and do not impact. vital liver function. Dr. Evans will talk more about, as Jan said, the evolution of treatment practice and the guidelines in HCC. So he will come back to that. So with improved first-line treatment, as we talked about, more patients will continue to second-line, which is good. And the need for effective tolerable treatment that can reduce the tumor burn in the liver is high. Fostrox is unique in that it is an oral, it's a liver-targeted chemotherapy with a selective cell-killing activity. in tumour cells, which means that it's sparing the normal cells and will not impact the vital liver function. It is a pro-drug with the active substance of troxacitabine and uses the first-pass metabolites.

It means that with this approach, it's possible to give the frostrox opium and achieve 100-fold liver-targeted exposure versus what you see in traditional IV chemotherapy. So the monotherapy data for false strokes has already been published and showed good safety and preliminary evidence efficacy. But as HEC is a difficult to treat disease, the plan has actually always been to combine false drugs with other treatments to achieve synergy efficacy and the greatest possible benefit. The most logical combination partner in second line, coming back to this again, is LENVIMA as it provides a strong rationale for the synergistic activity and as mentioned before

It is the preferred treatment in second-line HEC. So by attacking the tumor with two different mechanisms, we are expecting the clinical benefit to improve. But it is also important that safety and tolerability is not compromised when combining these two treatments.

In this updated data presentation today, we will show that adding foster drugs does improve the clinical benefit expected without compromising safety. the ability to tolerate this combination was actually very good. So the data, again, that we will talk about comes from the fully recruited and ongoing phase 1B2 study. In second and third line, the maximum tolerated dose in foster care was monotherapy. The published data was selected to 40 mg.

And the starting dose in this study, where it starts with the dose escalation phase, was 20 mg. And while we didn't see any dose-limiting toxicity or having a maximal tolerated dose, we still selected 30 mg to ensure that we have an optimal dose with a good balance between efficacy and safety and also possibility for a longer duration of treatment. Lenvima was given at standard doses, and the patients were treated until investigators evaluated tumor progression. So 21 patients were included in the study, and 18 patients now have more than 12 weeks of follow-up. So this update will really focus on these 18 patients to give a robust evaluation of the data from the study. The study took place in 15 sites in Spain, the UK, and in South Korea. And the primary endpoint was safety, with efficacy endpoints as secondary.

So the response evaluation was done with CT and MRI, and it was done every six weeks. And the today update will primarily focus on response evaluation. by the local investigator that is using the acknowledged method, a response method in oncology called Resist 1.1. In addition, are evaluated by an independent reviewer. And as this study is in liver cancer, the independent reviewer will also use something called the modified resistor. This is a method specifically developed for evaluating efficacy in HSE. It focuses really on the part of the tumor that contains active lining tumor cells. It is also important to know that all patients in this study had progressed on prior treatment and more than 80% had received received to Sandrika Wallstein in the first line. So the efficacy data continues, as you can see here, to improve with immediate follow-up of now 4.7 months. The overall response rate is now 22%, which is improved from the 70% which

We see continued control of the liver cancer with a disease control rate of more than 70% at 12 weeks follow-up. The median time to progress has also improved since the last update from 4.5 to now 4.9 months. But as we heard from both Magnus and Jens, 50% of the patients is still ongoing in the study and the data continues to mature and hopefully will improve. The data indicates improved clinical benefit than historically has been seen in second-line treatment of HCC. And on the next couple of slides, we will review the tumor response for the individual patients. So, thank you. This is a waterfall plot and it shows for each individual patient the best percentage change in tumor size. If the tumor shrinks more than 30%, it is classified as a partial response. And as you can see in this graph, four patients out of 18 patients are partial responders.

A few additional patterns

Patients have had tumor shrinkage close to 30%. With the study ongoing, we could still look further for improvements in patients. response rate. It is important also to note that response rates in second line are usually very low. Stable disease is considered a successful outcome in this patient population. Stable disease or tumor control is really when the tumor size change is between the green and the orange line you see on this graph. also can see here all patients had tumor control in the target and the clear majority of the patients 22% and experienced tumor reduction. Additionally, three patients that is not part of this analysis since they haven't been followed for more than 12 weeks. are ongoing and all the three patients have stable disease at the first imaging scan after six weeks. The fact that the absolute majority of the patients are experiencing experiencing shrinkage in the toleration is highly encouraging but it is also important to see if the two reduction is durable over time. So this next slide we

You can see a graph.

We see how each patient's lesion changed over time since baseline. Each dot represents an imaging scan measuring the tumor size and each line that has an arrow at the end represents a patient that is still on treatment. And we can see early and durable antitumor activity with a majority showing tumor reduction. So for many of the patients, we also see that the target lesion continues to shrink over time, including the longest running patient that has been on treatment for more than 14 months that Jens mentioned before. Previous studies in second-line HEC report treatment duration around 15 weeks, and usually also includes patients who actually have experienced tumor growth or tumor progression, but continue due to the fact that they have clinical benefit. In the current study with Foxtrot and Levima, the patient had to discontinue if they experienced tumor growth, which makes

durable anti-tumor activity and treatment duration seen in this graph even more promising. With encouraging data in mind, it is important also So to understand the safety and tolerability profile, and especially since this is a combination treatment. So as previously mentioned, safety and tolerability, vulnerabilities even more important in HCC's studies compared to many other tumor types due to the vulnerable patient population. In the study, only 10% of the patients had to discontinue due to Fostrox-related adverse events. And as many as 65% actually stayed on the Fostrox starting dose. And with less than in this study needing to dose modify Lenvima, the combination partner. And this should be compared with literature data where more than 60% actually dose modified. We are encouraging by the safety also in this combination. If you look to the right you can see the adverse event and we didn't see any that was unexpected and And the most common grade 3 and above events with four strokes were hematological, as expected, with non-fibromyalgia. febrile neutropenia and thrombocytopenia without bleeding. And these were transient and manageable.

Lenvima adverse event in this study were in line with what you can see with Lenvima monotherapy, nothing new. Hence, it seems like the combination is able to provide improved clinical benefit without compromising safety and tolerability. So as a quick reminder, we have previously reported independently reviewed MRESIST data for the six patients in the phase one part. And among these patients, one patient actually achieved a complete response with no viable tumor left, which is a rare event in second-line HEC. And together with two partial responses, the response rate was 50%. And with further two patients having stable disease, this resulted in a disease control rate of 83%. So we have now showed updated data with a combination that is encouraging with regards to both efficacy and tolerability. But a key question is obvious how these data compares with what could be expected

with Lenvima alone in second line HSE. So previously, Lenvima hasn't been evaluated in second line, but new published prospective data on Lenvima monotherapy after T-centric Avastin is now becoming available. We do not yet have a randomized trial or randomized data. on false drugs plus Levima, we will do an indirect comparison with this study, with the Levima monotherapy data, where both investigator and independent review data will be So the Lenvima monotherapy study was performed in Japan at 10 sites and had both first and second line patients. And the focus today will only be on the second line cohort. We had, there was 12 patients were included and was given anti-progression or intolerability and could continue as the investigator. deemed that the patient still had benefit despite progression. So the imaging was done four weeks after the first dose of Lenema and thereafter every eight weeks. And as I said, with limited clinical data, in second-line HG, post-analog care, this data set with all the limitations you can see with an indirect comparison can contribute to the understanding of the added clinical benefit of FOS-TROX to Lenvima.

So this is the characteristics of the patient included in these studies, and they were fairly similar with the exception that the FOS-TROX plus Lenvima study also allowed third-line patients in and also had slightly more patients with reduced performance status. The poor prognostic factors, such as extrahepatic metastasis, large tumor burden, and a high AFP, they were similar. The primary endpoint in both these studies was safety, since they were small studies. And compared to the Lenvima monotherapy study, no additional safety events were reported when FosTrux was added to Lenvima. The discontinuation rate due to reverse events was similar, though there were higher number of dose modification in the Lenvima monotherapy study. When comparing efficacy between these studies, we can see a consistently improved benefit with FosTrox plus Lenvima across the different endpoints. regardless if it was evaluated by a local investigator or an independent reviewer.

This is particularly the case when it comes to the duration of efficacy as seen. by the higher disease control rate at 12 weeks and at 18 or 20 weeks in the bottom table showing evaluation made by the investigator. So achieving high disease control over time is especially important in liver cancer as it has been shown shown to correlate with improved survival. The overall response rate was also higher with FOSTRUX plus LEMVIMA, including what you saw before. The patients were actually able to achieve a complete response. And this was not seen in in the Lenvima monotherapy study. So progression-free survival, I'm sure that you recognize this since this is a normal endpoint in phase three studies. It's an important point important endpoint since it includes all patients with or without responses that could benefit from the treatment. In the FOSTRUX plus LEMVIMA study, the PFS analysis has not been done yet, but we have time to progression. And that is a similar analysis with some differences. In this study that we are comparing with TTP, was similar to PFS, why an indirect comparison is possible with the FOSCO. So we did that, and both with independent and investigator-reviewed data, there is a

consistent improvement in PFS TTP when FosTrox is added to Lymvima in our current study, as seen in the two graphs to the left. So to support this, really, we looked also at Fostrox, we compared sort of the actual treatment duration, and that is the graph to the right. This is also longer with Fostrox plus Lenvima compared to Lenvima monotherapy. And sort of further support in this improved benefit that you saw to the left. Then, of course, recognizing the pitfalls of doing an indirect comparison between a limited data set, we still see the totality of the data is encouraging for Fostrox plus Lemvima. And when combining two drugs with different antitumor mechanism and a strong rationale for synergistic activity, the improved benefit is to be sort of expected if the combination is tolerable. So we are now moving to the next exciting step in the clinical development of post-trugs.

But before we talk more about these plans, I would like to introduce our clinical expert in HCC and and the principal investigator in the FOSTRUX plus Lamima study. Dr. Jeff Evans, who will talk about HEC clinical practice today and what to expect in the future. and how this treatment with Fostrex plus Levima would potentially fit in. So, over to you, Jeff. Thank you, Pia, for your very kind introduction and, of course, the opportunity to share some thoughts about HHC treatment today and tomorrow and can I have the next slide please so I think it's very important just to remind everybody about the scale of the problem in that This is one of the commonest cancers worldwide. It's, I think, the third commonest cause of cancer death, and about the fifth or sixth commonest cancer in the world. And the incidence is increasing. And it's also really important to bear in mind that this is not just an Asia-Pacific disease. Yes, there's a very high prevalence in China, Korea, Japan, and the Asia-Pacific region, but this is arising at a considerable and large in the West as well, and represents a somewhat different epidemiology potentially of the chronic liver disease that leads to HCC. As such, even if there is better outcomes from treating hepatitis B and C, with better treatments for those diseases worldwide, we will still continue to see considerably increase both in the tumor incidence as well as

the public health burden right across the globe in this instance. And therefore, worldwide, this is a very big public health problem when it comes to malignant disease and a cancer of high unmet clinical need. Next slide, please. Now, Before 2008, most of the treatments were attempts at treating very early disease with surgical treatments or local ablation or local regional treatment. And really systemic therapy was new agents within clinical trials. And this was before 2008, before the licensing of sorafenib. And we can see here that... It was quite a high proportion of patients who in this treatment algorithm were potentially accessible to curative treatments. That is certainly not the case in most places and probably reflects that this was designed, this algorithm was designed from centres that had very active HCC surveillance programmes. But HCC surveillance is very patchy worldwide. And we do get interval cancers despite surveillance. And, of course, the rise in incidence is driven as much by non-alcoholic fatty liver disease as distinct from, say, viral hepatitis.

And that is a much bigger group and a group that we really have less good screening data and less able to. capture those patients as well as the ultrasound may be less sensitive than those with a history of viral hepatitis. Excuse me. And therefore, the dominant group these days for those who are accessible to non-curative treatment. Next slide, please. This is the updated staging and treatment algorithm. And I want to show this to show the complexity of the disease and how much more patients now are treated with systemic therapy than hitherto would be in the case. And I anticipate this to only increase in the future, even if we are given in combination with what we currently consider curative treatments. And next slide. We will circle here the differences sorry, if we go back to the previous slide, just to show that area which is circling, which is what we call BCLCB. This is intrapartic liver only disease, which is a broad group from very small disease that might be suitable for surgery without or the majority which is bulky disease that will never be accessible and for which we really need better drugs as well as those with extra hepatic disease. This speaks to the fact that Feeding the liver burden is very important to this disease because a high proportion will never develop metastatic disease because it will ultimately succumb to the degree of burden of cancer within the liver. Next slide, please. Now, this is what is currently approved in the UK. We've had a number of approved regiments in the first line and moving from

right to left, serafinib, then limvatinib, then immunotherapy. And the general consensus worldwide is now that most patients are treated with a form of immunotherapy in the first line. And worldwide, the biggest coverage here is atezolizumab in combination with bevacuzumab. All the approved second-line trials were done when serafinib was the only first-line treatment. Therefore, there is no second-line phase one, a phase level one evidence for what should be standard of care after progression on atezolizumab, bevacizumab, or for that matter, on tremidover. The international consensus is that tyrosine kinase inhibitors, that is serafinib or lembatinib, would be considered as the standard of care after progression on immunotherapy. And most of us believe that Lemvatinib, although licensed in the first-line setting only, is a superior tyrosine kinase inhibitor. We've heard talk of Lemvima. Lemvatinib is the same compound. And I may revert to calling it E7080. I was involved in Lemvatinib in the very first inhuman study about 20 years ago now when it was known as E7080 and followed it all the way through. And I truly believed in that drug that it had the potential.

A little time during that development, Similarly, I believe that MIB818, a false drug, has the potential to be an active drug in this disease. Next slide, please. Now, significant advances have been made in the first-line treatment of systemic therapy with HCCC, undoubtedly, a test of birth superior to serafinib, but still associated with, ultimately, a disappointing prognosis. But there's high unmet need in second eye therapy. More and more patients now are fitter and better synthetic liver disease to proceed to consider second eye therapy. And as we give more and more systemic therapy in the first line, we do less. less and less taste, and therefore less and less damage to the synthetic liver function. So this represents a bigger proportion of our patients right now. And the standard of care in my centre is clinical trial. And for those with... There is no clinical... trial, if they progress on a TES or BEV, then Lembatib is my usual monotherapy TKI of choice in this second line setting. Next slide, please. So we have, in oncology, whenever we combine two agents, we want to have agents without overlapping toxicity, different mechanisms of action, potential symptoms. energy in action, and at least additive, if not synergistic. And we have the additional agent here that targets the tumour locally, giving an intrahepatic liver targeting treatment of a disease where the liver burden is clearly significant. in terms of outcome, even in the presence of extra pathogenic disease. Next slide, please.

Now, I won't talk you through the science of this, but there's a number of ways in which these two agents could be synergistic. That is more than additive effect of adding two drugs together. And adding FosDrox, which has a completely different mechanism of action, intrahepatic production of a potential cytotoxic agent, overcoming some of the challenges of peripheral administration of intravenous cytotoxic chemotherapy that we've had in the past in this disease, requiring hepatic metabolism, for example. Next slide, please. Now, cancer in the liver is different from many other tumour types because controlling the primary tumour in the liver is critical. This is such an important organ in the body. And up to 80% of patients, probably higher, have an underlying cirrhosis, negatively impacting the ability to tolerate anti-tumor treatments. We've talked about Lenvatne, but I could talk at great length about what dose we should use. Please note that the dose which is recognised in HCC treatment in monotherapy and in combination with FOS drugs is less than when we use it as monotherapy in patients without cirrhosis, for example, in thyroid cancer.

And therefore, Progression in the liver is unique because it occurs primarily in the liver. And patients may succumb to intrapartic disease far more than even if they have small volume metastases. metastatic disease burden. And there is some improvement along the lines of the long-term benefit from the meta-analysis of the TAE studies in the past. However, note that many of the patients who received TAE subsequently and still worldwide and not those who fitted the original clinical trial for many years we did taste because we could rather than because it was necessarily fitted the criteria defined by the trial because there were no suitable systemic therapy options. We now have better drugs and we're doing far less taste than we did so correctly. Next slide, please. And one of the reasons for that is each time we do taste, There's diminishing returns with the number of times we do it in terms of getting disease control. And conversely, each time we do it, we can get progressive damage to the synthetic immune function. So the whole question that we wrestle with in the HTC field is who should get TAS? And then once you've done it, at what point do you switch to systemic therapy without overexposing patients to a technique that ultimately can lead to liver damage and then make them not suitable to receive systemic therapy and miss that opportunity. So we're doing less and less tests as a frontline treatment and less and less repeated tests in those whom we do test. Next slide please. So we have potential of systemic anticancer therapy.

Firstly, we focus today on those who are treated with systemic therapies, their primary treatment, first line and second line, an increasing proportion of an increasing incidence of disease of HCC. But we also have the potential to move back the way, rather than assuming that we move from curative treatment through to local regional therapy to systemic therapy, but also to think where systemic therapy adds on to local regional therapy, TAS, RFA, or even substitute it if we have a liver activating therapy. liver prodrug treatments such as Fostrog. And then in those who are suitable for surgery with or without transplantation, and clearly if they're suitable for transplantation, we cannot use immunotherapy because of the fear of subsequent organ rejection. Clearly, we have now studies where we will look at these combinations and novel agents in either the pre- or post-operative resection, including transplantation. Therefore, I think the market share of systemic anti-cancer therapy is increasing within the standard treatment algorithm and will only increase, as we added in earlier and earlier, in the management of this disease. And with that, I'm happy to hand back to Pia.

Thank you so much. Dr. Evans, this very much highlights really the unmet need in second-line HGC and is providing the Where could we find the biggest benefit? And with this clear picture of the unmet need, together with the promising clinical data that we showed before for FosTrux plus Mimima, we feel confident. to raise our ambition when it comes to the clinical development of four strokes as we conclude that a phase 2B study with an accelerated approval intent in 2021 next step. So, one important key factor enabling this accelerated approval, it's already in place. You've heard that, right? It is that AGC is a serious life-threatening disease that with high medical unmet need. The second part is really to see that we replicate the magnitude of the promising data from the ongoing phase 1b2 study in a randomized phase 2b study as seen on this slide. And the randomized study design comparing phosphorous plus lenvima with lenvima alone also incorporates

operates a FDA regulatory acceptable endpoint already in this phase, in phase 2b, and that is PFS. And an appropriate safety database to further support the aim for accelerated approval in 2027, we need to make sure that that is also in place. So I will hand it over to Jens.

Thank you, Pia. Exciting opportunity for Fostrox to break new ground in second-line liver cancer. Let's look at what this means for the commercial opportunity. The potential to become the first approved treatment with level one evidence after T-centric plus Avastin and transform the treatment of second-line liver cancer clearly has a substantial impact on the commercial opportunity. The left-hand side of the slide shows the estimated market value and growth in the coming 10 plus years. And as you can see, it grows significantly and reaches almost two and a half billion dollars

by 2028. On the right, we are showing the key assumptions that underpins the market value and there are a few elements to highlight. As you heard from Dr. Evans before, the treatment options in first lines get better. And that means that more and more patients will get systemic treatments in second line, and with better treatments the duration of treatment will also increase in second line as well. Two factors that have a significant impact here. Another of course very important factor from an upper opportunity perspective is the fact that there are no medical treatments approved today after and when we look ahead there is There is a high likelihood that this situation will not change dramatically as relatively little development is taking place in second line. outside of sort of what we're doing at the moment with Fostrux plus Lenvima. So that means that the Fostrux in combination with Lenvima has a very realistic potential to become the first approved treatment alternative in second line after the centric Avastin. And I think as Dr. Evans alluded to, when it was approved in first line 2020 that combination had a transformational impact on the

treatment for patients and very quickly became standard of care. If approved as the first treatment in a second-line setting, it would be quite natural for a combination of Fostrock plus Lenvima to have a similar transformational impact in this population. We do see second line as our, if you want to call it, fast-to-market strategy for Fostrox. But again, building on what Dr. Evans outlined earlier, a liver-directed prodrug like Fostrox would likely provide perhaps even greater benefit in an earlier setting where patients have less tumor spread outside of the liver. Hence, we do see first line and in the intermediate stage HCC as a next step opportunity for Fostrox. populations that would then clearly add sort of significant commercial opportunity on top of second line. So, to sum up then, before we go to Q&A, I go back to the points I made in the beginning, just to reiterate them.

What we have hopefully shown today is that the combination of Fostrox plus Linvima does show improved clinical efficacy compared with Linvima study data without compromising on safety and tolerability and that there is a very realistic opportunity for the combination to move ahead with speed aiming for an accelerated approval as early as 2027. if the magnitude of the data can be replicated in phase 2b, of course. And then finally, FosTrox, together with Envima, has the potential to transform a 2.5-bit market without significant competition and low commercial risk. With that, thank you for listening. And we now open up for Q&A. The next question comes from Joe Pantginnis from H.C. Wainwright. Please go ahead. Good morning and good afternoon. Thank you very much for all the details today. very exciting data update. So, thanks for everything. So, a few questions, if you don't mind. So, first, I just want to go back to chronological

From the phase 1B, the external assessment that there was a CR patient just wanted to get a sense of what the status is for that patient currently.

So without going into too much detail, this patient is still ongoing.

That's actually great to hear. Thank you for that. And then I guess I wanted to get maybe Dr. Evans' views on COVID. you know, the data update today and the broader profile of the FOSTRUX here. So first, I guess I don't want to overemphasize it, but, you know, when you look at the patient population being all 100% of the patients having seen prior progression on their prior therapies, you know, maybe talk a little bit more about the importance of these data and responses that you're seeing since these are all, you know, prior progression.

that the fact that, you know, seeing responses, the importance of seeing responses once you've seen these progressions and then more overall where Dr. Evans might see, and I know he alluded to it a little bit in his prepared comments, you know, where FosTrox could really fit in the... broader opportunity, especially when they're phased to be data readout for potential accelerated approval. Thank you. Yes, thank you. the first question. Yes, these are all patients to enter into a second. Like trial, you have to progress after first line. Treatment and and and that is it. entirely standard for when we get studies in any line of treatment, in any tumor-launched STCC. We've never developed this as a maintenance therapy And that's few and far between in practice, as you probably know. So in terms of responses, yes, responses do matter. That's a question that's been asked all the time. seems somewhat obvious and self-evident to say so. But there was some controversy many years ago with... So there was... controversy many years ago about whether responses were important or the synthetic liver function in controlling the disease.

But we're now fairly convinced if you look at the data that we've published from the post-hoc or the reflex study that clearly responses matter irrespective of which end the patients were in. So responses matter, patients where we shrink the tumour burden, where you maintain patients' therefore symptoms and quality of life and also their synthetic liver function are important because then it gives better disease control, better survival, theoretically, and may even facilitate third-line treatments, which we begin to think about in patients in clinical trials at present. And therefore, it is certainly significant findings If you look at the response rates generally in HCC, and let's stick to Resist 1.1 when we're talking response rates now, I mean, getting responses are still a minority of patients with systemic therapy. I'm getting feedback actually on this, so I'm not sure if anybody else has got their audio on. It's an important thing to aim for is responses as hitherto responses are generally speaking be relatively low.

with systemic therapy in first and in second line therapy and each time we treat people it gets less each time. Now the second question is where does this fit in the treatment algorithm? Well, it's great that we've got a lot of new drugs that have been approved in mainly first line in in the last few years in heat cc plenty of room for development this disease has got overall disappointing survival And we've got something different, because most of the developments so far have been on TKI, so TKI combinations, which is actually fantastic. And on novel ways of targeting the immune system. In the future, we may be putting these drugs together. And here we have a drug that is cytotoxic insect activity, but without the disadvantage that we used to see of the intravenous cytotoxic chemotherapy in the pre-sarafna days back in the 20 odd years ago and allows conventional combinability with other systemic therapies without overlapping techniques or mechanisms of actions, as well as giving a potential to reduce the tumour bulk within the liver and we can speculate and it is only speculation at this point where they could remove some of the local regional therapies that are invasive basis, such as taste, for example, without the need for interventional radiology. But that is speculative, but that's the direction of travel.

We'd love to go in this disease.

That's very helpful. I really appreciate the comments. And I guess two quick, I guess, logistical or MOA questions, if you don't mind. Thank you for indulging me. So when you look at the spider plot, I was just curious if you have any... You know, theories or hypotheses, you know, there are a couple patients that have, I guess, relatively quick rebounds in the 6- to 12-week timeframe about why you think they might be fast progressors, number one. And then number two, my last question is, where do you feel business development might fit into the conduct of the upcoming Phase IIb randomized study? Thanks a lot, guys.

It's for you.

Okay, the first one, why we see, I mean, the HEC, and we can introduce Dr. Evans in this as well, is it is a heterogeneity in the patient that has HEC. There are different etiology, as Dr. Evans talked about, but also different molecular features.

And actually, Again, going into too much detail, some of the patients responded really quickly and with a 90% reduction, actually, in the tumor. tumor size, they had a transformation into another type of HEC that is more aggressive. So while we are looking into these different patients, I hope to present more in detail data on a future Congress. I cannot speak more about the individual patients at this time. I would add a generic comment at that point. I won't deal with the business development side of things, but I will give a generic comment on HCC and predictors of risk. This is something we've been wrestling with in the field, not just in HCC, but in all tumors, but particularly in HCC for a while now. And I guess we don't really have good biomarkers. of who's going to benefit from a specific treatment in what is a heterogeneous disease and in comparison perhaps with other tumour types and I treat other tumour types as well we've been somewhat slow to come to as a hcc field generically with in trying to tease out biomarkers that will predict for who's going to respond and the mechanisms of rapid progression.

And I think there's a very good reason for that, actually. in that it's the porosity of tissue with which we can work with. Because historically, this is a disease that's been made radiologically. And therefore, we probably, as a field, need to concentrate more on getting pre and on treatment biopsies in this disease so we can learn more about the biology, as you suggest. And this is the international direction of travel now for those of us who work in the HCC field are very much committed to getting more biopsies. And clearly, we've got biopsies in this study, and this is how we need to do it in the future.

And I'll take the business development question then. And we have communicated, Joe, I think sort of for quite some time that we are envisioning sort of the development of Fostrox going forward in Asia in partnership, i.e. we will be looking for a partner to take this forward in the Asian markets. The maturity of the data that we're seeing now and the strength of the data is better

basically that opens the door to those discussions. So it's been clear previously that feedback has been theoretically, logically, high interest in a liver-directed, liver-targeted drug. But there's always the question of what does it, when you combine safety, tolerability, clinically, et cetera, Now that we have the majority of the patients sort of followed up for more than 12 weeks and the maturity of that, that opens the door to those sort of deeper discussions with regards to partnerships going forward so definitely it does have a place from a business development perspective going forward with the first aim of finding an Asian partnership.