Dear ladies and gentlemen, welcome to the Idorsia conference call. At our customers request, this call will be recorded. As a reminder, all participants will be in listen only mode. After the presentation, there will be an opportunity to ask questions. If any participant has difficulties hearing the conference, please press star key followed by zero on your telephone for operator assistant. May I now hand over to Andrew Weiss. Please go ahead. Good morning, good afternoon, everyone. Welcome to today's conference call/webcast. My name is Andrew Weiss. I'm the Head of Investor Relations and Corporate Communications here at Idorsia. We are here to discuss our full year 2020 results, performance, as well as give you an outlook on 2021. With me on the call are our CEO, Jean-Paul Clozel, and our CFO, André Muller. They'll be presenting in the first part of this session. For the Q&A, we will also have our Chief Commercial Officer, Simon Jose, join us. Let's dive right in. Next slide. As customary, I need to remind everybody that we will be making forward-looking statements. You have therefore been adequately warned about the risks and benefits of investing in Idorsia. Next slide. We're now on slide three. Jean-Paul, the floor is all yours. Thank you, Andrew. Good morning and good afternoon to everyone. 2020 had been a very bizarre year and quite a dangerous one, if we think about this terrible epidemic. Despite these very difficult and tough conditions, Idorsia has done extremely well, and I have to say, much better than many would have expected and that personally, I would have expected. It's very rare, as you will see, to have met nearly all our goals and fulfill all what we were expecting for 2020. Next slide. Just let's have a look at the highlights. Clearly, in 2020, we have announced positive pivotal results for daridorexant in insomnia. We have been able, at the beginning of this year, to file this NDA, which has been submitted to the FDA. We have been able, in 2020, to obtain very positive results for the two registration studies, which are required for the clazosentan approval in Japan. What we have done also, in 2020, is to strengthen our liquidity. We have been able to raise CHF 865 million. What we have also done in 2020 was to establish our U.S. commercial operations under the leadership of Simon Jose. Also, just we happen to know very recently, we have won the case against the previous Axovan shareholders who were requesting the payment of the milestones after the J&J acquisition. Next slide. What makes really the engine of any biotech company is, of course, the pipeline. This slide summarizes our pipeline, which is comprising 12 products, without mentioning the T-type calcium channel blocker, which has been licensed to Neurocrine and which is in phase II of clinical development for rare form of epilepsy. As you can see, our pipeline from daridorexant already submitted to four and three additional phase III programs. Clearly now with selatogrel, which is going to start the phase III very soon. Of course cenerimod, where we are waiting the results before starting the final pivotal trial. You see that this pipeline is very rich, is also not only having late-phase product, but also phase II products and early project. We have been able to start new clinical developments of some very new innovative drugs. We will today focus on the later phase program, which are going to bring new products to the market within the next three years for Idorsia. Next slide. Daridorexant for insomnia. Daridorexant is quite a unique product because, as a orexin receptor antagonist with a short half-life, we have been able to show that this drug could improve the sleep, but also could improve daytime functioning. This improvement of daytime functioning has been measured using a validated instrument developed in collaboration with the FDA. As I mentioned, the NDA has been submitted in January of this year, and we are going very soon, in the coming months, to submit the market authorization for the EU. We are planning to be able to launch daridorexant in the U.S. in Q2 of 2022, and hopefully in Europe for the end of 2022. Next slide. Clazosentan has done also extremely well. As you know, this endothelin receptor antagonist, it's a selective ETA receptor antagonist, has been able to show in the two pivotal trial study in Japan, has been able to show that it could prevent the vasospasm and its clinical consequences following cerebral ischemia post-subarachnoid hemorrhage. The two studies, one was in patients treated with surgery or clipping and one with a patient with coiling, so without surgery. Both studies showed nearly the same very strong effect and a prevention of not only the vasospasm, but its clinical consequences. We are planning in the coming months to file clazosentan in Japan, and we are also pursuing in Europe and in U.S. another study, which will be required for the filing in U.S. and in Europe. This study is called REACT, and we are halfway through the recruitment. This study is the one from all our program, which is suffering most of this COVID crisis because all the patients are treated within intensive care, and a lot of intensive care units are extremely busy with the COVID crisis and situation. We hope to be able to finish, maybe this year or first half of next year, finish the recruitment within REACT. Next slide. Lucerastat. Lucerastat is an oral drug, which is distributing extremely well within the whole body. It can penetrate the tissue, and it can particularly penetrate the CNS, central nervous system, and prevent the buildup of lipids within this central nervous system. As you know, within Fabry, there is an accumulation of some of this lipid, and this accumulation within the nerves, in particular, is producing neuropathic pain. A lot of also consequences of the Fabry disease is the accumulation of this lipid within the heart, within the kidney, within the gastrointestinal systems. By having a drug which distributes everywhere in the body, we think we have a drug which is going to have a major clinical effect on the disease and on its symptoms. The main symptoms, which is a primary endpoint of the study, which is now going on and where we have finished the recruitment and we have the result in the second half of this year. This study, called MODIFY, is evaluating neuropathic pain with the patient's reported outcome, evaluating the complaints about the pain from the patients. Next slide. Aprocitentan is an oral endothelin receptor antagonist, and we are evaluating its effects in patients which are non-responsive to most of the generic antihypertensive drugs. The patients who cannot be controlled with existing antihypertensive drugs are included in the study called PRECISION. Once we have shown that these patients are true resistant hypertensive patients, we are testing on them aprocitentan at two doses. We are also evaluating the long-term effect on blood pressure of aprocitentan during eight months chronic treatment. At the end of this eight months, we are doing a randomized withdrawal to be able to show that the drug is still very effective after nine months of treatment. The study is going extremely well. We are finishing the screening, and the inclusion of the patients will be done in the coming months. The results are expected in the first half of 2022. We already had, I think, five review of the safety committee. The safety, which is very important in these very severe patients, extremely seems to be posing no problems. We are very optimistic that this drug is going to fulfill a very high medical need. As you know, a lot of patients, because of diabetes, because of genetic background, because of obesity, in the U.S., there is an increasing number of patients which are not controlled for their blood pressure. A new drug effective in these patients is going to be very important. As you know, Janssen will have the commercial rights about this drug, and we will get royalties. Next slide. Selatogrel. Selatogrel is also, I would think, a revolution in cardiology because it's a self-injectable device where the patient, in case of a recurring myocardial infarction, these are patients who already got a myocardial infarction. Once they have another pain, therefore they are at risk of a second myocardial infarction, they can inject themselves with the selatogrel, then be protected for four hours, which gives them the time to call an ambulance and to go to the hospital where they will be treated. The drug is not long-acting. Once they are within the hospital, every intervention, every treatment can be done without the risk of an interaction with selatogrel. I think it's very important. We have seen that in the time of COVID, for example, ambulances' delay is a huge problem. In New York, patients have to wait sometimes three, four hours to get an ambulance to be hospitalized. Such a drug will be extremely useful. The clinical program phase III is going to be initiated. The first patient of this program are going to be treated is the second half of this year. We're already contacting the centers and preparing for this phase III program, which has an SPA, which means that we have agreed with the FDA of the program and its endpoints. Next slide. Cenerimod. Cenerimod is the 3rd generation S1P1 receptor modulator. This drug has been selected not only because of its selectivity, its potency, because of a very specific interaction with the S1P1 receptor, which leads to a really very good safety profile. I think that with this drug, cenerimod, we'll be able to show that we are avoiding some side effects of the 1st generation or 2nd generation S1P1 receptor. It received a Fast Track designation from the FDA. The first pivotal study, called CARE, which is also a dose response, but which has a clinical endpoint, and therefore can be used if it's positive as a pivotal trial. This CARE study will have its recruitment completed by the end of February, and we get the results before the end of the year of 2021. We are planning to have basically a discussion before the end of the year with the FDA in order to start in 2022 as the second pivotal trial. Next slide. As you see, we are at an inflection point. Idorsia is really, because of this fantastic 2020 year, we are in a very good situation. We are going to see many, many important milestones crucial for the company. In 2021, you have seen that we have filed daridorexant in FDA, soon with the EMEA. Clazosentan will be filed also soon in Japan. Selatogrel phase III will be initiated. Lucerastat final phase III results will be available second half of this year. Cenerimod results we know will be available before the end of 2021. Also in 2022, we are going to have crucial results, crucial milestones, hopefully with the approval and the launch of daridorexant, of course, in the U.S., also with the results of aprocitentan, also the launch of clazosentan in Japan, and the results of clazosentan in Japan. The launch in Japan. Sorry. Andrew, I don't see the slide anymore. Yeah. I seem to have a network problem. I don't have the slides up on screen anymore. Okay. I just can go to slide 13. It doesn't really I don't know. It's the building of the commercial organization. Yes, it's building, but do people see? They will see it. They will see. Oh, good. What is also important is the buildup of the commercial organization. Simon Jose, within 2020, has been able to gather a team of very experienced people, and also not only in the central position in Allschwil, in Switzerland, but also we have the team complete, the U.S. team complete to be ready to launch in 2022, daridorexant. With Patty Torr as the President of U.S., we have the complete team now, and most of the pre-launch and the preparation of the launch operations is ongoing now in the U.S. We have been also, within 2020, to engage with key partners such as Syneos for the medical representatives, Ab sitcom for the branding, advertising, and Ruder Finn also for the PR activities. Finally, next slide. What of course has been extremely important is the raising of cash, and you will hear what is our financial situation and also how our financial means have been evolving in 2020. André, please, that's your turn. Thank you, Jean-Paul, good afternoon or good morning to everyone. Thank you for your continuous support. Maybe before jumping to the slide, giving you some color on the full year numbers published this morning, I would say that 2020 numbers were globally in line, even if slightly below our guidance updated last October. I would say the full year 2020 was almost uneventful until the 1st of February and the judgment of the arbitral tribunal regarding the Axovan litigation. Call it intuition or precaution, I asked my team to draft three version of financial statements. First one, if no final award would have been granted before publication. Second, worst case scenario, where the claim would have been granted to the claimants. The third one, which is published this morning, the scenario that eventually materialized, where the claim was dismissed. Now we can move to slide 15, US GAAP net results. As usual, we start with this waterfall showing how U.S. net results came about. First, on your left-hand side, you see CHF 72 million revenue. This includes mainly the license and R&D collaboration we entered into with Neurocrine for the T-type calcium channel blocker, CHF 50 million. We had also CHF 11 million deferred revenue from the collaboration with Janssen regarding aprocitentan, and the remaining CHF 11 million was Roche, CHF 6 million with the research collaboration, Mochida with daridorexant in Japan, and Santhera, at CHF 2 million for the assignment of the option to license vamorolone. We come back to the CHF 444 million non-GAAP operating expenses leading to a non-GAAP operating results of minus CHF 372 million with D&A of CHF 19 million, stock-based compensation of CHF 19 million. The US GAAP operating results amounted to CHF 411 million. There is a quite unusual amount below EBIT of CHF 35 million, which led to the CHF 445 million US GAAP net results. The reason for this 35 is mainly due to the financial results with US GAAP of net financial loss of CHF 39 million and non-GAAP financial expense of CHF 18 million. The CHF 18 million were mainly relating to the foreign exchange loss that we have on our U.S. deposits. The reconciliation between non-GAAP and US GAAP are relating to the accretion expense on the JNJ convertible bonds, CHF 8 million, and a relatively significant amount, CHF 13 million, on the loss of the mark to market on the 1.7 million shares of Santhera that we hold. Of course, we did not pay for these shares. We get them from the different deals that we entered into with Santhera. Some of the shares or most of the shares are blocked until the results of vamorolone. But of course, in U.S. GAAP, you value these shares at the market price. Now we can move to slide 16, non-GAAP operating expenses. The non-GAAP R&D expenses amounted to CHF 355 compared to CHF 412 in 2019. A significant decrease in R&D. Here, you can see how these R&D expenses broke down. Research, slightly below at CHF 107 million, with biology, chemistry, pharmacology, and preclinical activities. You see a development if you exclude the CHF 9 million and the inventory build that are also included in R&D. Development was really impacted by COVID-19 and the delay in some of the clinical trials. You see that we had CHF 212 million compared to almost CHF 300 million in the previous year. The CHF 9 million milestone, you may recall that we acquired some of the Axovan claims from non-claimants for less than 1/3 of their face value in June 2020. CHF 9 million. We started to build in the drug substance and drug product. We started to build inventory in preparation of the launch that is expected in 2022. As you know, as long as the drug is not approved, you can't book it as an inventory, so it hits your P&L in the R&D line. This was CHF 26 million. For the SG&A, as anticipated, we had an increase out of the CHF 90 million you see here. You have CHF 63 million in G&A and CHF 27 million in selling. CHF 444 million, less than the previous year, CHF 470 million, less than what we expected. We move to see a next slide, which is slide 17, you see on a quarterly basis that we spend much more in Q4 with CHF 142 million. You really see the impact of COVID in Q2, because if you exclude the CHF 9 million milestone in Q2, you see that we spend as less, I would say, than CHF 77 million. A catch-up in Q4 as we expected, which also gives you a clear hint on what will happen and will even increase in 2021. We'll come back to the guidance a little later. If we move now to slide 18, the cash flow. We entered the year 2020 with CHF 739 million liquidity. As we discussed, we spent CHF 444 million non-GAAP operating expenses. We cashed in milestone, CHF 61 million. That's the cash part of the milestone, not all recognized in the P&L, but in the 61, you have, of course, the CHF 50 million of Neurocrine. You had the CHF 9 million with Mochida. You had also CHF 2 million from Roche in connection with the research collaboration. Limited CapEx, CHF 9 million. Other means working capital requirements diminishing by CHF 10 million. As Jean-Paul already alluded, CHF 843 million cash raise, the net amount of the two equity raise made in 2020. We end up with a really round number, easy to recall, CHF 1.2 billion liquidity. The next slide 19, gives you the breakdown of this liquidity. On the left-hand side, you see the cash deposit that aims to decrease the negative yield on Swiss deposits and also benefit from the U.S. yield curve on our U.S. deposits. Right side, you see the breakdown between the main currencies, mainly CHF 927, and $268 million, which are aimed to cover our foreseeable expenses, which are denominated in U.S. dollar, of course, with U.S. organization that will grow in order to properly prepare for the launch of daridorexant, but also for expenses denominated in U.S. dollars, primarily for clinical trials. We can move to Slide 20 and the guidance. Before going into the numbers, I must say I'm really happy to mention that the guidance excludes, as usual, the unforeseen events. I'm more than happy that we could remove the language around any potential payment in connection with the Actelion arbitration. This is behind us, as we already mentioned, because the final award from the arbitral tribunal removes a serious Damocles sword above our head. Because the claim alleging a change of control with the acquisition of Actelion by J&J and the concurrent demerger of Idorsia from Actelion, that would have led to an immediate payment of all outstanding milestones for clazosentan. This claim was dismissed. The total amount would have been quite substantial, close to CHF 100 million, if you include also the late payment statutory interest on the late payment. Frankly, this CHF 100 million will be better used to fund 2021. You see the non-GAAP OpEx of CHF 640 million. I will start with the easiest one, CHF 5 million milestone. Because of the very positive results of clazosentan in Japan, we will file the dossier with the relevant authorities in Japan, and to this extent, we'll pay the CHF 5 million milestone to Roche. We will continue to build an inventory, but as long as the drug is not approved, it hits the P&L for around CHF 35 million, mainly with daridorexant, but also for clazosentan in Japan. Which means that we will have around CHF 600 million functional operating expenses, of which CHF 370 million with R&D expenses. We will actually, on R&D, spend a little more than what we spent in 2020. The reason for it is not so much on the fixed cost base. Even with this broad portfolio, we will need to increase our headcounts in R&D and in clinical, pharmaceutical, mainly pharmacovigilance, drug safety. More importantly, we will also increase the cost for study costs. In late stage, the lion's share is of course for the late stage. Here, daridorexant will go down. Because of some delay with the REACT trial with clazosentan and also Nuseart, that even if the enrollment is now well on track, as Jean-Paul mentioned, we will more or less spend what we had in 2020. Apro citentan is more or less the same. The main driver for the increase will be selatogrel with this integrated drug device developing with Antares in the U.S., and cenerimod, where we should get the results of the phase II-B by the end of this year, 2021. Of course, as you've seen, we have a richer pipeline with phase I and phase II assets. We also plan to spend a little more on phase I and phase II assets. Among others, the selective orexin-1 receptor antagonist that we want to investigate in binge eating disorders. That's the reason for increase of R&D expenses. Of course, the most significant increase is in SG&A. For this, of course, it's all about the preparation for the launch of daridorexant in the U.S. and clazosentan in Japan. There's a significant amount, around CHF 90 million, really only product-related external spend. As you can imagine, mainly with daridorexant. The rest is, of course, to gear up the commercial organization with marketing, selling, access, medical affairs, supply chain. G&A will increase both in the affiliates with the support functions, but also at headquarter, notably with IT assistance, because we need to be ready for launching these drugs. This gives you the reason for this CHF 640 million non-GAAP operating expenses. On top, we have planned for roughly CHF 20 million D&A. Slightly higher stock-based compensation with 25 because of a larger organization, not only in Switzerland but mainly in the U.S. and in Japan. U.S. GAAP OpEx should be around CHF 685 million. Let's move now to the next slide, which is slide 21. We do not guide on revenues. I say depend primarily on existing collaboration. Let us find a new one, namely out-licensing deals that by essence are not predictable. Looking ahead to 2021, we could have various sources of revenue. With Mochida, next milestone, first patient enrolled into Japanese phase III trial. With Roche regarding the R&D collaboration, which was actually extended until end of 2021. With Santhera, depending on the clinical results of vamorolone in DMD, which are expected by the end of H1 2022, and of course ponesimod. As you know, ponesimod was developed by the Actelion teams almost to the end and taken over by the Janssen team. Now, of course, it belongs to J&J according to the demerger agreement. With the NDA and MAA submitted in the U.S. and in Europe by Janssen in March 2022, we can reasonably expect the PDUFA for ponesimod in MS this spring. With this revenue sharing arrangement in place, i.e., granting us 8% of the annual net sales, this is very likely to become Idorsia first recurring revenue stream. Which brings me to the next slide 22, which is actually my last slide. Idorsia revenue model moving forward will be actually a duo. On the one side, you see it on the left-hand side. We'll have revenues coming from net sales from our own product developed in-house, that we will commercialize with our marketing and selling organization. It means that our commercial organization will market GP products using when needed partners, e.g., Syneos in the U.S. or Mochida in Japan. Orphan drugs products like clazosentan and hopefully lucerastat, also specialty products like cenerimod and selatogrel. We will hopefully, in different ways, launch these products and get a very diverse source of revenues. Idorsia is not a single asset company by far. On the other side, and you have it on the right-hand side, we count also on milestone and royalty stream coming from ponesimod. We just alluded to it. Hopefully also tiered royalty between 20% and 35% on aprocitentan with J&J. Hopefully beginning of 2022, we'll get the result of the phase III. Regulatory and phase milestone as well as royalty on our T-type calcium channel blocker from Neurocrine if, of course, the studies are positive. With this, I hand over for the conclusive slides to Jean-Paul. Jean-Paul, floor is yours. Thank you. As a summary, I just wanted to say that, thank you, André, first. Clearly the year 2020 has been key, has prepared for very exciting 2021. I know I am going to repeat, but first of all, this strong balance sheet is really helping us a lot because we have to do a lot in 2021. Not only we have filed, and we should file daridorexant and clazosentan this year, but we are starting the selatogrel phase III, and we will wait for the result of lucerastat and cenerimod. If these two drug make it, then basically it would mean that we would have six phase III asset within Idorsia in 2021. You see that this strong balance sheet was very important. We are in good shape, I hope that now this presentation has given you a reason to believe even more in the future success of Idorsia. Maybe Andrew. Thank you, Jean-Paul. With this concludes our session with our prepared remarks and opens the door for the Q&A, where Simon Jose is going to join us. Before I open the lines with the operator, I also want to remind that it's possible to reach me via email, andrew.weiss@idorsia.com, if you prefer to send your questions through like this. Operator, please open the lines. Ladies and gentlemen. We will now begin our question and answer session. If you have a question for our speaker, please press star zero and one on your telephone to enter the queue once your name has been announced, you can ask a question. If you find your question is question is answered before it's your turn, you can dial zero and two to cancel your question. If you're using speaker equipment today, please lift the handset before making your selection. One moment, please, for the first question. The first question is from James Gordon, JP Morgan. Your line is now open. Please go ahead. Hello. Thanks for taking the question. James Gordon from JP Morgan. A couple of questions, please. What was it in the release this morning? There was a comment about recruitment in the CARE study for cenerimod and the MODIFY study for lucerastat, how it had been impacted by COVID, but then you've made some adjustments in consultation with health authorities, and so you'd adapted the enrollment. The first question was, what were those changes? How have you changed the enrollment? Second question was, lucerastat looks like the big readout for this year, phase III data. I'm not aware that we've got data on this particular endpoint previously, the neuropathic pain primary. Just how are you thinking about the risk profile there and other, even if you haven't already got data on neuropathic pain, is there other things you've seen before that makes you encouraged? Just the third and final question, daridorexant, I think we know where we are in terms of Western and Japan plan, but what about China? When does that get fleshed out? What will you consider doing yourself in China versus letting a third party have a go? James, thank you for all those questions. I think the comment on the trial design at lucerastat, the endpoint, Jean-Paul, and then we can refer the daridorexant to Simon. Maybe there is about the recruitment of also of cenerimod. This was another question. I take that. Correct. Yes. I think that, first, for lucerastat, we have finished the recruitment. We didn't change the number. Because we had discussion with the FDA during the year to slightly modify the endpoint and, in fact, to really be able to get a more precise evaluation of the pain, especially with time. We got an agreement with the FDA, and this would have allowed to, in fact, decrease the number of patients needed in lucerastat study. We have been able in the last coming months to recruit a very big number. I think we are going to have more patients than what we anticipated. We really have tried to optimize our chances, and we will have with the pain for the pain PRO, we have more patients than what we had anticipated. Now you ask me, of course, we don't know. We have never shown an effect on pain. What tells us, what is giving us some optimism, and of course, it's a blinded study. The fact is that I think nearly 100% of the patients who have been offered to go into the open label study have decided to go into the open label study, which shows that at least they are patients like the drug, at least. Also what does also give us some, I think, some help with some anecdote from our first phase II, and some patients seem to have benefited. Of course, it's just anecdote. Really, for lucerastat, I think we need to wait until the last moment to really know if this drug works on pain. For cenerimod, we have decided, and in fact, we will have enough patients to really not modify our program. We had just discussed with the FDA what they really needed to see. In fact, the main change in the program of cenerimod is the fact that after the six months, which is the primary endpoint, we are going to follow the patient for one year. This is in the Fast Track situation. It is really to be able to have more patient long-term evaluation in order, in fact, to do a smaller phase, second phase III, and to be able to register with enough long-term data so that the FDA agreed, and we are continuing to treat the patients after having evaluated the primary endpoint for safety reason. That's for cenerimod. So we will get the results, and hopefully, it will be very interesting to see if we have a lupus drug. For daridorexant, yes, we are going to file in Europe and in the U.S. In China, we have done the first evaluation, and maybe Simon can give a little bit his opinion. Sure. Hi, James. Yeah, we're looking at China very carefully, actually. I think for Clazo and Lucy, with the recent changes of the regulatory process and the potential to sort of file off the back of foreign approvals is something that we're looking at, and certainly with clazosentan and the direct with hemorrhage, that is quite common as it is in Japan. Daridorexant, insomnia, it looks to be a very, very big market in China. I think we're looking at 140 million people. Even if you simply look at the number of people that are in the outpatients in the large hospitals, there's 26 million, which is more than we've got in the U.S. It's a big market. benzodiazepines are the standard of care, there's a big opportunity there. We haven't yet decided and determined the degree to which we'll go ourselves and use a partner, which is something that we're working through, but we are looking at China carefully and see a big opportunity there. Thank you, all. Thank you, Simon. Operator, next question, please. The next question is from Rajan Sharma at Deutsche Bank. Your line is now open. Please go ahead. Hi, thanks for the question. Firstly, just onto selatogrel, and I was wondering if you're able to further disclose any detail on the design of the phase III. Just specifically how you can ensure recruitment of the correct patient population, given the strategy for administration. Also, how you can ensure correct use of the device. Secondly, just on daridorexant, and if you could just expand on your pre-launch strategy for that one. Maybe any observations from the competitor DAYVIGO launch in the U.S. and any feedback on that launch that may inform your plans for daridorexant. Thanks. Yeah. I think that I will take the clinical development of selatogrel, and Simon will answer about DAYVIGO and the pre-launch. Just for selatogrel, it's a very good question. In fact, you are hitting a very end point. We have an SPA. The endpoint is really basically, I don't want to go in detail, but it's basically how many patients who took our drug, selatogrel, compared to placebo, are dead, got a severe myocardial infarction, a small myocardial infarction, or nothing at all. We looked at what are the consequences of this second pain and this second crisis. Of course, also we are looking at the, I would say, long-term, semi-long-term, after one month and three months. That's a secondary endpoint. Can we prevent, with selatogrel, can we prevent the occurrence of heart failure? This would have a major, of course, economic impact, because heart failure is for the life of the patient. If you could, by giving one drug in one day, prevent the long-term consequences, it has a huge economic impact. The question as you are asking is, how do we go for the right patient? The right patient is not difficult. They must have had a myocardial infarction. The diagnosis of myocardial infarction today is quite simple. They must have a myocardial infarction plus a second risk factor. It can be diabetes. It can be renal failure. All that is increasing markedly the chances to get a second myocardial infarction. We want to have a number of events sufficient to be able, a little bit like you see with the vaccine, to be able to take a conclusion. Of course, we will have many more events than what is done with today's vaccine, but it's the same principle. I think we need about 500 events, and we count that maybe 2/3 of the events will not be because the patient diagnosed himself his pain. We know that maybe two or maybe three times over four, the pain will not be a myocardial infarction. One over four times, it will be a myocardial infarction. The patients are high-risk patients. They need also to be able to remember that they have an auto-injector. We're not going to treat patients with Alzheimer unless, and this is also what is done, there is somebody next to this patient, a caretaker, which can guarantee that in case of a second infarction, this patient can inject himself or with the help of the caretaker. There will be, within the study, a sort of test that before entering into the trial, every patient should show that he can inject himself. It would be with a placebo, of course, but he will use the auto-injector, and he has to demonstrate that he can really inject himself. He's not afraid of the pain, and he doesn't have a psychological problem which would prevent him to inject himself. That's a way we guarantee that we are taking the right patient population. Maybe go to daridorexant? Yeah. Yes, Simon? Yeah, sure. Let me start with DAYVIGO. The DAYVIGO launch has been, at least seen through our eyes, disappointing. They've got, in the first six months, 6,000 prescriptions. If you compare that to suvorexant at the same time point, they had 28,000. The degree to which that is the profile of the product due to the long half-life, whether it's launching in COVID or the priority it's receiving in a portfolio company is hard to tell. Obviously you'd need to address that to Eisai. I certainly think it's been a disappointing launch. In terms of our own activity, we are now rapidly building and moving forward with our preparations for launch. We will build and own what I would call the core commercial capabilities ourselves of pricing, access, marketing, medical affairs, and supply chain. Obviously, as you know, we're partnering with Syneos to build the U.S. sales force. We'll control the strategic elements of that, and we'll work with Syneos as a partner to get to the primary care market where there's about 60% of the volume. We see this as a very strong consumer play. It's obviously a prescription product, needless to say, but nonetheless, we believe that activating consumers and being very focused on consumer channels, digital channels, is going to be very important for the launch. We're very focused on that and building that as we speak. Finally, obviously, over the course of the next several months and during the course of the year, we'll be engaging with the medical community and critically with the payer organizations to make sure that we're prepared for the launch when we turn into that in Q2 of next year. Thank you, Simon. Thank you, Rajan, for the question. Operator, next question, please. The next question is from Graig Suvannavejh, Goldman Sachs. Your line is now open. Please go ahead. Great. Good morning, good afternoon. Thanks for taking my questions. I have two, please. Perhaps the first, more strategic for J.P. Jean-Paul, when you look at the pipeline, it's quite diverse. From a strategic perspective, if you could help us get a view as to how you're thinking about which assets that you're developing are perhaps more appropriate for Idorsia to commercialize on its own versus potentially out-licensing opportunities or partnership opportunities. That's my first question. My second question, with key readouts in the second half of this year for lucerastat and daridorexant, could you give us a sense of what that threshold for success might look like in those trials? What would you consider to be a successful outcome in terms of some of the metrics that we should be looking at? Thank you very much. Yeah. Let's discuss about the strategy. The strategy is very clear. We have an incredible drug with daridorexant. To have a drug which can make you sleep better, can you really improve your day performance? Which drug improve your day performance? Everybody dreams of having the possibility to improve how you feel, what is your mood during the day, how you function. We have an incredible drug, and this drug by its own, I think with a 15 years long patent life, is sufficient to ensure a very big success for Idorsia, which should lead us to profitability alone with this drug. I think this is really justifying to set up the commercial organization, and we have decided to really not share, except maybe we do it in Japan, maybe in some countries, but in the main countries, really, we want to launch it and to keep the most of the value of this drug. That's the key for Idorsia. On top of it, we have the chance to get hospitalized and often type of drugs, which are going to increase our margin and which are going to not, once we have a commercial organization already in place, we are, of course, don't need to set up another organization. All the revenues will come, which increase markedly our margin, and not mentioning the addition as a third wave of revenues of the milestones and the royalties of which we'll get from aprocitentan, from also ponesimod, of course. You see, we have this wave, and in fact, the strategy is going to be increased. In fact, to reinvest the fantastic revenue, I think it's going to be massive. These revenues, we will have to have other drugs to ensure the growth because we will be a very big revenue. I can tell you will ask at one stage to say, what next after daridorexant? One day, people will ask, what next? Because it will be very big, and we will need to grow. This is where dronedarone and of course, selatogrel are coming. This is the second wave of growth, and this should really ensure the growth of the company for the many years to come. I think that's for the strategy. The other question was? The other question was, what looks good. Yes, sorry. Dronedarone and lucerastat. Thank you. Yeah, sorry. I think that for lucerastat, if we have a clinical effect, if we have a significant effect, that means, I think that, I don't know by heart, but we have a very meaningful. This has been statistically calculated. We have a clinically meaningful improvement of the PRO. The PRO was designed with the FDA, was approved with the FDA. The FDA worked with us to define in patients with Fabry, which type of question we should ask about this pain. We have agreed of a level of improvement, of course, which would make sense. I cannot give you by heart because it's a scale. If we have a statistically significant effect, it will be clinically relevant. Of course, all the secondary endpoints, being effect on gastrointestinal symptoms, effect on the renal function, effect on cardiac functions. All these elements are evaluated. The beauty that, of course, it's COVID has sometimes some advantages of this because we have been delayed by COVID for this study, but all the patients were continuously treated by lurasidone. Therefore, we will have an incredible, the biggest study ever in Fabry, with more than 100 patients, sometimes follow for two to three years. It's going to be a mine, a gold mine, if the study is positive, of long-term evaluation, which has never been done, never been seen. I think it's not tomorrow that you will see such a study. This is why we are so excited to have finished a recruitment of more than 100 patients with Fabry. For Stenares, we want to see, it's not only efficacy, it's the safety also, which is going to be very important. We think that we have a very effective drug, but we want to look at the safety, and we want to really know what is the optimal dose. That's going to be our view. I think that it's difficult to compare one study to the other. I would not say that with our study, we are going to know if we have a better drug than BENLYSTA, but we are going to get a really clear view if the drug is effective and safe. Thank you, Jean-Paul. Thank you, Graig. I hope that answers your question. Operator, next question, please. The next question is from Jo Walton, Credit Suisse. Your line is now open. Please go ahead. I'm sorry if you have a glitch. Let's try again. All right. Please go ahead. I'd like to ask a little bit about the timing of how these expenses are coming in, particularly as we're moving into the extra expense on SG&A. I wonder if you can just help us as we go through this year and how we sort of exit the end of the year. If you can also give us some idea, if you've got any, on the launch costs as we begin to model 2022. Clearly, the expenses that we need to model for 2021 are a little bit higher than people have been looking for. I just wonder whether we should carry that on and really look for a stonking great launch cost just to make sure that daridorexant gets a fantastic send-off into the U.S. Yeah, André, I think that one's for you. Thanks for this very good question, Jo. The operating expenses, especially in SG&A, will increase over time, over the next quarters. That's very clear. Second half will be more heavy than first half. 2022, even for us, it's difficult to predict, not so much the expenses that we could have in SG&A, at least in the U.S. and in Japan for daridorexant and then selatogrel, but maybe in other countries, depending on the strategy in Europe, in China, as asked by James previously. The point in 2022, yes, we can reasonably expect that the SG&A will go up, first also because we have the medical reps with our teams in the U.S. Of course, what we need, what we will also have is growing revenues and starting with daridorexant and then selatogrel. Here, we need to have more visibility also on the label, interacting much more with payers in order to better assess what could be the speed of uptake for the drugs and namely daridorexant in the U.S. You have to wait for 2022. Increase spend, but also increase revenue. We're not launching daridorexant not to be a blockbuster. Can I just follow up on daridorexant? Looking at the other similar new launches in that market, to what extent do you think that this is a market where you have to spend a lot of time giving away free product to start with so that the GPs are happy with it? I know that the prescription numbers are light for some of these other products, but is that because of very heavy sampling? Simon, I think that one's for you. Sure. Thanks, Jo. I think sampling will be important because one thing we know in this category is that the way that the patient responds is going to be critical for the long-term success and growth of the product. We do expect to sample. I don't think that we can at all look at suvorexant or lemborexant as benchmarks because really the problem they had was that the products didn't deliver against the promise. With suvorexant, actually, as I said earlier, 28,000 scripts in six months. They got off to a good start, it just went flat because patients weren't getting the benefit of the product that they were expecting, principally because the FDA, when they got the approval, they had to go down to a dose that wasn't even studied in the phase III program as their start dose, which didn't differentiate from placebo in phase II. Patients were starting on a low dose. Because of the AE profile at the higher doses and just didn't get the feeling. We're absolutely clear that patients are going to need to have a good experience, and we're very focused on both sampling, but also the way that we communicate expectations with patients that they experience a good first sort of few days and week of the daridorexant. In that context, the 50 milligram, we believe, is also going to be critical to ensure that does happen. Thank you, Simon. Thank you. Thank you, Jo. Operator, do we still have questions left? Yes, we have one more question from Thibault Boutherin, Morgan Stanley. Your line is now open. Please go ahead. Thank you for taking my questions, a couple. The first one on the launch of daridorexant in the U.S. market. Our conversations with sleep specialists in the U.S. indicate that they were facing quite a lot of prior authorization, barriers to prescriptions for the DORA class. Just if you could comment on that and how you expect to overcome this, in particular since I think you said you are targeting marketing to primary care physicians. That's my first question. The second question, it's about ponesimod. I know you obviously out-licensed this drug to J&J, when I look at consensus expectation for the BMS drug, for example, ZEPOSIA or ozanimod. I see a consensus at CHF 2.5 billion peak. Looks like there's at least CHF 500 million for MS. It looks like expectations for the J&J drug, for ponesimod, is not there. When I look at ponesimod, obviously, you had good efficacy data against an active comparator. Safety profile looks good. Just if you could comment on what consensus is missing here. Thank you very much. Thank you, Thibault. I think we'll kick it off with Simon on the launch of DORA and the prior auth and step edits and priority and payment, I guess, would be all in that same category of questions. Yeah, certainly. Thanks for the question. I think going back to suvorexant's profile, what's happened in the U.S. is that when you launch a new primary care drug, it's very common, as you well know, that you have step edits if you're launching into generic markets. It's very common that branded products are a Tier 3 copay. I think that in itself isn't necessarily a problem if the product delivers. We know that suvorexant has 90% access, but obviously there's 2/3 of that go through a step edit. Patients and doctors will go through the step edit relatively easily because most of them have been cycling through benzos, Z-drugs, and trazodone over the last few years. Their step edit requirement can be met relatively easily. You come to Tier 3 copay, if you then go to a tier 3 copay, you're asked to pay $30, $50 maybe. That's okay if the product works, but if the product doesn't work, then the patient will walk away from it rather quickly. Clearly, access in the U.S. in a generic market is something that we're very thoughtful about, but it's not solely an issue of access. It's actually about the profile of the product and whether it delivers. We believe that step edit won't be a barrier. We also believe that if the product works as well as we expect and we've seen in our clinical program, then patients will pay $30, $50 for a Tier 3 copay. Our research does support that. Just to go back on your very good question about ponesimod, I think that what we have done and what we believe and with our clinical, Guy Braunstein, our Head of Clinical Development, and everybody believe that in Idorsia and in Actelion, is what is very important is to show the benefit of any drug to the patient. Really, if we can show subjective improvement, if the patient feels better, it's going to be very important. This has been our strategy for daridorexant. This has been the strategy also for ponesimod. Not only we wanted to show with ponesimod that we have the same relapse rate like other drugs or decrease of relapse rate like the other drugs. That we could change the main symptoms of multiple sclerosis, which is fatigue. 50% or 60% or maybe even more than 60% of the patient with MS suffer from fatigue. We have been, I think the result, it's public, Johnson & Johnson has been able to say that the study, ponesimod was better than AUBAGIO on fatigue. I think this is going to be very important, I cannot speak about numbers, this is questions to Johnson, I think that like we do for lucerastat, like we do also for cenerimod because I didn't mention, we have a PRO for pain and fatigue into cenerimod. We want to show that the patient feels better. I can tell you, if the patient sleep better, he's going to continue to take the drug. If he feels better, he is going to want to get the ponesimod. If he's less tired, he will like to stick with ponesimod. If he has less pain, he will choose first line lucerastat in Fabry disease. I think that this is really in contrast with a lot of people like BMS, who have chosen as a comparator. It was not BMS, but it was at this time Receptos. The comparator was a drug which is nearly not used anymore, which is interferon. It's very rarely used in MS. They have chosen a relapse as a rate, as a main point. While we are really looking not only at the relapse, but how people feel. That can make a huge difference. Great, Jean-Paul. Thank you very much. Thank you, Thibault. Before we close down the call, I actually did get one question coming in from an investor through the email concerning strategic positioning of daridorexant going forward and other indications, Jean-Paul. What do you think about how we're going to develop daridorexant in the future over time? Yeah, I think the strategy of daridorexant was to get the umbrella of all type of insomnia in a way. People were asking us why you don't go to insomnia into depression, insomnia into neuropsychiatry or whatever. Of course, when you discuss with the FDA of such an approach, they would tell you, what is different into insomnia of depression versus other type of insomnia? Show us if you want to have an indication, you really have to show an effect on depression in addition that an effect of insomnia. We agreed with the FDA. Let's go to insomnia, what is more important is in phase IV. Since we will have the big indications, the largest indication that I think we can have, which is insomnia, basically, then we can start to look at the benefits into subclass, but I don't think we will need to get a label change. We can really demonstrate the benefit, maybe having it included in some sub-part of the label, certainly not in the indication. We can look at some class of patient being depression, patient with insomnia and depression, patient with insomnia and sleep apnea, patient, of course, we think. Jean-Paul, you're muted. Jean-Paul, we can't hear you anymore. I believe we lost the line. I can try to get him back in. Okay. Well, I think that concludes our comments anyway. I think we've come to Well, we're 3:20 P.M., we will exceed our time. Thank you very much for your interest in Idorsia. We've come through all the questions that we're going to be asked today. Next timed release is going to be the first quarter 2021 results on the April 22nd. That leaves you with just stay tuned, expect more. We will be progressing through 2021 with this very exciting story. Operator, close down the lines, please. Ladies and gentlemen, thank you for your attendance. This call has been concluded. You may disconnect now.