Medivir AB (publ) (MVIR) Earnings Call Transcript & Summary

Welcome to Medivir press conference. [Operator Instructions] Now, I will hand the conference over to CEO, Jens Lindberg. Please go ahead.

Thank you. Good afternoon and welcome, everyone. My name is Jens Lindberg. I am the CEO of Medivir. I am joined for today's call by our Chief Medical Officer, Pia Baumann, as well as our Chief Scientific Officer, Fredrik Oberg; and Magnus Christensen, our CFO. Today's call, we will follow up on the events at last week when we presented our first data for fostrox+LENVIMA at a scientific congress at ASCO GI in San Francisco and go through the data and also what that means, implications for our plans going forward. So we are now back in Sweden after a very energizing week with a lot of interactions with global experts in the field of hepatocellular carcinoma. And in the call today, we will focus on 3 elements. We'll start off with a bit of sort of top line takeaways that we are coming away with from the conference. Then we will spend most of the time going through the data that we presented for fostrox+LENVIMA in the ongoing study that was presented by Dr. Maria Reig at ASCO GI, plus some sort of additional sort of analysis and update that we have done with regards to median time to progression. But we will come back to that -- or Pia will come back to that in more detail. And as mentioned, we had extensive one-to-one interactions with global experts, sort of going through the data, the sort of fostrox program and the plans going forward to gain input and feedback on our plans, and that will be incorporated as we are moving forward. And Pia will talk a bit about sort of those discussions and the reflections and how that sort of helps influence our plans going forward. But before we then go into more detail, the 3 things that we did as a team at ASCO GI was that first data presentation at a scientific congress, a lot of expert engagement to gain advice regarding the fostrox development, and then, as I mentioned, insight sessions both with the members of our Scientific Advisory Council, but even more so reaching out to experts and potential investigators with regards to the upcoming Phase IIb study, so engaging with experts across the different markets and regions in the world. And top line, what we take away are a few things, and it's very clear that there has been a substantial development in the first-line space with regards to advanced HCC, whereas the second-line population is not at all in the same focus. And there has been, with regards to data, mainly sort of first-line data, both at the Congress and at previous sort of events, different types of IO combinations, together with new regiments in earlier stage HCC, whereas it continues to be quite limited second-line data presented. And the data that has been presented does confirm -- so if we focus on implications for fostrox, the limited second-line data that has been presented does confirm previous efficacy benchmarks in terms of what you can expect to see in that population. And there continues to be a lack of development from other companies in second-line. And feedback was very clear from the physicians we met with that the planned fostrox-LENVIMA study does fill a very clear research gap in second-line. And there was -- for many of the physicians or the physicians that we met for the first time that was exposed to fostrox, the compound and sort of the data, et cetera, we got positive response both on the mechanism, but also in terms of the data and plans going forward with regards to study design, et cetera. So overall, a very good Congress with a lot of fruitful, valuable interactions. But as mentioned, we will focus today primarily on the data that was presented at the Congress. And to do that, I hand over to Pia.

Thank you, Jens. And as Jan said, the first data from the Phase Ib/IIa study with fostrox+LENVIMA was presented at ASCO GI by Dr. Maria Reig. We can go to the next slide, please. So just a little bit of a background, and this was also something that was discussed at ASCO GI, is that fostrox is a type of smart chemotherapy that is liver directed. And this is really, really important because chemotherapy was and is still a major component of cancer treatment, either as monotherapy, but these days often as a backbone of different combinations with, for example, targeted therapies or immuno-oncology. However, in some cancer forms as HCC or primary liver cancer, it has been impossible to deliver doses that is high enough with standard chemotherapy to get an effective tumor killing effect without causing intolerable side effects. But with fostrox, doses that are high enough to be effective is possible due to that it is a liver-targeted mechanism. It is an oral formulation. It is a pill. But after you swallow it, it is stable in the GI tract and it gets directly delivered to the liver. And there, in the liver, the drug is activated by enzymes. With this mechanism, a 100-fold higher liver exposure of the active drug is achieved, and this is compared to what standard intravenous chemo can do. So the study presented here at ASCO GI had a dose finding part and an expansion part with a combination of fostrox 30 milligram, that was the selected Phase II dose, for 5 days in a 21-day cycle, and LENVIMA was given as a standard daily dose that is approved for HCC. There was 15 sites in the UK, Spain and South Korea that enrolled patients, and efficacy assessment was made both by CT scan and MRI every 6 weeks. 20 patients were elevated with a mean age of 63 years, and the majority were men who all had liver function Child-Pugh A. And when it comes to etiology, 75% were viral, [ 70% ] had metastasis outside the liver, and 85% had a prior treatment or what is considered standard of care, meaning TECENTRIQ-Avastin. The majority had one prior line of treatment, but 15% had actually 2 prior lines of treatment, and all had progressed on that prior treatment. We can go to the next slide.

Is it worth a sort of question, Pia, it's 20 patients versus the total 21 in the study in terms of commenting why it's 20 in the presentation here?

So, the 20 patient is because we could do a central review in September of 20 patients who had been assessed by the CT and MRI scan more than twice. So it's confirmed [ effective ].

And we move to the next slide.

The patients with HCC have often a relatively low tolerance for side effects because more than 80% of the patients have relatively malfunctioning cirrhotic liver. And it is important, therefore, to control and reduce the tumor, particularly in the liver. This is to preserve as much liver function as possible. And with that said, antitumor treatment for HCC cannot be toxic to the liver, and it needs also to be tolerable overall. So we did the monotherapeutic study that was presented in 2021 and saw that fostrox was tolerable, and we did not report liver toxicity there. And the most common side effects were neutropenia [indiscernible] low white blood cell count and thrombocytopenia with low platelet count. And why we saw this is, this is an effect of the some -- even if it is liver-targeted, some of the drug is leaking out from the liver due to the fact that these patients have a cirrhotic liver. This means that the incidence and magnitude cannot be compared to the hematological effect that you see and you expect with standard chemo because there, the compound is given directly intravenously into the bloodstream. So we did see that the patients in the combination also had non-febrile neutropenia and thrombocytopenia without any bleeding incidents in the combination trial. It was the most common side effect. And the fact that it was transient and temporary made it very manageable with 70% of the patients keeping the dosing schedule that was for fostrox without any dose modification. Only 5% actually discontinued fostrox due to side effects. And we didn't see any new unexpected safety effect when we combined it with LENVIMA. And this is really, really important because LENVIMA, we shouldn't affect the efficacy of LENVIMA. So what we could also see that the need for dose reduction of LENVIMA was not increased compared with what is seen with LENVIMA monotherapy. And the side effect with LENVIMA was as expected for monotherapy. Also important is that we didn't have any death or Grade 5 adverse event occurring. Can we go to the next slide? So fostrox and LENVIMA showed really promising efficacy with the best response of 30% with one complete response and 5 partial responses with the centrally reviewed mRECIST, the modified RECIST. And that is the solid bars that you see here. And this is confirmed but with higher magnitude with mRECIST than what is seen with RECIST 1.1, which is the second bar here. We also looked at locally-assessed RECIST 1.1 with response rate above 25% with 5 partial responses. And just to make a note, in some patients with good response in the target lesion, you could see progression elsewhere, which is the case with patient #17, if you look to the right. This patient had an almost complete reduction of the target lesion but progressed rapidly elsewhere and was found later on to have a transformed HCC because they are more aggressive from [indiscernible]. So even if it was a good response in target lesion, it was progressing outside. That is why it looks like [ it looks ]. Can we go to the next slide? So this waterfall plot with the locally-reviewed efficacy data is showing again an encouraging clinical benefit. And we can see that the treatment in some patients have done that they have been able to stay on treatment for a long period of time with sustained response, and that is the 2 patients on top here. And we still have more than 40% of the patients ongoing in the study. And currently, we have a median time to progression, and this is January 2 where this data is from, and the time to progression at this time point is 5.1 months, again with an overall response rate of 25% and a disease control rate at 18 weeks of 61%. And again, as visible with the patient on top that the target lesion seems to be -- continues to shrink over time. And when they have response, it is sustained also with a longer follow-up, as long as we have today. We can go to the next slide. So the conclusion from the presentation at ASCO was that we saw an acceptable safety and tolerability profile, and we had an encouraging efficacy outcome in these patients. The disease control rate was high and durable in this patient population with 61% still having clinical benefit at 18 weeks. And based on these results, as Jens already mentioned, we are planning to do a randomized Phase II study to further evaluate the clinical benefit. We can go to the next slide. So we showed you this data that you have seen here, and it is clear that combination with fostrox and LENVIMA has in this study shown good tolerability. With that, the patients actually -- they are able to stay on the treatment a little longer than actually we expected, and we have seen improved clinical benefit when we're analyzing the data, and this can be seen over time. So if you look at this slide, you can see that from 17% response in October, we are now at 25% response in January, and we have an increase in time to progression from 4.5 months to 5.1 months. So, yes it's -- I mean, we are looking all the time that how does this efficacy data really compare with what is seen in second-line after what is used in first-line as a standard of care in immune-oncology combination? And also why are we so encouraged by our data? So, at ASCO GI -- we can go to the next slide -- there was an independent [ symposia ] summarizing the current evidence from using sequential treatments in HCC and also what treatment regimens are used today. And this is important, right, because it was not that long time ago, there were no treatments for second-line HCC because they had a very poor outcome. But now, we see that this is increasing, but yet still unmet need. Can we go to the next slide? So, as previously said, IO combinations or TECENTRIQ-Avastin, it is the preferred treatment regimen in the first-line setting, and there is really no consensus in the best treatment in second-line, even if majority -- and we have sort of had this confirmed also in discussion at ASCO GI with several experts -- is to use LENVIMA due to the superior efficacy that has been seen in the first-line setting. But this newly published lenvatinib data that you see here on this slide, where patients had progressed on TECENTRIQ- Avastin shows a PFS of 3.7 months and an overall survival of 12.8 months, very much confirming our assumptions for our future clinical trials. There are other alternatives obviously also in the second-line setting, as you can see, as cabozantinib, but has inferior outcome. Can we go to the next slide? So there are studies ongoing also with IO combination in the second-line setting, even if they get IO in the first-line setting. But so far, the progression-free survival of 2.9 months here and an overall survival of 7.4 months has been disappointing. But nevertheless, there are no strong evidence for what you should select post an IO combination treatment, and clinical studies here are really wanted, and that is also something that we learned in all our communications. So we can go to the next slide. So we have benchmarked -- and I think we have shown something similar earlier, but now we have more information available. We have benchmarked the data seen with fostrox+LENVIMA in this ongoing Phase Ib/IIa study with what we see historically in second-line and the limited clinical data set that is available. And our data compares favorably with those with an overall response rate of 25%, disease control rate of 79% and a time to progression of 5.1 months. And this is again the data that we have from 2nd January. We can go to the next slide. So, with 3 more weeks of follow-up, so from the 2nd January to the 22nd of January, in the same study, further improvements in TTP has actually been shown, and it is now 5.8 months. We also wanted to understand if clinical benefit from a prior treatment influenced who would benefit from fostrox+LENVIMA in second-line. We did an analysis where we compared the duration of treatment in current study that you see here to the right with the duration of previous treatment. We can go to the next. And it showed no real correlation, and patients with short duration on prior treatment could have longer benefit with fostrox+LENVIMA, as you can see, on the patients on top here. And this is really, really important because you shouldn't exclude patients that haven't responded bad on first-line treatment. They can have a benefit, particularly if you switch to a different mechanism of action. That might be the case here. And again, a need for a study with a new treatment strategy, which is applied with fostrox, is really needed. So can you go to the next slide? So based on the high unmet need and the encouraging safety and efficacy data that we have seen, now we are about to finalize the planning for the next phase study. Can you go to the next slide? So this study is a randomized, double-blind Phase IIb study with fostrox+LENVIMA versus LENVIMA plus placebo in patients -- in advanced HCC patients that have progressed on one prior IO combination. And we received really important and positive feedback from the global experts at ASCO GI. And there was a strong support for the study design overall and confirmation that LENVIMA was the preferred second-line option because that is important, right? If we combine with something that's not going to be used in second-line, then this study is not going to be successful. We received also confirmation of LENVIMA estimated efficacy data and what would be a meaningful clinical benefit and what endpoint that could be used to measure it. And as you can see here, we have used progression-free survival, and that seems to be a reasonable endpoint for this. And overall, the patients -- and it's really, really important to have this information because we are going into discussing with the FDA and to understand sort of what the experts are seeing about the clinical study design. It will help us to value the most important question and also confirmation that our thinking has been correct.

Thank you, Pia. So in terms then of -- as we've communicated before, we've accelerated our development program, as we have been encouraged by the data, and it was really sort of positive interactions at ASCO GEI, sort of confirming our positive take on the data. So we have been kind of reinforced in our belief in terms of moving forward with speed and sort of aiming for a registrational study that could have accelerated approval intent. So we continue to accelerate the program. And what we're looking sort of here and now and sort of in the short term moving forward, acceleration activities are centered around 3 categories. There's the CMC or manufacturing elements. We've communicated in Q4 last year that we have an updated commercial formulation that is ready for production to be included in the pivotal Phase IIb. That's a super important step to take. If we are running a registrational study, it needs to be with the final commercial formulation that's in place. We also have a process development suitable for commercial manufacture, equally important, also announced in Q4 last year. And we have initiated manufacturer of new GMP campaign, as we are sizing up the study for registrational intent. So those were some of the critical elements within the CMC field. Equally, moving forward with the clinical engagement, as Pia mentioned, we do have our Scientific Advisory Council, which we are meeting on a regular basis, engaged with ASCO GI. So that's ongoing. But in sort of here and now, it was very important to have extensive interactions with new KOLs and potential new investigators at ASCO GI. And that will also happen at the EASL Liver Cancer Summit, which takes place in Rotterdam in February. And of course, planning for a registrational intent study. That takes a little bit of time, so you need to start early. So the CRO selection process has also been initiated and is also something that we've engaged with potential CROs, as we were traveling to San Francisco. And then finally, there's the regulatory category. We've communicated previously, the FDA Type D meeting that we had to confirm elements of the study design, positive feedback. But more importantly, we have initiated the process for an FDA Type C meeting. So, that will be an important meeting and engagement to confirm the study design. And that's also why the interactions around the study design were so important with the KOL community. And as part of the regulatory discussions with FDA, then we're looking to open IND and apply for Fast Track Designation. But overall, with the acceleration activities, I think the key message is that we are well on track with all the activities that we have set out in order to move forward to initiate a pivotal study as soon as possible. And the aim, as we've communicated previously, is an accelerated approval by end of 2027. And just to sort of sum things up, because the other element, that is also equally important looking ahead, is what does the market look like? Have we assessed the market correctly? Have we assessed the potential correctly? And again, the ASCO GI interactions did reinforce our previous estimates, one element being there is not a lot of development going on in second-line. That opportunity to become first to market is clearly there, and we are getting very strong steer from the KOLs that there is a big need here, and they are urging us to move with as much speed as we possibly can. And by 2028, this market will be worth $2.5 billion annually, with potentially no competitor, no approved competitor in this space for a significant opportunity from a fostrox perspective. So, to sum things up before we open up for questions, fostrox is, and as Pia alluded to earlier, super important. It is a smart chemotherapy. It's a liver-targeted chemotherapy that does have tumor-selective efficacy in the liver with the potential for accelerated approval by sort of end of 2027. We are seeing that the combination is showing clinical benefit, and that clinical benefit continues to improve as study matures. As Pia showed, patients are able to stay on treatment long term. And we are also seeing, when look at sort of historical benchmarks, efficacy benchmarks, that the combination does compare quite favorably versus what can be expected from LENVIMA alone. We continue accelerated development in second-line, and our interactions did confirm the value and the sizable value of the market at $2.5 billion annually by 2028. So with that, we stop there, and we open up for questions.

[Operator Instructions] The next question comes from Joe Pantginis from H.C. Wainwright.

Very encouraging data. Hopefully, I'm looking forward to the next steps here. So I have a few questions, if you don't mind. So first, you gave the impression coming out of ASCO GI, with all of your discussions with clinicians, it seems there's a bit of continuum, as you mentioned, people that are familiar with fostrox already and people that have been introduced. So I guess, I wanted to sort of gauge where does it stand of the clinicians' understanding and the MOA of liver targeting of fostrox resonate with the physicians and people that are newly introduced.

Joe, I do apologize. Probably something at our end from a technical perspective, so we lost a big chunk in the middle of your question. So, could I bother you to ask it again?

No problem. That's fine. I guess, I wanted to get a sense, like you said, you had a continuum of people that are clinicians at ASCO GI that were familiar with fostrox and also people that were newly introduced to the drug. How do you feel the mechanism of action with regard to liver targeting is resonating with the new introductions?

Thank you for that question. And I think that it is really important for us to explain it in a way so everyone understands the mechanism of action because that comes back when talking about the efficacy. So I think that the mechanism of action, when you understand that it is not a standard chemo, it is a chemo that is liver-directed and is activated in the liver. When we explain it in a thorough and a little bit comparing way, when we also talk about how ADCs or antibody drug conjugate works, which actually has a warhead with chemotherapy that is targeted to a receptor, this is targeted to the liver instead and is activated. And I think that with that more in-depth explanation, there is also an interest, particularly since this is another mechanism of action that is needed in the second-line setting.

I think it's fair to say without going into specific KOLs, but there were a few instances where in the beginning, if there was a perception that, okay, so this is a chemo, and there was maybe an assumption this is a standard chemo, the KOL was maybe leaning back and maybe not sort of as interested, but when we got to the targeted point and kind of the pin dropped on this being a quite different mechanism, then the interest switched immediately, and the person started leaning forward and started engaging much more. So the minute, as Pia said, you see it in the body language and you see it in their eyes that moving from standard chemotherapy to targeted and to -- targeted to the liver made a world of difference. So I think that one of the key elements for us is how can we communicate that in the simplest and clearest possible fashion?

No, that's very helpful. And I guess my next couple of questions, if you don't mind, and thanks for bearing with me, are forward-looking questions. So with regard to the Phase IIb, pretty straightforward design here, wanted to, I guess, discuss your optionality in bringing the study to fruition, and I guess, combination of potential business development, other non-dilutive support, say, from oncology groups, versus cash on hand. How are you viewing the -- looking to complete the study right now?

The one thing we have communicated sort of relatively clearly in the past is that we are -- an important element for us is to -- we're looking to establish industrial partnership with primary focus on Asia. But we are open to alternative discussions as well, depending on partners. I think our preferred sort of option moving forward is to establish a partnership, i.e. to identify a development and commercialization partner to have that -- we will run the study, we will move it forward, but to have a partnership with someone coming on board in terms of both sort of technical support, but more importantly, financial support as well. So I think that's our preferred option going forward with regards to kind of -- from a financial point of view.

And I can add also research consortium, obviously, always interesting. But again, we just started reaching out, and particularly in U.S.

Okay. No, that's great. And then, I'll just combine my 2 last questions because they're both logistics surrounding the study. So, first, as you're going into your next FDA meeting to discuss the final design, how confident are you that the primary endpoint could be PFS? What other sort of discussions are you having? What do you think is like the most relevant, outstanding question? And secondly, obviously, you said you have the new formulation. Where do you stand in capacity now to be able to be ready for the study?

So to start with the PFS, so PFS includes also patients who have a stable disease, which is considered more or less response, or at least clinical benefit in HCC. The response rate in second-line is really, really low. It's somewhere around 10%, some say 5% even, which means that in order to have a study that really shows what clinical difference or clinical benefit differences is, we have selected PFS. PFS is a surrogate endpoint for overall survival, which we need to have in the confirmatory Phase III, but overall response rate is often used. But again, in this case, I think that we are relatively -- we need to talk to the FDA first, but we are confident with PFS as an endpoint as it is right now.

It is -- we can't stress that enough that sort of everyone we speak with on this, especially in second-line, they are very clear that don't underestimate the value for patients and us physicians, of course, but for patients of just stable disease and being able to sort of break the cycle, if someone has sort of progressed on previous treatment and you stop that sort of tumor growing and you have a stable, even shrinkage, so that is an important clinical benefit. And as Pia said, PFS captures that, whereas overall response rate doesn't. With regards to the CMC, updated commercial, sort of updated formulation, et cetera, here we are sort of, well -- now I'm looking for a word. We're well on track now. We are well placed. We're not seeing any challenges with regards to ramping up and having enough material ready by the time study is to initiate. And that is why these 2 elements -- we're working with Lonza and Quotient, which we communicated in our press releases. That's why it was so important after our Q3 call to start off with those activities directly because they were on the kind of critical path. But since we were able to get those up and running so quickly, we are -- on that one, we're quite confident.

Great. Looking forward to the study start.