Hello, and welcome to our webinar on resminostat as a maintenance treatment in cutaneous T-cell lymphoma. My name is Susanne Danhauser-Riedl, and I'm the Chief Medical Officer at 4SC. Also with me is our CEO, Dr. Jason Loveridge, and I'm really happy to announce to you our renowned global CTCL experts, Professor Julia Scarisbrick from Birmingham, and Professor Rudolf Stadler from Minden, Germany. They are both very familiar with resminostat and the RESMAIN trial, because they treated a lot of patients already with resminostat in the trial, and they are belonging to the top recruiters of the RESMAIN trial. For those who are not familiar yet with 4SC, we are a public listed company, and our market capitalization is about EUR 100 million. We are headquartered in Munich, Germany. What are we currently doing? We are preparing to file for EMA approval of Kinselby resminostat, and we are really excited because we think that this will be a clinical practice-changing therapy and a new treatment paradigm in CTCL. We are also preparing to file in other regions. With that, I will hand over to Julia Scarisbrick, who will provide you some background information about cutaneous T-cell lymphoma, the unmet medical need there, and also resminostat as a drug. Thank you very much. Thank you, Susanne. So I'd like to tell you a bit about resminostat, which is an exciting new class of drug to treat patients with skin lymphoma or particularly cutaneous T-cell lymphoma, which are referred to as CTCL. And this drug, resminostat, is being found to be a maintenance therapy to improve progression-free survival in patients with advanced CTCL. Progression-free survival means the time for the patient to progress, and maintenance is referring to the fact that this is given in patients that had a response to a previous treatment. And rather than just letting that treatment wane, they can have something that they can take, which is taken orally at home, just five days of a 14 day course, so they get nine days off and can keep their disease from relapsing. That's so important in CTCL because we have a real unmet need for good treatments. There's no cure for this disease, and patients have painful, itchy, scaly, red patches and plaques over the body, and really, it's very disfiguring and very upsetting. They can have sleep disturbances and lots of difficulties with this disease, not least the fact it is cancerous. There's no standard of care for treatments. We have a list of treatments that we can offer patients, but most of the patients relapse quite quickly after treatment. This is when having a maintenance therapy can be really helpful, particularly because in this advanced group, survival is often less than five years. The longer that we can keep the patient well, out of hospital, and with minimal skin disease, the better. The concept of maintenance therapy has been established a long time and used in other types of lymphoma, but this is the first time we've been found a treatment, a maintenance treatment, or shown maintenance treatment in cutaneous T-cell lymphomas. A great opportunity for our patients. This slide just tells you a little bit about how maintenance therapy works. The patient can start off with a list of systemic therapies that will go into the veins or body, rather than just put onto the skin. There's retinoids, there's drugs like brentuximab or golimumab, and they're all immunotherapies. There's chemotherapy, which you tend to give later because of the side effects, which are quite stressing. Extracorporeal photopheresis we can use for leukemic patients, and total skin electron beam or radiotherapy can be used in patients who are developing thicker areas or even tumors on the skin. But what happens when you stop those treatments is the disease slowly relapses or quite quickly relapses in some cases. So within four months to 12 months, they have the same amount of disease back again, and as I say, no chance of cure. So it's once they've had that response to that therapy and it's been stopped, that's when you can put in the maintenance therapy and help the patient keep that level of response and minimal disease for a bit longer. So I'm now going to introduce Professor Rudy Stadler, colleague, who will tell you about the RESMAIN trial, which is the trial that used resminostat. Thank you. Thank you very much, Julia. I now have the privilege to introduce you to the RESMAIN trial. The RESMAIN trial was designed in 2016 as an innovative study concept for maintenance therapy and to establish a controlled study. The main RESMAIN pivotal trial design was for advanced cutaneous T-cell lymphoma, mycosis fungoides, and Sézary syndrome in the tumor stage, erythrodermic stage, and including blood involvement, as typical for the leukemic CTCL, the Sézary syndrome. The patient had to complete remission, partial remission, or stable disease lasting two weeks to 12 weeks after prior systemic therapy. As a controlled trial, the patients were randomized to the verum and the placebo arm. The patients received 600 mg of resminostat delivered in three capsules per os through day one to day five, every two weeks. And then they were followed until progressive disease, and the evaluation of the patient started. In the placebo group, the patients were followed until progressive disease, and all patients who progressed had the possibility to roll over in the verum arm to resminostat, and then follow up. The primary endpoint was progression-free survival, so from the point of complete or partial stable disease until progressive disease. This study made, for the first time, the primary endpoint in a randomized controlled study of maintenance therapy on progression-free survival. It doubled the survival and progression-free survival time from 4.2 months in the placebo group to 8.3 months in the resminostat group. The median progression-free survival was 8.3 to 4.2 months, nearly, as I said, a doubling of PFS. The ratio, the hazard ratio was 0.62, means that 38%, almost 40% of the patients had a reduction for disease progression. In this case, for the first time worldwide, RESMAIN has proven that maintenance therapy is beneficial in advanced stage CTCL. That means psychologically for the patients, that if they have reached, complete remission, or partial response, or stable disease, they can continue their daily life, and this is also a mainstay of quality of life. If you look to these, curves, you can see there is quite a lot of patients, more than 20%, who have long-lasting responses under this maintenance therapy. This is one of the greatest features we have, that there are certain population who will respond not only eight months, so now continue to response, and some, they are really long-lasting, stable. Resminostat is broadly superior to placebo across predefined subgroups. I want to draw your attention to a bad prognostic factor that is large cell transformation. And large cell transformation has been shown in the previous studies, performed by our cutaneous T-cell lymphoma, that these patients have a very, very bad prognosis. And even this group were included in the maintenance therapy to prove the power of resminostat also in this aspect. And you can see almost four times improvement from placebo, 2.2 months, against more than eight months in the resminostat groups of maintaining the median PFS in this devastating group with large cell transformation. And also, one point, which is also reflects PFS, but means changing from one to another treatment, so time to next treatment. And if you remember, patients with cytotoxic therapies, they had time to next treatment less than four or five months in all the published studies so far. This also was doubled from 4.2 months in the placebo group to 8.8 months, almost nine months, in the resminostat arm. Also in this secondary endpoint, resminostat significantly improved time to next treatment versus placebo. Resminostat was, in general, for an oncologic study, well tolerated. The side effects were merely mild to moderate, reversible and manageable. However, in this particular study with HDAC inhibitors, antiemetics were not used in the resminostat trial due to their known possible risk for QTc prolongation. However, resminostat was safe, very safe. It did not prolong QTc during the resminostat trial and the application to the patients. However, we could not reuse antiemetics to control side effects like nausea, diarrhea, or vomiting. This will be the next step in real life, that we can combine antiemetics to solve also these side effects for patients mainly treated for maintenance with HDAC inhibitors, and in this case, resminostat. The other secondary endpoint, time to symptom worsening, were not available because 80% of the patients were mycosis fungoides patients, so they don't have too much pruritus, they have more burning of the skin, and we have only few Sézary patients with pruritus. So there were too many counts that we could mean that we could result in meaningful conclusions. Health-related quality of life was itching. Skindex-29 were not, was not significant influenced by resminostat, so the patient stayed compared to placebo on the same level. The FACT-G questionnaire could not be applicable in this study due to the side effects concerned by gastrointestinal side effects. However, in general, resminostat was well-tolerated and fulfills aspects of maintenance therapy, that it is a safe kind of treatment with only less and tolerable side effects. By this, I will return and to my dear colleague, Professor Julia Scarisbrick, who will summarize the key points of our maintenance trial. Thank you, Rudy. So I'd just like to highlight the key points of the RESMAIN trial and resminostat as a maintenance treatment. This is the largest randomized controlled trial in cutaneous T-cell lymphoma. It's over 200 patients, and it is the only trial which has used randomization and double-blinded, and that means that patients don't choose which treatment they get, and neither the patient or the physician knows which treatment they're on. So it's a really good way of testing whether a drug works, and it's very exciting, as Professor Stadler has said. We increased the progression-free survival by doubling it from 4.2 months to 8.3 months, so that's a big difference for our patients. The time to next systemic treatment is also significantly improved, again, doubling that from 4.2 months to 8.8 months. If we look at the progression-free survival from the start of the previous treatment, because, as I mentioned, this maintenance treatment is to prolong a response which is gained from the treatment they've been on before. If we take the time from that treatment before starting, then progression-free survival of two years, just over two years, we're seeing in patients on resminostat, compared to just 14.9 months in those on placebo. I should also mention, and it's very important for our patients, that they're not have too many toxic side effects, and there was no increased itching in patients on the active arm, resminostat, and also there was no worsening of their quality of life scores. We're really excited to be able to introduce this new concept for resminostat as a maintenance therapy for advanced CTCL patients. I'd like to now hand over to Jason to summarize the end of the slides. So thanks very much, Rudy and Julia. That was a really good summary of the RESMAIN study and the advantages of resminostat in CTCL patients with advanced disease. I'm just going to summarize the opportunity here, where we're going with this drug. We have obviously published the pivotal data now for the RESMAIN trial. We met the primary endpoint. We have a very good hazard ratio and strong, significant data, so the marketing application is well underway, and our expectation is that we will file that in the first quarter, 2024. That filing will be followed shortly thereafter by the filing in Japan by Yakult Honsha, and then in the UK and Switzerland by 4SC. We have done some market entry work, although we've not talked about that today, and that's important preparation for when the drug becomes available to patients. We have done some initial work with both payers and reimbursement agencies to validate our pricing assumptions, and we're also in preparation for approaching the FDA with respect to registration in the United States. Obviously, it's an orphan indication, but a very significant one from a commercial point of view, with around about $600 million market potential over the first 10 years on market. We have very recently received orphan drug designation in the United States. Our application in the European Union is still pending, but we're hoping for a positive outcome and expect to hear about that very soon. Our market position is a unique one here in Europe. We are the only therapy in the maintenance setting in CTCL. We've demonstrated a doubling of time to progression, and almost two years in total time to progression. We will be the only HDAC inhibitor available to EU clinicians, and with that summary, I open the call to questions. Thanks very much. Thank you, everybody. I now have a number of questions coming through, which I will try and answer or pass to our participants to answer in no particular order. If I can just remind those participants to unmute so that they can answer the question if referred to. So the first question I have on the system is, "Both the PFS numbers of 8.4 months and 24.2 months seem very impressive. Can you please comment on the clinical significance of these data and how this could change treatment practice for CTCL patients?" And maybe I can refer that question to Julia Scarisbrick to answer. Julia? Thank you, Jason. Our patients with advanced CTCL have a very poor prognosis, and they have a lot of disease burden. Unfortunately, all of our treatments tend to result in only partial responses of a short duration. We're always looking to try and improve the response and also the response duration. Having a drug which we can use as maintenance after the initial therapy would be really helpful, and what we found with resminostat is that if you had taken the drug before, and then you go on resminostat rather than nothing, then you double your progression-free survival from just over four months to just over eight months. And that is really significant in a disease where your median survival is sort of three to five years, and particularly for patients in the RESMAIN trial, they'd already had three or four systemic treatments, so they weren't at the beginning of their disease. So we're seeing that improvement in this very difficult, relapsed, refractory group. We're hopeful that, you know, it might be even better for some of our earlier patients. At 24 months, obviously it's very significant because, again, these are late-stage patients going into a trial fairly late on in the course of their disease. When you looked at the date that they started their prior treatment, and then you followed through to those on the resminostat as the maintenance, you found that they didn't need another treatment for a median of two years, which is hugely significant compared to just over a year, 14.9 months, in those not receiving the maintenance treatment. We're very hopeful that we've got something which we'll be able to get to our patients to improve the time they do have, and improve their quality of life, improve their disease burden in between treatments. Thanks, Julia. That's helpful. I think actually along the same lines, we have another question, which I'll ask Professor Stadler to answer, which is, "Why is he so excited about the RESMAIN trial and its results? Thank you for this question. The idea of the RESMAIN trial was born in 2016 in Minden and Munich, together with 4SC. The steering committee, Professor Julia Scarisbrick, Birmingham, Professor Pietro Quaglino, Turin, and Professor Robert Knobler, Vienna. It was a dream for us to establish a proven maintenance therapy with an epigenetic approach with resminostat in cutaneous T-cell lymphoma, and for us, the dream came true. I have, on this occasion, to congratulate, especially the 4SC team, represented by Susanne Danhauser-Riedl, in conducting with us the largest maintenance trial in CTCL worldwide over six years, overcoming the COVID pandemic, including 55 active centers in 12 countries, 11 in Europe and one in Japan. The great efforts and perseverance have paid off. It is a huge effort to conduct such a well-designed clinical study of high medical and scientific value, and it has proven for the first time that maintenance treatment is a beneficial approach, and even as outlined by Professor Scarisbrick, for advanced stage cutaneous T-cell lymphoma, a devastating disease for the patients. I'm definitely sure and pleased that patients and physicians worldwide will thank us for this new achievement and development. In addition, a gap will be closed since no HDAC inhibitor are approved for CTCL in Europe. Resminostat as epigenetic therapy will give us the opportunity to increase our treatment options with this class of drugs, also for our cutaneous T-cell lymphoma patients in Europe. I think personally, we have a chance to open up a new era in CTCL therapy. Thank you. Thank you, Rudy. That's, that's really helpful. I have a couple of questions which all revolve around the pruritus issue, and therefore, I'll try and summarize them into one question, which I would pose to Susanna, please. So, first question: my understanding is you saw little worsening of pruritus in the trial because you had 80% mycosis fungoides patients. Is that correct? And, and then follow that with, and therefore, do you think the lack of time to treatment symptom worsening events will be an issue from a registration point of view? Susanna? Yeah. Thank you, Jason. Yeah, as we saw in the slides, it's correct. There were 80% patients with mycosis fungoides, and as Professor Stadler explained, though these patients don't suffer so much from pruritus, it's more the patients with Sézary syndrome, and therefore, we had only 20% of Sézary patients in the trial. So we don't believe that this will have an impact on the registration of resminostat. So because we saw a really very strong efficacy for resminostat, with a significant improvement of progression-free survival and really an exceptional hazard ratio for an oncology trial of 0.62. So furthermore, a lack of these time to symptom events of itching does not mean that resminostat will not have an impact on itching. It simply means that no conclusion can be made from this analysis, and so we don't believe that this will have an impact on the registration of resminostat. Thank you, Susanna. Next question is to do with the mSWAT analysis and skin lesions. Can you please expand a bit on the observed benefits of resminostat on skin lesions, the so-called mSWAT? And what is an mSWAT? And Julia, could I ask you to address this one? Thank you, Jason. Yeah, so the m stands for modified, and the SWAT stands for Severity Weighted Assessment Tool. And we modified the original, and that's why it's called the mSWAT. And what that number does or what that assessment tool does is it gives a recording of the patient's skin burden. So how much skin tumors do they have on their skin? We divide it according to the type of skin lesion. That can be patch, plaque or tumor. And then we divide it by the percentage of your body area that those lesions are covering. And it gives us an idea of how burdensome the skin is for a patient. It's out of 300, o h, sorry, out of 400, because we times four by the tumors, if the patient had the worst disease, it'd be out of 400. But really, realistically, most patients lie between sort of 50 and 200. And we use it in clinical trials to see how a patient has improved. And to get an improvement or what we call a partial response, you have to reduce that score by 50%. So sometimes in clinical trials, actually, patients don't necessarily reach a partial response of 50% improvement. It might be 45% better or 40% better. But because in a clinical trial, we want to be very stringent, we make it the 50%. So in our clinical practice, we are not as strict with what we would continue a drug on. If a patient's doing well, it's improving the mSWAT, we would perhaps be happy with a 20%, 30% or 40% improvement. But the mSWAT is critical for clinical trials for that 50%, and then if a patient does have a complete response, that would mean their mSWAT went down to zero, that would be called a 100% response. Thank you. Thanks, Julia. That's, that's very helpful. We have a couple of regulatory questions, which I'll, I'll answer myself. I'll come on to those in a minute. But there's another question on side effects, which I'll ask Susanne, maybe I think you're the best person to address this. So what side effects have been found, type, frequency, severity? What minimum dose could be considered sufficient to maintain treatment effectiveness when seeking to ameliorate side effects? Yes. Thank you, Jason. So when we look at the RESMAIN trial, and as Professor Stadler has mentioned during his talk, gastrointestinal side effects, nausea, diarrhea, and vomiting, among the most frequent side effects. So they were mainly mild to moderate and reversible, and patients experience they mainly during the treatment days, which means during days one to day five or only the first one, two days, and then they resolve during the treatment-free period of the nine days. So as Professor Stadler also mentioned, antiemetics were really limited in the RESMAIN trial because of their potential risk of QTc prolongation, which is a cardiac risk. And so as we now see, that RESMAIN did not show any risks of cardiac side effects, we believe that resminostat can be prescribed with antiemetics in the future if needed, and so this will come down dramatically. Okay. Thank you, Susanne, maybe there- I think there was another part of the question, maybe to dose reductions. Dose reductions were considered in the trial, and they could reduce the dose from 600mg to 400 mg. This was used in the trial, and so I think this is what is appropriate for resminostat. Thank you. Okay. A couple of regulatory questions, which maybe I will try and quickly address. Have you had feedback from US KOLs on how to proceed with filing for approval in the US? The answer to that is yes. We have been, Since we've had the data from RESMAIN, we've been talking to a number of US clinicians about, differences in clinical practice between different regions, and, clinical benefit of, the RESMAIN data and how that might be used in US clinical practice. So I think we are well along the way with respect to the US, strategy. A similar question for Japan, "What is the status in Japan regarding the submission of resminostat?" The status in Japan is that we will be working with Yakult Honsha to enable them to file their registration filing with the PMDA in Japan, and we expect that to take place in the first half of 2024. A question with respect to antiemetics: Do you really think that the real-world use of antiemetics in combination with resminostat will make a difference to patients and their quality of life? Julia, can I ask you to address that one? Thank you, Jason. Yes, of course. One of the things that's very important for our patients is that drugs don't make them feel awful because their life is limited, and this is an incurable disease. So quality of life and how they feel whilst they're taking the medication is all important. And with resminostat, we saw that there was a very manageable side effects for our patients. We're slightly limited in the trial, we weren't allowed to give certain antiemetics, as we talked about. We can't give topical treatments for pruritus, 'cause it can interfere with the trial results. So resminostat, even on trial, was tolerable. Most patients took it and continued on it for many months. So we're very hopeful. We saw that the quality of life was slightly improved in some areas in resminostat, but even in the real world, where we often see things different, we're very hopeful that with the right management of side effects, we're going to see a really good improvement for our patients, not only in their skin burden, in their time requiring their next treatment, but also in their daily well-being and quality-of-life scores. Thanks, Julia. I think we have a sort of a follow-on question that's quite similar to that, which I would direct initially to Rudi, and then Julia, if you wanted to add anything to Rudi's point. Can the professors please outline why the huge improvement in PFS does not directly translate into better quality of life? What was that quality of life compared to? Rudi, would you please. Thank you. Thank you so much. Yeah, because first time pruritus was not the symptom in this cohort of patients. 80% were mycosis fungoides patients, and second, the 20% Sézary syndrome patients were in complete remission or partial remission. So the key side effect of this cohort were also on a scale of zero to 10, less than five. So the changes were not observable in this small cohort, the effect on pruritus. And as Susanne Danhauser-Riedl pointed out, it means not that it doesn't work on pruritus, we couldn't show it in this kind of setting. And I'm sure that if we have a number of best new substances, the serotonin antagonist, to control any side effects in the given timeframe of resminostat, it's only five days. And the key side effect symptoms of the gastrointestinal tract are in the two days, three days during the maintenance treatment. So I think the quality of life will not be disturbed when we have, in real setting, the good practical management of these patients for a long time and preserve the stable disease which they reached in a highly advanced disease. And I have to remember, these patients, as Julia Scarisbrick said, is less than five years their- we can prolong them another two years or so on, then we get maybe new approaches to really prolong this survival time again. So that gives us a new perspective in managing advanced cutaneous T-cell lymphoma. Mm. Thanks, Rudi, and I, I'd just like to add to that. I totally, you know, support what Rudi said. I also just want to mention, when a patient's in a clinical trial, and particularly, one which is dosed like resminostat with two weekly appointments, this is very onerous on a patient. They have to adhere to a strict protocol of taking a drug. They're not allowed to take anything to, you know, help with a lot of the side effects. They can't go on vacation. You know, they often have to come to hospital one, one or two times a week, or at least every other week. When you're in a trial, there are certain things which are difficult to improve, which are different from when you're taking a drug in the real-world setting. So what we saw is that patients taking resminostat didn't feel any worse and felt in some areas, the quality-of-life score was slightly better than those who were taking nothing. Once we take out of the confines of a clinical trial, I think there's always room to improve that patient's well-being with adjuvant therapies for some of the side effects, and also the patient having a much freer lifestyle, and being able to be a little bit more able to travel more, be able to miss a dose if, or miss a course, cycle if they need to. We can have that flexibility, which we don't see in the rigid confines of a clinical trial. Thanks, Julia. That's helpful. We have a couple of questions that focus now around HDAC inhibitors. And I think the first one I would pass to Susanne to answer. So what is the different point from other HDAC inhibitors, such as romidepsin or vorinostat? Why only resminostat would be applied to maintenance therapy? Susanne? So the HDAC inhibitors, romidepsin and vorinostat, are not approved in the EU, and I assume they will never. So furthermore, romidepsin is given intravenously every two weeks, I think, and so this is not really appropriate for a maintenance setting, that patients have to come to the hospital or practice or to the hospital for an IV infusion for a maintenance treatment. So resminostat is an oral treatment, and in contrast to vorinostat, it's given five days on, nine days off. Vorinostat is given really daily, and we believe that resminostat is better tolerated than vorinostat due to this treatment schedule. This is an advantage here in the RESMAIN setting. Thank you, Susanna. There is a second question on HDACs, which I will try and answer, but Susanna, if I miss anything, please feel free to correct me or add to it. The question is: vorinostat was pulled by MSD due to concerns over study design and lack of comparity in the study. How do you plan on pushing back on this? I think vorinostat was not approved in the EU because of a lack of clinical data based on the study design. In particular, it was not a randomized study, it was single-armed, and there was no placebo control. In contrast, the RESMAIN study is a gold-label standard study, more than 200 patients, compared to, I think, something like 40 patients in the vorinostat study. The RESMAIN study was a randomized, double-blinded, placebo-controlled study, so I don't think there is anything with respect to study design that is in any way comparable with vorinostat. With respect to the different positionings, vorinostat was approved in the United States for progressive disease. We chose not to pursue resminostat in that indication because HDACs are not very proficient at debulking disease, and this is why the maintenance setting is a much more appropriate setting for this class of drugs, and resminostat in particular, for the reasons that Susanne just pointed out in the previous question. We don't believe this is an issue at all, and that the maintenance setting is the right setting for resminostat and for HDAC inhibitors in CTCL. Susanne, would you want to add anything to that? Great summary, Jason. I have nothing to add. Okay, that's good. Then we have a question on EU filing, approval, and launch, which I get to answer as well. So when do you expect EU filing, approval, and launch? We expect the filing in the first quarter of 2024. If the drug undertakes a relatively normal route through the EMA, then we would expect approval at the beginning of 2025, and we would launch immediately thereafter. We are considering a number of early access schemes in different countries through 2024, but this is now subject to internal discussion. As to commercialization strategy, the second of the question is, so at the moment, we're focused on the regulatory approach both in Europe, including Switzerland and the UK, and undertaking pre and NDA advice in the US. As you know, as we've announced in previous, we're actively engaged in talking to different groups about how to pursue the drug, from a commercial point of view, and we'll update the market as we make any substantial progress in that direction. I think the remaining just let me check the board again to see if there are any remaining questions. At the moment, we have a couple of questions, but unfortunately, answering them is not possible because of confidentiality. S o I apologize to those, questioners, and we'll come back to them, in the future, hopefully. I think there are no other questions on the board, so I would like to bring the Q&A session to a close at this point. I'd like to thank everybody who's dialed into this, webinar. I hope we've been able to provide you with a really good summary of the RESMAIN study and what we foresee are planning to do with the drug going forward. It remains for me only to thank everybody that's been involved in the RESMAIN study, the patients in particular, for sticking, sticking with things through the COVID pandemic, as Susanne pointed out, all the clinicians that have been involved in the study over the past couple of years, in particular to Rudy and Julia for their participation and ongoing support with the study, and not least of all, the 4SC team for the incredible work that they've done over the past six years in terms of executing on the study and generating these data, which I think are really exceptional and unique in the CTCL space. We look forward to taking this package to regulators at the beginning of 2024, and hopefully bringing it to patients as soon as possible thereafter. Thank you all for your attention.