Medivir AB (publ)

Thank you. Welcome everyone to the Medivir quarterly results webcast. We look back at a very eventful quarter marked by great progress and very optimistic outlook to the future. And today we very much look forward to sharing more details about the great progress, but also in our pipeline, but also how we see the future shaping up for the company. If we look back at the quarter, thanks to the recently announced directed share issue to Carl Ben at AB, we're able to add another program to our in-house pipeline as it enables us to initiate the clinical development with MIB 711 in osteogenesis imperfecta, which is a new and strategically important indication for us. And it has comparable market opportunity as we're already seeing with Fostrox in liver cancer. The news also comes on the back of MIV-711 being granted orphan drug designation by the FDA. Our second in-house program, the collaboration with Dr. Shon and the Korean Cancer Study Group continues to progress very well. And among other things, the eight hospitals that will participate in the study have been selected and are eagerly looking forward to get going with the study. And then finally, when it comes to our partner programs, we've seen very exciting news from our partner VetBiolix with the published landmark proof of concept study for MIV701 in periodontal disease in dogs. But perhaps even more importantly, they've already recruited, as recently announced, 20% of the subjects in their next study, which will be the key study to confirm that MIB701 is the first disease-modifying treatment, which is also then the critical step to unlock its blockbuster potential. If we take a look at the pipeline, we do have a broad pipeline of first in class programs, all of them targeting populations with significant unmet medical need and programs that have the ability to potentially transform care for patients. And today we'll focus on three of the programs. And those have been highlighted here in green, two in-house programs and one of the out-licensed. Please note, I made a slight, slight change to the MIB 711 line as I had some questions today. Just wanted to clarify that the next development step in osteogenesis imperfecta is in osteogenesis imperfecta patients. We don't see a need to do any sort of further healthy volunteer work as a phase one asset because we've already done that as part of our OA program. So the next step, clinical step, is in phase two and a phase two proof of concept study. important information and you'll see that sort of when you access the presentation on our website. Today's presenters here in the room are, apart from myself, our Chief Medical Officer Pia Bauman, uh and our chief financial officer magnus christensen and joining us for the q a is our chief scientific officer frederick so with that uh let's move into the the the meteor part of the session and we'll start with miv 711 then on the back of the the recent sort of directed chair issue and what that will enable us to do and pia will provide a bit more background on the disease and why we think it And there's exciting opportunity from year 7-11 and how we see things progressing going forward.

Thank you Jens. So just start with what is osteogenesis imperfecta. And it's a mainly inherited rare disorder where 85% have a mutation in the genes that actually is for collagen 1. and this results in varying degree and severity of the disease and it could also impact lifelines there's a significant unmet need in this population because there are no systemic treatment approved and for the disease itself it's characterized by you have defective bone and cartilage causing that the bones become fragile and stiff. It's also called, maybe you recognize this as brittle bone disease. And this leads to that you will have frequent fractures, and depending on the type of OI you have, I will come back to that, it leads to deformities, pain, and impacted mobility. So bisphosphonase are used off label and it's often used in growing children to reduce the risk of deformities and particularly in the vertebral spine and also to reduce pain and improve final adult life. So that is sort of the background. We can go to the next slide. So the next slide is showing the different types of oi and these subtypes are divided into one two and four primarily for those who can actually be suited for suitable for treatment and it's divided due to clinical severity So I've already said that it's a heterogeneous disease, which means that there's multiple different types. And some of them are actually not, they are lethal, like the type 2 and the others that are in the sort of below part of this slide. So we're only going to talk about type 1, type 3, and type 4, which are the main types. And type 1 is mild, is considered mild, but it could also be very different depending on how it actually is displayed in the different patients. And this is making up around 50% of all OI. And they have usually normal height or can have a short stature depending on how severe it is in that type. And actually have up to 30 fractures during the lifespan without any treatment. So when we say it's mild, it's still considerable impact on your quality of life. Type 3, which is the next one, is severe with the patients having considerable reduced length or statue with deformities and severe scoliosis and can have up to 100 fractures during their lifespan. And type 4 is somewhere in between. It's called moderate and they are usually short. and have variable form of deformities and scoliosis and can have up to around 50 fractures during their lifespan. So this is sort of what we have to work with in this type 1, type 3 and type 4 would be the types that are considered also for treatment with MIB711. We can go to the next slide. So just to put the effect of this OI mutation in context, as I said, it's causing mutation in the collagen 1 gene. And to put it in the context of what normally is going on when it comes to building and maintaining strength and functionality of our bone, and also to briefly explain what molecular play is, as you see here. that are involved in normal bone remodeling which is a con it's a continuous process that essentially removes the old bone and replaces it with no fresh bone and minerals and this is a simplified pictures as as you see here and there are essentially two players it's the osteoclast and the osteoblast And then you also have an enzyme, catapsin K, which is what we are inhibiting. So the osteoclasts are the ones that are responsible for resorbing the bone. Normally, it's the old bone, right? And it secretes an enzyme. That's the catapsin K. And that catapsin K cleaves and degrades type 1 collagen that is the main component of the bone. Then the osteoplasts are responsible for the production of new bone matrix and mineralization. Because when you have eaten up the old bone, you can replace it with new fresh bone. And the coupling between resorption and formation of new bone are crucial for maintaining this healthy bone. And this is the interplay that is impacted in OI. We can go to the next slide. So NOI, which affect type one collagen, I'm saying it a couple of times here because this is a little bit complicated. The type one collagen is the skeleton of the bone and it maintains flexible strength and normal mineralization, healthy bone. It is the major component of the bone making up to around 90% of the bone matrix. And the OI mutation leads to reduced or defect type 1 collagen, resulting in this imbalance between the osteoblast and the osteoclast interplay that we showed on the previous slide. And this results in increased bone resorption and reduced formation of qualitative bone. And we have also seen in studies increased level of catapsin K in pediatric studies, which also sort of is what we are trying to inhibit in order to restore this balance. We can go to the next slide. So we have the Catepsin K inhibitor MEF711 that is highly selective on inhibiting Catepsin K. And this could, as I said, restore the balance between the bone resorption and the bone formation in OI. So by inhibiting Catepsin K, the degradation of type 1 collagen can be prevented. The increased bone degradation activity can thereby be inhibited selectively while still preserving the continuous bone remodeling that you saw on the first slide, the interplay and coupling between the osteoclast and osteoplast. This results in the restoration of the balance between bone resorption and bone remodeling to ensure best possible quality of bone in OI. So this is sort of the hypothesis behind this. And we can go to the next slide. As I said, there are no approved systemic treatments in OI and MIV-711 have a different approach to those used of label or are under investigation. So MIV-711 inhibits, as we said, catapsin K and effectively prevents bone resorption while saving osteoclast functionality and preserves this bone remodeling. This is really, really important, this fact that we have the interplay intact. While, for example, bisphosphonates that are used off-label prevents bone resorption by killing off the osteoclast. And then you also lose the function and the coupling and the bone remodeling. And this creates a negative impact on the formation of new bone. Essentially, you keep the old bone that you have, but you inhibit more resorption. Antisclerostin has been investigated in OI and recently in December they announced that their phase 3 study had failed. It has been investigated due to the fact that it seemed to be effective in using new bone formation and also have an indirect reduction of bone resorption. However, the benefit diminished already after six to 12 months due to induction of, if you call it escape pathway or feedback loops that makes it more or less ineffective. So this is sort of where we are with other treatments that has been used or are under investigation in OI. So we can go to the next slide. So what data do we have that makes us believe that MIB711 could be very important for these patients? And that is that catapsin K inhibition have shown significant benefit across multiple bone-related disorders. In OA or in osteoarthritis with MIB711, it shows a statistically significant improvement in preventing bone and cartilage degradation. And other Catepsin K inhibitors have shown benefits also in osteoporosis, with reduction in fracture rate and improved bone mineral density. And just to say that osteoporosis itself shares commonalities with OI, such as bone fragility and bone mass loss. That's why this is important as well. And we have also seen significant and dose-dependent improvement in bone volume and quality versus placebo in osteogenesis imperfecta mouse model. So in essence, the clinical benefit that we have seen of Catepsin K inhibition, this is really supported by the proof of concept in this OI-MARS model, and it indicates for us that we would have a high likelihood of success in OI. That's why we can go to the next slide. We are now initiating or planning for a phase two proof of concept study with MIB711 in OI that eventually will inform the next pivotal development phase. This study will enroll about 20 patients randomized to two arms of MIB711 with a high dose and a low dose. And the patient will be treated orally, this is an oral compound, and it will be given once daily for 12 months. And the endpoint will include biomarkers for bone resorption and bone mineral density, PK safety, etc. And enrollment is planned to take place at sites in Europe. And there is a huge advantage when it comes to include these kind of patients into a clinical trial. And that is that the patients are already identified and known at the sites, why we are hoping that enrollment will be really, really fast. So I will leave it there to Jens.

Thank you, Pia. And I think the feedback that we've gotten from KOL so far is that these patients are also quite eager to participate in clinical studies due to the significant unmet medical need. From a commercial viewpoint, if we take the next step in terms of estimated prevalent population, candidates for treatment, etc., then we are looking at somewhere around roughly estimated 80,000 patients across EU, US, Japan, and Korea. And Pia broke down earlier the subtypes, which is type 1, type 3, type 4. There is a subgroup of type 1 that are many times not diagnosed because they might be too mild. So what we're estimating is that sort of two-thirds of patients are potential candidates suitable for treatment options and to be included in the study. So that leads to, because of the significant unmet medical need, no approved treatment options, we had anti-sclerostin antibody failure in Q4 and Ultragenyx are looking to sort of scale back, so the opportunity for So to be the first approved treatment option is definitely still there. So when we estimate that market opportunity across the market, we're looking at at least sort of a three and a half billion US dollars annually sort of commercial opportunity. And this is in these regions. It's a bit more difficult sort of due to prevalence sort of not having prevalence numbers in countries like China, but there's no reason why there would be less patients in China. So that's a potential upside opportunity. As the US administration has recently voted to prolong the pediatric disease designation program, we will, of course, move forward and file for that. There's precedent to receive it. And with that comes then, of course, the potential for a priority review voucher. So to sum up, we do have a highly selective catepsin K inhibitor that across multiple bone-related disorders and including our own sort of mouse model work in OI sort of signals sort of potential benefit with regards to improving bone volume, improving bone quality, preventing fractures. And as we now sort of move with speed to initiate the phase two proof of concept study, there is the potential to be the first approved sort of treatment options in this or for these patients. And as mentioned, the total market opportunity is significant. I would argue conservatively estimated at three and a half billion sort of across key markets then with other markets outside of US, EU, Japan and Korea as potential upside. So with that, we'll stop with regards to MIB 711. And we very much look forward to sort of sharing sort of further progress as we sort of continue to work to design and get the study up and running. And we'll move to our second in-house program, which is FOSTROX, which continues to be just as important as it was before. And we continue to move with as much speed as we were before with regards to initiating the FLEX-HCC study as the next step. And Pia?