Welcome everyone to the Medivir Q3 report. Today is a very exciting day. In addition to sharing the great progress and 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 Lenvima 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 Christensen. Our Chief Scientific Officer, Fredrik Öberg, is also here with us for the Q&A session towards the end.
Most importantly, we are joined by Dr. Jeff Evans from Glasgow, Scotland, who is Principal Investigator in the ongoing Fostrox Lenvima study. Jeff is joining us via link today from Scotland, where he is working clinically today, and he will be putting the Fostrox Lenvima data into clinical context. 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. Magnus?
Thank you, Jens. I will briefly comment on the Q3 report from a financial viewpoint. All the numbers you see are in million SEK. Most importantly, the result and cash flow in Q3 were in line with our estimate. No big surprises. The turnover for Q3 relates to royalty income from Xerclear. 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 the clinical cost for ongoing combination study. This is a positive sign as patients are benefiting longer from the Fostrox plus Lenvima combination, 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 SEK 61 million, 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 condition to carry out the financing for the group, continue operation, and continue the development of the Fostrox program. With this, I will hand over back to Jens.
Thank you, Magnus. Before we dive into Fostrox 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. 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. 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 Lenvima data and the benchmark against what could be expected for Lenvima 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, 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 Fostrox 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 Fostrox before we close with the Q&A session. 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 and from this session. First, the combination of Fostrox Lenvima 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 further. Number two, key focus ahead is continued development in second-line HCC. The great clinical benefit we are seeing in combination with Lenvima, in combination then with the significant unmet medical need there is in second line, opens a path for accelerated approval intent as early as 2027. Then finally, there are no approved treatments in second-line HCC today after sort of current standard of care, and Fostrox Lenvima 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. 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, Fostrox plus Lenvima study. In addition, I would like to put our data into context and compare it with the Lenvima monotherapy study data. These data are in second-line HCC 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 underserved disease where patients diagnosed in early stages are actually the only ones that have a hope for a really long-term survival. Unfortunately, around 80% of the patients are diagnosed in more advanced stages, where you see a five-year overall survival of around 20%.
The cause of HCC is sort of cirrhosis in the liver, which sort of damages the liver function and reduces the ability to tolerate medical treatment. It is therefore imperative that for new treatments to be successful in HCC, 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 Tecentriq and Avastin was approved, and the treatment paradigm in HCC changed very rapidly. This treatment is now used in the majority of the first-line patient, and as a result of this change, there are no systemic treatments approved, as Jens said, in the second-line setting.
Guidelines has since been recommending 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 regulatory 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 tumor in the liver as well, are tolerable and do not impact vital liver function. Dr. Evans will talk more about, as Jens 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 burden 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 tumor cells, which means that it's sparing the normal cells and will not impact the vital liver function. It is a prodrug with the active substance of troxacitabine and uses the first-pass metabolism. It means that with this approach, it's possible to give the Fostrox orally and achieve a hundredfold liver-targeted exposure versus what you see in traditional IV chemotherapy. So the monotherapy data for Fostrox has already been published and showed good safety and preliminary efficacy.
But as HCC is a difficult to treat disease, the plan has actually always been to combine Fostrox with other treatments to achieve synergistic 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 HCC. So, by attacking the tumor with two different mechanism, we are expecting the clinical benefit to improve. But it is also important that safety and tolerability is not compromised, when combining these two treatment. In this updated data presentation today, we will show that adding Fostrox does improve the clinical benefit expected with Lenvima alone without compromising safety. The ability to tolerate these combination was actually very good.
The data, again, that we will talk about comes from the fully recruited and ongoing phase 1b/2 study in second and third line. The maximum tolerated dose in Fostrox monotherapy, the published data, was selected to 240 mg, and the starting dose in this study, where it started with the dose escalation phase, was 20 mg. While we didn't see any dose-limiting toxicity or have a maximum 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 investigator evaluated tumor progression. 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 U.K., and in South Korea. 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. The today update will primarily focus on response evaluation by the local investigator that is using the acknowledged method, the response method in oncology called RECIST 1.1. In addition, response is evaluated by an independent reviewer, and as this study is in liver cancer, the independent reviewer will also use something called the modified RECIST. This is a method specifically developed for evaluating efficacy in HCC.
It focuses really on the part of the tumor that contains active or lining tumor cells. It is also important to note that all patients in this study had progressed on prior treatment, and more than 80% had received Tecentriq Avastin in first line. The efficacy data continues, as you can see here, to improve with a median follow-up of now 4.7 months. The overall response rate is now 22%, which is improved from the 17% we saw before. 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 progression 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. 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 patients have had tumor shrinkage close to 30%, and with the study ongoing, we could still look further for improvements in response rates.
It is important also to note that the response rates in second line are usually very low, and 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. And as you also can see here, all patients had tumor control in the target lesion, and the clear majority of the patients, 22%, experienced tumor reduction. Additionally, three patients that are 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 shrinkage in the target lesion is highly encouraging.
But it is also important to see if the tumor reduction is durable over time. So, at this next slide, we can see a graph. We see how each patient's lesion change over time since baseline. Each dot represent an imaging scan measuring the tumor size, and each line that has an arrow at the end represent a patient that is still on treatment. 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, like Jens mentioned before.
Previous studies in second-line HCC report, treatment duration around 15 weeks, and usually also includes patients who actually have experienced tumor growth or tumor progression, but continued due to the fact that they have clinical benefit. In the current study with Fostrox and Lenvima, the patient had to discontinue if they experienced tumor growth, which makes durable antitumor activity and treatment duration seen in this graph even more promising. With encouraging data in mind, it is important also to understand the safety and tolerability profile, and especially since this is a combination treatment. So as previously mentioned, safety and tolerability is 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 event, and as many as 65% actually stayed on the Fostrox starting dose. With less than 50% of the patients in this study needing to dose-modify Lenvima, the combination partner, this should be compared with literature data, where more than 60% actually dose modified. We are encouraged 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 new. The most common grade three and above events with Fostrox were hematological, as expected, with non-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. As a quick reminder, we have previously reported independently reviewed mRECIST data for the six patients in the phase one part. Among these patients, one patient actually achieved a complete response with no viable tumor left, which is a rare event in second-line HCC. Together with two partial responses, the response rate was 50%, and with a further two patients having stable disease, this resulted in a disease control rate of 83%. We have now showed updated data with a combination that is encouraging with regards to both efficacy and tolerability. A key question is obvious, how this data compares with what could be expected with Lenvima alone in second-line HCC.
Previously, Lenvima hasn't been evaluated in second line, but new published prospective data on Lenvima monotherapy after Tecentriq Avastin is now becoming available. Since we do not yet have a randomized trial or randomized data on Fostrox plus Lenvima, we will do an indirect comparison with this study, with the Lenvima monotherapy data, where both investigator and independent review data will be compared. 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. There were 12 patients included and given Lenvima until progression or intolerability, and could continue if the investigator deemed that the patient still had benefit despite progression. The imaging was done four weeks after first dose of Lenvima, and thereafter every eight weeks.
As said, with limited clinical data, in second-line HCC, in second-line HCC post-standard of care, this data set will, with all the limitations you can see with an indirect comparison, can contribute to the understanding of the added clinical benefit of Fostrox to Lenvima. So, this is the characteristics of the patient included in these studies, and they were fairly similar, with the exception that the Fostrox 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 were safety, since they were small studies. Compared to the Lenvima monotherapy study, no additional safety events were reported when Fostrox was added to Lenvima.
The discontinuation rate due to adverse events was similar, though there were higher number of dose modification in the Lenvima monotherapy study. When comparing efficacy between these studies, there 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 to correlate with improved survival.
The overall response rate was also higher with Fostrox plus Lenvima, including what you saw before, the patients who actually achieved a complete response, and this was not seen in the Lenvima monotherapy study. So progression-free survival, I'm sure that you recognize this, since this is a normal endpoint in Phase 3 studies, is an important endpoint, since it includes all patients with or without responses that could benefit from the treatment. In the Fostrox plus Lenvima 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 Fostrox Lenvima study data.
We did that, and both with independent and investigator review data, there is a consistent improvement in PFS, TTP when Fostrox is added to Lenvima in our current study, as seen in the two graphs to the left. 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 supporting this improved benefit that you saw to the left. 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 Lenvima.
And when combining two drugs with different antitumor mechanisms and a strong rationale for synergistic activity, the improved benefit is to be sort of expected in the combination if the combination is tolerable. So we are now, now moving to the next exciting step in the clinical development of Fostrox. But before we talk more about these plans, I would like to introduce our clinical expert in HCC and the principal investigator in the Fostrox plus Lenvima study, Dr. Jeff Evans, who will talk about HCC clinical practice today and what to expect in the future, and again, how this treatment with Fostrox plus Lenvima would potentially fit in. So over to you, Jeff. I think you are muted.
Schoolboy error, still do it.
Yeah.
Thank you, Pia, for your very kind introduction and for the opportunity to share some thoughts about HCC treatment today and tomorrow. And could I have the next slide, please? So I think it's very important just to remind everybody about the scale of the 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 centers that had very active HCC surveillance programs. But HCC surveillance is very patchy worldwide, and we do get interval cancers despite surveillance. And of course, the rising 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 predominant group these days are for those who are accessible to non-curative treatment. Next slide, please.
So this is the updated staging and treatment algorithm, and I only show this to show the complexity of the disease and how much more patients now are treated with systemic therapy than hitherto had been the case. And I anticipate this will only increase in the future, even if we are giving it in combination with what we currently consider curative treatments. And next slide. We will circle here the—sorry, if we go back to the previous slide, just to show that area which is circled, which is what we call BCLC-B. This is intrahepatic liver-only disease, which is a broad group from very small disease that might be suitable for surgery without transplantation, or the majority, which is bulky disease that will never be accessible to curative treatment, and for which we really need better drugs, as well as those with extrahepatic disease.
And therefore, this is, speaks to the fact that treating the liver burden is very important in this disease, because a high proportion will never develop metastatic disease, because they 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 U.K. We've had a number of approved regimens in the first line, and moving from right to left, sorafenib, then lenvatinib, 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 bevacizumab. All the approved second-line trials were done when sorafenib was the only first-line treatment.
Therefore, there is no second-line phase one level one evidence for what should be standard of care after progression on atezolizumab and bevacizumab, or for that matter, on tremelimumab. The international consensus is that tyrosine kinase inhibitors, that is sorafenib or lenvatinib, would be considered as the standard of care after progression on immunotherapy. ... and most of us believe that lenvatinib, although licensed in the first-line setting only, is a superior tyrosine kinase inhibitor. We've heard talk of Lenvima. Lenvatinib is the same compound, and I may revert to calling it E7080. I was involved in lenvatinib in the very first in-human 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, all the time during that development.
And similarly, I believe that MIV-828, Fostrox, has the potential to be an active drug in this disease. Next slide, please. Excuse me. Now, significant advances have been made in the first-line treatment of systemic therapy or HCC, undoubtedly, atezobev, superior to sorafenib, but still, associated with ultimately a disappointing prognosis. But there's high unmet need in second-line therapy, and more and more patients now are fitter and have and better synthetic liver disease to proceed to consider second-line therapy. And as we give more and more systemic therapy in the first line, we do less and less TACE, and therefore less damage to the synthetic liver function, so this represents a bigger proportion of our patients right now.
The standard of care in my center is clinical trial, and for those where there is no clinical trial, if they progress on atezo-bev, then lenvatinib is my usual monotherapy TKI of choice in the second-line setting. Next slide, please. So we have in oncology, whenever we combine, combining two agents, we want to have agents without overlapping toxicity, different mechanisms of, mechanisms of action, potential synergy in action, and at least additive, if not synergistic. And we have the additional agent here that targets the tumor locally, giving intrahepatic liver-targeting treatment of a disease where the liver burden is clearly significant in terms of outcome, even in the presence of extrahepatic disease. Next slide, please. Now, there is I won't talk you through the science of this, but there is 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 Fostrox, 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 tumor types, because controlling the primary tumor in the liver is critical. This is such an important organ in the body, and up to 80% of patients, probably higher, have underlying cirrhosis, negatively impacting the ability to tolerate anti-tumor treatments. We've talked about lenvatinib, and I could talk at great length about what dose we should use.
Please note that the dose which is recognized in HCC treatment in monotherapy and in combination with Fostrox, is less than when we use it as monotherapy in patients without cirrhosis, for example, in thyroid cancer. Therefore, progression in the liver is unique because it occurs primarily in the liver, and patients may succumb to intrahepatic disease far more than even if they have small volume metastatic disease burden. There is some improvement long-term benefit from the meta-analysis of the TACE studies chemoembolization in the past. However, note that many of the patients who received TACE subsequently, and still worldwide, are not those who fitted the original clinical trial. For many years, we did TACE because we could, rather than because it was necessarily fitted the criteria as defined by the trust, because there were no suitable systemic therapy options.
We now have better drugs, and we're doing far less TACE than we did historically. Next slide, please. And one of the reasons for that is each time we do TACE, there's diminishing returns with the number of times we do it, in terms of getting disease controlled. And conversely, each time we do it, we can get progressive damage to the synthetic liver function. So the whole question that we've wrestled with in the HCC field: Who should get TACE? 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 TACE as a front-line treatment and less and less repeated TACE in those whom we do TACE. Next slide, please.
So we have potential of systemic anti-cancer therapy. First, let me focus today on those who are treated with systemic therapy as 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, TACE, RFA, or even substitute it if we have a liver-activating, liver-pro drug to the treatment, such as Fostrox. 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 add it 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 HCC and is providing the context for where would Fostrox plus Lenvima fit in? Where could we find the biggest benefit? With this clear picture of the unmet need together with the promising clinical data that we showed before for Fostrox plus Lenvima, we feel confident to raise our ambition when it comes to the clinical development of Fostrox, as we conclude that a Phase 2b study with an accelerated approval intent in 2021 is the appropriate next step. So one important key factor enabling this accelerated approval, it's already in place. You heard that, right? It is that HCC is a serious life-threatening disease 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 1b/2 study in a randomized Phase 2b study, as seen on this slide. The randomized study design, comparing Fostrox plus Lenvima with Lenvima alone, also incorporates a FDA regulatory acceptable endpoint already in this phase, in Phase 2b, and that is PFS. 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. I would 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 Tecentriq plus Avastin, and transform the treatment of second-line liver cancer, clearly has a substantial impact on the commercial opportunity. The left-hand slide, the left-hand side of the slide shows the sort of estimated market value and growth in the coming 10+ years, and as you can see, it grows significantly, and it reaches almost $2.5 billion 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, so that the treatment options in first line 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 opportunity perspective is the fact that there are no medical treatments, approved regulatory today after Tecentriq Avastin. And when we look ahead, 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 Fostrox plus Lenvima.
So that means that the Fostrox, in combination with Lenvima, has a very realistic potential to become the first approved treatment alternative in second line after Tecentriq Avastin. I think as Jeff, 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 Fostrox plus Lenvima to have a similar transformational impact in this population. We do see second line as our, if you wanna call it, fast to market strategy for Fostrox. Sort of again, building on what Dr.
Evans sort of outlined earlier, a liver-directed prodrug like Fostrox would likely provide sort of 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 Lenvima does show improved clinical efficacy compared with Lenvima 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 Lenvima, has the potential to transform a $2.5 billion market without sort of significant competition and low commercial risk. With that, sort of thank you for listening, and we now open up for Q&A.
If you wish to ask a question, please dial star five on your telephone keypad to enter the queue. If you wish to withdraw your question, please dial star five again on your telephone keypad. The next question comes from Joe Pantginis from H.C. Wainwright. Please go ahead.
Hi, everybody. Good morning and good afternoon. Thank you very much for all the details today and a very exciting data update. So, thanks for everything. So a few questions, if you don't mind. So first, just want to go back chronologically 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.
Without going into too much detail, this patient is still ongoing.
... That, that's actually great to hear. Thank you for that. And then, I guess I wanted to get, maybe Dr. Evans' views on, you know, the data update today and the broader profile of the of Fostrox 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 progressors. 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 the Phase 2b data read out for a potential accelerated approval. Thank you.
Yes, thank you. So I'll take the first question today. So yes, these are all patients. To enter into a second-line trial, you have to have progressed after first-line treatment. And that is entirely standard for when we get studies in any line of treatment or any tumor, not necessarily HCC. This is. We've never developed this as a maintenance therapy, and that's few and far between in oncology practice, as you probably know. So in terms of responses, yes, responses do matter. That's a question that's been asked in the HCC field. It seems somewhat obvious and self-evident to say so. But there was some controversy many years ago with...
So there was a controversy many years ago about whether responses were important or the synthetic liver function in controlling the disease. But we now feel convinced, if you look at the data that we've published from the post hoc of the REFLECT study, that clearly responses matter, irrespective of which arm the patients were in. So responses matter. Patients where we shrink the tumor burden, where you maintain patients, therefore symptoms and quality of life, and also the 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 a significant finding.
If you look at the response rates generally in HCC, and let's stick to RECIST 1.1 when we're talking response rates now, I mean, the getting responses are still the 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 if 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 quite a lot of new drugs that have been approved in mainly first line in the last few years in HCC. There's plenty of room for development. This is still a disease that's got overall disappointing survival. We've got something different because most of the development so far have been on TKIs or TKI combinations, which is actually quite interesting, regorafenib, lenvatinib, sorafenib, cabozantinib, et cetera, and on novel ways of targeting the immune system. In the future, we would may be putting these drugs together, and here we have a drug that is cytotoxic in its activity, but without the disadvantage that we used to see of the intravenous cytotoxic chemotherapy in the pre-sorafenib days back in the 20-odd years ago.
allows conventional combinability with other systemic therapies without overlapping toxicities or mechanisms of actions, as well as giving a potential to reduce the tumor bulk within the liver. We can speculate, and it is only speculation at this point, whether that could remove some of the local regional therapies that are invasive, such as TACE, for example, without the need for interventional radiology. But that is speculating, but that's the direction of travel we'd love to go in this disease.
That, 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 of patients that have, I guess, relatively quick rebounds in the 6-12-week time frame, 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 2b randomized study? Thanks a lot, guys.
Yeah. First one is for you.
Okay, why we see... I mean, the HCC, and we can introduce Dr. Evans in this as well, is it a heterogeneity in the patient that has HCC. There are different etiology, as Dr. Evans talked about, but also different molecular features. And actually, without again going into too much detail, some of the patients that responded really quickly and with a 90% reduction, actually, in the tumor, tumor size, they had a transformation into another type of HCC that is more aggressive. So while we are looking into these different patients, carefully and hope to present more in-detail data on a future congress, I cannot speak more about the individual patients at this time point.
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 responses and progressors. 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. I guess we don't really have good biomarkers of who's going to benefit from a specific treatment in what is a fairly heterogeneous disease, and in comparison perhaps with other tumor types, and I treat other tumor types as well, we've been somewhat slow to come to, as a HCC field, generically, in with Lenvima, Tecentriq, Avastin, durvalumab, tremelimumab, 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 paucity 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 got biopsies in the, in this study, and this is how we need to do it in the future.
And I'll take the business development question then. 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 basically that opens the door to those discussions. So it's been clear previously that feedback has been theoretically and logically high interest in a liver-directed, a liver-targeted drug, but there's always the question of what does it sort of 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, it sort of, that opens the door to those sort of deeper dive 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 partner to take this forward.
Thank you so much, guys.
The next question comes from Richard Ramanius from Rede ye. Please go ahead.
Hello. Good afternoon. To start, just a quick question about Tango Therapeutics. Will they do you think they will start the trial this year, and should that lead to an income from a milestone payment?
Short question. I think they've been relatively clear that they are looking to start it in first half of 2024, and that's the communication that we have seen. So I would anticipate first half of 2024, right? That I would expect. What we have said is that the start of the Phase I program does incur a milestone payment, but we haven't sort of talked about the size of that milestone payment.
Okay, and I was also thinking about funding situation in relation to partner discussions. 'Cause mightn't it be useful to strengthen the cash position while negotiating? And do you think you could do that? I mean, that would not be a large sum just to finance continuing operations. Could that be possible through a directed rights issue to perhaps the main shareholders or a loan or something like that?
Financial question-
Yeah.
We hand that to Magnus.
Thank you, Richard. Yes. I mean, the guidance I can give you now is that we are really looking at different options or alternatives that we have at the moment, and of course, that could be an option as well. But I can't give you any more guidance on that. But as we're getting more data and as more than 50% of the patients still on treatment in the Phase 3, I mean, It's a balancing act. I mean, we have encouraging positive data, but of course, it's good to have money on the bank so we can start activities. But we come back when we have made a formal decision on the next step from the financial viewpoint.
Yeah. Okay, thanks. Also, wonder about what RECIST version the Lenvima benchmark used in these 12 patients that Pia talked about. Is that RECIST 1.1?
Yeah, that is RECIST. So they actually used four different measures. They used investigator-assessed RECIST 1.1, and also this modified RECIST, and so did the independent reviewer. So we were trying to compare with what sort of- where we could have the most patients that looked similar to each other. So that is the comparison you saw.
Yeah, okay. I'll go back and look at the slides.
Yeah. Please do, and come back with questions.
I think we've tried to be as disciplined as possibly can-
Yeah
to sort of compare RECIST 1.1 with RECIST 1.1 and modified RECIST with modified RECIST because I think
Exactly.
Would that be a fair statement?
That is a definitely fair statement, and that's why we show this smaller patient cohort also.
Yeah
of six patients, because obviously, we are waiting for our data, and we are waiting for analysis to be independent-
Mm-hmm.
But we will not share that here today because we hope to have that published on a future congress.
... Okay, thanks. And yeah, that's all for me, for today. Thank you.
Thank you, Richard.
The next question comes from Klas Palin from Erik Penser Bank. Please go ahead.
Yes, thank you. Thanks for taking my question. I would like to start with a question about this pivotal trial that you are planning for. Just to clarify, is this a study where you are planning to recruit patients globally, or is it purely in Europe and America?
Thanks, thanks for that question, and that is a global trial. So we haven't selected exactly what countries we are going to go to, but definitely include Europe, Asia, and the U.S. potentially as well. We need to include U.S. if we're going for accelerated approval.
Don't say U.S. potentially.
No, no, no.
US definitely.
Yeah, I was trying to be a little bit careful there, but U.S. definitely. Absolutely.
Mm-hmm.
But it-
I guess,
It's also fair to say, Klas. Can I say the following? Now, since we have Dr. Evans on the call here.
Yes.
But clearly, we tend to have the current countries and the current sort of sites that we are working with. We see that as the core of any development going forward, but then adding in-
Yeah
... sort of the relevant countries that are needed. And U.S., yes. Japan seems like, without promising too much, seems like a
Nicely
... a reasonable country to include.
Yeah.
Then we'll stop there.
Okay, perfect. What's the status when it comes to interaction with the regulatory authorities?
Can you please repeat that? Status when it comes to interaction with the regulatory office, was that what you said?
Authority, authorities.
Authorities.
Yeah.
Yeah.
We are already having interaction with FDA, and we are-
Mm-hmm
... obviously also planning to have interaction with EMA. So, and that is, something that we need to finalize before we have a final study design.
Mm.
So that's why I was a little bit careful also in talking about it. But what is clear is that we need to have a sample set, both for the efficacy and also for the safety set, in order... That need to be in place before actually we are planning a Phase 3 if we want to go for accelerated approval. And this is something that we are carefully evaluating, that we have all that pieces together.
Mm-hmm.
Mm-hmm. And, and can you give some sort of an indication of what kind of cost you believe this study could bring?
I think it's difficult to give, Klas, in the sense if you go back to sort of that question regarding-
Mm
... sort of having, needing to finalize regulatory interactions, which then drives potential study size, inclusion of what countries, et cetera. So it's a bit too early to-
Yeah, okay
... to provide that. Sort of, we, sort of we shared quite a bit of detail in terms of our thinking and the size we think is needed, but sort of we'll, we'll come back to that element, when we get there, which we need to do in, in the not-too-distant future, but it's a bit too early at the moment.
Perfect. Understand. Then my final question. I mean, in this combination study, it seems like combining Fostrox with Lenvima has a positive effect on the dosing of Lenvima. What could be the reason for this?
I don't think that you could say that it has a positive effect, but thank you for asking that question. What was the concern for us is that we, we believed in the efficacy due to the synergy of these two compound. What always worries you is that if you get any toxicity that is new and that is unexpected. What we saw was positive, right? That we didn't see more reduction in than what was expected in Lenvima, because then you add on to something that is effective and doesn't contribute with more efficacy if you had seen sort of more dose reduction, for example. So for us, it was more like a conclusion that at least we didn't see more. It looks a little bit better, but it's tiny data sets.
Yeah.
It's encouraging.
Yeah. Yeah.
We can speculate that-
Great. Great. Thank you so much.
... these are patients who've been previously exposed to atezolizumab, and the main side effects are patients who develop hypertension and proteinuria. Clearly, they would be ineligible from the study if that's been induced by bevacizumab. That's the only speculation I can make.
Yeah.
Thank you for that, Dr. Evans. Good comment.
Perfect. Perfect. Thank you very much.
The next question comes from Chien- Hsun Lee from Pareto. Please go ahead.
Hi, good afternoon, and thank you for the nice presentation. Just trying to get some more clarity on the data. So for the four partial responses, how many of them are already included in your previous cutoff, and how many of them are new? And the second question is that, I guess, it's based on local review. Have you also performed analysis based on central review? And if so, could you give us some hints on how you compare the data? Thank you.
Yeah, thank you for that question. And two of the partial responses was part of the first data set that we showed. So, in total, it was four partial responses, right? So two of them. And when it comes to the centrally or the independent review, that was also made on the six patients. Because we have a data set now on 18 patients, and we hope to get this, patient set centrally reviewed and actually, presented at the upcoming congress. And that's why we chose to, today, present the investigator-assessed, data set for the analysis.
... Okay, thank you. And maybe the last question from me. So have you also measured the systemic uptake of Fostrox, so compared to in the liver and compared to other body parts and yeah.
So I guess the question-
Yeah.
-you're asking is, has this been done in the patients? So what I can tell you is that we have measured-
Yeah, exactly.
We have measured by our analysis the metabolites and the active metabolite of Fostrox in the liver biopsies. And we can find that in the liver biopsies. But obviously we have not done the experiment the way that you would do in say a experimental animal. But we do know, we've confirmed that we do get Fostrox delivered into the liver and into the tumor by these biopsies.
Okay, thank you so much.
The next question comes from Joe Pantginis from H.C. Wainwright. Please go ahead.
Hey, everybody. Thanks for taking the follow-up. I wanted to link my question to the earlier comments on the spider plot and the patient heterogeneity. So based on today's data, how do you feel the today's data might impact the inclusion, exclusion criteria, you know, beyond what's on the slide here about one prior IO treatment and any potential to identify any biomarkers or what have you, for inclusion, exclusion criteria? Thanks.
That is a great question, and that's why we have Dr. Evans and the expert counsel actually. So with the knowledge that we have today, Dr. Evans really sort of explained the difficulties in getting a full molecular profile that actually can be prognostics or predictive of treatment. But we will try to use as many biomarkers as possible to be able to interpret the data from the Phase 3 a little bit, from the Phase 2b a little bit better, because today we only have 18 patients, and to draw sort of really long conclusions from this patient cohort, I think that is not going to influence our inclusion or exclusion criteria. I don't know if you want to comment on that, Dr. Evans?
Yes. In terms of, I mean, there's intense focus on choosing biomarkers and response in HCC. It's not likely to be a genomic answer. Next-generation sequencing is probably beyond genomics and of course, once you go beyond genomics into things like spatial transcriptomics, that becomes much more technically difficult to do in a broader group of patients as standard of care. Therefore, it's really only a research tool. So all I will say is that there's a lot of research going on at present to identify biomarkers of response to immunotherapy in all tumor types, but including in HCC as well as responses to TKIs. And most of those that have come out so far have been retrospective analyses of tumor samples we collected within clinical trials. We did that in Reflect, for example, and it's also been in TOPAZ and others.
Thank you, Dr. Evans.
Thank you very much again.
There are no more questions at this time, so I hand the conference back to the speakers for any closing comments.
And I think we have one question on the-
Yeah, we have one question, sort of looking a bit to the future. If everything goes well, when can we expect Fostrox to take part to reach the clinics and be used to help HCC patients?
I look at to Pia from a. If you start with the kind of-
Yeah
-study design and, perspective and start and how long.
So the current study design that you saw very briefly in the slides before, then it would be a potential to have an accelerated regulatory approval in the in late 2027. And then obviously, it depends on reimbursement in the different countries, but then it would be accessible for the patients. With that, there is a requirement always to do a confirmatory trial to get the full approval. And actually, we have that in our development program as well, because we are planning a master protocol where we also define that we are going into a Phase 3 trial. But this is a little bit too early to talk about any details, but in essence, it would be available late 2027, early 2028.
If we can replicate the data in the 2B that we see there.
That was very good. If we get an accelerated approval-
If we can
... and can replicate the data.
If we can, yeah.
But this is a sort of forward statement. Yeah.
This is the reason why, sort of, when I spoke about commercial opportunity, I chose the year 2028 as sort of the compound would be on the market, sort of at the first time. Okay, any more questions, Fredrik?
No, I think we have covered.
We've covered everything?
Yes.
Okay. Then, before we close out, sort of, I just want to sort of leave you again with the same kind of message or reminder that I had before. That hopefully, we have shown today that the combination of Fostrox Lenvima does show improved clinical benefit compared with Lenvima study data alone, without compromising safety and tolerability. And that there is a very realistic opportunity for the combination to move ahead with speed, aiming for accelerated approval in 2027, if we can replicate the magnitude of the data, of course, in Phase 2b. And then finally, that Fostrox has the potential, together with Lenvima, to transform the second-line setting without significant competition and low commercial risk if there are no other approved treatments on the market. So with that, thank you all for listening in, and have a great weekend!