Good day, thank you for standing by. Welcome to the Cenerimod phase III initiation webcast. At this time, all participants are in listen-only mode. After the speaker's presentation, there will be the question and answer session. To ask a question during the session, you'll need to press star one one on your telephone keypad. You will then hear an automatic message advising your hand is raised. Please be advised that today's conference is being recorded. I would now like to hand the conference over to our first speaker today, Andrew Weiss. Please go ahead. Thank you, operator. Good afternoon, good morning to you all. My name is Andrew Weiss. I'm the head of Investor Relations and Corporate Communications here at Idorsia. I want to welcome everyone to our webcast to discuss the initiation of the phase III program investigating cenerimod for the treatment of systemic lupus erythematosus, which we announced this morning. With me on the call here in Allschwil are our Chief Scientific Officer, Martine Clozel, and Alberto Gimona, our Head of Global Clinical Development. Next slide, please. As customary to these calls, we will be making forward-looking statements. You have therefore been appropriately warned about the risks and opportunities of investing in Idorsia shares. With that said, I hand over to Martine for prepared remarks. Next slide. Good morning, good afternoon. I'm happy to start this presentation about cenerimod by reminding you of why we are so excited by its potential in the treatment of SLE. Our research on S1P1 receptor modulator started more than 25 years ago, before S1P1 was even called S1P1. It fitted our interest in GPCR research and in the role of endothelium in pathology. Our research team was the first to discover and publish that selective S1P1 receptor modulators were going to be a very effective and safe approach for blocking the aggression of lymphocytes, T and B lymphocytes, from the lymph nodes to the circulation. Next slide. Cenerimod is the next generation product of this research, where we created an S1P1 receptor modulator, which would not only be highly selective, but also devoid of the side effects of vasoconstriction and bronchoconstriction associated with all previous non-selective or selective S1P receptor modulator. We now understand that cenerimod was devoid of this side effect because it has a unique intracellular endothelial signaling with around the 500-fold reduced intracellular calcium increase, probably explaining its very good profile. We are developing cenerimod for the treatment of SLE, not only because there is still a major medical need, particularly for better overall drugs, but also because we understand more and more how well the mechanism of cenerimod fits the pathophysiology of SLE. Next slide. Let's look at SLE in more detail. Next slide, please. SLE is an autoimmune disease which causes multi-organ inflammation. There are, of course, the frequent skin rashes and the facial erythema, which gives its name to the disease, but many more organs are affected, giving symptoms which affect the daily quality of life, including fatigue, alopecia, and touching organs affecting life expectancy, including the kidney. Next slide. I'm now at slide seven. It is considered that around 5 million patients in the world are affected by SLE, the large majority of whom are young females with a much higher frequency and higher severity in people of Afro-Caribbean and Asian origin compared to Caucasian. Next slide. Lupus is a systemic disease where basically all components of the immune system, the adaptive and the innate, contribute to autoimmunity against nucleic acid and nucleic acid-containing cellular elements. Genetic factors and probably other susceptibility elements make some people more likely to develop lupus than others. Upon a trigger, for example, a viral infection, an autoimmune mechanism begins a loss of tolerance. The adaptive immune system gets activated, and there is T-cell activation, T-cell infiltration into tissues, and production of interferon gamma and other cytokines. The T cell activation is followed by B cell activation, especially autoantigen-specific B cells, leading to autoantibody production and formation of immune complexes, which will start consuming the complement factors in the circulation. The autoantigens are transported by dendritic cells into lymph nodes, thus causing more lymphocyte activation. The innate immune system also becomes activated, stimulating production of type I interferon, which in turn stimulates endothelial cells, in particular, to produce chemokines and cytokines like interleukin-6 and TNF alpha, causing vascular and systemic inflammation. These multiple pathogenic pathways together create a vicious circle. Mortality in SLE remains about twofold higher than the general population, and renal and cardiovascular complications are the main reason. This is also why we wanted to have a very safe molecule, in particular regarding cardiovascular safety. Next slide. Now let's look at the compound we have created and the remarkable fit between its properties and SLE. Next slide, please. As an S1P1 receptor modulator, cenerimod inhibits the aggression of T and B lymphocytes from lymph nodes, preventing their migration and their infiltration into the different organs. Next slide. We now understand that cenerimod not only decreases the trafficking of T and B lymphocytes and the consequent production of pathogenic autoantibodies, but it also acts on the other key aspects of SLE. Indeed, cenerimod inhibits the transport of autoantigen by the dendritic cells to the lymph nodes, and cenerimod also inhibits the interferon-driven immunological responses, and therefore decreases inflammation. As a result, cenerimod will interrupt the vicious circle of SLE pathogenesis. Next slide. The potential of cenerimod to improve the different facets of lupus were evidenced by a study in a mouse model of SLE called MRL/lpr. In this model, many features of the human SLE disease are represented: T cell infiltration, inflammation, autoantibody production, progressive deterioration of kidney function, and decreased survival. Next slide. In this model, cenerimod reduced T cell infiltration and markedly reduced plasma levels of anti-double stranded DNA antibodies and of several biomarkers of inflammation. Next slide. As a consequence, after 11 weeks of treatment, cenerimod improved renal histopathology and markedly decreased proteinuria. Next slide. Ultimately, it improved survival. Next slide. In conclusion, as you can see, cenerimod is effective on multiple aspects of lupus pathogenesis. It is unique in SLE in tackling T cells, B cells, autoantigen transport, and the interferon related inflammation. As you know, interferon related inflammation is by itself a validated therapeutic approach in lupus. cenerimod does not cause a strong immunosuppression. In particular, it did not cause an increased risk in susceptibility to infection in preclinical models, nor, as you will hear, in our clinical experience so far. I'm happy to give the floor to Alberto Gimona, who will tell you how excited we are that cenerimod 4 mgs is now entering the phase III confirmatory program in patients with SLE. Next slide please. Thank you, Martine. Hello, everybody. I'm really happy and proud to be here to introduce to you to the Phase III OPUS program, in which we have already screened the first subject just a few day after opening the first centers in the United States. I would like you to follow me on a journey that has brought Idorsia from the phase I to where we stand today. I will discuss particularly CARE and how this study has told us how to perform and how to ameliorate the design of the phase III program. Next slide 18. In phase I... From phase I, we have selected four doses that we use in a phase II-A early study, which show that the compound does what it's supposed to do, decrease lymphocyte count, as well as early indication of disease reduction, disease activity reduction at threII months. We have performed a second phase 2 study, one of the largest dose-finding study in the field, with efficacy after six months with four cenerimod doses. With this learning, we designed the phase III program, which has been discussed with the FDA. I'm pleased to say again that as of yesterday, we have recruited the first patient. Next slide. I would like to share with you how the CARE study has helped us designing the OPUS program, basically to ensure three things. One, to identify the population in which the benefit risk of cenerimod will be optimized. Second, to select the dose, this is the role of the phase II study, which unequivocally can give the best efficacy and safety profile. Third, which is really important in lupus, is the choice of the endpoint. We learn a lot from CARE, and you will see a bit of it over the next 15-20 minutes, how the choice of endpoint important and how this endpoint will not only support regulatory approval, obviously if the study is positive, but also allow market access, and for me is more very important, being innovative and provide a more patient-oriented view on the efficacy of the drug in this population. Next slide, slide 20. Oh, in this slide you see the objective of the CARE study. In just a sentence, I would say that as I already mentioned, the main objective of the study was to identify the dose that is efficacious and safe at six months. You see that the study also lasted up to 12 months. Why we did a study of 12 months? Next slide. On this slide you see the design of the study. We had a relatively long screening period with the aim of optimizing or reducing actually, the corticosteroid dose. We did it that because to maximize the chance of showing a dose response, we wanted to keep the steroid stable during the first six months of the study. Why six months? You see here that at six months, the cenerimod 4 mg patients were re-randomized to cenerimod 2 mg or placebo. This request came from the FDA based on preclinical findings in dog. We were not allowed to go forward beyond six months. We discussed and included in this study, in the CARE study, a large echocardiographic study that will ruled out the safety concern based on preclinical findings. Now I'm very pleased to say that these results of this echocardiography sub-study are absolutely clean. Since the concern is lifted, we can go ahead with this dose of 4 mg in phase III. Next slide 22. On this slide you see the baseline and the disease characteristics of the population recruited. I put my finger on the high dose, the cenerimod 4 mg and the placebo that you see on the right of the slide. I would say that the population for many aspect is a typical SLE population. You look at the age, 42, and the sex, which is majority, I mean, predominantly female subject as the epidemiology tells us. We had a predominantly white population with approximately 8% of African Americans and 8% of Asian, which are maybe less than what we would have hoped, but it was driven by the allocation of the study. We will put in place measure in phase III to make sure that the racial representation will be appropriate, namely by increasing our footprint in the U.S. and in Asia. You will see that the patients were communicated with corticosteroids, immunosuppressive, antimalarials. The percentage is relatively high. Actually high. You can see that compared to some recently concluded studies, we have a little bit less patients with the immunosuppressants or antimalarials. The dose of corticosteroids actually happen to be a bit lower than in other studies. Next slide 23. Nevertheless, these are the results of the primary endpoint, and we observe a change from baseline with the 4 mg group. This is the red line decreasing by four points compared to placebo compared to baseline. You see also in the dark purple line the placebo which decreases as usual in these kind of studies. We did observe a difference which is significant, 1.2 versus placebo at six months. The fact is establishing over time as we expect with such compound that takes time to get the full efficacy. As you can see probably the efficacy is not limited, is not completely achieved at six months. Next slide. As I mentioned above, we had the impression that because of the study design, and namely the fact that we wanted to reduce the steroids before entering to the study, and we didn't allow to change the steroid, we basically probably included the population which was less severe than to what could have been done. That is why we look at subgroup in this slide, where we have a more active or a more severe population. On the top left you see the, basically the data that I've just shown in the previous slide in the overall population. In the middle top and the right top, you see the results in the population more serologically active. On the bottom you see the population more severe clinically either because of the SLEDAI or BILAG or because of higher corticosteroid. The treatment. Amazingly, actually, in each of these subgroups, you have an even better effect compared to the overall population. Just as an example, in the C4 complement 4 low levels, we have a difference versus a placebo of 3.12 compared to 1.2 in the overall population or in the anti-double stranded DNA high level - 2.55. We said, let's try to go into this subgroup to maximize the efficacy of the compound. On the other hand, we need to also take into consideration two factors: the size of the subgroup, because you don't want to restrict too much the population, otherwise recruiting the patient will be more difficult, and obviously look at the consequences in the label. You see here as an example that the complement C4 subgroup was only 16% of the patients. The anti-dsDNA high antibody population was 20%. When we were discussing these things, actually we got the results of a pre-planned biomarker analysis in which we look at interferon gene signature at baseline. Next slide. This is a complex slide, but we discovered actually that as in all other studies, by interferon gene signature we select two population, distinct population. In our case, 50% of the patients had high gene, interferon high gene signature. Half of the population had the low signature. This clear separation again is expected as shown in other compound, for example anifrolumab. What on the other hand was a bit surprising to us that the 50/50% split confirmed that we have probably a less severe population. As usually you would expect an 80/20 split or a 70/30 split. Indeed we said, "Okay, we have maybe a less serologically active population." Let's look at the results in that particular subgroup, which is 50% of the population with high interferon-1 signature. Next slide 26. Now, I repeat here on the left the results that you have seen, so the change from baseline at month six for cenerimod 4 mg -4.4, placebo 2.85, difference 1.2, what you have already seen. Here you see that interferon high signature actually the difference versus placebo is much bigger. We have a 279, 2.8 difference versus placebo at the 4 mg dose. It really seems that the effect is maximized with the cenerimod in a more active population. Of note, in the high interferon population, no difference versus placebo at lower dose was observed, which confirmed us that the 4 mg dose was really the dose to go, which is a good outcome from a phase II study when you have only 1 dose coming up. Just to answer a question that you may have, I want to go to the next slide, which is slide 28, to show the results on the SRI-4 response that from a regulatory purposes is probably the most relevant one. In the overall population, you see a difference between the two groups, 4 mgs and placebo with about 9 absolute percentage points, which is okay. It's in line with what has been observed with other previous medication. I would like you to see the next slide, which is slide 29, where we did the same analysis in the population with the interferon high signature, interferon 1 high signature. You really see here an amazing difference with 70% patients responding according to this criteria at month six versus the 45%, 46% in the placebo is a 24% difference. These are great results and these are actually you don't find it, if I'm not mistaken, but I think I'm not, better results with any of the biologics that we have now. You want to see whether the effect on the biomarkers was also at par with these great results. Next slide 30. It actually did. Here you see the anti-double stranded DNA antibody in the change from baseline at six months. On the left, interferon 1 high population with a decrease for 35%-40% of this biomarker, which again is at par of the effect which is observed with all other biologics. Actually, with the last biologic, anifrolumab or deucravacitinib. Based on these results, at the end we decided in phase III to enrich the population to get at least 75%-85% of subject with interferon high population in our study. Before going to the design of the phase III study, a few, two or three slide about obviously the safety data. As Martine Clozel said, it's important that the compound in this population is safe. Next slide, slide 31. In this complicated slide, again, you see the summary, high-level summary of the safety data. We were happy to see these results. Cenerimod was well-tolerated in all treatment groups. Similar rates of adverse events were reported across treatment groups during these six months. These are the six months results. We did observe, as expected, a higher discontinuation due to predefined criteria due to the mode of action. If the patients had a decrease of lymphocyte below 200 cells per microliter, the patients had to be discontinued. There are two things that are important to note here. First, that there was not much of a difference between the 2 mg and the 4 mg group. Actually, probably even more important is that we observed and we evaluate the incidence of infections in these patients with low lymphocyte count. We didn't find any relationship between a decrease of this lymphocyte below 200 in any infections. Therefore, in the phase III, we have amended, because now the study is ongoing, we have amended the criteria to make a bit more liberal and not exclude patients that may still continue to benefit from the drug. Finally, you see SAEs are very low, 2.4% with cenerimod 4 mg, 3.5% with placebo. I'm sure you notice also that there is on the adverse events greater than 5%, there is a hypertension, so actually 6% on 4 mg, 4.7% on cenerimod, and lower in other groups. I'm going to touch on that on the next slide. We are dealing with an S1P1 selective. These are on both, you have the different effect that you would expect. Nothing really to mention here. There is nothing but two things I would say. First of all, I will look at the low incidence of opportunistic infection that you see, 3.6 versus in 4 mg versus 7% on placebo, which is a very good sign. Overall infection were on par, 19% and 20%. The blood pressure, to answer the previous question in the question in the previous slide, you see that there is basically no difference versus placebo in the blood pressure. As I wrote, as I put on the right, all lights are on green. We have a 12 months study, therefore, adjust the next slide number 33, to summarize the safety of 12 months, and basically the same exactly findings as in the previous slide. Of note, you know, cenerimod 4 mg, after six months, all the patients, as I mentioned earlier, were re-randomized to placebo or 2 mg, and this is obviously all together in this slide. Again, low incidence of serious adverse event in a one-year study and low incidence of opportunistic infections. Next slide 34. In a nutshell, CARE delivered to the promise. We really found extremely helpful looking at the phase II, a large phase II study to inform the design of the phase III. Now let's go there. Next slide 35. Next slide. We call it the program OPUS. We'll include two pivotal studies. Each study has 420 patients. 210 each. A long-term extension will be offered to all patients completing the one-year study to increase the safety exposure to the 4 mg. The treatment period is one year, as you can see, we have been able to convince to bring only one dose to the phase III. Next slide, please. The target population doesn't change. It's the moderate to severe SLE population. We target, as I mentioned earlier, a higher representation of patients with interferon high signature and a more balanced racial representation. How we are going to do that? We have different things. We have put in place different things to achieve this objective. First of all, we have adapted the inclusion criteria. Interestingly, we have performed with the help of so-called artificial intelligence an in-depth search on the baseline characteristic of the patients in CARE to see which of those characteristics were more predictive of interferon high signature. We adapted the inclusion criterion for accordingly. We also increase the population. We are going to increase the population coming from Asia because we have seen, and this is also described in the literature, the SLE patients in Asia are basically, let's say 80%-90% of high interferon signature. With one move, having more Asian patients, we increase the racial diversity and we increase the interferon high signature. Although we are still excluding from the study the patients with lupus nephritis, we have actually relaxed a bit the inclusion criteria for the kidney, so the patients with moderate kidney disease or can enter into the study. This again, from this exercise was shown that patients with renal disease are more likely to be interferon high. We will increase the, as I mentioned earlier, the percentage of patients coming from the U.S. therefore we will increase automatically the African-American population. Finally, as I mentioned earlier, I think in CARE, the fact that no corticosteroid reduction was allowed during the study was a bit going against the study because we selected a population which was not as severe as we would have wished. Now, in this study, we have included a forced titration of steroids in the middle of the one-year study to allow patients with higher corticosteroid therapy at the beginning to enter the study because they will have the possibility to decrease their dose. Next slide, which is slide 38. The primary endpoint remains the one that has been successfully used in the CARE study, but we have upgraded SRI-4 response as a key secondary endpoint to ensure regulatory acceptance of the study. Of course, this has been discussed with the FDA and the European authorities. Next slide, 39. As a secondary objective, for which we adjust for multiplicity in order to add the data into the label, we introduce two innovative endpoints based on sustained response. The first one is basically a sustained SRI response as the reduction of four points in SLEDAI-2K is the main driver of SRI response. A sustained response you see need to be maintained for four months at least. We also introduced a sustained response for the mucocutaneous manifestation of lupus for two reasons. One, because this is really one of the main concern of the patients with lupus because this is the visible part of the disease which may affect more the patients. It also because in the CARE, I didn't show you the results, but we have a very nice effect on this parameter. Next slide 40. In here actually, we used the data in the CARE study to see how the sustained SLEDAI-2K response would look like. These are real data, is the 4 mg versus placebo. It's a 4 mg then placebo and 2 mg. This Kaplan-Meier show how this sustained response is observed much more frequently in the patients with cenerimod than patients on placebo. At 12 months, we have basically 75% of patients who respond to treatment. It was good encouragement to select this endpoint for phase III. Next slide. We have discussed with the patients association, you see here six patient associations from different parts of the world, who actually were very useful in designing the study and make it, in a word, more patient friendly. As an example, we asked them, we have one every month visit for SLEDAI, we ask, "Do this is bother you coming every month to the center?" They say actually, "No," because it's like for patients with SLE, it's important to get in touch with the caregiver. They said, "What is important for us is that we are helped with the logistics of coming to the centers." We put in place measures to help the patients to come to the center. We ask actually about the endpoint and we introduce a very, very innovative endpoint which is really patient's focused. Among the different areas of the SLEDAI and among myositis, arthritis, rash, alopecia, and mucosal ulcers, each patient will choose what is the symptoms that more affect the patients. Each patient will have his or actually her, 95%, or his, 5%, chosen symptoms. We will look at the end of the trial whether these symptoms have disappeared. This is really something that I like for because it takes what the patients needs. I would like now to tell, to give you just close to the finish a little anecdote about alopecia, which is among those symptoms. We got during the study, we received a phone call from an investigators who said, "Hey guys, your sys-- your treatment seems to very help, very effective in alopecia." Obviously, the study was blinded, so we couldn't say anything, so thanks for the comments. This raised the interest to look at alopecia by itself. Actually, we look at these results, we saw it in the next slide, is slide 42. Interestingly, among the, there were 70% of patients, and remember 95% are female, who had alopecia at baseline. After only six months, basically the symptoms disappeared, so alopecia was recovered in 1/3 of the patients on cenerimod, while on placebo only 10%. This is an amazing results in my view, three times more than placebo. Actually, this seems to be something which is important for the patients. This again is just an anecdotal finding now. Next slide, actually my last slide. In conclusion, I really hope that I was able to share with you my enthusiasm or, and the company enthusiasm about this program, amazing program, which has really been crafted, I would say, on the learning from all previous studies, but in particular for CARE study, which was just completed and presented at ACR a month ago. I would really like to thank the investigator again. I know that I did it already, I think it's important to thank the investigator and the patients who contributed to CARE. A special thank you to the first patient who is currently now as we speak, in screening in the OPUS program. With that, I would thank you for listening to me, and now I get back to Andrew to open the QA session. Andrew, please. Thank you, Martine. Thank you, Alberto, for your prepared remarks. We have time to address your questions, but before, a few housekeeping rules. I'll ask for everyone to please limit yourself to one question only and jump back into the queue if you have more to ask. Second, this is a call on a clinical program, and hence, we encourage you to use the occasion to ask questions to the experts on their finding in the field of expertise. We will not be answering questions on funding or finance in this call. Without further ado, operator, please open the lines. Thank you. Dear participants, as a reminder, to ask a question, you will need to press star one one on your telephone keypad and wait for a name to be announced. Please stand by while we compile the Q&A roster. This will take a few moments. Once again, if you wish to ask a question, please press star one one on your telephone keypad. Dear speakers, there are no questions at this time. Please continue. Thank you, operator. All right. Well, it is the holiday season, when sending out the email this morning, it was not coming as a surprise that there were a lot of out of office messages. Anyway, thank you for your attention. This concludes the call for today. We thank you for your ongoing interest in Idorsia and look forward to speaking to you again. Operator, please close down the lines. Thank you. That does conclude our conference for today. Thank you for participating. You may now all disconnect. Have a nice day.