Cosmo N.V. (COPN) Earnings Call Transcript & Summary

Good afternoon, everyone, and thank you very much for joining us at this very important day for us. This is an Investor Day, and we haven't hold one for quite in a while. So we're very happy that we've been able to gather such a marvelous audience. And my understanding is that we have more than 80 other people that are connected to our webcast. On the table, you have Mauro Ajani, our Chairman; Luigi Longo, our Chief Scientific Officer; Diana Harbort, our Head of Business Development and Senior Vice President of Dermatology Division; you have Mara Gerloni, head of our preclinical activities; and you have Professor Carmelo Scarpignato, a world-renowned gastroenterologist. I will try to be very, very brief in this very first part of the presentation because the next person that's going to speak after me is Nhan Ngo Dinh. Nhan is the President of our AI division, and he's currently in California, participating to the GTC event run by NVIDIA, which is one of the most important and if not the most important, artificial intelligence event in the world. So the title of this presentation today is A Great Leap Forward, which is what we believe that Cosmo has done, very, very meaningful progress, very, very meaningful advancement. I think, I can fairly say that everything is going very well, it's going as we would have hoped it to go. So management is happy. The company is happy by how things are unfolding. Very quickly, this is the agenda. We will briefly speak about perspective and strategies, and we'll talk to you about our preliminary unaudited figures. Then Nhan will speak about GI Genius and the Medtronic collaboration and what's happening in AI. Diana will speak about Winlevi and Breezula, giving you updates. Luigi Longo and Professor Scarpignato together will give you an update on the advancement of our clinical pipeline on the pharma products, and then there will be an extensive Q&A session. So I'll try to cut short my part. The company is focused in 3 areas: gastroenterology, healthtech and dermatology. We have signed a very, very meaningful agreement with Medtronic in December 2023, which became effective end of February 2024. The reason for that is that the agreement was subject to clearance from the U.S. Federal Trade Commission, which is basically the U.S. antitrust authority. The clearance arrived at the end of February, and hence, the agreement becomes effective in that moment. Just for the satisfaction of all people that have already invested in the company, Medtronic has already paid $100 million, the $100 million that was due as an upfront, and we will analyze our cash position in a moment. Now notwithstanding that you're going to hear a lot about healthtech and about AI, you will also hear a lot about gastroenterology and dermatology. For Cosmo, it is very important to reiterate that we don't feel ourselves as an AI company, will feel ourselves as a pharmaceutical company with a very meaningful and growing AI business. Our investment strengths are here more than ever. We have growing revenue streams, which comes from our established product. They all continue to grow. We have 2 revolutionary growth drivers, launch in very large markets and entrusted to world-class partners. We're clearly speaking here about GI Genius for healthtech and Winlevi for dermatology. We have a very exciting development pipeline full of catalysts, you will hear about some new programs, which are being announced today for the first time that the market didn't know anything about. We have made our financial position stronger than ever. We have fully reimbursed in cash our bond at the end of November. At the end of the year, we had [ EUR 50 million cash ]. As you will see, the business is generating meaningful cash flows we've added up the $100 million just received from Medtronic. And we've been now for some time, quite sometimes profitable with associated dividend distribution. We've distributed a dividend in year '22 over financials of '21. We have distributed an increased dividend in '23 over financials of '22, and we will distribute an increased dividend in '24 over year '23. Some of you might remember that in the past, we said that we wanted to be also a dividend company. So the intention of the company is to pursue this policy and try to make the shareholders as happy as possible. Something that I've said many times, but I think it's always the case to stress. I don't think you're going to find many company our size that can claim to have so many approved products in the market, that has 2 meaningful growth drivers, as I said, and has a very exciting development pipeline. The other speakers will drive you through what's happening. But it's important for me that you focus on the overall snapshot because this should give everyone sufficient confidence to believe that Cosmo is able every time to deliver. It may happen that it delivers later than program, but the fact is that it has always relentlessly delivered. Once we've said that we would do something, we normally end up doing it exactly as we said we would. These are our preliminary unaudited figures for '23. You might have read in the press release of this morning that the reason why these figures are unaudited is because we have couple of items, which is actually only 1 item, still pending with our auditors, which we expect to solve quite quickly, but that unfortunately was not sold in time for us to publish audited results. So we expect that, as we said already in the call this morning, that at the latest, by the time that we're going to have our General Meeting, which is going to be Shareholders' General Meeting, which is going to be on the 24th of May 2024, this issue will be solved completely. It's also nonetheless minimal issue, as you might have seen in the press release, but still meaningful for us, and it was important for us to try to give as much as possible the fair and true representation of what the real performance of the company in '23 has been. So here, you can see revenue EUR 96.7 million, EBITDA of EUR 26.5 million, operating profit of EUR 12.2 million, and profit before tax of EUR 7.6 million. What is particularly meaningful for the management team is the net cash inflow from the operations. So you see a cash generation of EUR 33.6 million over a turnover of EUR 96 million, which means more than 1/3 of revenue translated into cash flows. As I said, meaningful cash position, EUR 50 million at the end of the year, but EUR 142 million as of yesterday. The company has been a relentless buyer of its own shares in the market, believing buying our own shares back was one of the best possible investment for the company. And here, you can see the size of the buyback close to 1.5 million shares bought at the end of 2023, with an additional 7,000 shares bought up until the 19th of March yesterday. So if you -- given the fact that these shares have been bought in view of their subsequent future placement and not in view of their cancellation, we believe that it gives a fair representation of the financial structure of the company to add the value of this to our cash position so that if you put together treasury shares, which we can dispose of and cash at hand, our financial position is EUR 245 million as we speak. We were talking about the strong dividend policy. The purpose of this chart is just to show you how the dividend policy has evolved in the last 3 years, we have recorded an increase in the dividend distribution of 10% from year '22 to '23, but now we are proposing a 90% increase in the dividend from year '23 to year '24. And the EUR 2 per share that you see there is what will be proposed at the Shareholders' Meeting on the 24th of May. The guidance clearly is in line with the fact that the business is growing very, very meaningfully. So we have total revenue projected for year '24, current year, between EUR 260 million and EUR 270 million, quite sizable, I believe, and an operating profit between EUR 155 million and EUR 165 million. For the first time ever in the history of the company, we have decided to provide an outlook for next year as well. The reason we're doing that is that now we have a growing confidence in the capacity of predict what is likely to happen. And we have been pressed in the past by the community to provide some -- shed some light on what we believe should happen. We think that giving an outlook, which is not yet a guidance, it's an outlook for next year is going to be helpful. And this is what we have come up with. We're expecting revenues in 2025 in a range between EUR 240 million and EUR 260 million. I would rather stop here and then answer to any question you may have later on in the Q&A session. Our friends in Santa Monica, they have limited time window, and I'm sure you're going to find their presentation way more interesting than whatever I said so far. So I'm going to pass the word to them, and I'm sure you'll enjoy their presentation as well. So thank you very much again.

Can you hear me Nhan?

Yes. Yes, Mauro.

Yes, it should be 7:20 in California, no?

Yes, more or less, it's 7:15. Yes.

So let me say why don't we start by sharing with us why you are in California and not here? Don't tell for the weather because I know that the weather is much better.

Yes, absolutely. And first of all, good morning, everybody. So yes, actually, it's getting a bit lighter here and actually, the weather is fantastic. But of course, the real reason, as Alex said is for the GTC Conference of NVIDIA. And yes, let's maybe explain a little bit what it is, the GTC Conference. If we can go with Slide 16, please. So Slide 16, please. Okay. Yes. So actually, the GTC stands for GPU Technology Conference, which is a conference from NVIDIA, and has quickly become, let's say, the global conference for developers, tech companies, health care companies as well and much more. And at the conference, you can learn about advancements in AI and technologies. And listen, there are 300,000 participants worldwide, both virtual and present. So it's very busy here in Silicon Valley these days. If we can go to Slide 17, please. I think you've already seen this very influential guy, who is the CEO of NVIDIA. His name is Jensen Huang. In this clip, he is presenting actually the GI Genius platform in his keynotes. And we are the only company that has already implemented the latest IGX.

Nhan, he did a good job in the presentation or not?

So yes, absolutely, very spectacular presentation, his keynote as always is...

It's being presented by him or by the [ Avatar ]?

Yes. Actually, it was him apparently on the stage. Of course, I mean, there's always surprises when it comes to look to keynotes then. So I was -- let's say, saying that we are implementing their IGX NVIDIA technology in our platform as first company and this is exciting news because we are definitely leading the way at the conference. And maybe for those who are not familiar with IGX, so let's explain that. So IGX is the sector of electronic boards and chips that has been specifically designed for the health care industry. It's a cutting-edge technology, and we are going to implement that in our continuous [indiscernible]. So we can go with Slide 18 please. So that's a great R&D development and innovation that is coming to life. Definitely, there couldn't be better commercial and marketing partner to accelerate the adoption of our technology actually like Medtronic, I would say. And this is summarizing, the slide you see here, to appreciate the real -- the difference between roles and responsibilities between us, Cosmo MD and Medtronic. And actually, this is why we are very excited about the future.

I believe that this is a great introduction. Thank you. So first, congrats to you or your AI team to being for the forefront of the AI health care company in the industry. Let me say that I am very proud of you. And just to let us know I believe that if you start with the presentation and starting with the presentation, I do believe that there are -- the first part of the presentation should be, you explain the approval that we got by FDA exactly one month ago, more or less, that allow us to be in the future, see the future in the midterm, in the short and the long term, very, very positive.

Yes. First of all, thank you, Mauro, for your words. So definitely, yes, I mean, let's cover this one. I think it's very interesting. So our GI Genius platform is the most widely-distributed real-time AI platform for health care in the world. As you can see from Slide 20, that I would ask, let's say, to project here. So our installation base, just looking to only Europe and the United States, it is very impressive. And even more impressive is that our technology reached 3 million patients. It's an outstanding number, 3 million patients. I definitely would like you to remember this slide because it's very important for what is coming next. Next. So the user base here. And just think even that we are just at the beginning of our journey because our vision has always been to enable AI in endoscopy by building a patient-ready, computing-edge platform that would allow multiple AI software to be run simultaneously on a single piece of hardware. So let me show you how. So if we can go to Slide #21, please. In simple words, think about GI Genius as a Trojan horse. Inside it, we have like many soldiers which are the multiple AI software, where we are either building in Cosmo or we are deploying from external partners. I would like to paint to you a picture here. So remember the slide I was showing you before with the map of the installed GI Genius units. So the users of those units have been successfully using the colon detection application. Now with this FDA approval, we can deploy to the same customers using the same hardware, additional multiple new AI software. So back to the analogy that we were making before, GI Genius is the Trojan horse and the soldiers are clearly the applications. Now it's time to get those applications out.

This is really great. Can you explain it? So I believe that if I go -- well, we are the only technology that is still in the market -- is in the market in all the world. There are no other technology, no?

Yes. Actually, this is definitely the only platform for hosting AI applications for real-time that is currently available ever, and it has this global distribution, definitely.

Should be the reason why Medtronic is so excited, was so excited, is still excited just to enlarge our -- their agreement with us. Just because the possibility to enlarge to enter in other possible indication, application and deal is really large, no?

Yes, yes, absolutely. We definitely are running this program to have other applications down in our platform. We can go to Slide #22 for that one, please. So we received an overwhelming feedback from our innovation center. So our innovation center is a hub where we receive applications for onboarding in our program to have third-party applications being released in our platform. So, so far, we received about 40 applications from third parties. And so we are offering a service here to Medtronic to screen them, assess their clinical value and pick the ones that we believe are relevant. And then...

Sorry, Nhan. Sorry, Nhan. This is the reason why we do believe that we can deploy other application, let me say, the other -- even another disease, our technology.

Yes, yes, absolutely. And that's not only confined to, let's say, only polyp detection, but definitely going also in other areas which could be any of the procedures that are executed within maybe GI endoscopy and even more, if you would like to apply this one to any camera-based procedure that you can have and the platform is able to run real-time AI to assist physicians, definitely, yes.

So could you tell us what is the application or -- that excite you more?

Yes, absolutely. So for that one, I would like to, let's say, first of all, say that it's very hard to say because there's a lot in and we are actually -- so are you asking me about, let's say, the applications that are in the program that is exciting me most?

Yes. Hello?

Yes. In our program, we have, let's say, a short list of 5 applications that's, let's say, are currently in active development. And their readiness level is very good. The one I would say, it's very attractive, it's very compelling, is an upper GI application that would allow to really contribute to the quality of upper GI procedures. So this is just to mention one. But frankly, there are 5 and all of them are very interesting. And this is, let's say, in the program of AI axis, so to speak.

Great. So...

Yes, and Mauro, if I may add, for what concerns instead other developments that we have in our pipeline, which I would be very excited to cover, and I would ask to go to Slide 23 for that. I would mention definitely the automated reporting system, which I believe it's groundbreaking here. So I believe that this audience has been hearing about big challenges in health care for what concerns manpower, the amount of time that is wasted in performing administrative tasks. So data shows that doctors are spending maybe about 10 minutes per patient to manually reporting things and filling forms after procedures. And if we do a very simple math here, we can think that GIs are maybe seeing 15 patients a day. And so if you just do a simple math, it's more than 2 hours a day that are spent in documents instead of with patients. Actually, it's insane. So if we can go with Slide 24, please. So we already have built a solution to bring this time back to them, back to health care professionals. And then we are sure that they will be loving that. So imagine a place where you finish the endoscopy procedure, and the AI purposely built into GI Genius will automatically generate a report on this patient. So [indiscernible]...

Sorry, Nhan, just to recap because sometimes, this can create confusion because for people, colonoscopy is mostly detection. So it means that thanks to the approval that we got from the FDA, now we can cover under the AI umbrella, the entire system, all the colonoscopy procedure that is not only detection because detection is one of the part of the procedure. Just -- for sure, is the most important but is only one. The second development is to the reporting and the reporting [Technical Difficulty] tricky job for the [Technical Difficulty] because they have to spend meaningful, meaningful [indiscernible] that means that they are losing time for other procedures. This means at the end of the day, the reason why you strongly believe that is a great opportunity.

Yes, absolutely. And I think it's a tremendous opportunity because this is expanding the use of the platform not only to what is happening in this time, but also what is happening after that. And the good thing is that we can apply this to every endoscopy procedure that is happening in endoscopic side potentially and definitely also to any of the instances of the equipment that is already to customers. So this is what I would say, Mauro, it's going to be disrupting, again, the space as we did with detection. So detection was definitely a disruption back when we launched it. And we are definitely sure that this new tool, this new set of tools is going to be a road map of tools increasing even is going to be disrupting the space again.

Now this is important to underlay because -- so for many of us, for people, colonoscopy is only detection. So -- and GI Genius is only detection, no? Detection is one of the smallest part of maybe 1 of the 1,000 applications that we can deliver through our system. This is important that we explain properly. And thank you very much. And again, I am proud of you and your team, and let me say that we cannot do better. Thank you, Ngo Nhan.

Yes. Thank you. Thank you very much, Mauro. Thank you. Thanks, everyone.

Okay. Yes. Now we -- there is Diana that is going to present.

Thank you. Now we're moving to the next item, the update on Winlevi and Breezula.

Well, hello, everybody. It's so nice to see so many familiar faces that I remember from the Cassiopea roadshow and the time we were public, and now we're back into the Cosmo family. I've got some exciting information to share with you on both Winlevi and Breezula. As many of you know, Winlevi is the first-in-class androgen receptor inhibitor for the treatment of acne. And it has had one of the most successful launches in the U.S. topical acne prescription space in the last 15 years. Importantly, this product addresses the 640 million patients worldwide that have acne. Since launch, over 927,000 prescriptions have been generated in the United States for Winlevi being written by almost 18,000 unique health care providers. So this product in 3 months of launch became the #1 branded prescription topical acne product in the United States, and it remains that way now. As many of you know, we partnered with Sun Pharma for the U.S. and Canada and a handful of other countries. In the U.S. and Canada, we have a very attractive set of deal terms where we get double-digit royalties and could receive up to $190 million in commercial and sales milestones. This product was recently launched in Canada in September of last year by Sun. And just earlier this month, we received approval in Australia, so the product will be launched in the summer by Sun. Now we're embarking upon global expansion for Winlevi. Over the last few years, we have put together a set of very strong, experienced derm players to launch Winlevi in 40 countries over the next 3 years. We continue to expect nice strong revenue growth in the U.S. and Canada. And now the regulatory process is underway in this year in the EU, the U.K., New Zealand, Singapore, Malaysia and the Philippines. We have further regulatory submission planned along with our partners in Brazil, Mexico, the Middle East and North Africa, 15 countries there and Korea. And in those countries that require local clinical studies, those studies are either being planned or being embarked upon in the not-too-distant future. And those studies will be done in China, Japan, Russia and India. So like I said, imagine where we started developing Winlevi so long ago, been now launched in U.S. and Canada and over the next, like I said, next 3 years, will be launched in 40 countries. And by the year 2027, it will be launched in 9 more countries. This will result in a revenue increase to Cosmo for Winlevi of over 70% by the end of 2025. So let's talk about Breezula. Breezula is the first-in-class androgen receptor inhibitor for the treatment of androgenetic alopecia, otherwise known as male pattern baldness. Just to remind everybody, Breezula contains the same active as in Winlevi that is clascoterone, but in a very different dosage form, in this case, a solution, and in a very different strength. Breezula has a tremendous market potential. There are 2 billion males worldwide that suffer from androgenetic alopecia or male pattern baldness. And in fact, AGA, as we call it, affects over 50% of males worldwide. And interestingly enough, this is what we call a dormant market. These -- the only 2 products that were approved in the United States were approved 30 and 40 years ago. So treatment options are very old and a new product has not been launched in a very long time. Now in the United States, 80 million to 95 million Americans suffer from AGA, but only 10% of them are getting treatment. That's because the treatment options are old. And there's not much promotion happening at all at the level of the health care provider, doctor's office or at the patient level. So again, Breezula is a very attractive opportunity for us in androgenetic alopecia. In fact, our product is poised to disrupt the market, which hasn't seen a product in a very long time. And these patients have been looking for a new product for a very long time. So in summary, it's a very large global opportunity. It's an underdeveloped market with old, old products. And in fact, no significant competitive products are expected on the horizon. And in fact, to be truthful, like I said, there is no promotion going on to stimulate these patients to seek treatment either at the patient level or at the doctor level. Now over the last few years, we've conducted a substantial amount of market research to help us really better understand what the market potential of Breezula would be in the U.S. We have tested the patient profile or the product profile of Breezula as it was determined in our Phase II studies. We tested that with 300 health care providers and 500 sufferers of androgenetic alopecia. And not only did we test the profile with androgenetic alopecia patients who use products, but we also tested it with those people who suffer from the condition but aren't using products. And I've listed some of the highlights here. 70% of these AGA patients say they're highly concerned about their hair loss. And most users of AGA products and half of nonusers have a very positive opinion of the Breezula product profile. In fact, these patients report a very high level of adoption of Breezula. Half of these product, AGA product users say they would use Breezula, along with the 1/3 of AGA sufferers who I say, remember don't use the product, would use Breezula. Also, when we tested this with the doctors, doctors expect to use Breezula in 60% of the androgenetic alopecia patients they see in their office. And interesting with Breezula, Breezula -- that will compete in a market that is what we call a lifestyle drug market. This is a market where it's a cash pay situation. It's not covered by health care reimbursement. And when we tested what the price consumers would be willing to pay, they would be willing to pay $75 to $150 per month for the product, similar to how other lifestyle drugs are priced in the United States. When we ran our financial models and really tried to estimate what the peak sales potential could be of Breezula, we're looking at $1 billion in the United States. And let me just run through some of the assumptions.

Trillion -- billion doesn't impress people, especially Americans, only the trillion, the billion is billion.

So let's just talk a little bit about how did we even arrive at that number. We took the very conservative assumption that we will target the existing physician-driven androgenetic alopecia market. That's where patients visit a doctor because they're concerned about their androgenetic alopecia, and then the doctor either prescribes them a product or recommends an over-the-counter product. That's what's happening now. So in 2024, this market is estimated to be about 11.5 million units of an androgenetic alopecia product, 60% of those units or 7 million, are in males. And we are expecting a 6% market growth per year. At peak, we assume Breezula, the only new product in the space, will have a 35% market share, by the way, competing against those products, minoxidil and finasteride, which were approved 30 and 40 years ago. Again, this is a lifestyle drug, cash pay market. We took a conservative position that will be launched at $110 per month, and that there will be important promotion to both doctors and to patients, to stimulate growth and stimulate the patients to come to the doctor. So that is how we arrive at the peak market potential for Breezula. One of the most important things I can say that we have going on at Cosmo right now, and certainly, the most important thing for me is the Phase III program that we're currently embarking. You may recall, we published in June of last year, our press release that said we had begun this important Phase III program. Now first of all, in Phase III, we are testing the most effective dose that we discovered in the Phase II program. That's the 75-milligram BID, and we're using similar endpoints that we used in Phase II. In this Phase III program, we are enrolling 1,500 androgenetic alopecia patients with mild to moderate AGA across 50 sites in the U.S. and Europe. Now this...

Sorry, Diana. At the time of the Phase IIb, we achieved good results, if I remember well.

Yes, we had statistical significance in our primary efficacy endpoint, with a 75-milligram BID versus the vehicle, which is the one we are taking into this Phase III program.

Crossing the finger, we should achieve the same result because we are not -- we didn't change the study. We have the same active principle. We have the same quantity where everything is the same.

Everything is the same. And also, of course, we have this tremendous confidence in the active that now has been used in almost 1 million Winlevi prescriptions.

Okay. Thank you.

You're welcome. So let's just quickly talk about the study. This Phase III program consists of 2 identical studies, SCALP 1 and SCALP 2. Each of these studies have a part 1 and a part 2. In part 1, we are testing clascoterone versus vehicle for 6 months, with the goal of evaluating the efficacy and safety of the drug at 6 months the co-primary endpoints just as we're in our Phase II program is the target area hair count and the patient-reported outcome. Part 2 of the study is an additional 6 months of treatment in the patients who responded in part 1. And the purpose of that is to determine the long-term safety and the durability of treatment. So this is quite -- this is a study that, by the way, is quite similar in size to the study we went on Breezula. So let's talk about the time line. This study is currently over 60% enrolled and we will complete enrollment here in the next couple of months. Then a year from now, we will have the top line results of the 6-month endpoints. And so we'll be making an announcement, hopefully, perhaps at R&D Day next year. Later in the year, next year, we will be filing with the U.S. FDA and the European Commission the new drug application for Breezula and then a year later, will receive approval. That completes my prepared comments on Breezula and Winlevi, and I look forward to your questions.

Now we move to the novelties in the other clinical development of Cosmo.

Hello. Hello, Welcome, everybody. Thank you for coming here and listening to our presentation, our developments. I'm here with Professor Scarpignato, who is our reputed the consultant, and we are here to present to you our GI pipeline. So since the beginning of Cosmo's journey, we based our developments on some very important pillars that are identify an unmet need, exploit our technology for new product development, put into practice, fill in the gap. This characterized our story since the beginning and we exploited our MMX technology throughout the years to achieve different and important products starting with Mesalamine MMX, the first once daily mesalamine tablet for ulcerative colitis to end with latest approval of Methylene Blue MMX, the patient-delivered chromoendoscopy. And here, we are here now to present you the latest MMX product, the latest one in our long list. This product is addressing as always an unmet need. I think that most of you have heard at least once in your life about irritable bowel syndrome. This is a very prevalent disease. It affects 5% to 10% of the population worldwide. In the United States, 6% of the population have IBS. Consequently, this disease is very prevalent and also very attractive from an investment point of view because the global market size is really huge. Now Professor Scarpignato, can you walk us through the features of this disease and the challenges?

The IBS is very prevalent, and it is very common everyone in the life at the moment of difficult stress getting IBS symptoms. The key symptom, which is the hallmark of the disease is representing by abdominal pain and some discomfort, always are contained by changes in the bowel function that could be either diarrhea or constipation. That's why we have, let's say, 2 main subtypes of IBS, D-IBS and C-IBS, which impacts on quality of life, impairing it. The main difference between D and C is that while patients with IBS-C are very homogeneous and easily to treat, patients with IBS-D are a very heterogeneous population with a very complex part of physiology and difficult to treat. As you can see here, there is not an easily identifiable cause. In the sense that each patient is different, you cannot use the same drug for all the patients and you cannot actually use the same drug for the same patients in different moments or ease their life. This is the main difficulty. And you see that many drugs have been developed for treating IBS and the very fact that we needed many drugs or actually many drug classes testifies that no single drug is available to really address the complex symptom pattern and to give patients the symptom relief we need in everyday clinical practice. Well, IBS-D, as I said, is a very heterogeneous, but the recent evidence pointed out that almost 1/3 of these patients have a very clear identifiable underlying cause, which is the so-called bile acid malabsorption. What is that? Bile acid are produced by the liver and stored in the gall bladder which contracts after meal to deliver the bile acid into the small bowel, where they are of vital importance for digestion. After that, they are reabsorbed and go to deliver again. This is called enteropathic circulation. When this physiologic mechanism will fail, the bile acid that will enter the colon produce an amount of water and fluids leading to the so-called bile acid diarrhea. At the present time, we do not have any, let's say, FDA or even another agency-approved drug to treat bile acid diarrhea. But we should do something for our patients to help them and improve their quality of life. So we use drugs off label that is not approved, but because we know they can work, and we use the so-called resins, which are sequestrant generally speaking or everything, and they have been developed for hypercholesterolemia, but we found afterwards that they can bind heavily bile acid and help their expression through the stool. There are several bile acid binders, but the most widely-used compound is colesevelam which is widely used, but I have to say it is far from being ideal drug and needs to be improved.

So we have -- thank you, Professor Scarpignato. We heard how challenging this disease is because we are speaking of a very heterogenous disease with the very same symptom. And the fact that the population is heterogeneous makes also the clinical trials extremely challenging. In fact, there is no diagnostic test available thus far that allows to identify the precise cause that is causing the diarrhea that is a very as specific symptom present for a lot of different GI problems. And therefore, this results in a very low drug response of the approved drugs as compared to placebo. Less than 15%. As you can see here displayed in the slide from the 2 most recent drugs approved for this indication by the U.S. FDA. And why is that Professor?

I have to say, why it was that? Because it is true that until very recently, we had a very difficult test not applied outside referral centers. But we do have today a very simple bloody test, which is a sensitive and very cost effective, allowing us to identify precisely those IBD, the D-IBS patients having bile acid diarrhea. Identifying them means that we can treat them selectively, and that we can select them to recruit them in clinical trials which are not, therefore, any more blind trial but are very -- BAD-directed trials, which will have more success than the previous one.

And these are the basic pillars of this new development. We have an unmet need because there is a very prevalent condition and no approved drug to treat that condition, and also, we have available this diagnostic test that is very specific and acts like a sort of [ gun ] immediately identify the patients who have this disease. And now so we started the development, and we applied our MMX technology to colesevelam. Colesevelam MMX releases the active substance exactly where it is needed to bind the bile acids and prevent the diarrhoeic effect, contains a high dose of colesevelam to improve the patient compliance and this is expected to provide remarkable therapeutic effects that are here depicted on the right of the slide. And in this slide, we are showing the design of the study that we are going to start towards the end of this year. So patients with IBS-D symptoms, so this very heterogeneous population will be precisely diagnosed for bile acid diarrhea by utilizing this very specific test. People who are tested positive and so are confirmed to have bile acid diarrhea will enter the study. People who are testing negative will be excluded. This allows us to have 3 arms study with a limited sample size as compared to what is normally the sample size in IBS-D trials. And to end our presentation of this product, why are we starting this very long journey with this new project? Because there is a big opportunity there. The IBS-D market is huge and it is expected to increase over the years. And about 1/3 of the patients with IBS-D actually suffer of these bile acid diarrhea. And so we estimate that U.S. market potential for colesevelam can be about EUR 800 million per year at peak sale. And now we are also going to present to you a new development project that we started quite recently. UC exactly. We play at home because it's where everything started at Cosmo. So Professor Scarpignato, can you teach and speak about the disease in a synthetic way?

Conversely, from IBS, which is functional, IBD, inflammatory bowel disease, of which you see is 1 of the 2 forms, including the so-called Crohn's disease is an organic disease. It's challenging and it develops in genetically predisposed patients. Symptoms are very heavy and impairs heavily the quality of life. They include pain, abdominal pain, urgency, rectal bleeding, diarrhea and so on. And the pathophysiology is very complex, leading always to one main symptom, inflammation, which is mainly due to a dysregulated immune response, our body starts to work against us instead of against the external stressors like viruses and bacteria and dysbiosis, which is the prevalence of a bacteria in our small bowel. The prevalence is relatively high, less high than IBS for sure, but it is steadily increasing, either because of the live condition, but also because we are more able to diagnose UC or IBD in general compared to the past. We do have now better endoscopy, better imaging and better biomarkers of the disease.

So over the past years, the possibilities to treat the patient has increased so there have been a lot of new drugs approved for this indication especially in the past years we have seen lot of new and very potent immunosuppressive drugs like biologics to treat this disease. But mesalamine and steroids still represents the pillars of the UC treatment. Nowadays, most of the patients start with treatment with mesalamine and steroids. And who knows better than us. We are the leader in this field. We developed and currently manufactured 2 main products for the treatment of UC: mesalamine MMX, Lialda and Cortiment. And it is -- thanks to our knowledge that we also know one thing, one peculiar aspect that is the following: We know that all the overall treatments fail delivering the active substance to a very crucial and important area of the colon that is the rectum, where is -- where everything starts, right Professor?

Absolutely. These are the so-called clinical presentation of the disease. Some patients may have only the rectum involved, and they have, in this case, the so-called ulcerative proctitis. In some other, the inflammation can go upward until the splenic flexure and they have the so-called distal colitis, and in some, fortunately less patients, the inflammation can involve the entire colon leading to the so-called pancolitis. Now fortunately, 70% of the patients, they have a proctitis and/or a distal colitis. It is evident that you can have proctitis alone, but if you have distal colitis, you also have proctitis because here is where the inflammation will start. Therefore, we are faced, as doctors, with 2 kinds of patients, those who have proctitis and we need to deliver them the anti-inflammatory drugs, be they mesalazine or steroids. And we can only use suppositories because if we use enemas, we can reach and go up until their splenic flexure, but unfortunately, we pave the rectum. That's why in all the studies where mesalamine or steroids have been employed, proctitis have been excluded. They were part of the so-called exclusion criteria. Therefore, having no large clinical trials on ulcerative proctitis, we do not have any evidence-based treatment. And what we do is merely empirical. We need a drug specifically developed for ulcerative proctitis. Please...

Sorry professor, this is well described in the guidelines, no?

No. They are not even mentioned in guidelines, like the ECCO, the European Cronh's and Colitis Organization, which is in Europe, at least the leader organization. Not mentioned, forgotten.

Okay.

So thank you, Professor. So we know that the current standard of care of treatments for distal ulcerative colitis and proctitis suffer of several drawbacks. Very simply, the enemas that are on the left, deliver the active substance solely to the distal colon. While no active substance or very low amount is delivered to rectum, and this means that you are treating only one portion of the inflamed area. Conversely, suppositories only delivered to the rectum and don't deliver active substance to the distal colon. So if you have distal ulcerative colitis, where you have inflammation in both the descending colon and the rectum to achieve the maximum therapeutic effect, we should combine suppositories and enemas, which is obviously unpractical. This is why we conceived...

Obviously, before us.

Obviously, before us. Yes. And this is why we first conceived a new delivery system that is very simple. Normal enemas only have an apical hole for delivery of the solution, and the solution is sprayed upwards. We applied a cannula with lateral holes, allowing further delivery of the solution also, laterally to the rectum.

This is the tricky part of...

This is the tricky part [indiscernible]. This is a commercial enema, both at the pharmacy...

You can understand it only if...

No, there is nothing...

Sorry, you can understand only if you see because it's very simple, but the life is simple. Sometimes, we do the best just to complicate our life. But it's very, very simple.

[ Mauro ] life is simple, but we make it complicated.

No, the best -- the best to complicate...

Just to be clear, you're not going to see a real-live demonstration. Okay.

No, no. Don't worry. We're not asking also for volunteers, let's say...

Now we are...

Not with real patients.

We are looking for a volunteer now.

So just imaging, this is the rectal cavity -- you see the movements.

This is a normal enema.

This is both at the pharmacy. So you see, it goes only on the top. We show you very simply how this simple concept work. So it covers the holes and goes up. And by this very simple delivery device, we will be able to cover both the rectum...

over where there is the need.

Where there is the need.

It is very simple.

But we want to innovate because -- the driving force of our company.

It is not too simple -- not too simple...

We need to make something more. So we also conceived a delivery vehicle that is liquid at room temperature and becomes a bioadhesive gel at body temperature, thus prolonging the residency time in the target organ. We have prepared this very short video. Of course, it is always a laboratory test. So you are not going to see any bloody or splatter movie. Where we want to display how this basic technology works. On the left, you see our formulation, on the right, the very same formulation that I showed you live here, they are poured, and then they are heated at body temperature. You can see that on the left, our solution has become a very viscous and bioadhesive gel that is remaining on the bottom of the flask, while the commercial enema remains liquid. These are the basic differences between our new platform and what is currently available on the market. So on the left, we have a solution that becomes a viscous gel, while commercial enemas remain liquid. Our product has high adhesiveness while commercial enemas do lack adhesiveness. Our is long-lasting and remaining in situ while the commercial enemas do not have any adherence.

We're never satisfied. We have another improvement for...

Exactly.

Go. So you have seen this very nice new delivery system and new formulation because I am a GI pharmacologist and gastroenterologist, and I have to tell you that for the GI tract, often the formulation is even more important than the active ingredient. So this is already a step forward. But the question is what's in the bottle? In the bottle, we have an antibiotic, which is a very peculiar one. First of all, it is not absorbed. It's a wide spectrum of antibacterial activity. And being not absorbed, it stays in within the GI tract with very high concentration and very high bioavailability. And again, being not absorbed, there is no risk of any adverse effect because it will never reach systemic circulation. You know all that antibiotics are life-saving compounds. We cannot live without antibiotics after the discovery of penicillin, second world war. But antibiotics are not clever enough. They kill the bad bacteria, but they kill also the good bacteria that are our microbial flora, which is now called the microbiota, the third organ. And this organ is extremely important for life, it synthesize vitamins, for instance stimulates immune system and so on. So it's important to leave them alive, and rifamycin Is different in this context, the next one, compared to the other antibiotics because rifamycin instead of killing bacteria, it modulates bacteria. That is, it kills the bad bacteria and actually increases the concentration of good bacteria, what we call probiotics, what we can have with yogurt or commercial probiotics. But the increase is this, Lactobacilli, Bifidobacteria, which are endogenous probiotics. That's why..

[indiscernible] than the yogurt now?

That's why -- absolutely. That's why we have called it eubiotic biotic and not more antibiotic because of this peculiar activity. And in addition to the eubiotic activity, there is an anti-inflammatory activity, which is independent from the antibiotic activity, which is extremely important in ulcerative colitis where the symptoms is inflammation. So ladies and gentlemen, the use of this drug is a really step forward because until now, Luigi told you that the pillars are mesalamine and steroid, which are only anti-inflammatory drugs, whereas rifamycin is anti-inflammatory and eubiotic, correcting dysbiosis. So this is the first drug for ulcerative colitis, which goes a step forward in pathophysiology.

And this slide here displays you the study design. We have just started the study because the study is now active. We activated it just yesterday. So patients with ulcerative colitis symptoms will receive colonoscopy and biopsy to perform a precise diagnosis of the severity of the disease that there is a real inflammation and also to confirm the extent of the disease. The patient with inflammation confirmed and with inflammation localized either in the descending colon and/or in the rectum will be then randomized between the 2 arms, rifamycin enema or placebo in double-blind fashion.

So what we can expect in 2026? I do not have a crystal ball like I would like to. But on the basis of my long life experience and on the basis of, I would say, the real good technology and conception of these 2 innovative drugs, I -- ladies and gentlemen, will expect very positive results of clinical trials. And let me end this presentation reminding you what a great thinker of the past century was used to say, "I never think of the future, it comes soon enough." And let me believe that with the Cosmo technology, the innovative drugs for GI diseases are already there. Thank you very much.

Mara?

Okay. Here we are. Last but not least, this is the oncology program. Cosmo doing oncology because we are using CB-03-10. CB-03-10 is a part of a family of compounds that are property exclusive of Cosmo Technologies. And it's very similar to the compound that we are using and we develop for the treatment of acne and also alopecia, but is characterized by a broad anti-cancer activity. How does it work? It's bought an inhibitor of the androgen receptor likely the most commonly used anticancer drug to treat prostate cancer. And at the same time, as also an activity against glucocorticoid receptor. It's the only one that has this dual activity. And this has been unknown for -- has been discovered by us. Lately, in the past 6 months, we also discovered that is also an additional activity that it is -- it works very well in combination with immuno checkpoint inhibitors. I will try to make this simple. What are immuno checkpoint inhibitors? Probably a lot of you know that cancer is being treated probably for 50 years with very potent and very toxic anticancer, what is called cytotoxic drugs. Lately, in the past 6 to 7 years, this category of immuno drug has been discovered and also James Allison has been awarded a Nobel Prize for that. How does it work? Cancer is not recognized by the immuno response. That is why when we get a virus, we are able to clear it. When you get cancer, we are not. Why is that? Because -- where is the pointer? Okay, here. So I can guide you through this. Thank you. Yes. So this is the tumor cells. And this is what is called PD-L1. So the tumor cells start to express this kind of flag. We interact with this part on the immuno cells. When this is happening, the immuno cells that should clear out the tumor cells does not work. And this is when cancer kills you. Immunotherapy drug, what did they do? What was this discovery? You still have PD-L1 on the tumor cells. You still have the anti-PD-1 on the immuno cells, was created a biologic and antibiotic that goes, stop this interaction. So at this point, the immuno cells can see the tumor cell and can kill it. So this is the theory and actually, it's the practice between how immunotherapy works in cancer. So what was our recent discoveries was that CB-03-10 when it goes and it treats a cancer cells, it decreased the expression of this PD-L1. So it makes it clear, it makes it flagged and the immuno cells can recognize it. So this is an experiment that we have done in the mouse, where we administer -- we, first of all, implanted colon cancer in the mouse and we treated them with the vehicle, so like in our treatment, our CB-03-10, and you can see that the tumor volume decrease. Then we gave them a human actually immunotherapy and here it is. But the most important thing and the most interesting thing to us is when you couple, when you combine CB-03-10 and the anti-PD-1, here, the tumor goes up much less is cleared in a significant way. To make it very clear, these are the tumors that are taken out from this category of mice, and these are the tumor after the treatment with the combination. So with this set of experiment, we were able to effectively demonstrate that adding CB-03-10 to an anti-PD-1 antibody, we increased the tumor growth inhibition and tumor and the cancer clearance. Where are we now? We are, that CB-03-10, as I explained to you earlier. Not only we were able to demonstrate that it kills several type of tumor in vivo in the mouse, but we are using it in a clinical trial, in a clinical trial with the oral dosing. So it is an oral compound that we administered in patients with solid tumor and in a dose escalation clinical trial. Until now, we treated 14 patients. And the most important thing here is, is very safe and tolerated, means that all these 15 patients do not have very serious side effect. Why I'm stressing you this, not only because of the fact that we are in a clinical trial, so very close to see this applying therapy in the real world. But here, one of the key is, safe, because if you remember in the earlier slide, I propose the combination with the immunotherapy. Immunotherapy is a great way how to treat cancer, but it's not devoid of side effect. So you cannot combine a therapy that already give you some side effect, even a little bit toxin with something that is also toxic. So one of our -- in my opinion, one of our -- the most important property of these compounds, CB-03-10, is that is also very safe. So this is to give you some number because otherwise, I'm going to bore you just with the science. We know that less than 9% of people affected by pancreatic cancer that is one of the cancers that are sensitive to CB-03-10, is not going to reach the 5-year survival. Then we have colon cancer, another cancer that is sensitive to CB-03-10, that is becoming the tumor fastest increasing tumor in patients under 50 actually. Latest number are saying that is there's more rapid increasing tumor in male under 40. And then we have the prostate cancer patient, where we have approved the antiandrogen therapy, 1/3 of them are resistant. And again, our CB-03-10 is able to tackle that resistant part of the prostate cancer people that become resistant to common treatment. And then we have the addition in my opinion, very important and cutting-edge aspect that we can combine this compound with immunotherapy with PD-L1 antibodies. I would like to remind you that PD-L1 antibodies are the second best seller drug in the world wide and a big pharma company have their own immuno drug treating cancer. I'm talking about Bristol Myers, Johnson & Johnson, Merck. And right now, we are at the point that we are starting to talk to them about proposing CB-03-10 to be combined with drug that is already in the market, is already effective. However, when it can be combined with our compound, it can be more effective, but most importantly, not less safe. And this ends my presentation.

And now we're very happy to move to the question-and-answer session. So please, the audience is welcome to ask anything. Hazel is coming with the microphone.

Everybody can hear you on the webcast.

So thank you, everyone, for the very informative day. I'm [ Jana Denes ] from UBS Asset Management. First, maybe could you clarify the funnel for the GI Genius you had the numbers progressing. Are those representing the successful 5 out of the 40? Or should we expect the other 35 to keep coming through?

You should expect many of those to come. That is just the initial screening. The innovation center, in fact, has the purpose to allow external developers to bring their own ideas and embed them into the system. I think it's important that you realize what is the advantage for the developer because this is key. If you have a guy, a company, an institution, they want to develop, let's say, their own device for detection of gastric cancer. They have to gather the data, they have to develop the algorithm, they have to develop the software, but then they have to develop the hardware as well and they have to procure the manufacturing. They have to go through a hell of a lot of complexities that are not strictly linked to being able to do the application for the detection, but that are needed for them to bring their product as a stand-alone in the market. And this is incredibly complicated. And it's -- and the part that is not qualifying for them, it's the part that's taking more energies. Just imagine, you have to figure out how you build your own computer, how you get this validated by the FDA differently from the algorithm being validated. So what we have...

90% of the people believe that algorithm [indiscernible] thing to go to the market. Algorithm, it's like, let me say, a drop in an ocean. It's nothing. Yes, you have to start for an algorithm. When you get patent algorithm. Welcome, now the journey is going. You have to -- long, long, long way. By the way, sorry, Alex. Nhan, are you still in the conference? Nhan?

Yes, I am.

Okay.

You want to add something, Nhan.

So I believe that it's really important if we can transfer to the audience, the reason why we do believe that the innovation center is the real key driver of the operation because -- so let me say that the normal people don't understand properly the complexity, they go to the market. I can -- just to help you, there is something that you can compare. In the year ' 90, only in San Diego, there were 551 biotechnology company, startup, medium-sized. 20 years later, you know how many go to the market with one product? Less than 6. The other collapsed. Why collapsed? Just because there is a need of money, a lot of money. You are continuing to raise money, to raise money, to raise... Second, there is a need doing larger clinical trial because just for validation, a few patients are enough, but just to convince the FDA, you have to pass 1,000 patients. Take time and millions, okay? This is the reason why I do believe that we are just in the beginning of these projects, and we can help institutions that could be university rather than academic board, rather than hospital, rather than just to enter in this play. Just to give you another -- so if you can compare our device in the Trojan horse, try to figure out a Trojan horse rather than the box. They try to figure out that the soldiers, the Greek, are already in the horse. They are already in the device. Now Mr. Nhan, is not easy. Mr. Nhan that allow the other to get out, to fight, get out and fight together. Nhan, try to explain better than me the -- without the Trojan horse.

Yes. You say it correctly. The innovation center is our way to work on opportunities and that's why it is a funnel process. So as every funnel process, just also back to the question, we are filtering out a lot of requests based on for instance, maturity level, compliance and other things. As Mauro said, also there are 2 main work streams here. So one is external developers. Those are companies that have a quality system, they have regulatory affairs and they are able, let's say, to clear the product on their own. And they are reaching out in the innovation center to enter into the qualification process. And the second group is instead with institutions, for instance, research entities that would provide a meaningful, for instance, clinical need and also data and also help with the clinical development. But then they would need us to do the remaining part. So those 2 work streams into the innovation center are very different, but the goal is the same. So to qualify what is called responsible AI products that would, let's say, raise the bar of quality in our marketplace, in our ecosystem. So just to, let's say, go back to the question, we filtered out a lot of requests. Some of those requests will -- coming back later, maybe because they need some time to, let's say, process and get maturity. And some other things that have been excluded because we found them not to be suitable. I would like also to say that in the last months, we got a sharp increase in the requests. So I believe that this is going very well in the, let's say, remaining part of the year. And the opportunities that are emerging from let's say, those submissions are incredible and our spending across the whole endoscopy field and going beyond endoscopy. So it's a very unique way to collect all those opportunities, so -- they are coming from for instance, routed by Medtronic. Those are coming directly from, let's say, directly from external players, they are coming from opportunities like GTC, for instance. A lot of...

Sorry, Nhan. How many contents do you have now, with people that want to deliver their technology or their algorithm or their AI with us?

I said, I mean, 14 is our last, let's say, freezing -- the last number that we've frozen, let's say, 14. But those are continuously [indiscernible].

But can you share with us the name of maybe the institution or the hospital there. So if you can, I don't know if you have something that we cannot, if we can disclose. They can understand the magnitude of interest, no?

Yes. So let's say, taking a high level of the institution names, I think we can share them, maybe we cannot share, let's say, the specific initiative that has been the subject of the submission. But let's say, institutions are like Mayo Clinic, Johns Hopkins University.

It's more than enough.

Yes. So let's say anymore, I would say, it's very interesting that a lot of companies, even that are in the space, you would think about them as a potential, maybe competitors, then of course, I mean, you have to be in the market to be a competitor. But let's say, those are reaching out because actually, we are really creating this program is unique because it's not only a technical platform. But also, it's a distribution opportunity. So it's definitely something that a lot of other companies are just seeing as an opportunity beyond the technical thing.

Thank you, Nhan.

May I ask one more?

Please.

This one is very different. But if perhaps you could give me a bit more insight on the Breezula cost sensitivity analysis when this was done? Was this pre or post-Ozempic or pre or post-inflation?

So the first time we did this, the round of market research was around 2018, 2019. And the next round we did was in 2022 before, of course, we were funding our large Phase III trial. It could be with, of course, the Ozempic situation, that price could increase, right, because the lifestyle drugs in that category are priced much higher. But clearly, we would -- we plan to partner this drug. So we will work very closely with our commercial partner to do another round of what is very important in terms of price sensitivity analysis, as you can imagine.

Go ahead, please.

It's Laura Hindley from Berenberg. I've got some questions for Diana as well. So on your Breezula slide, you said that half of current AGA users would use Breezula. Given that you spoke about the limited treatment options, it actually feels quite low that only half would use Breezula. So can you speak to what your research showed as to why they wouldn't be using it? And then within your $1 billion peak sales assumption, how long are you expecting that patients will stay on therapy?

So the first question is based on their likelihood of use. And when we described the product, we had to use what would be called patient-centric descriptions of the product, right? We're not going to use a very technical clinical description because that wouldn't be appropriate for a patient. So we used descriptions, this product grows hair in x percent of patients. These are before and after pictures, et cetera. So when you take a look at this sort of research that is done with patients, it's not uncommon for patients to be split in the middle, half would, half wouldn't. In fact, this sort of research having 50% of patients that are currently using products, say that they would use your product is actually a massive response. So that's -- does that help answer that one?

Yes, it does. And then how long are you expecting patients to stay on therapy for within your $1 billion peak sales?

So what happens in the AGA market is, patients go on and off drug. So we didn't alter how long they were on drug. We just know how many units are sold per year right now in this market, how many are used by males and what the market growth is? And then we are taking a share of that, which, by the way, a 35% share is a pretty low share given the patient adoption figures I gave you and the doctor adoption figures. So we didn't segment that into how long the product would be used because we're saying we know the market is 11.5 million units right now. So it didn't -- it already captures the normal behavior of AGA patients who come off and on drugs.

Okay. And then I've got one more question on GI Genius, if that's okay. You noted in your preliminary report today that subscription revenue had increased, but the number of devices shipped to Medtronic have decreased. Does that reflect a slowdown in demand for new device installations in clinics?

It is just a problem of stock. So by the way, we have to look at the entire business, though the entire business is progressing very well.

It's [indiscernible] from Finance [indiscernible]. In your presentation, Nhan, you mentioned those 5 apps in development and you named one, but I didn't get which one it was. Could you repeat, and eventually mention 1 or 2 more. And then is the automatic reporting app that you presented, is that part of those 5? Or is that an additional one?

Yes. So interesting question. The one I mentioned is on upper GI quality.

Sorry, can you say that again?

So upper GI quality.

Upper GI quality.

Yes. And the other that I could mention -- let's say, application stuff -- or not, let's say, in the lower and the upper GI. We have a couple of them in those spaces. So we cannot disclose at this point the areas. But let's say, the other is about the automatic reporting system. So that one is in addition to the 5 that we've mentioned. So the 5 are specifically those that are coming from external entities. The automatic reporting system instead is something that we are developing internally.

Ram Selvaraju, H.C. Wainwright. Just a couple of questions for Diana. One is with respect to the IP exclusivity profile for Breezula versus Winlevi. Can you just give us a sense of when those respective market exclusivity periods end? And if as and when Winlevi loses market exclusivity, you continue to expect Breezula to enjoy protection? And then the second aspect of my Breezula question is with respect to the DTC promotional activities that you expect to be most appropriate for this product as and when it reaches the market, particularly when we consider the United States. And if, in particular, there are specific marketing channels that you think are likely to be most appropriate or if you expect to be using Super Bowl ads and high-cost kinds of advertising in order to support this?

Thanks. So the worldwide patents on Winlevi expire in about 2028. However, as you know, in the United States, there's patent term extension. And we estimate along with Sun that those patents will expire in around 2030. Now the patents for Breezula are distinct to Breezula and those patents expire worldwide in 2036. Does that answer it?

Yes.

Now as it relates to direct-to-consumer advertising, there's several approaches that could be done here. And we are now beginning, you can imagine, discussions with various commercial partners about how they might envision selling and promoting Breezula. That could range anywhere from online, social media sorts of promotion, which, by the way, is very effective, as well as -- and well, that would be on one end of the spectrum. And on the other end of the spectrum would be like you said, Super Bowl ads. My personal feeling from talking to many of the partners is that these patients are relatively engaged. They often search on hair loss. In fact, the biggest question that comes into me from patients are people for the last -- since I've been involved with these products, asking, when is Breezula coming? When can I be in the trials? When is it launching, et cetera. So we're expecting, I think, a more efficient way of direct-to-consumer advertising that probably would involve those massive Super Bowl ads. At the same time, though, there are some very interesting channels that are starting to emerge and becoming -- starting to become mature in the United States, where there is a situation where a patient can engage, have a telemedicine appointment without ever seeing the doctor, be diagnosed with androgenetic alopecia because, by the way, it's very easy to diagnose and receive a prescription without ever actually seeing the doctor and have the prescription turn into a subscription where the product is sent to them on a monthly basis. We're already seeing this happening within this androgenetic alopecia market with the old, old products, with telemedicine companies like forhim.com, forhers.com, Get Roman or Keeps. And these companies are focusing on these sort of lifestyle drugs that are cash pay. So I think, in summary, there's a lot of very interesting opportunity to use technology, to use social media, to use patient engagement and to look at some very interesting channel opportunities that could make the distribution be very efficient for this product and, in fact, make it easier for patients to get their product.

Let me just add one thing, which could be interesting in respect of patent life. Diana, we're working -- we -- extensively working with Sun and we've recently signed an agreement to this purpose, to develop life extensions. So we're really involved meaningfully with Sun in life cycle management, and we're expecting let's say, a next-generation Winlevi to be available soon. So the program we're working together with Sun is to meaningfully expand the useful patent life of Winlevi with new patents because new developments are ongoing.

Can I just ask one quick technical question about the rifamycin product candidate. With respect to the adhesive gel...

If you go to Google. So Mr. Professor Scarpignato is the father of rifaximin. You can check in Google. So there are no major aspects that can answer your question. I don't know the question but I know that he can answer properly.

Question for you. So it's just a technical question. This adhesive gel formulation that solidifies inside the body, does it utilize any novel excipients or substances that are likely to require additional regulatory scrutiny? Or are these things that are all readily utilized already in a medical purpose?

I can answer. I don't need Professor Scarpignato. Sorry, it's too easy to one answer. We use -- normally. We try to get the easy way. So we are not going. We're not inventor of excipient or -- we use a normal gel. Let me say that in this case, the tricky part of the story. What is the key driver, in my opinion, is their possibility to reach exactly where the need is, stay, with the drug that Professor Scarpignato's play very well that for the first -- doesn't have only the antiinflammatory activity or eubiotic activity that can improve better reaction and better treatment.

Diana, do you still have a plan to sell...

Is this a personal discussion between you and Diana because...

No, no, no...

Because...

[indiscernible] for you. Do you still have a plan to sell Cassiopea at the right time, at the right price?

Well, Cosmo is the owner of Cassiopea.

So I have to ask Mauro. Do you still have a plan to sell Cassiopea at the right time, at the right price?

I cannot understand the question because we show to the market that we were smart enough to anticipate the collapse of the derma market because the true -- is that the derma market collapsed in the last 10 years. If you take, for example, what's happened to the funds that has bought by [indiscernible] looks the numbers, how much they pay, how much the value is all the other company. I believe that the shareholder of Cassiopea to thank you, us, because we anticipated the collapse. Cassiopea alone was collapsed already 3 years ago, 5 years ago. No chance. If the market change, you cannot control the environment. You can control maybe your house but not the total environment. We didn't know at the time in 2010 that the market could collapse. The market completely collapsed. You know the $ 5 billion markets now in the U.S. are worth? $1 billion. What could happen if Cassiopea was just alone with all the reps to pay and the reduction of the market that we couldn't control, and we couldn't play against towards the 80%, 80%, 8-0. I have a question for you now? Did you understand properly the case at the time? Or do you believe that was only a speculation for Cosmo? We protect the company. It was not just to speculate. It's just to protect the company. And the only way to protect the company was try to put the as the good family, the child in the family. We put the child in the family. We save 89% or 92% of the cost. This is something that I know the analyst doesn't know because you are not in the 100% of the value chain. Exactly. We are not in the 100% of the cost. We are not in the 100% of the investment, but you cash only the milestone. Yes, because we don't have the commercial and the marketing. And when we go to the end, let me do an example. At the time of Breezula finish results are good enough to enter in negotiation. We already spent at the time, $100 million and in your opinion, I'm going to ask a payment that cover my cost, I say, no, give me your $10 million for each year because the analysts can analyze you better because there is -- we can compare that is not milestone down payment once in a [indiscernible] because there are people that today, the question are we can consider a milestone one-off for Cosmo. Do you know Cosmo is 25 years? Do you know how many milestones we already cashed, I tell you, 51, is one-off for each year we are slightly tired to answer this question, slightly tired. I am old and slightly tired, is not one-off. It's one [ center ]. It's one each year. If you don't understand this problem, it's not my problem, it's only to -- just to understand, you have to know. If you don't know, you don't understand, but we cannot, for each year answer the same question. Why this year you had the milestone payment, the next year? Then next year, we will have other milestones to say if the business progressed well. If the business is not going to progress, we don't have milestone. Very simple.

Thank you very much for your time. Just the simple question and thank you very much for...

I would like to [indiscernible] because sometimes people believe [indiscernible]. We didn't speculate. We never speculate. I am an entrepreneur. The company is a pharma company and never -- we have no interest in speculation. No. Thank you.

Bob Pooler, ValuationLAB AG. Then going to the future maybe GI Genius.

It's much better to jump.

Just going back to GI Genius with the 5 apps and the reporting app as well that's internally done. How close to market are they? And then also with all the information that you also provide with the app developers, the externals, do you also look at pricing, market pricing because that's, of course, quite important, of course, for the app and the success of the app. And also, could you just look into the economics of these apps, how they will work for the company?

Well, let me tell you this, just to clarify the division of costs, of tasks between the companies. One of the advantage that we are providing to developers. It's not just that they don't have to develop certain things because they will embed the app into our system. But that -- there will be Medtronic as a business partner and as a commercial partner. So that part of the commercial evaluation is left to Medtronic. Medtronic has to do the final call on whether something is worth being commercialized and at what price that will be commercialized? That's not our call. That is their call. Nhan, I don't know if you want to add something or Mauro, is there anything to add to this because...

[indiscernible]...

Pretty difficult to say.

The problem is to go through the market for the other. If we can help the institution, university, or company, or start-up or professor, go to the market just because Medtronic has the access because you have to understand that in the market, there is a barrier. This barrier has been created by Medtronic, make difficult that the other company can fit another device, device [indiscernible]. The horse is already there. Now the Greek, our soldier are in the horse, the ability is try to fight with the soldiers that are in the horse. But we have the horse in the [ hospital ]. The other they have to put.

Okay. And then just on the devices you see that NVIDIA is developing new chips. Is this something that there's like a renewal every 5 years that a new GI Genius device will be placed?

There is not a new GI Genius. There is a GI Genius whether -- for each moment, we have 80 engineers in Milan, Milan, Rome and Dublin, but we have the world that is working with us, is working with us because we have a lot of people that are developing algorithm in the AI, in the healthy program. And I believe that they realized that go to the market is practically impossible. Believe me. So they can go to the market through us. We can pay them through Medtronic and their royalties and everything once again, is very easy. Very easy. It's not -- so let me give you this, this is our device, okay? Our device has -- this is our device. It is the app, the people -- not only the people sell on [indiscernible] we have people in-house. They are developing and trying to build more apps, more apps, more apps, more apps, but taking consideration that this device is already in the hospital. It is not something that is -- not [indiscernible].

I see growth is coming from the apps in the future, but also potentially like an iPhone where you have the apps you have to renew them because the apps, be the AI, the algorithms [indiscernible]?

[indiscernible] Because -- it is enough. Nhan can explain better than me for sure, but there is not a lot to do. Is it just enough, the key or something that through the cloud, but maybe you can try to explain not a technical -- not technicality, very difficult to understand. Very simple. Nhan, if you can?

No. Yes. So we see the importance of our initiative very much leaning to the software for several reasons. So we are, let's say, creating software-defined medical devices. So something that is in essence, everything in the software. Technology that is supporting those softwares is definitely important. So we create -- we created a platform that is far more powerful than it was necessary at the time that we developed GI Genius. And we definitely will update the platform whenever a key technology is coming to the market. So -- but let's say, what I believe it is important to say is that, we are already providing excess power and excess, let's say, flexibility to the platform. So let's say, for several years, algorithms can be deployed on the same platform. Just to make an example, our first system was based on version 1 of the software was doing polyp detection. We launched it in 2019. And that algorithm was just with a single one shot neural network. Today, we got approval in January of version 4, which name is ColonPRO. So ColonPRO has 11 neural network concurrently working together to let's say, do polyp detection, but also is doing video understanding. So a lot of other things. We are deploying on the same hardware. So that's the kind of difference that I would like to just highlight. As Mauro was saying, hardware is a little bit less important if the platform is conceived in a way that has excess power, excess flexibility. And then, of course, if key technologies are coming through, we are implementing them. And because our mission is to provide, let's say, the state-of-the-art platform for applications to be deployed.

Thank you, Nhan.

Okay. Then maybe just one question on rifamycin SV. It's sold for traveler's diarrhea for -- as Aemcolo and now rifamycin as MMX. How does that work with your current partners in the UC that you're looking to distal UC and proctitis? And also, what is the IP situation? Because I think now the protection is the QIDP exclusivity.

As regards the IP -- I will start from IP. As regards to the IP, we have a brand-new IP protection for these applications. So it's very specific. It's not of course, overlapping with the patent protection for the other application of rifamycin. And we currently have 3 different patent applications on this technology, on different features of this technology.

How long do they run roughly?

You mean expiring?

For the expiry, yes.

I would say 2040, the earliest one. The latest one we filed just last week. So it will be expiring in 2045.

Okay. And then just on the cooperation with the existing partners in this?

No, no. I can tell you for 100%, it is not the partner that are -- who are in mind. Because in the ulcerative colitis, we can play as a leader. So just to give you the example, because sometimes I have still read that our weaknesses, we have no -- the commercial, we have to find a partner, oh, welcome. So there are people that [ '25 ] later, they understand, welcome. But there is a big difference. If you take UC, for example, we have, let me say, all the companies that are interesting to touch with us. It doesn't mean that they are interested in the program or in the product. But I am sure that we can get their -- meeting with a 99% UC company because we need a UC company. When we talk around my product, for example, it's clear that we cannot complete the program in-house and alone. In this case, we have to find someone or company that can be in a position to decide that our drug can be the drug that can combine with their product that it is in the market, just because we have to show an improvement. But everything in this case, should build. So it's not something that is easy. For the other, let me say, for colesevelam, for the enema. So we are still a leader position in the market.

I understand. The current partners, commercialization partners for TD, they are not in this...

No, no, no.

So it's a -- we can see there's a totally different or a separate product.

Totally different.

[ Prego ], Isabel.

About this amazing product, CB-03-10, which could already increase the life expectancy of someone with developed pancreas cancer. This is amazing. How do you see the evolution to this product eventually to a total healing within which time, what do you think about that? I was quite flabbergasted to see that you can use it for almost any kind of cancer. And did you use people from every stage of the cancer, mainly beginning stage, Stage 1 or also Stage 3 or 4?

Okay. How we are running Phase I clinical trial in oncology are peculiar in the way that you have usually a first stage where FDA is asking you to find the effective dose. For ethical reason, you cannot use patients that either have an alternative treatment or they are early stage because you don't know the efficacy of your drug. And moreover, you do know what is going to be your dose. So what you do, this is a classical Phase I escalating dose, you start with the dose that you've been showing in the 2 animals model, usually one is a rodent and one is a non-rodent that is not toxic. So the FDA and the [ EMA ] too is reassured that you are not doing anything back to the patient. And you treat 3 patients. You wait, usually for 28 days, to see if there is anything wrong with the patient. They have any toxicity, so blood work, so [ analysis ]. If the 3 patients are fine, then you go additional 3 patients, we double the dose and you go on, on, on, on. So we are, right now, of 5 doses. So let's say, we started from 100, 200, 400, 700, 1,000. We treat 14 patients extensively now, no side effect. However, this patient were very late in their cancer journey unfortunately. Some of them even died because again, for ethical reason, they don't let you treat people that have alternative or they are -- they may survive. So the next step, what is going to be. At this point, we are going to find a dose that we think is efficacious. So we are going to take that dose and try it in a population. So at this point, it's going to be most likely 20, 30 patient. And at this point, we can screen the patient. My idea, and again, I still have to present it to the FDA, is to select cancer that could be pancreatic, that could be colon cancer, but they are stratified. So as you remember, these drugs work through an androgen receptor antagonist, glucocorticoids antagonist. So I'm going to look most likely for a tumor that express these 2 things that I can attack. It is not going to be a general. Could be colon, could be prostate...

Sorry. This is a point that must be underlined. So we are not so stupid to believe that we are a cancer therapy in house. I do believe that we tried to, in a transparent way to show exactly what we believe. In this, we believe. We believe that in the last 20 years, there is in the onco treatment, the company are used to be combined with other products. Mara have seen and already touched with a big pharma present in the market that they have a need to combine their product that usually is very toxic, with other product that, for sure, doesn't charge any toxicity, but can improve their drug because -- so we must be clear, this is my opinion. We are not stupid and they don't have to say that we have a cancer therapy, or we are studying a cancer therapy in-house. We are studying a product that can be one of the candidate to be used in what is only the normal guidance, the normal guidance around multi-therapy, multiproduct for each [ passion ]. I do believe that we can play our role, but it's clear, this is the...

Can you stop the development of metastases with that, for example?

We start and no development because the development that we are doing is a development that can allow us to enter in a negotiation. All the other clinical phases, all the decisions, all the -- are faced by the company that I hope we will find and we [indiscernible] our partner.

Do we have other questions in the room or maybe there are questions from people attending online?

[Operator Instructions] This question is from Lucy Codrington from Jefferies.

Just on the recent milestone product. Just regarding the current Breezula protocol and the acceptability, am I right in thinking this would be a daily [indiscernible] for 6 weeks. Is this something patients would likely expect? Is that standard process in [indiscernible]? And then just in terms of the endpoints of the Phase II, it seems to be colonoscopy appearance and biopsy, would you then need symptomatic endpoints in a Phase III trial?

So in regard to the treatment, yes, you are correct. This treatment is once daily before going to bed for 6 weeks. This is the current way of utilizing any rectal treatment for ulcerative colitis. So the patients will self-administer this product prior to going to bed and remain lying on the bed, hopefully for the entire night, which is something that with the current enemas is not so easy, as you can imagine because they have several diarrhea episodes. In regard to the endpoint, that is the classical endpoint of -- that is recommended by the FDA and the EMA guidance. and it comprises 2 main descriptors that are the clinical symptoms that are recorded by the patient. These are rectal bleeding and stool frequency, the number of diarrhea discharges per day and endoscopy. Nowadays, histology is utilized to make a precise diagnosis of the status of inflammation of the mucosa because it is known and maybe Professor Scarpignato can explain that...

Let me add something. So the use of the, not only colonoscopy but all the pathology...

Biopsy and histopathology.

The histopathology. Let me say, has been invented by us at the time of the steroids because when you are in a position to be in a trial that is induction of remission, just to induce something must be a flare. The ulcerative colitis disease is a disease that doesn't kill the people, but the people have to live all their life with the disease. And what is very important is treat the symptoms. You cannot cure. And one of the major problem that you have is the understanding because it's a relapse remitting disease, means that maybe you are going to treat a patient in the trial in an induction of remission, there is no flare. If there is no flare, there is no result because you are exactly the same than the placebo. That is the reason why when we, at the time, we use the combination was only because we use as an entry point. The entry point, we must be sure that there is an inflammation. If there is an inflammation that is in flare, we can induce something. Otherwise, we cannot induce. And so thanks to this experience that we gathered 20 years ago, we follow the same line because it's the only line that allow us to be in a position to understand if we cure patient or people that are not in flare and people that are not in flare are not the right patient for us.

Mauro, can I add something, please?

Yes, sorry Professor...

The histopathology is of vital importance because in the past, when they started with the mesalazine, MMX, the let's say, endpoint was the clinical endpoint and also the endoscopic endpoint but not the histologic endpoint. Nowadays...

[indiscernible] is here. Can you stand up? Sorry, this is the inventor of this guidance. Sorry. We are not -- just because -- this is the professor invented this guidance because we proved to the FDA, as an entry point that the use of the histopathology was the unique, the guarantee.

But the reason is that if you get histologic healing the remission time is much longer, first. And second, it was shown that people in remission with healing have less colectomy because unfortunately, some patients can go to the surgery with ulcerative colitis. And finally, the long-life inflammation will drive cancer. Ulcerative colitis patients have a very high risk of cancer, colon cancer, of course, compared to the normal individuals. And it was again shown that if you heal the mucosa, you reduce the risk of cancer. So that's why the really very good endpoint should be clinical, endoscopic and histologic.

The truth is that you cannot teach [indiscernible], the [indiscernible]. Only one thing, only, I give you only one thing. 15 seconds.

Sorry, 10 second only to say that if you don't have the disease, you couldn't have the remission...

I think that's...

It cannot be debated. If you need to have a patient that tests the disease in order to test if your drug is able to remit them.

If there is no flare. Because it is important to understand. It is relapse or remitting. relapse or remitting.

Can I -- I had one question, [indiscernible] from [ BIO 101 ]. Can you clarify again what is your agreement with Medtronic because we understood that the device is there. It's very good. You have a great position. And the CEO of NVIDIA has even personally promoted the GI Genius. So what is your economical exposure? What is the upside? What are the milestones? Let's say, they were...

Forget the milestones. Forget the milestones. The [ money ] with -- forget the milestones.

How much money would you make? Are you capped basically? Are you capped?

Capped, what?

You cannot make more money than, let's say, [ $200 million ].

We can catch the money that we are able -- they are able to sell. So we're in a position, there is no cap. There is nothing. Maybe 1x they are going to buy us. You never know. They are Medtronic, we are Cosmo. You are [ so small ]. We are 300 or 400 people, they are 100,000 people. They are [ $8 billion or $ 9 billion ] revenue. We have EUR 300 million. There are $110 million valuation in the market. We are poor EUR 1 billion. So how we can answer. So feel free. I feel -- and relax. If there are major possibility, we are ready to cash everything. There is no cap, everything. Please don't ask me again on milestone. We cash money because I spend money, no milestone. When I'm going to spend money, the people doesn't ask me if I come from the milestone or from the royalty, our money, money.

Have you disclaimed percentages or?

No. No, no. We have not. So we make money selling the devices, and we make money receiving royalties on their sales.

There is no cap.

There's no cap whatsoever.

So this is the story of my life. I try to -- there is the moon. The people still look in my finger. So I am even a smoker. My finger is yellow. They still look in the finger, look the moon, please, look the moon. There is the moon, not the finger. You're still looking by finger, sorry, [ milestone ]. This finger. Unfortunately, [ smoke ] is yellow finger. But the moon is great. You can walk in the moon, you can walk, you can dream, you can dream in the moon.

No cap.

No, no milestone. No, no cap.

No milestone and no cap. Do we other questions? Oh, sorry...

How many milestone do you know?

So [indiscernible] question. So maybe just one question on GI Genius to make sure I understood everything. So these apps that are developed by the people that join your lab. Are they entitled to some of the revenues that you will get from the app, kind of related to [indiscernible] And then 2 questions on rifamycin. The first one will be, are you mostly for the Professor, but isn't there a risk that if you treat patients for a long time with antibiotics that you will get some antibiotic resistance and things like that, that could refrain the use. And then the last one on rifamycin again. Could you clear the time line on when do you expect to sign a deal, for example, in the [indiscernible] market?

Very quickly on very quickly on GI Genius. Each app will have its own economics. Clearly, if the developer of the app is an external developer, he will be entitled to a share of the revenue. That will depend on the app. It will depend on the task. It will depend on what that performs. It would depend on what the market is ready to pay. But if there's an app that's developed by a third party, then you will have 3 entities making money. It will be Medtronic, it will be us and it will be the developer. Can you please answer on the rifamycin question?

The question is a very good one because we leave an award of increasing bacterial resistance and the World Health Organization is pushing all the physicians to do antibiotics stewardship, which are often used improperly, especially for viral diseases. So the question is the right one. But in the case of the refinancing families because we do have rifamycin SV, is the member of big family of rifamycins to which other molecules belong. They are a very unique class of drugs because it is possible that over time, some especially enteric bacteria can become resistant, but this resistance in our experience is, let's short lasting. If you just stop for one week actually the bacteria became again sensitive to rifaximin, first. And second, the studies we have done with similar molecules on IBS have shown that over time, there is no increase cross-resistance between rifaximin and other classes of drugs. So I would say that for the long-term therapy, rifamycins are the best antibiotic. And by the way, the antibiotic resistance is dangerous when it is systemic. In the case of rifamycin enema, it will be a topical therapy. So eventually, if you could even get resistant, you will get the local resistance and never a systemic resistance.

Other questions?

Yes, please. [indiscernible]. Very quickly, 2 questions, please. My first one is on Breezula. Considering your market assumption, do you see any difficulties to produce clascoterone in short or midterm to achieve the market. Could we imagine maybe new capacity of production or new investment in your CapEx? Or it is not an issue at this stage, and we could imagine to achieve your expectations in short and midterm, thanks to your -- currently CapEx?

No. To be clear, we don't manufacture the active. We will manufacture the final product, but not the active and no, no, no. We have 2 different very large suppliers that will produce the what is called the API, the active ingredient, this is not us. So we don't have to do any -- have to bear any cost to expand any capacity. We don't manufacture the active.

But it will be not an issue to increase this for your....

We hope that can become an issue. We hope. It became an issue. It means that we sell [indiscernible]. We hope, we don't know. We hope.

It is my second question on the financial aspect. You have a strong cash position at this step, so what are your priorities on the cash allocation in short or midterm?

As we have said in the call this morning, we believe that the task of the company is try to make the shareholders as happy as possible. We have stated that we want to be a dividend, stock also. So you should expect that if things goes well, we will continue to distribute dividend. And hopefully, increase the dividend. Then we have a vast array of opportunities that are currently under development, so you should expect cash to be allocated on development opportunities as well. As we said this morning, if there is one thing that Cosmo is not short of is ideas developed internally on how to do new things. So that is what we intend to finance.

Other question?

Looks like we are done.

I think, Alex, this is a question from the webcast, and I think it's directed to you, Diana, so I'll just read it out. As many of the stakeholders are aware, Breezula is far and above the most important aspect to Cosmo's future success. With the delays during its development process, it has opened the door to competitors such as Kintor, who are now catching up with their time line. Can you offer any level of assurance in Breezula's efficacy beyond the data we have already been given, which may help restore some faith in its future success. I leave it to you Diana.

So thanks for the question. First of all, as it related to the Kintor asset, they announced in November, not good clinical results. So the Kintor asset has stalled and is, as far as we know, not proceeding because they did not show statistical significance over vehicle. And the next question was I think there was...

I think there is 2 cuts, one second.

There was a delay in development. And then what was the question? The clinical results, I think they said, can we be confident in the clinical results?

Can you offer any level of assurance in the Breezula's efficacy?

So like I explained, we studied this compound in Breezula in a Phase II program in 400 patients. And we found the most effective dose that has statistical significant results versus vehicle was a 75-milligram BID, that was in an arm of 80 patients. We are not, right? One of the 5 arms in the study. So there is a 400-patient study. One of the arms was the most effective dose. We now are studying that most effective dose with very similar endpoints, the target area hair count and the patient-reported outcome, but this time in 1,500 patients across 50 centers. So we feel confident that we have appropriately designed the study to at least get the results, if not better, than what we got in Phase II. This is actually the same thing we did with Winlevi. We had a smaller Phase II program. We identified the most effective dose. It was statistically significant. We then tested the most effective dose with, again, the similar endpoints that we had, had in Phase I with a very large study, again, with Winlevi, it was also 1,500 patients, and we had statistically significant efficacy and safety results that were ultimately approved by the FDA and now will be approved in 40 countries around the world. So we feel like we've designed the appropriate study and done the appropriate level of diligence on what the dose should be, what the endpoints should be, and so we feel very confident about our study design and that the results should indicate at least as good as a result of what we saw in our Phase II program.

Other question?

We're done.

Thank you very much.

Thank you very much.

Thank you.

Thank you.