Study Result

Sep 16, 2021

Slides

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 MIB-eight eighteen Phase 1b monofibril study that was presented today at ESMO. And second part is the next step in our development on MIB 818 and then we will open up for Q and A session. Today's presenter will be myself, Magnus Christensen, but foremost by Frederik Gerbei, our Chief Scientific Officer and Tom Morris, Medevich Chief Medical Officer. Please go to Slide number 3. I will not go through this in detail, but I recommend you to read it at our homepage, where you can find the presentation as well. Please go to Slide number 4, and I will hand over to Frederik Erberg. Good afternoon. So please move to Slide number 5. As Magnus mentioned, today, new clinical data from our Phase 1b study with MIB-eight eighteen, monotherapy was presented at ESMO Congress by Doctor. Debase Saker. The bottom line of this data is that we're encouraged in our development. The safety, tolerability and signs of efficacy further supports our development of MIV-eight eighteen in hepatocellular carcinoma HCC. And we're really looking forward to starting the recruitment in the planned combination studies later this year. So if we move to Slide number 6, what is NID-eight eighteen? Well, NID-eight eighteen 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 creates 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 number 7. Miban 8.8 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 up studies ongoing Phase III studies at clinicaltrials.gov. There's a daunting large number that are ongoing. However, vast majority of these studies are investigating a relatively narrow range of mechanisms of action. The majority of them fall into 2 categories, either checkpoint inhibitors such as anti PD-one 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 MIR-eight eighteen, 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 Espoo Congress. Right. Thank you, Frederic. And if we can move to Slide 8. This slide is just giving an overview of the study population and the objectives of the Phase 1 monotherapy study. So the population that was included in the study was patients with advanced inoperable Cancers with either hepatocellular carcinoma, intrahepatic baudic 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 valve that 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 part of the study was to assess safety and tolerability of LIV-eight eighteen as monotherapy and to determine what the recommended Phase 2 dose for monotherapy would be, to what those would be investigated next in the development program. As a secondary objective, we had evaluation of the tumor response based on standard RECIST Version 1.1 methodology. Exploratory objective included the assessment of pharmacokinetics and dynamic effects of VB-eight eighteen. 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 NIVEK1.8, but these resolve rapidly and are very common with other anti cancer therapies and easily monitored. So overall, the safety profile is supported moving forward with NIVE-eight eighteen 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. The graph 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 MIVEC-eighteen. 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. As you can see on the right hand figure, there was little change in the size of tumor during 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. 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 LIV-eight eighteen is absorbed and that the active compound Is indeed formed in the liver, which is what we very much hoped and expected to see. Clear signs that LIV-eight eighteen induced the desired DNA damage within tumor tissue from the liver biopsies that were taken from these patients with advanced cancer. And this was observed across the different types of liver cancer that we studied in the Phase I study. And importantly, we didn't see any DNA damage occurring in normal liver tissue. So moving on to Slide 12, which is a conclusion. The safety profile to date very much supports moving forward with development of miB-eight eighteen. As I said, we've seen decreases in gut cell counts occurring commonly in these patients, but these are expected with anticancer therapies and these resolved quickly. 4 out of the 7 patients with primary liver cancers, that is hepatocellular carcinoma or cholangiocarcinoma, bardic cancer had Stable disease over an extended period of time is the best overall response. And as I said, one stayed on treatment for 8 months. The liver biopsy data demonstrated delivery of miB-eight eighteen 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 with the continued development of MIVV-eight eighteen. 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-eight eighteen with a checkpoint inhibitor in the form of KEYTRUDA pembrolizumab and an anti androgenic agent in the form of Lenbema, then Martin. So with that, I'll hand over back to Frederic to take us through more of the NIVEA1.8 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. The basis for defining this strategy going forward is, of course, multiple reasons. But one important fact is that the combination of MIIB818 with anti PD-one, in this K. Chuga, 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 is 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 MIIB818, which further suggests that this combination can potentially have a better effect than either drug alone. The underlying scientific rationale is that NID-eight eighteen 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-one therapy has a modest efficacy in HCC at monotherapy. So there's room to improve the response to anti PD-one in these patients. The 2nd combination agent, if we move to Slide 15, It's the tyrosine kinase inhibitor type of drug. We've chosen lenvatinib or LENVIMA. And again, addition of MIV-eight eighteen-two 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 metabolites of miB-eight eighteen, The last phosphorylation step is 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 induced lack of oxygen in tumors and therefore, potentially may synergize with with 818 in a combination. So if we move to Slide number 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 miR-eight twenty eight is safe and tolerable in combination with these approved drugs. Thereafter, we will conduct an expansion phase with the chosen dose level of 818 in combination with either Lamina or Quechua. And in this case, we'll be looking to explore preliminary clinical efficacy at the correct dose. So if we move to Slide number 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 or 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 the VIMA treatment. The primary objective is still in the Phase 1 part of this study to assess safety and tolerability of miV-eight eighteen in combination with KEYTRUDA or NIVEEMA and to determine the recommended Phase 2 dose for miB-eight eighteen in these combinations. As a secondary objective, We expect to evaluate tumor response rates based on RECIST criteria. If we move then to Slide number 18. As we previously communicated, this the study has been a full size regulatory authority in the UK, and we expect to open additional sites in the UK 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 millivate.8 in several levels. One is, of course, that in the West, HGC 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 The 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 sites 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 I hand over to Magnus. Thank you, Felix. Please see Slide number 19. We know that liver cancer is the 3rd most common cause of cancer related deaths in the world, and HCC is the most common form of liver cancer. And we can see here is the potential market in HDC is growing and rapidly over the coming years from $111,000,000,000 up to $5,000,000,000 in the year 2029. Liver cancer incidence and mortality are increasing, but will be the major driver of the market growth is the introduction of the new combination therapy. Then go to next slide, please, Line number 20. And to sum up, today, We have presented supporting data from the MIIB 818 Phase 1b in one of the various studies that were presented at ESMO, which show good safety, tolerability and science efficacy in HCT 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 and A session. Thank Our first question comes from the line of Joe Pantginis of H. C. Wainwright. Please go ahead. Your line is open. Hey, guys. Good morning, good afternoon. Thanks for taking the question and 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 GCSS and support most of the patients. It was just a matter of interrupting the dosage for period and they resolved on their own. Got it. Got it. That's helpful. Thank you. And the second question with regard to Love seeing PRs and CRs, which are obviously important to impact survival. But maybe some perspective On why the stable disease is seen in 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 Objective responses, reductions in tumor size, but they are relatively uncommon. We've got Ten patients in this patient population in the study. All these patients, as I said, had advanced disease. They'd already been on multiple therapies beforehand and exhausted those. So, realistically, seeing a response It 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 and especially gratifying to see that one of these patients Normally progress very quickly. It's gone for 8 months on the therapy. So, Doug, I think we've moved that we could see improvements in delaying progression ultimately. As you know, objective response on its own is probably not 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. No, thanks for that. 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 If the logical 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. Sure. Yes. It won't be a biomarker select population from the point of view of LIV-eight eighteen To add to that, we expect NIVE-eight eighteen 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 you know, 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 at the Eso Bev 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. So thanks for that. And then lastly, thanks for bearing with me, is 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 site 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. Great. Thanks for all the information, guys, and bearing with me. Thank you, Erik. Thank you. Our next question comes from the line of Richard Romanius of Redeye. Please go ahead. Your line is open. Hello. I had one first question concerning the 3 plus 3 setup. So how many cohorts did you go through in this study? I noticed in the abstract that you had the disease There's limiting toxicity at which cohort did that occur? And Is that something you can handle easily? Yes. So I think as we said in the poster, yes, we did have that dose limiting toxicity of rash occurred in a patient in the first cohort in the first three, which necessitated including another 3 patients at the same dose level following the standard 3 plus 3 design. And then I think 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 Can get some longer term data, which is why we ended up with 9 plus 1 patient, 2 dropped Very early because of disease progression. So the DLT was a rash. And again, it's one of those that resolved Exclude quickly, but it did cover more than about 30%, 40% of the As I recall, and therefore was counted as a grade 3 and therefore a DLT. Okay. And Did you measure serum levels of the metabolite? And did you find any variation in serum levels? And And the 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 D and P, 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 a predicate too early to draw any firm conclusions on that. And the last question, did you find any Also correlation between the histology samples and the response in patients, for example, did you Not if anything in the patients that tell them stuff to face if the solar samples 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? Okay. Thank you. Those were all my questions. Thank you. Thank you. 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 MIB-eight eighteen. And we're really looking forward to the remaining part of this year and especially our plan to start our combination start date with 818. Thank you all.