Thank you. Welcome, everybody, to this R&D Day of Calliditas Therapeutics. Unfortunately, under the present circumstances, as we're all aware, we're not able to do this in person. I hope that you will, despite this, find these sessions interesting and informative. As Lars pointed out, we have a pretty full schedule, and I hope that you will walk away from this day feeling that you have a good overview of our programs, our strategy, and the execution that we are putting in place. I will take you through a brief overview of the company and also our lead compound, Nefecon. An R&D wouldn't be complete without starting with the vision statement. We always do this also on internal strategy days, so all of my staff knows that this is what we always start with. In terms of Calliditas' vision statement, we are addressing niche indications with high unmet medical needs. We're leveraging agile and cost-effective development and commercialization approaches to do so, with a goal to deliver quality-oriented and impactful solutions to patients in a timely fashion. You will hear again from our management team throughout the day. You will be hearing from Dr. Richard Philipson, our Chief Medical Officer, on the clinical development. Dr. Frank Bringstrup will take you through regulatory. Andrew Udell will be heading up the U.S. section of commercialization and market access. I will be annoyingly probably popping in and out of your schedule as the day goes on. I will start with just an overview of the company, as I indicated. In terms of Calliditas, we're a late-stage biopharma company. We're focused on novel treatments in orphan indications. We have a special interest in hepatic and renal disease, where there is an unmet medical need. Our lead product candidate, Nefecon, is being developed in IgA nephropathy, which is a autoimmune disease of the kidney. It's a serious progressive autoimmune disease where there today are no approved treatments. We believe that there is a significant market opportunity amounting to about $4 billion-$5 billion in the U.S. alone. Our strategy really is to build an integrated orphan and nephrology-focused business. We do this both through exploiting our internal pipeline as well as selectively in-licensing or acquiring additional compounds that we feel have a strategic fit. We recently acquired a first-in-class platform for NOX inhibitors, and you will hear more about that later today. We are listed both in Sweden and in the U.S. We are today the pioneer and global leader in IgA nephropathy. We recently read out a phase III clinical trial which met both its primary and secondary endpoint, and we will also be reviewing some more of that data today. We are very well positioned to be the first-ever approved drug, hopefully in IgA nephropathy. We also, through partnership, hope to be well positioned to be the first approved drug even in China for IgA nephropathy. A little bit of looking back to start with. What were our 2020 targets? This is a list, I would say, of the most important targets, and you've seen these also in a lot of my corporate presentations previously. We were focused on reading out our top-line data for the NefIgArd pivotal phase III trial in Q4 2020. We wanted to broaden our footprint and our pipeline. We had significant amount of FDA interactions, both regards to IgA and obviously also some technical interactions with regards to IgA. We're building out our U.S. organization, strengthening the European organization as we grow. We wanted to obviously manage and develop our existing collaborations. We also wanted to increase the profile of the company, and that meant in broadening our shareholder base, improving research coverage, et cetera. How did we do? Well, in terms of execution, I think that we have done incredibly well. We have delivered on our core targets on time. I think we've also, obviously as you have seen, read out very positive data in phase III, which is very exciting for the entire organization. We have also spent a lot of time working with our good partner in China, we've also therefore been able to include Chinese patients in what we called our Part B of our phase III. We have also been growing our organization significantly over the last year. We did this in a year that wasn't completely normal. As we are all painfully aware, 2020 was a year that was really dominated globally by COVID-19. To actually run this global trial in 19 countries and almost 150 sites really proved to be a challenge. I think the organization really rose to the occasion. I think all our partners, really we had an excellent interaction with our partners in this endeavor. We know that because this really did change almost every aspect of the way we are used to conducting our business. It did draw incredible amount of resources across both corporate and clinical. Again, I think we really showed that we are truly solutions oriented, and we are execution driven, and we have been able to deliver this on time. Looking forward a bit to 2021. We have, again, a very exciting year ahead of us. We have regulatory submission for Nefecon, both with the FDA and EMA. Frank Bringstrup will take you through more details on that. Also in terms of the planning and the readiness for commercialization in the U.S., you will hear from Andrew Udell and Christopher Ngai on details around that. Initiating open label studies with Nefecon. These are supportive studies in terms of dosing regimens, as well as then initiating some late-stage studies, and clinical development plans for setanaxib. Dr. Philipson will take you through that in more detail. Again, I think we now have data in the phase III, and as we have been saying is we're really focusing on the U.S. in terms of commercialization, and so we will be looking for a commercial partner in Europe, which we hope to also establish sometime during this year. A very kind of brief summary before I hand over to all the more detailed, is to kind of say, so where are we? Where are we starting in terms of having an outlook for 2021? The filing process is going very well. It's on target, progressing well. We are continuing to grow the organization. I know that many feel like we've already grown a lot, and we will continue to grow over this year. We have a very senior and experienced team in the U.S. that is managing a large part of that expansion. We recently announced a positive readout in a phase I, which was being managed by Genkyotex, related to higher dosing of setanaxib. This will enable us to really launch a pivotal trial in PBC that we'll talk more about. It also gives us an opportunity to help characterize this drug candidate with looking at some proof of concept trials, where we'll look into an oncology indication. As I mentioned, we'll have the open label studies. The open label study extension is already open and enrolling, and the extended dosing will start this year. As I said, we were also having interactions with FDA. We also, as I've been mentioning before, have been talking to them about AIH. With regards to that, we've had very constructive interactions with the FDA, and we believe that we have kind of an agreed regulatory pathway forward there. We will have some additional interactions with the FDA this year in order to finalize that design and be able to give you some more details in that area later. We also have a very strong budgeting and cash management focus, which I think is helpful in the overall processes when we have quite a lot of things and strands that we are doing in parallel. I will now just take you briefly through our lead compound, Nefecon, and IgA nephropathy. You will hear a lot more from experts in this area. Just to give you a very brief summary, for those of you who may not be that familiar with our lead compound and core indication. IgA nephropathy, as I said, is an autoimmune disease of the kidney. There's nothing approved today, and there is a really significant unmet medical need. We know that there is a genetic predisposition that's required, but there are triggers required to actually start the disease, be they environmental or bacterial, or dietary. That's not been completely clarified exactly what starts this disease. Clearly, there are triggers that are required. In terms of what we also know is that people are generally diagnosed often in their 20s and 30s. We also know that a lot of the patients, despite kind of being put on standard of care, which today really are blood pressure lowering agents mainly, that they do contain a significant portion, up to 50%, will progress and end up being at risk of end-stage renal disease. What we also know is that obviously the symptoms that these patients get in terms of both leaking of protein as well as hematuria, so blood leaking in the urine. They are basically managed very much by their nephrologists, in terms of tracking these patients on the basis of this proteinuria leakage, as well as obviously their underlying kidney function. We've done our own prevalence study in Europe, resulting in about four in 10,000, and we're estimating the U.S. population to be around 130,000 to 150,000. In Asia, and particularly in China, we know that this is not an orphan disease. It's a very common occurrence in terms of IgA nephropathy. This obviously is an opportunity that we're exploring together with our partner, Everest Medicines. Again, very briefly, we are talking about something that actually starts in the gut rather than in the kidney. This is the kind of the dominant pathophysiology, and I will leave the details to the expert here, Dr. Barratt, who's going to go through in detail. Basically, there are these undergalactosylated IgA antibodies which are produced where we have the majority of our immune system in the distal part of the small intestine. These secretory IgA antibodies do find themselves into the circulation with this disease, where they are considered a foreign body. It's not supposed to be there, and so they cause these kind of autoimmune reaction and therefore these autoimmune clusters to be formed. Ultimately, they do deposit in the kidney, which starts this inflammatory cascade and leads to this leakage and the symptoms of proteinuria and hematuria. What we wanted to do is rather than trying to target the kidney with a drug where the damage has already occurred, is really to try and interrupt and disrupt the very beginning of this disease cascade. We are delivering our medication not to the kidney, but actually in the gut, with the view to, again, really have a very potent autoimmune suppression there, and therefore affect the actual disease at its origin. We do this with a unique two-step formulation with a capsule that contains beads that are triple-coated with a variety of polymers and also the active ingredient budesonide. As we know, budesonide is very effective in terms of a local treatment of mucosa. We know that from asthma medications, for example, and this is exactly what we're doing. We're just targeting a different mucosa with this approach. What we see as well with budesonide is that it actually has a pretty terrible bioavailability. It's not really used for systemic dosing, and that's exactly what we want. We want to have a strong, potent local effect with a much more limited spillover into the systemic circulation. As you can see on the cartoon on the bottom right here, what you see is basically that this capsule remains intact throughout the stomach, throughout most of the small intestine. There's a pH trigger where it releases all the beads. You get a very quick onset, and you get a sustained release, but over a very short period of time, so really the time it takes for this to pass the ileum. This is really an extremely targeted approach to try to really address the origin of this disease. To summarize, obviously, in terms of what are the top questions and answers that I and we get in terms of making these presentations and talking to a variety of stakeholders. I'll cover them briefly and then hand over to the next speaker. These tend to be the top five kind of questions that we get. Budesonide is part of a corticosteroid family. There is a very different mode of action here. It's very important in this case to differentiate the use and the effect of systemic corticosteroids, which really are meant to be systemic. They have a very high bioavailability, 70% or 80%, and they are meant to really systemically treat the entire body. In this case, this is exactly what we're not doing. We are treating this very locally. It's a very differentiated approach. Again, it's really a combination of targeting a very small area and combining that with a differentiated safety profile. Second area of questions that we get are around proteinuria and eGFR. Here, obviously, proteinuria, what we're using proteinuria for is obviously a surrogate. What is the surrogate for? In this case, obviously, proteinuria is something that is easily observed in patients and measured more easily and faster, being affected in a faster way than the underlying kidney function. The basis here is obviously that we are using proteinuria as a surrogate for the underlying kidney function. Again, it is important to think about what is the actual treatment goal in this indication. The purpose is obviously to address and protect the actual kidney, and therefore the impact or the results on eGFR are obviously critical. Once you've actually addressed and solved the problem or the treatment goal, the symptoms obviously become far less relevant. Third area really is about the regulatory pathway. This is a surrogate marker, but this is actually a surrogate marker that the FDA has been working on and with for many, many years. This is something where they have collaborated with NKF, they've collaborated with a variety of academics. There's been white papers published. They've looked at this surrogate marker across CKD broadly, not only in this indication. From a regulatory pathway, we feel very comfortable actually that this having been something that the FDA has worked on for at least, what, five, six years by now at minimum, is something that's actually fairly well-established. As you are aware, there are quite a few companies who are also following the same regulatory pathway as we are. I also think that this is important in terms of thinking about this as an orphan disease. As always in orphan diseases, the FDA retains their ability to always look at the totality of the data. In terms of then efficacy, safety, tolerability, body of evidence, I think in this area we are clearly very leading in this indication. We've had a large phase IIb that was published in "The Lancet" in 2017 that met both primary and secondary endpoints, 150 patients. We recently then reported out, obviously in our phase III, 200 patients in a global trial, also with a very similar design and identical endpoint in terms of reduction of proteinuria. As a key secondary endpoint, obviously then the effect on eGFR, which in our case led to stabilization of eGFR, which again, is obviously the treatment goal here. So we have a broad patient group that we've looked at, both moderate, mild, and severe in terms of the different studies. We have a very consistent and robust data set. I think that we're extremely proud of what we could deliver, as I said, even under a very difficult environment in terms of the data in phase III. The last question, obviously, is our capability to launch in the U.S. There, I think hopefully as well today, you're going to get some more information on that. We do have a very experienced team, and we do combine with best-of-breed providers. This is also a rare disease, and so it is not something that is in any way, shape, or form unmanageable for a company of our size and structure. Again, I think you'll find that we are very data-led, we are very solutions-oriented, and also very execution-driven. Again, we feel very comfortable about where we are in that. There will be a lot of anticipated milestones. We will come back to this at the end of the presentation, and hopefully you will have had enough information or more information once we cover this slide at the very end. With that, this is the agenda for the day. As I said, it's a full day. I hope that you will find it interesting and informative, and I will therefore hand over to Lars to introduce our next section. Thank you very much, Renée. I'd like to introduce Professor Jonathan Barratt from the University of Leicester, who's going to be talking to us today about the pathophysiology of IgA nephropathy and the Nefecon clinical biomarker data. Thank you, Richard. Thank you for the opportunity to talk today. I'm going to really run through the current understanding of the pathophysiology of IgA and where the gut immune system fits into that, and the data we have from the phase II study in terms of biomarkers that help us understand how Nefecon impacts on mucosal immunity and IgA nephropathy. If we think about IgA nephropathy in a global sense, the key pathogenic feature of this disease is the formation of circulating IgA-containing immune complexes, as you can see in the diagram here. We believe the major substrate for immune complex formation is the presence of excess undergalactosylated IgA molecules. These IgA molecules have very distinct changes to the sugars that are attached to the IgA1 hinge region. We believe that this type of IgA is a mucosal type of IgA and is derived from the mucosal immune system. This type of IgA is prone to forming immune complexes through a variety of different processes. There is generation of IgG and IgA antibodies with specificity against the IgA1 hinge region. This may occur through the development of autoimmunity, or it may be through cross-reactivity of the normal antibody response to a range of mucosal pathogens. Of course, this all occurs on a genetic background with the identification of genetic risk alleles that both increase the risk of developing IgA nephropathy, but also the risk if you have IgA nephropathy of developing progressive kidney failure. If we think about what happens when the IgA deposits within the glomeruli of the kidney, you can see that the IgA triggers activation of these cells called mesangial cells. These mesangial cells proliferate, and they release a range of chemical factors that recruit into the kidney a variety of inflammatory cells that make that inflammation worse. This inflammation can get to the point where you have significant inflammation and the formation of structures called crescents, which are extremely damaging to the fine filters of the kidney. These chemical factors that mesangial cells and the infiltrating inflammatory cells produce can cross the filtration barrier and interact with other cells of the nephron. They can interact with the podocytes, which are critical to maintaining the selective barrier of the glomerulus. They can also interact with the tubular cells and cause those to transform into scar-forming mesenchymal cells. In addition, as there is damage to the permeability barrier of the glomerular basement membrane, IgA immune complexes can actually cross across this barrier and interact directly with these cells. If you look at this diagram, you can see here that each of these processes maps very clearly to the Oxford classification, which is the way we classify all kidney biopsies with IgA nephropathy. Because each of these individual components, the M, the E, the C, the S, and the T, are known to independently predict outcome in patients with IgA nephropathy. Of course, all of these processes are amplified by the activation of the complement system, which we know occurs in over 95% of patients with IgA nephropathy. What evidence do we have that the mucosal immune system is dysregulated and abnormal in IgA nephropathy and responsible for the production of this abnormal form of IgA? We've known since the very first description of IgA nephropathy back in 1968 that episodes of mucosal inflammation and infection are associated with a rapid exacerbation of the nephritis. The typical scenario is a young man in their 20s, late teens, who picks up a cough or a cold, an upper respiratory tract infection, and within 24 to 48 hours is peeing fresh red blood. This occurs with a variety of different mucosal infections and inflammations and shows a very strong link between activation of the mucosal immune system and the development of nephritis in IgA nephropathy. We know that the IgA that's produced at mucosal surfaces, secretory IgA, is abnormal in IgA nephropathy as well. We know there are high levels of this secretory IgA in the blood. We know that this secretory IgA can be deposited in the kidney in IgA nephropathy. We know that during an episode of mucosal inflammation that this IgA is increased in the serum. We also know that a range of antibodies against antigens that we see at mucosal surfaces, so the things we eat, bacteria that we know infect the gastrointestinal tract, that in IgA nephropathy, patients have elevated levels of these IgA antibodies compared to healthy subjects, again suggesting the mucosal immune system is dysregulated. We also know when we look at the very fine biochemistry of the IgA molecule, that the IgA that is stuck in the kidney causing disease in IgA nephropathy very closely resembles the IgA produced at mucosal surfaces. We know that the IgA that is deposited in the kidney is polymeric, i.e., two molecules of IgA stuck together, and that is exactly the type of IgA that's produced at mucosal surfaces. We know that this mucosal IgA carries those sugar changes that we know is elevated in the bloodstream of patients, but is also enriched in these deposits of IgA in the kidney. We really are focusing our efforts now on understanding what it is about the mucosal immune system that is dysregulated in IgA nephropathy that results in these downstream consequences of elevated levels of mucosal type IgA in the circulation and the formation of immune complexes. Indeed, some very interesting data has come out of the genome-wide association studies, which are looking at the genetic basis of IgA nephropathy. This is the largest meta GWAS that's been published. It contains genetic data from patients from North America, Europe, and from Asia. When you take all of those genetic risk factors that were identified in this study, and you look at where these factors converge in terms of biochemical pathways, what you can see on this diagram is that they converge on the intestinal IgA secretion pathways and processes important in that, suggesting again that it's mucosal dysregulation, and from the genetic studies in particular, mucosal generation of IgA within the gastrointestinal tract that is important in the generation of IgA nephropathy. When we come back to our understanding of the pathogenesis of IgA, it seems to make perfect sense that we should think about targeting the mucosal immune system in IgA to turn off at source the production of this pathogenic IgA, what fundamentally leads to all those downstream consequences and eventually kidney failure in patients with IgA nephropathy. Indeed, we have a drug which is well known to, I'm sure, all of you on the call, which is Nefecon, which is a steroid-based therapy, which is a steroid called budesonide, which is encapsulated in a very particular formulation. That means that this drug, while taken orally, only delivers budesonide to the terminal ileum of the bowel. It's important that it delivers it to the terminal ileum because this is where there is the greatest enrichment of mucosal immune cells. This occurs in structures called Peyer's patches within the last 20 cm to 30 cm of the terminal ileum, which is exactly where Nefecon delivers budesonide. We can think of Nefecon as a delivery mechanism for delivering, in a very precise and controlled way, budesonide to these mucosally enriched structures within the gut that are targeting the immune cells, targeting the immune development of IgA-secreting cells that fundamentally are responsible for producing the pathogenic IgA. We know that we have a variety of lines of evidence that this strategy is likely to be effective. We have the phase IIb data, which clearly showed that a nine-month treatment with Nefecon delivered both a reduction in proteinuria and also stabilization of GFR. This really is the basis for the NefIgArd study, which we're going to hear more about in a minute or so. We took the samples from that phase IIb study, and we wanted to understand how this drug worked. Were there signs that it impacted on the mucosal immune system, and how was it impacting on those pathogenic pathways? The first thing we looked at was secretory IgA. Now, secretory IgA is exclusively produced at the mucosal immune system, and what you can see here is that nine months treatment with Nefecon resulted in a statistically significant reduction in secretory IgA in the bloodstream. We went on to look at antibodies generated specifically against mucosal antigens, and here you can see suppression of IgA against the milk protein casein. When we compared this response in the same patients to the IgA against a systemically administered antigen, such as tetanus toxoid, which will have been administered through vaccination, we can see this drug had no effect on IgA against a systemic antigen, but very clearly suppressed the IgA in the serum against a mucosal antigen, again, pointing at a mucosal mode of action. We went home to look at circulating immune complex. As you can see here, there was a dose-dependent reduction in the level of circulating IgA, IgG immune complexes in patients, consistent with the targeting of the key pathogenic pathway in this disease. When we looked at that basis of immune complex formation, the abnormally glycosylated form of IgA, we similarly saw a significant reduction in the levels of this type of IgA following nine months treatment with Nefecon. If we come back to the key signaling pathways that are involved in IgA production within the mucosal immune system, BAFF and APRIL are two chemical signals that are critical to B-cell survival and the production of IgA within the mucosal immune system. Intriguingly for us, we found that Nefecon treatment suppressed significantly serum levels of BAFF while leaving APRIL levels unchanged. This is particularly interesting because there is a great deal of literature supporting a role of BAFF in mucosal IgA synthesis, and you can see here two papers looking at a transgenic mouse model that overexpresses BAFF in the mucosal immune system, which results in high levels of circulating IgA and development of an IgA nephropathy-like illness. We're starting to tease out the biological mechanisms that are through which Nefecon is working in the mucosal immune system, targeting mucosal IgA synthesis and that pathogenic IgA production. If we put all this together, we can see that a drug that is targeting the gut, and in particular the Peyer's patches of the terminal ileum, possibly through the BAFF signaling axis, is turning off the production of pathogenic IgA, which is fundamentally downstream, turning off the production of these immune complexes that deposit in the kidney, cause kidney inflammation, kidney scarring, and kidney failure. That's why I think from a biochemical and a basic physiology point of view, the NefIgArd study is so exciting because it will allow us to confirm those findings from the phase IIb study and look at the ability of Nefecon to both target the gut and protect the kidney in patients with IgA nephropathy. Indeed, the NefIgArd study answers a very key important unmet need in IgA nephropathy, which was identified by the International KDIGO organization, which is we need to have therapies that minimize systemic corticosteroid exposure in IgA nephropathy. The NefIgArd study will provide us with the data that hopefully will show that Nefecon is a safe and effective treatment in IgA nephropathy. Thank you for your attention, I'm going to hand back to Richard now. Thank you, Jonathan. I'd like to now move on and present a summary of the results from the NefIgArd phase III trial in IgA nephropathy. I know that many of you will be familiar with the design of the trial, but just to review that briefly, in the phase III clinical trial, patients with IgA nephropathy were enrolled in the study having been stabilized and optimized on RAS blockade, who were then randomized to receive Nefecon at a dose of 16 mg per day or placebo for a nine-month double-blind treatment period. The primary endpoint was assessed at nine months, and then they underwent a three-month follow-up, and then subsequently entered Part B of the study, a further 12 months of follow-up. Again, throughout that treatment period, patients remained on optimized RAS therapy. The top-line readout of the Part A of the trial, the first 200 patients performed in the fourth quarter of 2020, and we expect to complete enrollment of the remaining 160 patients by the end of this quarter in 2021. Before coming on to the results from the Part A analysis, it's just worth spending a couple of minutes looking at the differences between the phase IIb and the phase III clinical trials, and this is presented on this slide. Of note, in the phase III trial, with respect to urine protein, patients needed a urine protein level of at least 1 g per 24 hours. This was a little higher than the phase II trial, where patients with a proteinuria level of 0.75 g per 24 hours or higher were enrolled. Similarly, there were some differences in the eGFR requirements in the phase III study. Patients were enrolled with an eGFR of 35 mL per minute or higher, up to an upper limit of 90 mL per minute. That compares to the phase II trial, where patients were enrolled as long as they had an eGFR of 45 mL per minute or higher. There were some blood pressure requirements in both the phase IIb and phase III trials, and essentially, the blood pressure requirements in the phase III trial, again, were a little more stringent, requiring patients be excluded if the systolic blood pressure was 140 mm of mercury or higher and the diastolic blood pressure was 90 mm of mercury or higher. Then finally, and importantly, it's worth noting that patients with diabetes were excluded from the phase IIb clinical trial, whereas in the phase III trial, we permitted patients with both type one and type two diabetes to be enrolled in the study as long as their diabetes was adequately controlled. I'll now move on to summarize the results from the Part A analysis, and just to orientate people with the population, we enrolled and randomized 199 patients into the Part A of the phase III clinical trial. That's what we describe as the full analysis set, and we'll refer to that population throughout the summary. That's the full analysis set. Those are the patients who are randomized to the trial. Of those, 197 patients actually started treatment, so a couple of patients were randomized but weren't able to start treatment. One had a positive result for tuberculosis, and the other patient had a sudden marked increase in proteinuria. We'll now look at the demographic characteristics of the population enrolled in the study. Again, here we have the full analysis set of the 199 patients in the phase III trial, and we also have the phase IIb clinical trial presented for comparison. In terms of the median age, the median age enrolled in the phase III trial was 44 years, a little older than in the phase IIb trial. The majority of the population enrolled were males, and the majority were white in race. In terms of blood pressure, the blood pressure in patients enrolled in both the phase IIb trial and the phase III trial indicated patients had excellent blood pressure control, and essentially, there was no meaningful difference in terms of baseline blood pressure in the two populations. In terms of UPCR, because we did make those adjustments to the requirements for enrollment in terms of proteinuria, there was a higher level of baseline UPCR in the phase III trial. That was 1.3 g/g in terms of UPCR, whereas in the phase IIb trial, it was 0.8 g/g. Finally, again, because we made some adjustments to the eGFR requirements in the phase III trial, the median eGFR was 55 mLs per minute, which was substantially lower than the eGFR of patients enrolled into the phase IIb clinical trial. Looking at the demographic characteristics in a little more detail, and here just looking at the phase III clinical trial population. In terms of baseline proteinuria, just under half of the patients enrolled had a baseline proteinuria of less than 2 g per 24 hours. A further approximately a third of patients had a baseline proteinuria somewhere between 2 g and 3.5 g per 24 hours. Finally, around about a quarter of patients enrolled had a baseline proteinuria of greater than 3.5 g per 24 hours. Looking at baseline eGFR, again, there were a substantial number of patients, just over 60% of patients, with a baseline eGFR lower than 60 mL per minute, with the remainder with a baseline eGFR of 60 mL per minute or higher. Again, I think looking at the demographic characteristics and the baseline characteristics, you can see that this is a population of patients at the phase III clinical trial with significant kidney disease, but also a broad spread of patients across a range of baseline proteinuria, but a substantial number of patients with quite significant reductions in eGFR. Moving on to summarize the headline efficacy and safety data in the 199 patients who were enrolled into the Part A full analysis set. In terms of the primary endpoint, this was the reduction in proteinuria. We saw a statistically significant 27% reduction in proteinuria as measured by UPCR, observed with Nefecon at the 16 mg dose compared to placebo. That was at the nine-month time point where the primary endpoint was measured. It's worth noting that we also continued to see significant improvement in UPCR at the 12-month time point. In terms of the key secondary endpoint, the stabilization of eGFR, we saw that stabilized in the patients receiving Nefecon 16 mg per day, whereas in patients who received placebo, there was a 7% reduction in eGFR at the nine-month time point, which translates through to a loss of eGFR of around about 4 mg per minute, compared to essentially eGFR remaining stable in the Nefecon-treated patients. This is as we would expect in this population in terms of the decline in the placebo-treated patients. This would be a typical kind of observation we would see in this population with significant kidney disease. In terms of tolerability, the treatment was generally well-tolerated with a safety profile that's consistent with the known active ingredient. It's worth noting that there were no severe infections and significantly fewer withdrawals versus the phase IIb clinical trial, and we'll say a little bit more about that. When we look at the safety observed in the clinical trial in terms of adverse events, vital signs, and metabolic effects, then with respect to adverse events, we saw that the most common adverse events observed in the trial were similar to those that we saw in the previous phase IIb clinical trial. There was a lower frequency in reporting of some of the AEs in the phase III trial. This is likely due to the fact that we used a solicitation approach and solicited specifically glucocorticosteroid-related and gastrointestinal-related adverse events in the phase IIb clinical trial. We did not see any adverse clinical effects on body weight. Similarly, we did not see any adverse clinical effects on systolic or diastolic blood pressure. We didn't see any adverse clinical effects on HbA1c. We did, as I've mentioned earlier in the presentation, we did enroll patients with diabetes in this clinical trial, whereas we didn't do that in the phase IIb clinical trial. When we look at patients without a diagnosis of diabetes in the phase III trial, they showed a pattern of HbA1c results, which was very similar to what we observed in the phase IIb study. In the patients who did come in with a diagnosis of diabetes, we did observe some clinically manageable increases in HbA1c during treatment in some patients, and this resolved on treatment discontinuation. Looking in a bit more detail at discontinuation of study treatment, again, looking at the Part A full analysis set, in total, 19 patients or 9.5% of the population discontinued study treatment, and of those 19 patients, 10 discontinued treatment due to adverse events. Those patients still remain in the study in terms of being followed up. In terms of discontinuation of the study, we saw a very low rate of discontinuation from the study. Only seven patients, or 3.5% of patients in the full analysis set, have discontinued fully from the study. In conclusion, we can say that we saw a robust demonstration of efficacy, clear reductions in proteinuria, and stabilization of eGFR in patients who received treatment with Nefecon in the phase III study. The tolerability and safety profile was in line with the active ingredient, and we also have seen a highly consistent efficacy across the phase IIb and phase III clinical trials in a broad range of patients with IgA nephropathy. Jonathan Barratt, now that you've seen the results from the phase III clinical trial, it would be really interesting to hear your comments about it. Yes. Thanks, Richard. I think there are some key messages really from your presentation for me. The first is the population of patients that you've included in the study. They are clearly patients that me, as a nephrologist, would want to be treating with a new therapy. They have high levels of proteinuria. They already have evidence of kidney damage, and when you look at the results from your placebo group, the rate of progression is a rate of progression that tells me these patients are at risk of developing kidney failure in the future. I think that tells me that the results of this study are going to be directly translatable to the patients I'm seeing in my clinic who I want a treatment for, and currently I have no treatment to offer them. I think the other very interesting piece of data for me is that the efficacy that you've shown, the reduction in proteinuria, maps very nicely to the data from your phase IIb study. That the tolerability and safety of the drug is what we would expect for this type of therapy, which means that when I'm discussing with a patient why they should take a drug such as this that gives that level of proteinuria reduction, I can give them a balanced argument about what they're likely to see in the short term, the long term, and what safety is related to that drug. I think this is really critical information I will need as a practicing clinician upon which to base whether I'm going to use this drug or not in the future. Thanks for that, Jonathan Barratt. It's interesting to hear you talk about the conversations you have with patients with IgA nephropathy, and it'd be interesting to hear your comments about what these data might mean in terms of longer-term outcomes for patients with the condition. Thank you, Richard. I think the best way to illustrate that is to talk about some data that was actually generated by Travere Therapeutics looking at the long-term outcome in my own cohort of IgA nephropathy patients from Leicester that I presented recently. Here are some slides from that presentation which are publicly available, and here you can see the relationship between proteinuria reduction and long-term kidney protection. This is data that was generated as part of the Kidney Health Initiative, which is a collaboration between the FDA and the American Society of Nephrology, and has been published and was the data upon which it has been agreed that an early change in proteinuria is a reasonably likely surrogate as an endpoint for clinical trials in IgA nephropathy. What this graph here you can see on the screen capture is that for as you have a reduction in proteinuria with progressive reducing proteinuria at nine months following institution of a new therapy, you will see that that is related to a reduction in the hazard ratio of a risk of a doubling of serum creatinine, end-stage kidney disease, or death three to five years in the future, showing a very clear relationship between proteinuria reduction happening early at nine months and future kidney protection. If you look at this data, what you can see and what the analysis that was performed showed is that if you are able to generate a 30% reduction in proteinuria, that halves your hazard ratio of the likelihood of you developing a doubling of serum creatinine, end-stage kidney disease, or death, and that will prolong the time to reaching that endpoint by a mean of 10 years. That is incredibly important for a patient with IgA nephropathy who's in their 20s or 30s. If you can tell them that you can delay the time at which they are going to have a significant change in their kidney function, a significant change in their general health by 10 years, because this is a critical period in their life where they are starting a family, developing their career, buying a house, doing all the things they want to do, to know that they can defer and delay by at least 10 years. The time they reach to having significant kidney failure is incredibly important to the patient and to nephrologists. If we take that analysis a step further, we look at what the impact would be if we had a greater reduction in proteinuria. Here you've got the 30% reduction, as I showed on that previous screen capture. Here, what happens if we have a 40% or a 50% reduction to that delay in development of progression of kidney failure? Here you can see that for a 40% reduction, you delay that time by 15 years. If you have a 50% reduction, you delay that time by 21 years. This has a significant impact, both on what we can talk to patients about, but also as nephrologists, the importance of this therapy in protecting our patients. As Richard has already alluded to, when we think about the phase IIb data, which showed a continued reduction in proteinuria after the nine-month period, and the data that is available from the current analysis that proteinuria may well continue to fall in the phase III study. If we were to see a 42%-48% reduction in proteinuria at 12 months, then that would translate to delaying the time to development of significant kidney failure by 18 years. That is an absolutely phenomenal change in how we would handle and manage patients with IgA nephropathy at the moment. Thank you, Jonathan. Hello, my name is Frank Bringstrup. I'm the Vice President Regulatory Affairs in Calliditas. I will present our submission plans and the plan for the regulatory review of Nefecon. Our plan is to submit the new drug application to the U.S. FDA this quarter, followed by the submission of the marketing authorization application to EMA next quarter. Considering serious conditions with a high unmet medical need, there are a number of reasons to try to expedite the regulatory approvals to get the product approved earlier. There is an obvious public health interest in obtaining an approval earlier to get the medicines to the patients. The companies are interested in, of course, getting their drug approved earlier, and the individual patients benefit from the earlier approval. There are pathways established to support expedited regulatory approvals. One element is about enhanced regulatory guidance. That is interactions that happen between the company and the regulatory authorities during drug development, and it's important to make agreements on, for example, the clinical endpoints for phase III to support an approval, and so that you align between the company and the authority on what is in the dossier to support an approval. An additional dimension is facilitated regulatory review. That is about the time spent from submission to the approval, the time spent by the regulators while they review the scientific content of the dossier. It can sometimes be reduced, and it can sometimes imply more interactions between the company and the regulators during review. A third element in expediting regulatory approvals is potential licensing based on a limited clinical data package. That can, for example, be a certain amount of clinical data, for example, based on a surrogate endpoint that is likely to predict a clinical benefit, and that will be the basis for an approval, followed by submission of additional data to verify the benefit for a full approval. In addition to these elements, there's also other incentives. For example, for a rare disease, there's the orphan drug incentive. If an orphan medicine is approved, it can obtain market exclusivity, and that it means for a U.S. approval that it can be seven years market exclusivity, and for an EMA approval, it can be 10 years market exclusivity. Speaking about the approval based on limited clinical data, the FDA accelerated approval is an example of that. It allows for an earlier approval based on a surrogate endpoint of a drug. It has to treat a serious condition and fulfill an unmet medical need. The surrogate endpoint is then likely to predict a clinical benefit. That clinical benefit will be verified by the submission of additional data that will lead to a full approval. The use of such a surrogate endpoint can considerably shorten the time required to receive an FDA approval. The similar program in Europe is the EU Conditional Marketing Authorization, CMA. It may be granted for medicines addressing an unmet medical need on a less comprehensive clinical data set than normally required. It is in such a situation where, I quote, "Where the benefit of immediate availability of the medicine outweighs the risk inherent in the fact that additional data are still required." It's a trade-off. You can get an earlier approval, and you will, post-approval, submit additional data to obtain the full approval. The benefit of getting the early approval outweighs the risk. It is eligible for medicines that are intended for treating, preventing, or diagnosing a serious debilitating or life-threatening disease, and this includes orphan medicines. Let us look at the U.S. new drug application that we are planning for submission this quarter. We have had interactions with the FDA during drug development and agreed on the endpoints for phase III. We have also had pre-submission interactions with FDA in 2020. Our application is a so-called abbreviated 505(b)(2) new drug application, and the goal of that is to avoid unnecessary duplication of studies or tests that has been done for other products approved. In our case for Nefecon, it is the non-clinical animal studies that we are referencing from other approvals, relying on that for the approval. We are requesting a priority review, it means that if it is granted, the time spent by FDA on reviewing our dossier will reduce from the standard timeline of 10 months to only six months. In addition, we are pursuing an accelerated approval that I just mentioned, the Subpart H approval. For Nefecon, it is based on a surrogate endpoint that is reduction of proteinuria, followed by a full approval when the results of the Part B of the study are submitted. Orphan drug designation has been granted by FDA. Let us look at the EU marketing authorization application planned for next quarter. We have had interactions during development with the Committee for Human Medicinal Products, the CHMP, and have agreed on the endpoints for the phase III. We have had pre-submission interactions in late 2020 and here early in 2021. We are using the centralized procedure for the approval. That means that upon approval, and it is granted by the European Commission, we can market the product in all 27 member states at the same time. The application is a so-called hybrid application following Article 10(3) of the directive. The goal here is similar to the U.S. 505(b)(2) procedure, where it is to avoid the unnecessary duplication of studies or testing that has been done for the approval of other products. Here we are referencing the non-clinical animal testing from other budesonide-containing products approvals. We are also requesting a priority review in the EMA system. It's a so-called accelerated assessment. If that is granted by the CHMP, it will reduce the time for review of the application from the standard 210 procedure days to only 150 procedure days. We are pursuing a conditional marketing authorization, as was just mentioned, based on limited clinical data, followed by a full approval when we have submitted the data from Part B of the study. An orphan drug designation is granted by EMA. After submission, EMA will perform a validation of the dossier and ensure that everything is there in the file as it should be, and then the scientific content review is being handled by the CHMP. Instead of having all 27 member states reviewing the dossier, the system is so that rapporteurs are appointed who will do the thorough review on behalf of the other member states. The committee has, for our Nefecon MAA, appointed a very experienced team of rapporteurs. As rapporteur, the Austrian Medicines Agency is appointed. As co-rapporteur is appointed Germany. As CHMP peer reviewer, Portugal. As pharmacovigilance rapporteur is Denmark appointed, and the PRAC committee, that is the Pharmacovigilance and Risk Assessment Committee, have appointed a rapporteur, and that is also from Denmark. This concludes my brief presentation, and I look very much forward to our submissions and to work with the authorities to obtain the approvals. Thank you. Hi, I'm Andrew Udell, head of North America Commercial. Last year, I stood in front of you in person and provided you a review of our 2019 blueprint and plans as we first began preparing Calliditas for commercialization in the U.S. We discussed our IQVIA expansive market landscape research with over 100 nephrologists as well as payers that work for plans that cover over 225 million U.S. lives. We reviewed our onboarding and initial work with a top medical education company in developing a scientific communication platform and a fully integrated publication plan for us to execute on. We talked about our initial market sizing, which included a KOL mapping exercise indicating a nephrology audience of about 3,700, which would result in a sales force of approximately 40 sales representatives. We showed a video from the founder of the leading IgA Nephropathy Foundation as we had begun to establish relationships with key advocacy organizations and the IgA nephropathy community, and we discussed our research surrounding the patient journey. While a lot of things have certainly progressed, I would like to remind you of some key takeaways that still ring true today. IgA nephropathy has an estimated prevalence in the United States of 130,000 to 150,000, with up to 50% of these patients at risk of progressing to end-stage renal disease within 20 years. End-stage renal disease leads patients to dialysis and transplantation, both of which are extremely debilitating and costly. In market research and discussions with nephrologists and our audience, we have been using a product profile that contained the results of our phase IIb trial. Oftentimes in our industry, you need to pivot or adjust if and when you receive different clinical results in phase III than you had initially tested from prior trials. With the announcement of our consistent and encouraging phase III results, which you heard earlier from Richard, nephrologists continue to view Nefecon as the backbone treatment for IgA nephropathy. They tell us that Nefecon will be positioned as the first agent after or in conjunction with supportive care, which is ACEIs and ARBs. At the end of my presentation last year, we discussed how 2020 would be the year we would build a strong foundation for our launch, comprised of increased share of voice and medical affairs activities, enhanced relationships and involvement with the relevant patient advocacy groups, further developing key marketing initiatives, and a large focus on market access to ensure launching a product with appropriate access for all patients that are appropriate candidates. I'm very happy to stand in front of you, well, actually I'm sitting and I'm behind a monitor, and report to you that we remain on or ahead of plan and have accomplished all of that and more during what I think we can all agree was anything but a typical year. Let's briefly review the highlights from our progress over the last year, beginning with medical affairs and our educational outreach and communications. In 2020, we grew our team. We established and held meetings with a U.S.-based academic steering committee consisting of KOLs from many centers of excellence spread out geographically throughout the U.S. We executed on our publication plan with abstracts, posters, and presentations at all key nephrology meetings. The information and education provided included items that are specific to Nefecon, like phase III trial design and results of phase IIb clinical trials, as well as important information on why our drug, unlike other medications on the market and in development for IgA nephropathy, targets delivery to the ileum. During 2020, we had a strong presence at all relevant conference and congresses. We had to navigate through uncharted territory of virtual exhibit booths and spared no expense in developing a virtual presence that matched or exceeded many of the large pharma companies attempting to reach nephrologists. We initiated outreach with our growing team of MSLs that are establishing relationships and beginning educational efforts to key nephrologists. Most important, we provided our team the assets and information to effectively engage with their audience. This includes videos like this. We approached our audience on many platforms, including social media. We joined the social media conversation with regularly scheduled dissemination of key and relevant information to our audience. This certainly included providing educational value and building and growing our following in our community. While the U.S. has many restrictions on travel and face-to-face gathering these days, the IgA patient and advocacy community has grown, and Calliditas has taken the lead in supporting them. We were the lead sponsor of the first annual patient forum organized by the IgA Nephropathy Foundation of America. They needed to pivot from a live retreat to a 10-week virtual educational series. We presented at the kickoff session. We were also the driving force and sole sponsor of a nationally televised segment on IgA nephropathy. We introduced a television network to the talent they featured, which included Dr. Jonathan Barratt, whom you've heard from earlier, and the featured patient advocate that sits on the board of directors of the IgA Nephropathy Foundation of America. Have a look. The doctor at that time said that there was no treatment, there was no cure for IgA nephropathy. We just have to manage the symptoms. The doctor suggested a high dosage of prednisone as a way to try and manage progression of this disease. I had many of the side effects of prednisone. The weight gain, the irritability, the insomnia played a major factor in my life as far as not having the energy to go out on weekends or evenings with my wife or friends. Playing golf came to a screeching halt. This management of the disease had many side effects that were worse than could've been imagined before. A patient's care plan can include a healthy lifestyle and medication management. Immunosuppressives aim to reduce inflammatory response and turn off the production of the abnormal IgA. Non-immunosuppressives are used to lower blood pressure and reduce the amount of protein in the urine. None of these options, however, are enough to protect the kidney from future decline. Patients tell us that actually the side effects of taking these drugs can often be worse than the possibility of developing kidney failure. This means we have a significant unmet need in the treatments we can offer our patients. They want new therapies that are safe, that they can tolerate taking, and that we can show will protect their kidneys against future deterioration and stop them needing dialysis or a kidney transplant. We know in IgA nephropathy that actually the kidneys are an innocent bystander in this disease because they are having to deal with this abnormal IgA that is being delivered to them every minute of every hour of every day. 2020 also included the initiation and completion of some key marketing launch preparation milestones. Since last summer, we've expanded our team to include the award-winning creative agency, CDM. We have a dedicated team that has dozens of years of rare and orphan disease launch and marketing experience. We have developed, tested with market research, and finalized our product positioning. The consistency and strong results of the research further support our unique position for Nefecon, which was specifically designed for IgA nephropathy. We will begin market testing our unbranded campaign concepts and messages next week. This is just one of several concepts that will head into testing. We are on schedule to launch our multimedia campaign at the end of the first quarter of this year. We've explored and developed our brand identity and elements. This involves research and analysis to ensure we will stand out and provide the intended feeling and perception with our target audience. Over the last year, we have made great strides in our market access efforts. This includes the addition of Vice President of Market Access, Christopher Ngai. Christopher Ngai joined us at the beginning of 2020 after 20 years of market access experience working for both large pharma companies like Pfizer and Bayer, and most recently, a small startup biotech company. Chris' experience also includes him leading many rare and orphan disease launches. I am pleased to introduce you to Christopher Ngai to discuss and update you on our progress in market access. Thank you, Andrew Udell, for your introduction. Good morning. Good afternoon. In the next few minutes, I would like to share with you what we know about this market from a market access perspective, our accomplishments last year towards launch preparation, and highlight areas of focus in first half of this year to ensure launch readiness. What do we know? First, IgAN is not a disease that U.S. payers manage today. It lacks three key ingredients that payer looks for. One, IgAN is a rare autoimmune disease. The patient population is typical of a rare disease, and yearly diagnosed incidence in the U.S. is less than 5,000, estimated based on literature. Two, kidney function deteriorates over time. Few newly diagnosed IgAN patient progress rapidly. Three, standard of care today are mostly available as generics. When we asked our payers what are the unmet needs for this disease, they gave a consistent answer. Given the disease burden, impact on quality of life, and significant spending when patients enter end-stage renal disease, it should not be a surprise to anyone that they point to delay to ESRD as an unmet need. Being a targeted therapy is also a highlighted unmet need. There is also a shared view among payers and prescribers on the value drivers for new therapy. Naturally, payers weight mechanism of action and AE rates slightly lower than prescribers. On clinical endpoints, both rated eGFR stabilization being more important than the reduction in proteinuria. Lastly, there is a willingness to pay in this disease, not just because this is a rare disease without an approved treatment. The government, our Medicare, provides care for end-stage renal disease patients. However, employers and private insurance companies are also responsible for the first two and a half years, let alone the care they provide to patients pre-dialysis or transplant. In summary, there is an opportunity for Nefecon to achieve optimal pricing and reimbursement when approved as the first and only targeted product to treat IgAN. The critical success factors are to demonstrate and communicate our value proposition, develop a robust access strategy, and flawless execution. What did we accomplish in 2020 towards that? We conducted a systematic review of literature on epidemiology and burden of illness, focusing on the U.S., so that they can be shared as evidence with our access stakeholders. We engaged a leading agency in market access and payer communication to build out a platform that will support our future engagement with payers and customers. We engaged a leading market access consultancy to research and design a distribution network and patient support services model for Calliditas and Nefecon. The supply and distribution network for pharmaceuticals in the U.S. is a complicated ecosystem. There are many players. Everyone has a financial interest, many agreements, many contracts. Our objective for engaging ZS Associates is to simplify and customize this model for Calliditas and Nefecon to achieve operational efficiency. We looked at analogs based on product characteristics, developed hypothesis, consulted with stakeholders, and leveraged ZS industry know-how. We believe a limited exclusive distribution network is to our best interest. It will simplify our operations and likely improve our profitability while having the room to grow and expand in the future. We also established contract with CMS, a Centers for Medicare and Medicaid Services, so that we can participate in government-run health plans. We initiated application process to obtain necessary licenses from states that require them for us to conduct our business. What's next? Our milestones for the first half of 2021. We will bring on board our selected partners for third-party logistics and specialty pharmacy in Q1. Have account managers in place and trained to engage payers beginning late Q2, early Q3, depending on our PDUFA date. Complete quantitative pricing research and conduct payer advisory boards to inform our launch price decision. Back to you, Andrew Udell. Thanks, Christopher Ngai. In addition to all of the progress we've reviewed commercially, we have kicked off our in-depth analytics to support a sales force that we are preparing and planning to have in action beginning in the fourth quarter of 2021. We have engaged with top consultants, advisors, and vendors to ensure we will have the optimal sales structure and strategy in place for launch. This all begins with in-depth analytics and includes items like segmentation of both patients and physicians, territory alignments, and incentive compensation plans. We are in the process of meeting with several experienced and highly qualified candidates to head the U.S. sales and look forward to onboarding this individual later this quarter. 2020 also included some important operational and support progress that are also key to success. We opened an office in New York City. Despite 2020's pandemic making it a fairly lonely place, we have already outgrown the space and are in the process of looking for a larger space. We grew the size of our team. This does not only include the commercial team. We added experienced leaders in key functional areas, like our group general counsel, Jonathan Schur, and the consulting services of former Allergan Global Commercial chief information officer, Patrick Ratliff, who has developed and is executing on the IT blueprints and rollout plans as seen on the lower right-hand side of the screen. We have well-designed plans by functional experts that we continue to execute on in a cost-effective and efficient manner. We are very confident that with the right tools, plans, and personnel, we established building blocks designed for a timely and successful U.S. commercialization in 2021. We look forward to a bright future launching and building the brand and Calliditas in the U.S. Thank you. Good morning, good afternoon. My name is Philippe Bielz. I'm a medical advisor at Calliditas. I will provide an overview about the biology of NOX enzymes and about setanaxib, the first-in-class NOX inhibitor, which is currently in development in several fibrotic indications. NOX enzymes include a family of seven enzymes, which all produce reactive oxygen species, or ROS. This is their unique sole function. NOX enzymes are the only enzymes fully dedicated to the production of reactive oxygen species. NOX enzymes are typically induced in situations of cellular stress and injury. NOX enzymes include a family of seven enzymes, which all produce reactive oxygen species, or ROS. This is their sole and unique function. NOX enzymes are the only enzymes and unique function. NOX enzymes are the only enzymes fully dedicated to the production of ROS. NOX enzymes are typically induced in situations of cellular stress and injury. If we think about liver disease, this can be caused by viral infections, alcohol exposure, steatosis, or the accumulation of bile acids in primary biliary cholangitis, which we will review in a moment. ROS produced by NOX enzymes can cause cellular damage. This is a concept known as oxidative stress. They can also modulate signaling pathways. NOX enzymes producing ROS can oxidize target proteins, which can be ligands, receptors, kinase, phosphatase, transcription factors, and through that process, NOX enzymes can modulate signaling at multiple steps in the signaling cascade. Over the last decade, there has been tremendous progress, and now we understand better the role of each of these seven NOX isoforms. For instance, we now know that NOX1 plays a key role in the activation of inflammation through NF-κB and other pathways, but it is also important in pain processing and in angiogenesis. NOX4 is essential for fibrogenesis and wound healing. It mediates multiple fibrogenic pathways, in particular TGF-β, which is a master controller of fibrogenesis. We took advantage of these selectivities and developed a selective NOX1/4 inhibitor, setanaxib, as the first-in-class NOX inhibitor. Setanaxib targets NOX1/4 and therefore has potent anti-inflammatory and anti-fibrotic properties. There's an important medical need for safe and effective anti-fibrotic therapies. Fibrosis has a major impact on human health, but no anti-fibrotic therapy has been approved to date. Fibrosis is a key driver of many liver diseases, in particular non-alcoholic steatohepatitis or NASH, but also viral, alcoholic, or cholestatic liver disease. Fibrosis is a major contributor to lung disease with, for instance, idiopathic pulmonary fibrosis or IPF, and to kidney disorders such as chronic kidney disease or diabetic kidney disease. Here we show that the key event in the progression of fibrotic disorders is the activation of quiescent fibroblasts into myofibroblasts. These myofibroblasts produce the fibrotic scar tissue, in particular collagen, which is the main component of scar tissue. Therefore, the objective for anti-fibrotic compounds is to prevent the activation of myofibroblasts, to deactivate them, and ideally to clear them by making them sensitive to apoptotic cell death. The challenge has been that, as shown here, multiple redundant pathways drive myofibroblast activation, and therefore targeting one pathway is not sufficient. This may explain some of the recent failures in the development of anti-fibrotic therapies. What is exciting about NOX enzymes is that they can coordinate multiple fibrotic pathways which can now be blocked with setanaxib. With this broad anti-fibrotic mechanism, setanaxib was able to effectively target myofibroblasts and induce potent anti-fibrotic effects in multiple animal models. In this mouse model of NASH, setanaxib reduced inflammation, as shown here by the reduction in MCP-1, a chemokine, and reduced transaminase levels, ALT, and deactivated myofibroblasts. The result was a marked reduction in fibrosis, as shown by the reduction in collagen staining. What is remarkable is that steatosis was still present, and despite this, setanaxib was able to markedly reduce inflammation and fibrosis. Turning to lung fibrosis, the bleomycin model is the gold standard to assess the efficacy of anti-fibrotic compounds in interstitial lung disease. In this model, bleomycin causes maximal fibrosis three weeks after instillation in the lungs. When we monitor these mice over several months, we see that in young mice, those generally used in these models, there is spontaneous regression of fibrosis. However, in patients with IPF who are elderly, lung fibrosis is fixed, and it is irreversible. We see here that in contrast to young mice, aged mice lose their regenerative capacity. Remarkably, in these aged mice with fixed fibrosis, setanaxib, even started when fibrosis was at its peak, was able to reverse fibrosis and improve survival in these mice. We conducted a global phase II clinical trial of setanaxib in 111 patients with primary biliary cholangitis or PBC. PBC is an autoimmune orphan disease which leads to cholestatic liver injury. PBC progresses to cirrhosis and end-stage liver disease. Recent results in a long-term longitudinal cohort have shown that the presence of advanced fibrosis predicts poor transplant-free survival, even in patients who achieve a biochemical response. In addition, fatigue is the most common symptom in PBC patients and is not improved by current therapies. This was a 24-week phase II trial in patients who did not respond adequately to UDCA, the current first-line therapy. After 24 weeks of treatment, we assessed the effect of setanaxib on liver function tests, on non-invasive markers of fibrosis, and on quality of life, including fatigue and itching. As we see here, setanaxib was able to reduce plasma levels of alkaline phosphatase, ALP, in a dose and time-dependent manner. ALP is a marker of cholestatic liver injury and the main component of the registration endpoint in PBC. However, because the presence of advanced fibrosis predicts transplant-free survival even in patients who achieve reductions in the ALP, we had pre-specified that we would evaluate the anti-fibrotic effect of setanaxib in patients with advanced liver disease in this trial. In order to assess fibrosis, we used non-invasive methods, including the assessment of liver stiffness using FibroScan and circulating collagen fragments which reflect turnover in the fibrotic liver. As shown here, patients with elevated liver stiffness at baseline, setanaxib achieved a reduction of 21% in liver stiffness when dosed at 800 mg per day, compared to a 4% increase in the placebo group. This corresponds to placebo-adjusted difference of about 3 kPa, which has been shown in multiple clinical studies to represent a clinically meaningful effect. Setanaxib also achieved a statistically significant improvement in fatigue. Here we're looking at the percent change in fatigue from baseline to week 24. At the 800 mg dose, setanaxib had potent effect on fatigue and on the emotional and social domains, which are typically modulated by fatigue. Importantly, setanaxib was safe and well-tolerated at all doses tested. As we can see here, setanaxib had an adverse event profile indistinguishable from that of placebo. The only difference was a reduction in the number of infection-related adverse events, which was lower in the two setanaxib groups. In summary, these results provide a clinical proof of concept for a new therapeutic class, NOX inhibitors, and shows that setanaxib can provide important therapeutic benefits in PBC and potentially additional inflammatory fibrotic disorders. Thank you. Good afternoon, everybody. It's a pleasure to be speaking with you today. My name's Gareth Thomas. I'm Professor of Experimental Pathology at the University of Southampton. Today I'm going to tell you about some of the work we've been doing with setanaxib, and how we think we can use this drug to improve response to immunotherapy. Cancers are composed of lots of different cell types beside the tumor cells. These other cell types can have a profound effect on the way that these cancers behave clinically. For example, my laboratory is interested in cancer-associated fibroblasts. We're interested in these cells because they cause cancers to behave aggressively. On this slide, I'm showing you some data from patients with head and neck cancer. In these patients, we've taken some samples from the patient's tumor, and we've stained them for a molecule called SMA, which is a marker of cancer-associated fibroblasts. The SMA staining is shown in brown, and then we've stratified these patients according to whether their tumors have low levels or moderate/high levels of these cells. You can see from the capitalized survival curve that tumors with moderate or high levels are associated with much poorer survival. Now conversely, patients who have high levels of lymphocytes, immune cells in their tumors, their survival is much better, and this implies really that the patient's immune system is recognizing the cancer as something foreign and trying to clear it in the same way that it would recognize, for example, a virally infected cell in the body. The presence of these immune cells, these T cells within the tumor, really that underpins this whole concept of immunotherapy that's caused such interest in cancer research over the last 10 years or so. Really, the immunotherapy has caused the greatest step forward, really, in cancer therapy since the mid-1970s, and immunotherapy has been shown now to be effective in most tumor types. Still, only a small proportion of patients are responding, usually about 15%-20% in the patient population for any given tumor. The focus of immunotherapy really has been on anti-PD-1 or anti-PD-L1 checkpoint inhibitors. These inhibitors are predicated upon boosting a preexisting immune response to the tumor. We can see this preexisting immune response as these T cells which sit within a tumor. Clearly, they're not working effectively because the tumor is still present even though the T cells can see the tumor cells. These drugs are designed to switch back on the immune response so that the tumors can be cleared by the immune system. As I've said, only about 20% of patients respond to this sort of therapy, which begs the question, why don't most patients respond to this type of treatment? That's one of the research questions which has been the focus of my lab. Really, if we can understand some of the mechanisms by which tumors escape immune recognition, then maybe we could target those and get immunotherapy to work more effectively in these patients. We're particularly interested in cancer-associated fibroblasts, or CAFs, because they're associated with poor survival in most tumor types. We've looked across survival in multiple types of cancers. Here, I've shown you examples of head and neck, esophageal, and colorectal cancer. For patients where these sort of cells accumulate in the tumors, their survival is generally very poor. Most solid cancers have a subgroup within them that have high levels of CAFs. For example, around 50% of patients with head and neck cancer have tumors with high or moderate levels of CAFs. It's higher in tumors such as pancreatic or colorectal or esophageal cancer. A very high proportion of the cancer patient population has tumors with this sort of phenotype. Because these cancers behave aggressively, one of the sort of questions, again, which has shaped our research is, well, what are CAFs doing to make tumor cells behave so aggressively? CAFs do lots of things. They cause tumors to metastasize, for example, and spread around the body. We've become increasingly interested in what these cells do immunologically because we were finding some very interesting inverse correlations between the presence of CAFs and the presence of CD8 T cells, which are essentially the soldiers of the immune system and responsible for cell killing. That may be a cell infected with a virus, but it could also be a tumor cell. In patients with tumors with lots of CAFs, they generally have very low levels of CD8 T cells. What is a cancer-associated fibroblast? It's a cell that's a lot like a myofibroblast, which is an activated fibroblast found in a healing wound situation. These cells upregulate expression of SMA. They become contractile. That's important to contract a wound. They also secrete the extracellular matrix, the scar tissue, which enables a wound to heal. In a healing wound situation, these cells are very tightly regulated, but they can be dysregulated, in which case this can lead to things like organ fibrosis, and they can accumulate in subgroups of cancers as well. They're typically generated through TGF-β signaling. There's been a lot of interest in these cells in the last two or three years because it's increasingly recognized that these cells are an immunotherapy resistance mechanism. Analysis of human trials where they've tested anti-PD-1 or anti-PD-L1 to try and understand what the resistance mechanisms are in patients that don't respond. They're pulling out CAF gene signatures in non-responsive tumors, suggesting that CAFs are quite an important resistant mechanism across different cancer types. We were really interested in trying to find out what these cells were doing in terms of immunotherapy resistance, what the mechanism underpinning this could be. We started using different mouse models, which are standard models of immunotherapy in a mouse setting. We were looking at TC-1 tumors. These are our lung cancer model. In this model, which expresses E6 and E7 human papillomavirus antigens, we can vaccinate mice that have these tumors against these antigens, and the mice will mount an immune response against the tumors and clear the tumor. MC38 is a model of anti-PD-1 therapy. Similarly, we can grow tumors in mice, we can treat them with anti-PD-1, and the mice will clear the tumors. 4T1 is a breast cancer model. When we first started looking at these models, bearing in mind that we were interested in looking at CAFs within these models, we stained these models with SMA, which is our standard CAF marker. We found that really these models had very low levels of CAFs, so they weren't suitable in their current form for studying the biological roles of CAFs in resistance to treatment. Certainly, you can compare levels of SMA in the mouse tumors, which is shown in the top panel, with human equivalents, and you can see that they look quite different. We started co-injecting tumor cells with cancer-associated fibroblasts. Again, these lower panels are showing staining for smooth muscle actin. You can see that when we co-inject the CAFs with the tumor cells, then we're producing a tumor stroma which is much more reminiscent of what we see in human disease. We started then looking at these models of whether CAFs can affect the response to immunotherapy. Firstly, we looked in the MC38 model. This is our anti-PD-1 model. We looked at control CAF low tumors, and we compared them against tumors which had high levels of CAFs within them. If you look at the growth curve on the right, you can see that blue shows a response to anti-PD-1 in control tumors which have low levels of CAFs. When CAFs are present, which is shown by the orange line, then this response to anti-PD-1 treatment is lost. You can see the individual growth curves from the individual mice, which are shown on the right. Similarly, our vaccine modeling produced similar results. In the TC-1 model, again, we're comparing control CAF low tumors with CAF high tumors. You can see the response to vaccine in our CAF low tumors, which is shown by the red line. Mice are responding very well. Tumors start to grow, the vaccine kicks in, the tumor is clear. When CAFs are present, which is shown by the blue line, this response to vaccination is lost. We can look more closely at the effect on tumors, what it's doing to the immune system, we were doing this in a number of different ways. We were looking at pathology analysis of tumors, we were looking at flow cytometry analysis. You can see here, I'm showing you data from both TC-1 and MC38 tumor models, they both show me exactly the same thing. The growth curves show that when CAFs are present, the tumors grow much larger and much quicker. We confirm the presence of CAFs by doing this SMA stain for our CAF marker, shown by this brown staining. Then we started looking at different immune cell populations. To summarize, what we found is that CAFs exclude CD8 T cells from tumors. When CAFs are present, CD8 T cells seem to get stuck around the edge of the tumor, and they can't penetrate into the tumor to kill the tumor cells. Conversely, when we look in the center of CAF-rich tumors, there are very few CD8 cells present. This is very interesting. The data from human and from neuro tumors rather, suggestion that CAFs are a major resistant mechanism to immunotherapy. Which begs the question: how can we actually target these cells in that case? Over the years, there have been various clinical attempts which have been unsuccessful. These are the sort of different concepts you could consider if you want to target a CAF. Maybe you could block CAF activation, stop them being activated in the first place. This would probably be a bit too late by the time a tumor's already developed. Maybe you could block CAF function. If you could understand how they were excluding the CD8 cells, maybe you could inhibit that mechanism. Maybe you could simply just kill off the CAF population in the tumor if you had some sort of CAF-specific marker. But an attractive concept is to normalize CAF. To take a CAF and turn it back into a normal fibroblast because a number of studies have shown that actually normal fibroblasts are tumor suppressive. They actually do something beneficial within tumors to stop them progressing. We started looking at, five or six years ago, at really what regulates CAF differentiation. We did this initially by doing some simple in vitro experiments in the lab. We took some fibroblasts, we put some TGF-β on them to activate them. When we do that, they start expressing SMA, which is shown by the green staining in this immunofluorescence figure. Then we did some RNA sequencing. We looked at what genes were being upregulated during this differentiation process as a normal fibroblast becomes an activated CAF. We identified NOX4, the enzyme which is producing intracellular reactive oxygen species. We found that this differentiation process as a fibroblast turns into an activated CAF was associated with two waves of reactive oxygen species being produced. You treat a cell with TGF-β, there's an initial wave after about the first hour, but then there's a much longer and larger second wave over about 24-48 hours. It's this second wave which is critical to CAF activation, and it's this second wave which is being regulated by NOX4. We did all these experiments in the lab, we then went to look at human tissues to see if we could find this same association of NOX4 with CAF activation, and we could do this. I'm showing you in this correlation network analysis. This is analysis of patients with head and neck cancer. Because this is a correlation analysis, the closer these genes sit together, the more tightly correlated they are. We found a very tight correlation between NOX4 and our CAF marker SMA, and this was true across lots of different cancers that we looked at, not just head and neck. We looked in breast, pancreas, colorectal, et cetera, and lung. We also found that the genes associated with CAF activation really were very closely linked to those genes which correlated tightly with NOX4. We started culturing CAFs from human patients and from murine tumors. We found that CAFs that are cultured, they are still producing high levels of intracellular reactive oxygen species and still have high levels of NOX4. Even they've already differentiated, it still seems that NOX4 and reactive oxygen species are required to maintain this activated CAF differentiation in culture. We started working with Genkyotex, again, around about six years ago because they had a drug which could target NOX4. This was the most advanced drug in the market, setanaxib as it's known now, GKT as we've termed it throughout our experimental work. The data from CAFs suggests that maybe if NOX4 was still required in culture to maintain the CAF phenotype, that if we could target the enzyme, maybe we could switch a cancer-associated fibroblast back into a normal fibroblast. That's indeed what we could show. Again, this top panel is showing immunofluorescence for SMA in green. The lower panel is showing immunofluorescence for SMA in red. The top panel are human CAFs, the lower panel are mouse CAFs. You can see that in culture, these CAFs have high levels of SMA arranged in these sort of stress fiber formation, but when we treat those fibroblasts or those CAFs with GKT, they reverse back to a normal fibroblast phenotype. They downregulate expression of SMA, they lose their contractility, they stop expressing these extracellular matrix genes. We performed some mouse experiments, and we could do exactly the same thing in vivo. Again, I'm showing you some data here from TC-1 tumors where we've treated mice bearing CAF-rich tumors with GKT. We lose this SMA-positive stroma, and that's because the CAFs have disappeared. They've reverted back to a normal fibroblast phenotype. We overcome this exclusion effect from CD8 cells, so the CD8 cells are no longer stuck around the edge of the tumor. They actually penetrate into the tumors. As you'd expect, even just treating mice with GKT causes a significant reduction in tumor growth when you use it as a monotherapy. Because you can be criticized when you're using a drug that you may be having off-target effects on other pathways, we repeated these experiments knocking out NOX4 gene in cancer-associated fibroblasts, and we produced exactly the same results. You can see that where we've knocked down the gene using shRNA, we've lost this SMA-positive stroma. We've lost the CD8 exclusion effect. The CD8 cells now sit within the tumor, and the tumors grow much smaller. Our final question is really, could you start combining GKT with immunotherapy to overcome CAF-mediated immunotherapy resistance? Firstly, we looked at our Anti-PD-1 MC38 model, and in this experiment, there are four arms to the experiment. All the mice are bearing CAF-rich tumors, and we're looking at mice treated just with control, with monotherapy for Anti-PD-1, GKT by itself, or the combination. In this first experiment shown in the top panel, we've stopped the experiment at day 21, so we could look more at the immune response in some detail. You can see even at this point, although both monotherapies have produced significantly smaller tumor growth, when you actually combine GKT with Anti-PD-1, the tumor growth is significantly smaller. As you would hope, when you look at CD8 staining for tumors from mice treated with a combination of drugs, they have far higher levels of CD8 cells within the tumor. We then performed a longer experiment, which is shown in the lower panel. You can see that mice treated with Anti-PD-1 have poor survival in these CAF-rich tumor models. When you combine GKT with Anti-PD-1, the survival is significantly improved, and this CAF-mediated immunotherapy resistance has been overcome. Similarly, we did the same sort of experiments in our TC-1 vaccine model. Again, this top panel shows an experiment which has been stopped at day 24 to look at the immune response. Similarly, all of these mice are bearing CAF-rich tumors. They've been treated with vehicle alone, vaccine alone, GKT alone, or GKT combination. You can see that mice receiving the combination have significantly smaller tumors, and that the mice receiving the combination have these tumors which are really rich in CD8 T cells. We did some longer survival experiments. Now, in this first experiment, we stopped treating the mice with GKT at day 30. It's really interesting because you can see that the mice receiving the combination were responding really well up to this point. After cessation of the drug, they relapsed pretty quickly. Even having said that, the survival was still significantly improved in these mice. We thought we could improve it further by modulating the way that we were giving GKT and perhaps by altering the vaccine dosage as well. In this experiment, again, all of these mice are bearing CAF-rich tumors. We've repeated the experiment using the same conditions as in that previous experiment where we stopped GKT at day 30. When we've done that, we're getting the relapse that we observed in the first experiment. When we extended GKT treatment out to day 70, we had significantly fewer relapses, and then we tried also extended GKT treatment with a second dose of vaccine at day 30, and we did that, and we completely cured the mice of cancers. Again, in this separate immunotherapy model, we show how GKT can be really used effectively to overcome this CAF-mediated immune resistance and to promote response in this CAF-rich type of tumor. Just to summarize, CAFs tumors, they're aggressive, they're treatment-resistant, not just to immunotherapy, but to other types of therapy, again, which I haven't had time to talk about today. They form a significant subgroup of most solid cancers. They promote tumor progression in multiple different ways. They can promote metastasis, they can promote treatment resistance. One of the primary functions I think is that they do have a profound effect on the tumor immune microenvironment. They exclude CD8 cells from tumors, and in doing so, they promote immunotherapy resistance. Clearly they promote it to anti-PD-1, but they would promote similar resistance to any form of immunotherapy that depends on CD8 T cells being able to get into tumors. We've shown that NOX4 is really a critical enzyme in regulating this CAF phenotype. It's needed not just for differentiation, but also to maintain the phenotype both in vitro and in vivo. We can reverse that by targeting this through setanaxib. We were really excited about these findings, and we're really looking forward into translating this into clinical testing. Thank you very much for your attention, and if you have any questions, I'd be delighted to take them. Few minutes to discuss our ongoing and planned clinical activities. I'll start with the ongoing phase III clinical trial of Nefecon, the NefIgArd study. We expect that study to complete full enrollment of the 360 patients by early in this quarter, the first quarter of 2021, and we therefore expect to complete two years of follow-up in the study cohort by the first quarter of 2020. Moving on to our plans with setanaxib. Firstly, in primary biliary cholangitis, we have a pivotal phase IIb/III clinical trial in early PBC. This clinical trial will be subject to discussion and comments from the FDA, but at present, we anticipate that this will be a double-blind, randomized, placebo-controlled adaptive design. There will be a dose response component in the phase IIb part of the trial. Patients will be enrolled and randomized to one of two doses of setanaxib versus placebo. There will be a futility analysis, and then one of the active doses will be taken forwards into the phase III component of the clinical trial. We anticipate that approximately 300 patients in total will be enrolled into the study. We plan to start the study in the second half of this year, with the futility analysis likely taking place in the first half of 2020, with the full readout of the clinical trial expected at the end of 2021 or in early 2025. In terms of the oncology program, again, this currently is a study in the design phase, so it is subject to finalization of the design and subsequent finalization of the clinical trial protocol. This will be a proof of concept study in head and neck cancer, where we will explore the efficacy and safety of setanaxib when given with an immuno-oncology agent. This will be a trial likely to be in approximately 30 to 40 patients. We will start this trial in the second half of this year. We expect to get data from the trial in 2020. With respect to the kidney program with setanaxib, we have some preclinical in vivo animal model work planned for this year to assist in exploring a variety of potential kidney indications. As I say, that work will start this year in terms of the preclinical in vivo effort. We have a couple of clinical trials which are investigator-sponsored. Firstly, we have a clinical trial of setanaxib in interstitial pulmonary fibrosis. This is an NIH-funded study being conducted in the U.S. It's a double-blind, randomized, placebo-controlled study. It has a biomarker primary endpoint and will enroll 60 patients for a 24-week treatment period. That study started in the third quarter of 2020. The second investigator-sponsored study is in type one diabetes. This is a Juvenile Diabetes Research Foundation-funded study conducted in Australia and New Zealand. It's a double-blind, randomized, placebo-controlled study with uACR as the primary endpoint at week 48 in the treatment period. There'll be approximately 100 patients with type one diabetes and established proteinuria enrolled into that trial, which is currently ongoing. Coming back to Nefecon, we have an open label extension study ongoing. This is a single arm open label trial for patients who participated in the pivotal NefIgArd trial. In this trial, in the open label extension trial, all patients receive active treatment, that is 16 mg of Nefecon daily for nine months. The inclusion criteria are essentially the same as for the pivotal study. We anticipate that approximately 250 patients will come into this open label extension. Enrollment started at the end of 2020, in the fourth quarter of 2020, therefore should be complete in the first quarter of 2021. Finally, I will mention the NefExtend study. Again, this is an open label single arm study, which will enroll patients who have a baseline proteinuria of 2 g per 24 hours. In this study, patients will receive Nefecon 16 mg once daily for nine months. They can then go on to receive a further nine months of treatment based on the investigator's judgment, taking into account the clinical and the renal outcomes in the patient at nine months. The patient could continue on the 16 mg dose level or could continue on a lower dose level of Nefecon. That study is scheduled to start in the second half of 2021 and should therefore complete in 2021. That therefore completes my summary of the clinical activities that are planned or ongoing for Nefecon and for setanaxib. Welcome. Thank you. Yes, thank you. Welcome to the last segment of this. Obviously, there's been a fairly heavy science component in this segment, but I hope you enjoyed it and found it interesting. I'm going to talk very briefly now before we have the final Q&A session about how we actually look at the positioning, both in IgA nephropathy as well as in PBC on a kind of high level. With regards to Nefecon positioning in IgA, you've heard today, obviously, a lot of information with regards to what the data that we have is, how we see that being positioned. I think one of the things that's obviously also, it's clear from a lot of the questions, is that it's quite surprising actually, that in this indication, there is very little data actually, considering how long this indication has been known. That really leaves us with a lot of thesis and assumptions which yet have to be proven in order for us to kind of address some of the questions that have been raised here today. With regards to Nefecon, obviously we do have, this is one of the few compounds really where there is a lot of data. We have had positive data both in, as I mentioned, in phase IIb as well as phase III. With regards to looking at 16 mg dose versus placebo, we actually have 300 patients dosed to date. As you've also seen, it's in a very broad patient population. What we've seen in terms of the data is this relevant reduction of proteinuria, so 31% versus baseline at nine months. As we've mentioned, there is this significant continued reduction at 12 months. There is also then, Professor Barratt has taken you through some of the analytical frameworks that then would reflect this kind of significant impact in terms of delay, in terms of years to ESKD or doubling of serum creatinine. We've also, obviously, in terms of positioning, looked at the stabilization of eGFR. Again, obviously at nine months of treatment, we've seen them both in the phase IIb as well in the phase III. Again, to be clear, this is obviously kind of the actual treatment goal. We do want to get to a point where we can see no further deterioration. Proteinuria is obviously a symptom. This is obviously where we all want to get to. Again, there are some analytical frameworks I'm going to mention very briefly that looks at that probability in terms of clinical relevance at two years. We have a very robust and consistent data set. I think it's important, again, hopefully that's come across again, that yes, we are talking about a substance within a certain class. It is incredibly differentiated, and it has a completely different mode of action, which also then leads to a very different kind of efficacy and safety profile of that compound in this particular disease. Obviously this is budesonide within the corticosteroid family. On the base of the data, we're positioned to be the first approved drug in IgA nephropathy. We also obviously then have this opportunity to really do what's really important here, actually address this significant patient need. Actually there's been quite a lot of information released, actually in a white paper as well last year, there was an externally led patient-focused drug development event that was really organized by the FDA in 2019. That white paper was published last year. Again, just to remind us all about this is obviously what the whole point of this is, really to try and address this unmet medical need that patients have. We do think that with the actual profile that we have and the data that we have, that we really can be positioned as the backbone treatment in this patient category. As we've always mentioned, I think you've heard this also from the U.S. team, there's obviously a lot of work still to be done. A lot more detailed work, a lot more market research. Yes, there is obviously potential for enhanced pricing, et cetera, based on the phase III data. I would say that even on the market research we have to date, I think it really shows and lays out a very significant opportunity for Calliditas in this indication going forward. This really reflects the data that was previously explained and reviewed by Professor Barratt in his presentation. This relates to a trial-level analysis and the kind of predicted treatment effect on ESKD, doubling of serum creatinine, et cetera, from a reduction in proteinuria. These have all been published, this is when I refer to the fact that the surrogate endpoints, et cetera, and the regulatory commitment to this area has obviously then also been published in Clinical Journal of the American Society of Nephrology, Kidney Health Initiative, and actually, Aliza Thompson, who was actually from the FDA, is actually one of the lead authors on that paper. If you look at this, what we're trying to do here is really obviously to say the reduction in this hazard ratio that Professor Barratt mentioned, it's based on the treatment effect that we can see will then result in this estimated delay in terms of disease progression. We can look at this and say, obviously, we've seen a significant effect at nine months. We saw a 31% reduction at baseline. We saw 27% treatment effect versus placebo, as we had a small placebo effect in the phase III. We've also mentioned too, obviously, there's a significant continued effect after treatment. As Dr. Richard Philipson reminded us all of, obviously, this is not containing all of the patients as the data cut was done at nine months. Obviously, there are patients who have reached 12 months, and it's on that basis that we have some trend base that we can look at. This is obviously something where in terms of a clinical effect, if we look just within this statistical framework, would give us a significant impact in terms of a potential delay of anywhere from 10-20 years, which is obviously highly significant. I believe that we do have a very robust data set from our phase IIb and our phase III, and I think that we're very well-positioned for regulatory interactions on that basis. However, at the end of the day, obviously, proteinuria, as I mentioned, is a surrogate. There is also taking into account the eGFR. Again, this is obviously important. We don't want to stare ourselves blind in one direction and risk therefore to not see the forest for all the trees. eGFR is obviously the underlying kidney function here. Again, as I mentioned, protecting the kidney is obviously the end purpose here and the treatment goal. Here is another publication from lead author Inker from the Journal of the American Society of Nephrology. This was really a study looking at, again, data sets in CKD, looking at eGFR and eGFR slope. In the CKD analysis, you can see that a difference in a one-year slope of 1.31 mL per minute per year, there is this very high probability that there will be a delay in the clinical endpoint. This is the same type of clinical endpoint that was mentioned in the prior slide. This is ESKD, doubling of serum creatinine, et cetera, and death. It's the same type of endpoint. You can see that obviously this is not immediately translatable from the nine-month data that we have. The difference that we've seen in absolute terms at nine months between Nefecon and placebo is obviously very significant. Again, we feel very good about the position that we have and the data package that we have to support our interactions with the regulators. Obviously, we will, as we go forward, also have additional data to support this as we go through Part B. Turning now to a little bit talk about the PBC. This is obviously a situation where we're a little bit earlier in that. Again, with setanaxib, we believe that we have a differentiated mode of action from the other drugs which are approved or in development for PBC. The safety profile that we've seen to date would indicate that there could be very possible combinations with standard of care and the drugs under development. What we've obviously seen is really significant impact on fatigue and also this anti-fibrotic activity and data that has shown impact not only on FibroScan measures but also on biomarkers. You've seen some of the preclinical data, et cetera, that's been presented to you here today by Professor Gareth Thomas. That also is a basis for that anti-fibrotic activity. As we've also just recently released, obviously, the phase I data, there is also possibility for higher dosing than what was used in the phase II. In terms of looking at setanaxib from a positioning perspective, we think that this could be a very interesting compound to use in PBC for the reason that it is slightly differently positioned. It really has its primary impact on inflammation, autoimmunity, and fibrosis. It has, as far as we believe, is the only compound that's really seen this very significant impact on fatigue, which is the most common symptom and a real issue for patients with PBC. I will start with a historical reminder of our operating expenses. As you know, the NefIgArd trial have been driving our R&D operating expenses for the last three years from when we started the trial in 2018 and up until the nine months numbers of 2020, which we're presenting in the graph here. It's been the clinical activities for the NefIgArd trial and also the CMC work for Nefecon to bring Nefecon up to a position where we'll be able to be ready for regulatory submission. Looking at our administration and selling expenses, we've seen an increase in 2019 and also for the nine months of 2020 compared to before. That is primarily because we have a ramp-up in our pre-commercial activities, which is natural, but also that we, in the third quarter of 2020, had a dual listing, and since we are small, those numbers shine through pretty dramatically in our numbers. Looking at the organizational geography. Our headquarter is based in Stockholm, Sweden, and here where most our resources are located. We have the clinic, we have the CMC, we have the quality, we have the regulatory, together with the corporate and the group admin. It's our primarily development hub, and we are, as we told you before, specialized in the orphan diseases, with focus on renal and hepatic. As a company striving to be cost-effective and agile, we have a small but quite effective and notable organization. We only try to bring in external parties where we need extra footwork and when it's cost-effective. I would say the organization is very effective. In 2018, we started to engage our first person in U.S., way three years ahead of a potential commercialization in U.S. 2019, we started a U.S. subsidiary. We have, since 2019, started to recruit experienced and skilled persons in pre-commercial and medical affairs functions. Being more than two years into this, we have established a very good team over there. We've been gaining a very good understanding of the U.S. market and the requirements needed for us to commercialize on the U.S. market. I think it's very beneficial for us to have had the teams so long that it's also been gaining a very good understanding of the European organization and how we work, which are bearing for a good cooperation forward-going. Just a few months back, we, as you know, acquired a vast majority in Genkyotex, adding the exciting platform of NOX and a new product candidate, setanaxib, to our pipeline. With Genkyotex, we added a small but skilled discovery organization specialized in the NOX platform, which we can contribute very greatly to the group. All in all, our FTE, as we communicated as the end of Q3 together with the Genkyotex addition, we were way above 45 FTEs at the time, and since then we have grown during the fourth quarter. The coming year is a very exciting and important year for us with a potential U.S. approval and a potential U.S. commercialization. Of course, much focus and resources will be directed to this, but we are well prepared, as Andrew Udell already described to you. We are investing quite heavily in the growth of the U.S. organization when the sales and marketing team and the medical affairs are the most prominent areas, with the U.S. sales force as the largest part when time is. We also invest in group wise in the supporting functions like IT, supply chain, and financial control, all to ensure that we can be on the market as soon as possible after a potential approval. We also plan to perform a number of new trials during next year, which you have heard when Richard talked about the pipeline. Both the supporting trials for the Nefecon and setanaxib trials. When you look at the pipeline chart as of today compared to before, it looks like we have a lot of new trials potentially ongoing. As Renée told you in the Q&A just minutes ago, we have had this in our plans for a long time, and especially the late-stage trial had been planned. All in all, it's needless to say that our organization is growing significantly over the next year, but we've been very successful so far to attract and retain experienced staff, both in U.S. and in Sweden. We are very confident that our plan is both executable and appropriate forward going. With increased activities in both the commercial side and the clinical side, cost control and financial experience is of great importance for us. We are always very mindful of how we're spending our cash, and we have a very well-drilled organization, and we have an excellent budget track record. As of September last year, end of September last year, we had a cash position of SEK 1.4 billion, which is equivalent to $168 million with the last Friday exchange rate. In the fourth quarter, besides the normal operating expenses, we paid EUR 27.8 million for the Genkyotex shares, equivalent to $34 million with the same exchange rate. We expect, as Renée said before, our cash position to last into the third quarter of 2022, and we expect us to be funded through the regulatory filing in U.S. and EU through a potential U.S. approval and through a potential commercial launch in early 2022 and in the U.S. We also expect to conclude a European commercial partnership within this time frame, and we believe that this can give us some upfront cash. We also assume that in this forecast, we assume that there will be some conservative sales estimates from early 2022. In this projection, we don't expect us to have any. Well, we doesn't count any debt or other structured financing, which may be available to a company like us that are closing into a potential approval and a potential commercial launch. All in all, I'm very pleased with our cash management to date and our cash position. With that, I leave over to you, Renée, for the concluding remarks. Thank you. I promise this is the last time you're going to have to hear from me today. I just want to have a very brief summary. I think, again, to kind of just sum things up, I think we've been hopefully what you've gotten out of this day that we have a strong and consistent data set in IgA nephropathy. We have a supporting biomarker data, and we have a clear differentiation and mode of action from anything out there today. We are very well-positioned to be really the first approved drug in this indication and where there's a significant market opportunity. Our submission process is on plan. Our U.S. planning and execution really is targeted at readiness for the earliest possible approval. We have a well-balanced pipeline between both Nefecon and setanaxib. We have very strong cultural strategic alignment, all kind of focused on continued success. In terms of milestones, I think if you go over and go back to what we've achieved, I think, again, we are truly very solutions-oriented and execution-driven. We have consistently delivered and created value to all stakeholders, and that is clearly our goal and what we intend to continue doing going forward in this year. Which as you can see, also has a really significant amount of activities that we intend to deliver which has been mentioned several times today. It was very exciting in terms of the filing process, the potential approval, and depending on the review timeline, even a potential launch in the U.S. this year. Most importantly then is how do we do this? What is really keeping all of this together is our strategy and our focus on execution. We are building a business that's focused on orphan and nephrology. It's really focused around that. It's an integrated business model. We have a very strong European-based R&D, CMC that's a center of excellence. We have a very experienced and effective U.S. commercial operation that we're just completing to build out. As an organization, we actually embrace cross-cultural differences. We know and understand and embrace all the integration challenges that this brings. We actually also have an enormous focus on communication. I think this is really driving towards that solutions orientation and execution that we have delivered to date. In terms of we have critical in-house expertise, we continue to build on that. It's a very experienced team that we have here. We are partnering really with best of breed in terms of the service providers that are necessary for us to really move forward as quickly as possible with the highest quality also in mind. We have a very cross-departmental structure. There is actually no silos. We are still small enough, agile enough, and effective enough to basically make sure that we really do challenge each other and bring out the best in each other, and therefore, hopefully arrive at the best solutions that we can. Again, we are truly driven around execution and those solutions and creativity. It is a creative approach. We have always an eye on the risk versus reward. We are highly aligned both with our particularly in the U.S. and Europe, which is not actually that easy to be for those of you who have run or been in international businesses. We are truly agile and ambitious. As you can see from our presentations as well, we are very budget-centric and cash-aware, which I think also serves us well in terms of creating that balance between really delivering execution and delivering value to all of our stakeholders. I hope that you found this session helpful and informative, and we look forward to spending another year with many of you. We will certainly continue to be focused on delivering value and consistently executing according to our plan. Thank you very much.