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

Welcome to the Medivir Conference entitled News Supporting Clinical Data and Further Studies with MIV-818. [Operator Instructions] Today, I am pleased to present Magnus Christensen, Interim CEO. Please begin your meeting.

Thank you, operator, and welcome all to this presentation. This presentation will be in 2 parts. First part will be regarding new data from the MIV-818 Phase Ib monotherapy study that was presented today at ESMO. And second part is the next step in our development on MIV-818. And then we will open up for a Q&A session. And today's presenter will be myself, Magnus Christensen, but foremost by Fredrik Öberg, our Chief Scientific Officer; and Tom Morris, Medivir's Chief Medical Officer. Please go to Slide #3. I will not go through this in detail but recommend you to read it at our homepage, where you can find the presentation as well. Please go to Slide #4, and I will hand over to Fredrik Öberg.

Good afternoon. So please move to Slide #5. As Magnus mentioned, today, new clinical data from our Phase Ib study with MIV-818 monotherapy was presented at ESMO Congress by Dr. Debashis Sarker. The bottom line of this data is that we're encouraged in our development. The safety, tolerability and science of efficacy further supports our development of MIV-818 in hepatocellular carcinoma, HCC. And we're really looking forward to starting the recruitment in the planned combination study later this year. So if we move to Slide #6. What is MIV-818? Well, MIV-818 is a novel nucleotide prodrug. It inhibits DNA replication in tumor cells and it targets the liver. So it's designed to deliver high levels of active metabolites, which is generated in a series of metabolic steps to the triphosphate, which is incorporated into DNA and create DNA damage and cell death. While it gives high levels of exposure in the liver, it's designed to minimize systemic exposure and effects on organs in other regions of the body. It's once daily oral dosing, and it has orphan drug designation granted in the indication HCC, by both FDA and EMA. So if we move to Slide #7. MIV-818 within the HCC space represents a unique mechanism to treat the tumor. It selectively targets tumor cells in the liver. And despite recent advances in treatment of HCC, there's still a large group of patients that do not respond to or are intolerant to current treatments. So there's a great unmet medical need still. If you look at studies, ongoing Phase III studies at clinicaltrials.gov, there's a daunting large number that are ongoing. However, a vast majority of these studies are investigating a relatively narrow range of mechanisms of action. They -- the majority of them fall into 2 categories, either checkpoint inhibitors such as anti-PD-1 alone or tyrosine kinase inhibitors or anti-VEGF or VEGF receptor antibodies, which are anti-angiogenic drugs, or a combination of these 2. And we believe that the unique mechanism of action of MIV-818 makes it attractive to combine with both these treatment modalities. So with that, I will turn over the mic to Tom Morris, our Chief Medical Officer, to describe the data that was presented earlier today at the ESMO Congress.

Right. Thank you, Fredrik. If we can move to Slide 8. This slide is just giving an overview of the study population and the objectives of the Phase I monotherapy study. So the population that was included in the study was patients with advanced inoperable cancers with either hepatocellular carcinoma, intrahepatic bile cancer or cholangiocarcinoma, as it's called or patients with metastatic disease in the liver from cancers elsewhere within the gastrointestinal tract. So in this part of the study, we had 5 patients with hepatocellular carcinoma; 2, with intrahepatic bile cancers; and we had 3 patients with metastatic disease from elsewhere. It's important to point out that all these patients are very advanced in their disease and all have been -- all have exhausted existing approved therapies. So the main objective -- the primary objective of this partner study was to assess the safety and tolerability of MIV-818 as monotherapy and to determine what the recommended Phase II dose for monotherapy would be, so what those would be investigated next in the development program. As the secondary objective, we had evaluation of the tumor response based on standard resist version 1.1 methodology. Exploratory objective included the assessment of pharmacokinetics and pharmacodynamic effects of MIV-818. So moving on to Slide 9. This slide is just summarizing the safety findings from the Phase Ib monotherapy in the patients. Overall, the safety and tolerability profile we saw was very much in line with expectations for this type of drug in these patients with advanced cancer. We did see decreases in blood counts occurring frequently with MIV-818, but these resolved rapidly and are very common with other anticancer therapies and easily monitored. So overall, the safety profile supported moving forward with MIV-818 and evaluating it in combination with other drugs in the next phase of development. Moving on to Slide 10. This is now looking at the efficacy of the drug in the treatment of these patients. So the graphs on the right is showing us how the size of the tumor lesions changed over time. So we measured the size of the tumor lesions before patients started dosing and then at various points during the treatment phase with MIV-818. We did see that those patients with metastatic disease from elsewhere in the body that have gone to the liver, they unfortunately progressed quickly. But in patients with HCC, these patients had stable disease for an extended period of time. And as you can see on the right-hand figure, there was little change in the size of tumor given the course of the treatment period, as I said, for an extended period of time. So 4 HCC patients showed stable disease in the liver over an extended period of time. 1 HCC patient remained on treatment for 8 months in total. And as I said, we have these 2 patients who unfortunately had quite rapid progression of their cancer. So overall, this supports our decision to move forward to study HCC in the upcoming next phase of the study. Moving on to Slide 11. Just summarizing the pharmacokinetics and pharmacodynamics objective. This further supports that MIV-818 is absorbed and that the active compound is indeed formed in the liver, which is what we very much had hoped and expected to see. Clear signs that MIV-818 induced the desired DNA damage within tumor tissue from the liver biopsies that were taken from these patients with advanced cancer. And is -- this was observed across the different types of liver cancer that we've studied in the Phase I study. And importantly, we didn't see any DNA damage occurring in normal liver issue. So moving on to Slide 12, which is our conclusions. The safety profile to date very much supports moving forward with development of MIV-818. As I said, we've seen decreases in blood cell counts occurring commonly in these patients, but these are expected with anticancer therapies, and this resolved quickly. 4 out of the 7 patients with primary liver cancer, that is hepatocellular carcinoma or cholangiocarcinoma bile duct cancer, had stable disease over an extended period of time as their best overall response. And as I said, 1 stayed on treatment for 8 months. The liver biopsy data had demonstrated delivery of MIV-818 to the liver and the selective effect on cancer cells with no effect on normal liver tissue. So overall, these data support very much moving forward for the continued development of MIV-818. So the next step will be to explore the drug in combination with 2 drugs with completely different mechanisms of actions. So we're combining MIV-818 with a checkpoint inhibitor in the form of KEYTRUDA, pembrolizumab, and an anti-angiogenic agent in the form of LENVIMA, lenvatinib. So with that, I'll hand over back to Fredrik to take us through more of the MIV-818 story.

Thank you, Tom. Let's move to Slide 14. So as Tom said, we're moving into combinations now, and the combinations will be with 2 different mechanisms of action. And the basis for designing this strategy going forward is, of course, multiple reasons. But one important fact is that the combination of MIV-818 with anti-PD-1 in this, Keytruda, results in stronger inhibition of tumor growth than either drug alone. And you see an example of such a tumor model experiment on the right-hand side of this slide. That gives us an indication that, at least in models, these 2 drugs can act together and provide an improved response to hepatocellular carcinoma tumors. We also observed signs of enhanced immune activity by treating tumors with MIV-818, which further suggests that this combination can potentially have a better effect than either drug alone. The underlying scientific rationale is that MIV-818 does induce DNA damage and tumor cell death. Potentially, this generates increased tumor antigen presentation and increased immune responses. And as you probably know, single-agent anti-PD-1 therapy has a modest efficacy in HCC at monotherapy. So there is room to improve the response to anti-PD-1 in these patients. The second combination agent, if we move to Slide 15, is the tyrosine kinase inhibitor type of drug. We've chosen lenvatinib or LENVIMA. And again, addition of MIV-818 to LENVIMA in preclinical models significantly enhances tumor growth inhibition. And here, the underlying scientific rationale, we believe, is that one of the enzymes conducting the last step in generating the active metabolite of MIV-818, the last phosphorylation step, is it that expression of that enzyme is increased by lack of oxygen. And this leads to higher level of active metabolites. Tyrosine kinase inhibitors such as LENVIMA induce lack of oxygen in tumors, and therefore, potentially may synergize with MIV-818 in a combination. So if we move to Slide #16, this describes the overall design of the combination study. The first step of the study will be a dose-escalating phase to decide which dose of MIV-818 is safe and tolerable in combination with these approved drugs. Thereafter, we will conduct an expansion phase with the chosen dose level of MIV-818 in combination with either LENVIMA or KEYTRUDA. And in this phase, we'll be looking to explore preliminary clinical efficacy at the correct dose. So if we move to Slide #17. This describes the population and the objectives of the Phase Ib combination study. The patient population is then slightly different from the one that Tom reported on just now in the Phase Ib monotherapy. We're zooming in on advanced inoperable hepatocellular carcinoma. And the patient population are also healthier and earlier in their treatment lines. These are patients that have progressed on or are intolerant of first-line standard therapy for HCC and would be candidates for KEYTRUDA or LENVIMA treatment. The primary objective is still in the Phase I part of this study to assess safety and tolerability of MIV-818 in combination with KEYTRUDA or LENVIMA and to determine the recommended Phase II dose for MIV-818 in these combinations. As a secondary objective, we expect to evaluate tumor response rates based on RECIST criteria. If we move then to Slide #18. As we've previously communicated, this study has been approved by regulatory authorities in the U.K. and we expect to open additional sites in the U.K. for this study. We also plan to open sites in Spain and South Korea. The sites in South Korea will be beneficial to the study of MIV-818 in several levels. One is, of course, that in the West, HCC is an orphan disease, whereas it's much more common in Asia. So it will probably impact patient recruitment in a positive way. The second benefit is that Asia is an important future market and exposure in the Asian population will aid in our discussions with potential future partners. So both from a recruitment point of view and from a strategic point of view, moving into Asia and having a site in South Korea is going to be beneficial. So we are on track to initiate this study as we have planned. And with that, I will hand over to Magnus.

Thank you, Fredrik. Please see Slide #19. We know that liver cancer is the third most common cause of cancer-related deaths in the world. And as you see, it's the most common form of liver cancer. And we can see here that the potential market in HCC is growing and rapidly over the coming years from around USD 1 billion up to USD 5 billion in the year 2029. Liver cancer incidence and mortality are increasing. What will be the major driver of the market growth is the introduction of the new combination therapy. And then move to the next slide, please, Slide #20. And to sum up, today, we have presented supportive data from the MIV-818 Phase Ib monotherapy studies that we present at ESMO, which showed good safety, tolerability and signs of efficacy in HCC patients. And we believe this is very encouraging, and we're really excited with our plan to start the combination study later this year. And with this, and next slide, please, I will hand over back to the operator, and we will open up for a Q&A session.

[Operator Instructions] Our first question comes from the line of Joe Pantginis of H.C. Wainwright.

Thank you for the data update. So I have a few questions, if you don't mind. First, when you look at the comments in the study about the impacts on blood counts, I was just curious if it required any therapeutic interventions.

Well, the short answer is yes. In a small number of patients, they did get the TCS and support. But most of the patients, it was just a matter of interrupting the dosage for a period and they resolved on their own.

Got it. That's helpful. And the second question with regard to the clinical efficacy, I was hoping you can provide a bit of perspective. Because a lot of times, obviously, investors, they just love seeing PRs and CRs, which are obviously important to impact survival. But maybe some perspective on why the stable disease is seen and this patient population is considered clinically meaningful for this patient pop?

Yes. I mean it's a good question. I mean, obviously, it would have been very nice indeed to have seen objective responses, reductions in tumor size, but they are relatively uncommon. And we've got 10 patients in this patient population in the study. All these patients, as I said, had advanced disease. They've already been on multiple therapies beforehand and exhausted those. So realistically, seeing a response was unlikely to occur in this patient population.

That's completely fair. Yes, sorry. Go ahead.

Yes. I think stable disease is very good to see as well, especially gratifying to see that one of these patients normally progress very quickly had gone for 8 months on the therapy. So it gives us improvements that we could see, improvements in delaying progression ultimately. As you know, objective response on its own is probably not an acceptable endpoint for full approval of drugs. Agencies would be looking to see improvements in progression-free survival at the very least, and stable disease could well be a precursor for seeing improvements in progression-free survival.

Of course. I mean it's always important or very nice to see a clinical benefit better than the previous line of therapy so thanks for that perspective. And I guess my next couple of questions have to do with the next steps when you look at these combo studies. I guess, first, would you be looking to have a histological biomarker type of component within the study?

So I can answer that. Yes. Yes, we will. We will extend the analysis that we have done in the monotherapy to get more information about the type of response and what we're actually seeing in the tumor in the combination study as well, so yes.

Yes. It won't be a biomarker select population from the point of view of MIV-818, to add to that. We expect MIV-818 to be working independently of any sort of molecular signatures.

Sure. Sure, sure. And then regarding the combo study as well. I was just curious. I don't know if it's too early for this, but can you maybe provide some of your benchmarks for success? Obviously, the primary is safety and tolerability, but you are going to be looking at observations of responses, so what your benchmarks might be that you look to beat?

Well, I think it's important to remember also that we're moving into a patient population where there are actually no benchmarks. Of course, we do internally have thoughts about what we need to reach. But given the improvement of [indiscernible] and the change in the second-line population, there is no really studies yet to provide a good benchmark within this patient population.

And that in itself is a good answer, too. And then lastly, can you give a sense of the extent or what you're planning with regard to regulatory discussions either with the FDA or other regions, obviously, like you said, for Spain and South Korea?

Well, if we take the sites that we were planning, we're working right now with our clinical CRO to get those up and running. In terms of regulatory interactions, we will come back and announce those when we do have them.

Our next question comes from the line of Richard Ramanius of Redeye.

I have one first question concerning the 3+3 setup. So how many cohorts did you go through in this study? I noticed in the abstract that you had the dose-limiting toxicity. At what -- which cohort did that occur? And is that something you can handle easily?

Yes. So I think as it said in the poster, yes, we did have that dose-limiting toxicity. A rash occurred in a patient in the first cohort in the first 3, which necessitated including another 3 patients at the same dose level following the standard 3+3 design. And then as it says on the poster as well, the Safety Review Committee recommended that some view of the blood count decreases that we've seen with prolonged therapy that we try and collect some more data in another cohort of patients and plan to get some longer-term data, which is why we ended up with 9 plus 1 patient who dropped out very early because of disease progression. So the DLT was a rash. And again, it's one of those that resolved quickly, but it did cover more than about 30%, 40% of the body, as I recall, and therefore, was counted as a Grade 3, and therefore a DLT.

Okay. And did you match the serum levels of the metabolite? And did you find any variation in serum levels and any correlation between serum levels and toxicity?

I think we can say that we do measure both in plasma and in tumor biopsies. But there's, first of all, too few patients really to make any correlations. And so far, we have not seen any correlation between the exposure and the DLT, for instance. So -- but it's I think too early to say. We will gather more safety data in the upcoming combination study, and we will see.

Yes. So no correlation of that. The data are limited at the moment. So I think it's just, as Fredrik said, too early to draw any firm conclusions on that.

And last question, did you find any -- also correlation between the histology samples and the response in patients? For example, did you notice anything in the patients that metastases if the [ following ] examples looked different as they responded and did not respond as well?

I think -- I mean, that's a great question, and this is something that we're working on to try to determine if we can identify factors that predict response or resistance for that matter as well. So we're looking at these correlations, but we don't have any data to share today.

[Operator Instructions] Okay. As there are no further questions coming through, I'll hand back to our speakers for the closing comments.

Thank you, operator, and thank you all for participating in this webcast regarding new data from the Phase Ib monotherapy study with MIV-818. And we're really looking forward to the remaining part of this year and especially our plan to start our combination study with MIV-818. Thank you, all.