Good morning, and welcome to the Cyclacel Pharmaceuticals R&D Day. At this time, all attendees are in a listen-only mode. A question and answer session will follow the formal presentations. If you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player or by emailing your questions to questions@lifesciadvisors.com. As a reminder, this call is being recorded and a replay will be made available on the Cyclacel website following the conclusion of the event. I'd now like to turn the call over to Spiro Rombotis, President and Chief Executive Officer of Cyclacel Pharmaceuticals. Please go ahead, Spiro. Thank you, Tara, and good morning, everyone. Let me also extend a warm welcome to those of you who will be listening by webcast. Before I make my further remarks, and so with my colleagues, I would like to draw your attention to the usual disclaimer regarding forward-looking statements that we'll be making about our programs, which are subject to change, and I would refer you to our filings with the Securities and Exchange Commission. We will cover today a great deal of material about our two clinical candidates, and we are honored to have two of the world's leading authorities in their respective cancer types joining us today for this event. Dr. Jasmine Zain from City of Hope National Medical Center, and Dr. Do-Youn Oh from Seoul National University Hospital. Our Chief Medical Officer, Dr. Mark Kirschbaum will then cover the clinical update on our leading agent, fadraciclib, or Fadra for short, our oral CDK2/9 inhibitor. He'll also make a few remarks about emerging preclinical and recent clinical data with our PLK1 inhibitor, CYC140. We'll then open it for questions in the Q&A section of the event. Let me take a few minutes to remind you of Cyclacel's strategy and what the resources are that we're putting to deliver on this strategy. We are a small company, but we leverage our understanding of the area of cell cycle biology. We have dedicated decades of research to bring drug candidates to proof of concept stage and therefore help patients in need. We may be a small but focused team, but our resources and capabilities are not small. We have a tremendous talent pool of skilled drug developers who are committed to our strategy of bringing our molecules to proof of concept stage. We're well on our way to achieving that with at least the first agent, Fadra, and we'll soon be in the position to do the same for CYC140. Now, for many of you that are familiar with checkpoint inhibition in cancer, there are two types of checkpoint inhibition. Of course, there's immune checkpoint inhibition, but also cell cycle checkpoint inhibition. Remember the four Cs. There is a Nobel Prize behind this field of biology from 2001, but it has taken a long time, almost two decades, before drugs started to reach the bedside that could harness the power of cell cycle checkpoint control. We believe that we are a leader and oncology innovator in this area, as we're the first company to test in humans cell cycle and transcriptional modulating agents, tracing back to the work of our academic founders, Professor David Lane, who discovered p53 and proposed the CDK2/9 hypothesis, and Professor David Glover, who discovered many mitotic kinases, including polo kinase, and is the proponent of the PLK-centric hypothesis, enabling our studies with CYC140. Many companies have followed our lead, but we remain excited about the fact that our assets remain differentiated. As you will hear later on in the presentation, we have achieved not only first-in-class properties, but also potentially best-in-class. The central scientific tenet behind our work is that cancer cells undergo apoptosis when subjected to cell cycle checkpoint control. Importantly, we're not pursuing that via cytotoxic strategies, which was the case with drugs in the last 50 years, but rather by enabling apoptosis or the body's natural way of disposing of dangerous cells. Over the next 18 months, we expect multiple data readouts, some of which you will hear today, from registration-directed phase I/II studies for both fadraciclib and CYC140. Fadraciclib is almost complete with dose escalation phase I of its respective study and will soon enter phase II proof of concept stage with initial data expected in the middle of next year. CYC140 is a bit earlier in dose escalation in phase I, and we expect to have initial data from this study at about the same timeframe. As I mentioned, our key strategic tenet is to enable apoptosis, and frankly, this is best achieved by having a durable suppression of proteins associated with resistance. In other words, when cancer cells overexpress or amplify these proteins and current therapies fail, that's when drugs like fadraciclib and CYC140 come into play. Because these mechanisms are redundant and oftentimes patients express multiple of these proteins that block apoptosis at the same time, it is important to have a broad therapeutic target profile, ideally with a single drug, which is the case with Fadra and CYC140. It is critically important in early development to optimize mechanistically relevant dosing strategies, and you will hear in Dr. Kirschbaum's section how this was achieved. Finally, we already have one drug, which is FDA-approved, in this class of apoptosis enablers, and is the agent venetoclax, although it works, of course, by a distinct mechanism. By way of a very quick vignette for fadraciclib, before I introduce our first speaker, I would like to remind you that this is a dual inhibitor by design of CDK9, a regulator of transcription and cell survival, and CDK2, implicated in cell cycle control. There are a number of anti-apoptosis biomarkers available for us to test in patients from pharmacodynamic evidence of killing activity on mechanism, including cyclin E, relevant to CDK2, and Mcl-1 and MYC, and possibly KRAS mutant forms relevant to CDK9. Of the tumor types of interest which are embedded in our phase II proof of concept study, of greatest relevance are breast, endometrial, ovarian, uterine, colorectal, hepatobiliary, and lymphomas. So far, in unselected late-line phase I patients, we have achieved early indication of activity and we're encouraged to see two out of three patients with lymphoma achieve PR, and 11 of 15 patients with various solid tumors of interest achieve stable disease with tumor shrinkage. Before I hand over to our first speaker, Dr. Jasmine Zain from City of Hope, let me mention that we are very pleased to have her on our program. She's a world authority in the area of T-cell lymphomas, a field we have already seen activity with this drug as a single agent. She will be followed by Dr. Do-Youn Oh from Seoul, who is a world expert in hepatobiliary disease. As we have often been asked why we have chosen investigators to present, it's because one of our patients in dose Level 5 has gallbladder cancer. Therefore, it's quite pertinent to bring a world leader in this area of cancer treatment to also educate us on the emerging landscape of available options. With that, I would like to turn over the floor to Dr. Jasmine Zain from City of Hope to discuss T-cell lymphomas. Dr. Zain? Thank you very much for that introduction. I'm gonna be starting with a brief overview of what exactly is T-cell lymphoma. In the big landscape of non-Hodgkin lymphoma, this is a rare disease. Most lymphomas tend to be of B-cell subtype. There are some unique characteristics about this disease group that are pertinent to this discussion and important for new drug development. T-cell lymphomas basically arise from T lymphocytes that circulate in the blood. Initially, you know, they form from stem cells that sort of are born in the marrow. They mature in the thymus. This is an important distinction. Out of thymus, they go into our peripheral lymphoid organs like the spleen. They go into our lymph nodes, peripheral blood, skin. Lymphocytes are everywhere, including T lymphocytes. The diseases that arise from this set of cells that have not matured in the thymus are basically leukemias that are not considered a T-cell lymphoma. They are treated by, you know, leukemia experts, T-cell leukemia. Leukemias are those that arise from these peripheral lymphoid tissues, also known as mature lymphoid tissues, called T-cell lymphomas. Then based on the cell type of origin, which cell subtype of T-cell has T-cell malignancy, you can have different subtypes. It's important to kind of understand this concept to realize that there are many different types of T-cell lymphomas. There's about 25 different subtypes. I'm not gonna make you memorize any of that, but I will try to simplify that a little bit. In general, they are still considered a rare disease, about 4,800–8,000 cases per year in the U.S. The median age is in the 60s, depending on some of the subtypes that may occur more frequently in younger patients. It's slightly more common in men. This is very typical of lymphomas. They present in advanced stages. There is some risk factors associated with T-cell lymphomas, asthma, family history of hematologic malignancies, smoking, some alcohol consumption, textile working and so on. There's some subtypes that are associated with celiac disease, for example. These are the intestinal T-cell lymphomas. Generally, if I just move on to the next slide. It's hard to memorize all of these subtypes, but one important distinction about T-cell lymphomas is that they can be classified based on their site of presentation. There are certain types of T-cell lymphomas that arise primarily in skin tissues. These are not skin cancers. These are actually lymphoid malignancies that manifest themselves in the skin tissue. They're called cutaneous T-cell lymphomas. This is based on the 2016 WHO classification, which will be updated shortly. There are the subtypes that arise outside the lymph nodes, and they can be the NK/T-cell lymphomas arising in the nasal passages. You could have intestinal T-cell lymphomas where the presentation is primarily in the intestinal tract. You can have a hepatosplenic. These are all different subtypes of extranodal lymphomas. The nodal arising in lymph nodes are of course the most common. These include PTCL -NOS, angioimmunoblastic T-cell lymphomas. There will be anaplastic large cell lymphomas. Again, these tend to be more common. I'll show you those statistics in a minute. Then you have the leukemic forms, where they don't form any solid tissue, but they can live in the circulating blood. Now, the boxes that are in green indicate that these tend to be more indolent diseases. For example, T-cell LGL is an indolent subtype of lymphoma. Most of them, as you can see, are in the gray boxes, and they indicate that these are aggressive diseases. In general, the skin lymphomas tend to be a little bit less aggressive than some of the systemic diseases listed in these boxes. This is a slide showing a sub-distribution of these different subtypes of T-cell lymphomas. I just wanna point out or focus your attention to the fact that at least, you know, the most common subtypes are either PTCL -NOS. Again, this is a weird term that, you know, coined by a hematopathologist. PTCL, peripheral T-cell lymphoma, not otherwise specified, meaning it doesn't fall in any of these categories. It's a little bit of a basket diagnosis. Then you have angioimmunoblastic T-cell lymphoma. You have the NK/T cells and the anaplastic large cell lymphomas. The other subtypes are very rare. As we advance our understanding of these diseases, it is not just based on histochemical findings to how we classify these diseases. We are actually figuring out that these are actually distinct diseases. For example, the anaplastic large cell lymphomas are driven by genes that are very different than genes that drive the angioimmunoblastic T-cell lymphomas or PTCL-NOS. I must say we are lagging a little bit behind in this information compared to B-cell lymphomas, but we are getting there. Keeping that in mind, why are we making such a big deal about T-cell lymphomas? They are associated with a poor prognosis compared to their B-cell counterparts. That is really the crux of drug development in T-cell lymphomas. We do feel that we need to find, you know, distinct treatment options for these patients that are different from the other subtypes. This is data from a couple of registries looking at the overall prognosis of these diseases. This is a U.S. registry, British Columbia, and then Sweden. All of them kind of point out the fact that, you know, if you look at their five-year survival, it's not looking very good. Again, putting all these three together, the most common subtypes, taken into account, median age is about 60. Most of the characteristics are pretty similar. However, there are some geographic variations, noted in some of these lymphomas that tend to be a little bit more common in the Far East, for example, the EBV-associated and the T-cell lymphomas. If you look at a combined five-year overall survival, early-stage disease tends to do reasonably well, 55% survival, but very rarely do patients present with early stage disease. As you go into a poor prognostic category like ECOG 3 or 4 or high on a higher stage, the five-year survival is considered to be roughly about 25%-30%. Even post-transplant, if these patients relapse. Stem cell transplant given in post remission is standard of care for these patients. If they relapse, their prognosis is even worse. There's a lot of patients with relapsed refractory PTCL. This is just a breakdown based on subtypes. There are some subtypes that actually do a little bit better, mainly anaplastic large cell lymphoma. There are two categories of this, either ALK-positive or ALK-negative. They tend to have a better five-year prognosis. If you look at this here, it's over 70%, 80%. Other subtypes, PTCL-NOS and angioimmunoblastic T-cell lymphoma, these are the more common subtypes. Five-year survival here is somewhere between 30% and 40% in the best scenarios. Then you have the really aggressive types, ATLLs and other subtypes, where the five-year survival is coming down to about 20%. This is actually a U.S. prospective study. The previous slide was from retrospective registry data. This is coming from sort of a prospective study that we all did to look at outcomes in the U.S. Again, the data are very similar. First of all, we found that there's no real standard of care in the U.S. for treating nodal disease. This is just focusing on PTCL-NOS, AITL, and anaplastic large cell lymphoma. A lot of, you know, physicians chose different regimens based on their experience or their understanding of the disease, but the outcomes remained poor. Again, anaplastic large cell lymphomas seems to be separated in prognosis a little bit. They do a little bit better with known therapies, but other subtypes tend to do poor. Again, if you look at performance status or IPI, a higher IPI, the prognosis is worse. This is a very interesting slide looking at use of anthracycline, which is one of the drugs used for upfront therapy in CHOP, plus or minus, you know, anthracycline plus or no use of anthracycline, outcomes were pretty similar. This is just a slide to show prospective data in the U.S. about outcomes of T-cell lymphomas. This is a very interesting slide, showing the changes of failure-free survival and overall survival in PTCL- NOS and angioimmunoblastic T-cell lymphoma, the two most common subtypes, by years. As you see, over time, we have not made a lot of progress. You know, the five-year survival is still hovering around 30%, and so, we still have a lot of work to do. Moving on to treatment. Upfront treatment is, you know, unclear for most cases. CHOP, which is used to treat aggressive lymphomas, is a combination chemotherapy. It is a general treatment regimen for most lymphomas, including B-cell lymphomas and indolent lymphomas as well in some cases, and it remains the backbone of T-cell lymphoma therapy, even though we, in our world, always say that this is not the best option. So far, we haven't discovered anything other than anything better than CHOP, even though several trials have been conducted with different combinations of CHOP. There's been one study where it was combined with a CD30-directed therapy called brentuximab vedotin, which actually in the randomized, was shown to be superior compared to CHOP by itself. BV-CHP became standard of care for CD30-expressing T-cell lymphomas, which is seen in anaplastic large cell lymphoma. As you remember, they tend to have a better prognosis anyways. Now we have even better therapies for that subtype. About 30% of other subtypes also express CD30, and so this can be used as an upfront regimen. It's in the NCCN guidelines. For other subtypes, it's unclear what the best upfront regimen will be. We are going to be focusing on patients with relapsed and refractory PTCL. Again, as I showed you, prognosis for these patients remains poor. There are a few treatments that are actually FDA approved for T-cell lymphomas in the relapse setting. These were developed over the last 10, 15 years. The first one was pralatrexate, approved by the FDA in 2009. As you can see, the overall response rate is about 28%. Response rates were pretty similar for the different subtypes, and durations of responses were not prolonged. None of these treatments are curative. Then came romidepsin, which is a histone deacetylase inhibitor. It's a biologic therapy, an epigenetic therapy. Response rate is 25%-30%. A little bit better in angioimmunoblastic T-cell lymphoma, but otherwise, you know, again, not curative. belinostat, a similar agent, HDAC inhibitor. Response rates are low. Duration of response, again, not curative. Brentuximab vedotin was a bit of a star. It for CD30 positive anaplastic large cell lymphoma had a response rate of about 87%. Mogamulizumab was approved in 2012 for ATLL, which is a rare subtype of T-cell lymphomas in the relapse setting. It's also approved for cutaneous T-cell lymphomas. Chidamide is an HDAC inhibitor approved in China. Cytotoxic chemotherapy regimens that have been used in other B-cell lymphomas, other subtypes of lymphomas as well. Response rates are high, but the duration of response remains low, which means that we are not doing great in this space either. You can have some other approaches to T-cell lymphoma. Dr. Zain, are you still with us? Please hold while we fix the technical difficulty. Hi, everyone. We apologize for the technical difficulty. We are gonna go to Dr. Oh's presentation now and then go back to Dr. Zain when she rejoins. Please go ahead, Dr. Oh. Thank you for inviting me to this interesting meeting. I'm Do-Youn Oh, medical oncologist in Seoul National University Hospital. Today, I will briefly talk about the new drug development in biliary tract cancer. This is my COI disclosure. The incidence of biliary tract cancer globally is relatively low compared to other solid tumor types. However, in Korea, biliary tract cancer is non-rare cancer. Developments in systemic therapy of biliary tract cancer has been done using cytotoxic chemotherapy and targeted agent and very recently, immunotherapy. In advanced stage first line setting, gemcitabine cisplatin combination has been long-lasting standard of care based on the ABC-02 phase III study research. Which was reported in 2010. The median overall survival by this GemCis combination regimen is around 11-12 months, less than one year. The prognosis of advanced biliary tract cancer is poor. This is the list of current trials targeting first line in advanced biliary tract cancer or randomized trials. The effort to improve the overall survival compared to standard of care, GemCis regimen, sometimes the GEMOX regimen. So far there has been no one global randomized study to improve overall survival compared to GemCis regimen so far. Previously, I tested the combination of cytotoxic chemotherapy and immunotherapy in first-line biliary tract cancer. I conducted a investigator-sponsored trial named BTC first -line treatment. In this study, I used the GemCis current SOC cytotoxic chemotherapy and as immunotherapy, I used the durvalumab and or tremelimumab. This study was phase II study, which is composed of three different cohorts. This was not a randomized trial, this was just a phase II study, but I wanted to test three different strategies to combine immunotherapy and cytotoxic chemotherapy in first-line biliary tract cancer. To make a long story short, a total 128 patients were enrolled in this study. In terms of treatment response, you can see very good tumor shrinkage, including all CR case across three different cohorts. Objective response rate ranged from 50%- 72%. Quite encouraging data actually. Progression-free survival was 12 months and overall survival was 18 months. Quite encouraging data. Based on this phase II by IST trial, we actually launched a global phase III study named TOPAZ -1. TOPAZ-1 is a double-blind, multicenter global phase III study, which compared GemCis plus durvalumab and GemCis plus placebo in terms of overall survival as a primary objective endpoint. The primary endpoint overall survival was met its statistical significance at the pre-planned interim analysis. The hazard ratio of overall survival by adding durvalumab on top of GemCis compared to placebo GemCis was 0.80. The left side is the ABC-02 survival curve. GemCis, the dark one, and right side is TOPAZ-1 survival curve. We made the first-line advanced biliary tract cancer patients overall survival Kaplan-Meier curve like this, violet color, by adding durvalumab on top of GemCis in 12 years. This is one step progress since ABC-02, 12 years ago first report. Last month, I reported the long-term follow-up data of TOPAZ-1 study. How more follow-up? 6.5 more follow-up data. At this time, hazard ratio of overall survival is 0.76. Better hazard ratio compared to primary report, overall survival hazard ratio 0.80. Which reflects the long-term benefit of immunotherapy. Based on this TOPAZ-1 data, this July NCCN guideline adopted durvalumab plus GemCis combination as preferred regimen category one. September 2nd, FDA approves durvalumab for locally advanced or metastatic biliary tract cancer. In terms of molecular characteristics, biliary tract cancer have diverse range of genetic alteration. Very interesting. Among them, the targeting FGFR2 fusion translocation in advanced biliary tract cancer refractory setting already shown the success. Infigratinib, pemigatinib, futibatinib received FDA approval already, all FGFR inhibitors. Next, targeting IDH1 mutation in biliary tract cancer also showed a positive result in the ClarIDHy global phase III study, which used ivosidenib. This is a mutant IDH1 inhibitor. Again, this ivosidenib received FDA approval. From the tissue-agnostic approach, MSI-high and NTRK fusion is also applicable in biliary tract cancer. MSI-high BTC, we are treating them with pembrolizumab. NTRK fusion positive BTC, we treat them with larotrectinib or entrectinib. How about targeting CDK 2/9 in biliary tract cancer? This has not been tested at all in this field. Now I'm conducting preclinical study using fadraciclib, which is CDK 2/9 inhibitor in my BTC preclinical model. When you treat BTC cells with fadraciclib, we found that majority of cells showed growth inhibition. However, when we correlate the cell sensitivity with some molecular characteristics of cell lines, we found that Mcl-1 high expression is quite well correlated to the fadraciclib sensitivity. Cells with Mcl-1 high is more sensitive to fadraciclib. Furthermore, fadraciclib down-regulates the expression of HR factors, homologous recombination factors, including BRCA1, especially in Mcl-1 high BTC cells. With that, fadraciclib sensitizes Mcl-1 high BTC cells to olaparib, PARP inhibitor. Very interesting finding, I think. This is in vivo data. Fadraciclib monotherapy shows growth inhibition in BTC xenograft model and fadraciclib in olaparib combination shows strong antitumor activity in BTC xenograft model. I think targeting CDK2/9 inhibition should be further investigated in biliary tract cancer. Let me conclude my talk to say that about the current status and future perspectives in biliary tract cancer. Now, we have new standard of care in first line advanced BTC using immunotherapy plus chemotherapy combination. In this case, durvalumab plus GemCis based on TOPAZ-1 trial success. In targeting FGFR2 fusion and IDH1 mutation has already shown success. Many clinical trials for various targets, including genetic subset immune, are ongoing in biliary tract cancer. Biliary tract cancer is really a blue ocean in drug development. Thank you. Thank you, Dr. Oh. To the audience, Dr. Zain is now back with us, so I'm gonna ask her to pick up from where she left off. Please go ahead, Dr. Zain. Dr. Zain, you're on mute. Is this better? Can you guys hear me? Okay, great. Sorry. Sorry about that. I was talking about combination targeted agents in T-cell lymphomas. As I had shown you, single agents that are FDA-approved for T-cell lymphomas, a lot of them have low response rates, around 30%. What about combining them? You can see on this table, there are multiple combinations that are currently in small clinical trials. Response rates are definitely higher now in the 70s and 80s. You know, none of these combinations are currently approved for the treatment of relapsed disease. Moving on to the next slide, please. There have been combinations in the upfront setting as well. I showed you earlier in my slides. Again, other than the brentuximab vedotin plus CHOP chemotherapy, none of them have been approved, and none of them have been evaluated in randomized studies as well, that were positive. Moving on to the next slide. There are a few other novel agents that are currently in clinical trials. I think what we have to look at is the NCCN guidelines. If you look at the NCCN guidelines, the first line at the top of each column of each subtype of T-cell lymphoma, is a clinical trial preferred. These are guidelines for relapsed refractory disease. To me, this indicates that the patients, that we really don't have good options for these patients. All the agents that are approved or otherwise used are listed in an alphabetical order. It's the physician's choice. Depending on the side effect profile, they choose whichever agent they feel the patient can tolerate. None of them are considered to be curative. Next slide, please. Next slide, please. This is again a slide showing single versus combination chemotherapies. This slide shows that if you use targeted agents that have been approved for T-cell lymphomas, they tend to do a little bit better than combination chemotherapies like ICE or DHAP. These are combinations used in relapsed refractory B-cell lymphomas or aggressive lymphomas. Again, a reason to really develop treatments that are very specific to the T-cell lymphomas. Next slide, please. Next slide. These are just upcoming therapies. In the newer trials you see for T-cell lymphomas, you see diagrams like this, pictures like this, looking at different targets that can be developed. Next slide. I think we're going backwards. We're not moving forward. Yeah, I've already done this slide. Sorry. Keep moving forward, please. I wanna talk a little bit about cutaneous lymphomas. These are lymphomas that arise primarily in the skin. The reason I'm bringing this up is because these are different diseases and again, an interesting target for drug development. Next slide. They arise primarily in the skin. Can I have the next slide, please? Dr. Zain, this is your last slide. Which slide are you referring to? You know, I think it's all out of order. Anyways, I just want to say that these are skin lymphomas. They arise primarily in the skin, and they tend to be more indolent. Again, we don't have curative therapies for these, and we can develop new agents that can help these patients. I think that would be very helpful. We need agents that are effective, have fewer side effects, and can be given to these patients for long periods of time. The slide up there is showing the different subtypes of T-cell lymphomas. Next slide, please, if you have one. I think these are just examples of different types of skin rashes that these patients can have. As you can see, they can be pretty disfiguring and uncomfortable for the patients. Next slide. I think you can go to my last slide, which is the thank you slide. You can move on. This is the conclusion. T-cell lymphomas are heterogeneous. They are incurable with current therapies. They tend to be aggressive, and we really need new approaches to treat these patients. Finally, this slide is a City of Hope slide. Just showing pictures of said City of Hope. I apologize for all this confusion, technology issues. I will now move on, and pass the mic over to Dr. Kirschbaum. Thank you, Mark. All right. Can you hear me? Yeah. Yeah. We hear you. The excitement of live television. Good morning, everyone. On behalf of my team, I'd like to present to you the latest update of our exciting trial. Tell you how we got here and why, and what we're seeing. Next slide, please. I can control this. In order to really understand what we're doing, it's good to understand how this drug works and what it does. It's kind of a really interesting story. As Spiro told you before, it was in long development by Nobel Prize laureates. Essentially, this drug has two major functions. The most well-known function of this drug is that it's a CDK9 inhibitor. What that means is that it inhibits transcription. In general, it's a transcription inhibitor, if you can think about that. It inhibits RNA polymerase II. As a result of that, it directly inhibits Mcl-1, which is a very important anti-apoptotic protein. By inhibiting that, you increase the chance that a cell will undergo the apoptosis that it needs to do when it's an abnormal tumor cell. It'll also inhibit MYC in two ways. One is that it actually can, in certain circumstances, inhibit the transcription of MYC. I think most well-known and very well described is that MYC is a transcription addiction, as it were. When MYC is on, it means that the cell is in go, go mode. One thing that this drug does is that it stops MYC from transcribing. As you'll see later, one of the hallmarks of showing this kind of inhibition is that there's over 1,000 genes that, as a result of MYC overdrive, are transcribed, that should be stopped. We'll show you how that looks later on in the presentation. The other aspect of it is that it is a CDK2 inhibitor. This is by a different mechanism, in that CDK2 binds to this and then becomes active and is a very important resistance mechanism for, particularly well known, in two types of breast cancer. It's a resistance mechanism for palbociclib, which is a major drug that's used in breast cancer. It's also a resistance mechanism for really the first drug that was shown to be important in changing the fate of breast cancer patients, and that was trastuzumab. One of the well-known mechanisms for resistance to trastuzumab is through the Cyclin E, which is the binding partner for CDK2, and thus inhibited by our drug. With that in mind, the early studies that were done with this drug in the development, there was a phase I that was done with the IV form of the drug. It already showed proof of concept, as it were, in the sense that one patient with very refractory endometrial cancer had an amazing, excellent response that is still ongoing now for three years. This is a patient who received many therapies, including some experimental therapies and immunotherapy. With all of this in mind, and the availability of an oral agent, the oral agent being exactly bioequivalent to the IV drug, which gives us a lot of advantages. This drug has a half-life of four hours, so clearly giving enough of it IV over time will be difficult. And even in that patient, that in the initial patient that you saw, that had that great response, that was the patient who got the drug already more than once a week. The patient got it two times a week, two weeks out of three. It was clear that the more that we can give of this drug, the more we can suppress these mechanisms that I described earlier, the more likely it is that we will broaden the activity and the response. This is the trial that we're gonna present to you now. We've been through multiple dose levels. Of course, that time only patients received a maximum of two days a week. We increased to three and then to five. We started with three weeks out of four, and now we're at 100 mg twice daily, four weeks out of four. We did all this in the space of a year. Again, thanks to our wonderful team internally and our incredible group of investigators, two of whom you heard from now, we're at major sites globally in the United States at MD Anderson, at City of Hope and overseas at Vall d'Hebron in Barcelona, and in Seoul National. The leading phase I sites in the world. Now, one of the things that we did in this trial to really make it meaningful, and you'll see this in the results, is that we identified the tumors that we were interested in from the start. This trial rolls in automatically once we achieve the proper phase II dose into Simon's two-stage phase II, which means that a couple of patients will be treated for the various diseases to make sure that there's no futility, that there are responses. If responses are seen, each one of these automatically unfolds into a full FDA type regulatory phase II trial. We save a lot of time, and we're very focused. All these tumors that we've identified for this proof of concept are tumors that, as you heard, have either very urgent need, like the T-cell lymphoma, and as well have molecular correlates that make sense for treating with this drug. For example, T-cell lymphoma has both McL-1 and MYC. You heard the story in cholangio. We have a history with this drug in terms of other studies with hepatocellular, and of course, the breast story, as I mentioned earlier. There's also a rapidly developing story in KRAS mutant colon cancer, and we do have preclinical evidence that suggests that this would be important here as well. That is also included and a basket for other tumors that may have McL-1, MYC, or Cyclin E that makes sense. With responses in any of these groups, they can go on directly with contact to the FDA onto a accelerated approval type single agent study if warranted. Let me present to you the results that we have so far. Now, again, this is an ongoing study. We're not done. I will present to you the data up until dose Level 5, which is 100 mg twice daily, five days a week for four weeks out of four. Fortunately, and I'm proud to say, we've had very little in the way of toxicity getting to this point. There are no formal DLTs related to study drug up until dose Level 5. Just to give you a brief overview of all the toxicities that we're seeing, almost all. Everything that we've seen has been pretty much related to underlying disease of the patient. As the patients progress, this is at all cycles, right? Patients develop these toxicities usually as a result of their disease progressing at some point. But we have not had direct toxicities related to the drug. When you see not applicable there, it's one of those gray areas that those are toxicities as it were that are called so because the patient's dosed incorrectly. It's related to the drug, but it's not really a toxicity, and there were no adverse outcomes related to that. Just to give you the breakdown by dose level, you can see here all grades. We've listed essentially all the treatment-emergent adverse events, not just the tumor-related ones. I'll give you a quick moment to look at this, but you can see they're all minimal. The primary things that we've been seeing consistently through the study is nausea related to the drug, which is a pretty common toxicity with drugs of this sort. This is the full set of toxicities here. This is even at dose Level 5. Seeing what we have is a pretty well-tolerated dose regimen for a drug that's taken twice times daily, continuously. I can show you the responses that we have thus far in the dose escalation. We have two formal PRs in T-cell lymphomas. We have 11 patients out of the 18 patients treated thus far have, after their first cycle, been formally stated as having stable disease, with five progressing in the first cycle and primarily at the lower doses. As you see, it's interesting that as we get to the higher dose levels, for the most part, the duration on treatment also increases. Here are the responses broken down by tumor types. It's interesting that even at a pretty low dose level, we already had a response in a CTCL. This is encouraging for going forward. That may have been by a CDK2-related mechanism, as I'll show you in a moment. This is a waterfall plot of the responses and the non-responses that we've seen in stable diseases. As you can see, technically, we have six patients who had a disease reduction in the course of the study. That's four of the solid tumor patients and then the two T-cell lymphoma patients. For those who have seen the poster, it's broken down that way as well. It's four and then the two additional lymphoma patients. The two lymphoma patients, as you said, one was a CTCL and one was a very aggressive angioimmunoblastic T-cell lymphoma. I'll show you a scan of that in a moment. Had very dramatic responses. We have these responses as seen in solid tumors, some of which were accompanied by long duration of, on study. It's worth noting that in dose Level 3, there was a pancreatic cancer patient who had stable disease for over five cycles. The reason the patient actually came off study, not immediately because of progression, but because the patient's husband also had very bad tumor, and they opted together to go to hospice. That's a very, very promising signal for going forward. Here's a PET scan of the dramatic response that we saw in the angioimmunoblastic T-cell patient, which is really the worst kind of T-cell lymphoma. For those of you who are not used to seeing these, it's sort of backwards here. On the right is the original scan, and on the left is the follow-up scan. Ignore the kidney area. That's just the dye. This is a scan of uptake of sugar. It's more than an X-ray. It's also a sign of the activity of the tumor. If a mass becomes both smaller, which is that it's decreasing in size, but also lighter, which means that it's less tumor active and probably on the way of dying. You can see that there are multiple tumor sites that have gotten smaller or disappeared in color all across the patient's body. All of these are on the skin, so these are all over, all external. You can see on the shoulder, in the mediastinum, in the chest area, number of tumors, and then all along both sides, tumors have become smaller and lighter. Let me tell you a little bit about where we are, both in terms of pharmacokinetics and pharmacodynamics and the science accompanying with it. One of the things that we ascertained was the target engagement levels needed to inhibit the two major targets that we've talked about in a cell system. This is more than the usual, just, you know, inhibiting in a test tube. This is expressing these markers in cell lines and then treating those cells. This gives us a more representative idea of what doses we need to inhibit these targets in reality, not just in a test tube. As you can see here, we have the levels of sensitivity for CDK2 and for CDK9. These are all the dose levels. On the left graph is the first-day treatment, so they only get one dose on that day. On day 17, which is the end of a week, the end of week three, that's a more representative picture of what it looks like, you know, after the first dose. You can see that we're achieving in the higher dose Levels in 4 and 5, we're achieving levels over the inhibitory points for by target engagement of CDK9 as well for about five hours per dose. Five to seven hours per dose. Again, this is twice daily, so we're getting a lot of coverage of these targets per day with the current dosing regimen with the oral drug. Now the question is, what does this change in dose do? This is a complicated slide. It's hard to see in small. It is on the poster, so you can look at it a little bit more carefully. I think the major point that this makes, this is a heat map that gives you 3,000 genes in terms of what happens to the transcription after we treat, before and after we treat. The easy way to look at this, you can see, first of all, just looking at it like as though we were looking at some kind of impressionistic painting, that there are swaths of purple with swaths of white. Now, white here is zero, the zero point. Purple is decrease in transcription. The gene disappears when it's more purple. We don't see much of it here. When you see red, it means that a gene goes up. As you can see, and if you look at it carefully, you see those color codings on the bottom, those are for individual patients, and that is over time. I think they're mostly from the first day. There's some also includes the day 17. As you can see, we reproducibly every time, show a large amount of gene transcription inhibition every time we dose. This is consistent with the kind of activity that one wants to see with this kind of drug. You can see it sort of in a graphic form there. Those bars represent all change in all directions. You can see the zero point, and then you see this activity overall. We're still ongoing in the study. There's still more work to do. We have more correlative studies that will be coming over time. I think it's fair to say that where we are at the study now, we're seeing activity and it makes sense in terms of the PK and the molecular activity that we expect to see. Here's the summary for this study. We treated 18 patients with solid tumor or with lymphoma. We haven't covered all the tumor types that we'd like to treat. Hopefully, that'll happen when we get to the phase II. For the tumor types that we've seen so far, we're doing pretty well. The median treatment duration is 2.4 cycles, and we've treated as far out as five cycles with some of these patients. It's been well-tolerated in all of those levels thus far. As I said, this includes data up until the 100 mg twice daily, Monday through Friday, four weeks consecutively without breaks. We have seen thus far two PRs in T-cell lymphoma patients. Four patients with the tumors enumerated here show target lesion reduction, and we had, in that, very advanced pancreatic cancer patient, stable disease for five cycles. We are achieving the levels we want that we predicted with target engagement that will be necessary to have the biological activity that we want. Enrollment continues at dose Level 6, which has jumped to 150 mg twice daily at the same schedule. Just as an update, that one patient in the earlier study that had a CR continues three years out. This is the data for the five-cycle study that will continue onwards and hopefully we'll be able to present the completed study, and the answer to the phase II in a very short period of time. Thank you very much. Now I'd like to. I don't have a formal break here, so I have to do my own introduction. I'd like to tell you about our very exciting new trial that's coming. It's still early, so there's just a little bit to say, but I think you'll be excited to hear it. Hopefully, you'll be excited to hear it as we are. PLK1 is a very important target. Let me jump to the molecular biology in the interest of time. It's a target that is in evolution. When I was in my academia days, I actually worked on this target primarily as a cytokinesis agent, in other words, to inhibit the cell division, the mitosis. You mess up the way the cell divides. We know tumor cells divide more rapidly than they should, and the normal cells, so they're very sensitive to this kind of disruption. In the last few years since then, a lot of new things have been found out. It turns out to be much more of a control element for many, many different pathways, including some epigenetic ones. So, let me show you why we think our drug is exciting. You know, so this was the old mechanism that was known. You can see that, just very briefly, you can see that when the cells get treated, they pile up in this peak over here, which is G2. In other words, they have aberrant division, and you can see that very graphically in the color pictures there. The top one is normal cell division and the lower one is cell division on drugs. It's not consistent with viability for the cell. With that biology that was known at that time, these drugs were studied. There was, as I'll tell you in a moment, one drug that showed single-agent activity as a PLK1 inhibitor in leukemias and lymphomas that went to the point of a phase III. We'll talk about that in a moment, but keep that in mind. This is a drug with single-agent potential. To give it even more weight, this is an interesting study that we did here a few years ago that was published. We found that there was more to this story than was known before. The slide on the left shows you that if you give these drugs at high dose versus low dose, you can see the two different sets of bars. When it's given at a high dose, many of the cells just stop growing. It's like a toxin. Like the pictures though before. Growth is not possible. That continues at the low dose. However, if you look at the figure on the right, interestingly, at the low dose, they do go into cell division, but they then undergo apoptosis. At the end of the day, you actually get, perhaps even equivalent or more cell death with the lower doses than you do with the higher doses. We'll come back to that in a moment when we talk about how we designed the trial in the way we did, but it's important that this drug may have different activities at different dose levels, and some of these are new that haven't been really seen before. One of the reasons that we think that our drug may have this potential is that our drug has a secret weapon, as it were. Aside from being a PLK1 inhibitor, it is also a BRD4 inhibitor. Now, those of you who know the field know BRD4 is a very important epigenetic regulator. It's like a central control for epigenetic downstream targeting, which is again, the control of how genes are turned on and off in a broad way. This is a property that we share with the drug that had the activity before, the Boehringer Ingelheim drug. Other drugs in the class, such as another one that's in development now, don't have this property. These are the drugs that I've mentioned. The drug on top is the Boehringer Ingelheim drug. It was a really active drug. As I said, it went to phase III with single-agent activity. Its problem was that it was given IV and had a half-life of 100 hours. 100 hours at the high doses with your myelosuppressive means that any benefit, clinical benefit you have is also offset by the infections and other toxicities that you get, and that's exactly what happened. It's an active drug, but that drug as it was, it was too toxic to go forward. There is another drug in development that doesn't seem to have much public single agent activity. It seems to be very active in combination chemotherapy in colorectal cancer. But it doesn't have these other activities that we, that I've outlined for you until now. And of course, our drug, which is oral and has a 10-hour half-life, which means that we have the benefit of the activities, but the short enough half-life to be able to control the toxicities. Very briefly, I'll just show you that we have activity in a broad range of tumor types. The lower the bar here, the more cell kill you have. You can see that the bar all across is pretty low. Some of these have lot bigger error bars because they're different. There are different cell lines in there, so some of them are more sensitive, some of them are less sensitive, as you heard Dr. Oh’s talk. Overall, there's a large number of tumors that are potentially sensitive to this, even at the normal dose, at the higher dose level. What will happen in the lower dose level, I think, is a really interesting question. We just to flash this before you, we have this in various tumor models. We have it in GI tumors, in esophageal, we have it in leukemia. These are in vitro data. We also have the KRAS story that was mentioned. I would say that from that preclinical work, it's probably not only limited to KRAS colorectal cancer. With all of that in mind, just one more, two more slides. Let me show you the trial design that we have ongoing, and I'll tell you something, a preliminary result that's really astounding. We started out at the very low dose, partly because this is the first in human, so this hasn't been really dosed to patients before, so we want it to come in safely. Also because we were interested in seeing what happens with the low doses, whether that will be a clinically relevant story. We started out at a low dose, just 5 mg a day, for three weeks out of four. The way the trial is designed is that every time we escalate, first we do week on, week off, so that pulse effect, and then we add the third week if that's tolerated, and keep going from there. We alternate between the schedule increases and the dose increases. With this study, we'll be able to learn really all the potential activities that this drug may have. The tumor types that we have identified are all tumor types that we either have preclinical data for or have molecular reasons to be treated this way. As you saw before, when we introduced this to our phase I sites, they understand what we want on the tumors and then the correct tumor types get accrued even to the phase I. We don't have a lot of off-target types of tumors enrolled that we know won't work. Here we have bladder cancer, breast cancer, lung cancer. All of these have been shown to be very sensitive, particularly non-small cell lung cancer, hepatobiliary and biliary, as we've mentioned, and then the lymphomas and the colorectal story, which is very important. Now, here's the exciting thing, hanging on to this point. We have a drug that we believe has very favorable properties. We believe may have multiple dose effects as we go along. But even to our amazement and surprise, even at the lower first dose level, at the 5 mg per day, which is, we didn't even think that would be substantial. We saw two really dramatic responses in the sense that two patients with very advanced disease had stable disease for a long period of time. We have one patient with non-small cell lung cancer who is still ongoing at six cycles. That's six months of treatment. A patient with metastatic ovarian cancer to lung and spleen had stable disease for little more than four cycles. That's four months. This was very exciting sensitivity even at the low dose level. We're very excited for this study as it goes forward. Of course, no DLTs have been seen so far. Hopefully, we will be able to update you with the full data on this study that's accruing very rapidly in a short period of time. Thank you very much. Let me turn it over to the moderators. Thank you, Mark. At this time, we will be conducting a question and answer session with our speakers. As a reminder, if you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player or by emailing your questions to questions.lifesciadvisors.com. Please hold for a brief moment while we pull for questions. Our first question comes from Jonathan Aschoff from ROTH. Please go ahead, Jonathan. Thank you. Hi, guys, and thanks for doing the R&D Day. My first question is, what was the tumor type, dose level, and course number received of the one progressive disease patient of the five that is not shown on the Fadra poster's waterfall plot? Sure. You know, that was a breast cancer patient who had stable disease in the lesion that was identified for follow-up, but then had a new lesion and then came off study. That's why it looks the way that it does. Okay. How about dose level at the course number they had? Give me a second. I'll tell you in a second. I think it was dose level. I just identified it. I think was it Level 3? Yeah, dose Level 3, I think. Yeah, I think it was Level 4. Okay. Thanks for fixing that waterfall plot, by the way, compared to what was in the poster regarding that CCA patient. That obviates my next question. One other is, you know, you showed a bunch of genes differentially regulated in your Fadra poster. Do you have any sense of what any of them do that might be relevant to Fadra’s anti-cancer effect? As I said, this is something that's still in development. We don't have all the full data yet, and it requires a lot of data mining. You know, if you look at some of the MYC studies, for example, there's many drugs that target MYC that are being shown now, and you see a very similar picture that's presented because these things regulate. The MYC itself is a driver for over 1,000 genes. In general, we look at it, we look at the big picture of what we are, we are trying to break this down with our stats company that's doing these assays to break it down to pro-apoptotic and other type targets. We should have that, you know, when it's time, when we finish the study. Okay. Are there any DLTs that you're, in particular looking out for with Fadra? Well, so far, we haven't seen any yet. The one problem that we're having consistently that will probably, you know, become a problem down the line is we're having some issues with nausea. I think that's a pretty common abnormality, nausea, vomiting, that kind of thing. That general tolerability. That's the one repeating thing that we see over time. In the animal studies, pre-clinically, we didn't really identify any targets, you know, any toxicities that we had to alert for. We'll see. We're jumping to a big dose jump now to the 150, and we'll see what happens there. Lastly, in your 140 presentation, you mentioned down at the bottom left of one of your slides that it's a three to four week cycle. These aren't all gonna be four-week cycles? No, it's a four-week cycle. I don't know. I'm not sure. I can't go back and see what exactly you're referring to, but the schedule alternates between week on, week off over four weeks or three weeks out of four. Yeah. Yes. Okay. That footnote's just a bit misleading. Okay. I can't go back to it. If it is, we'll correct it. Okay. Thank you for the questions, Jonathan. Our next question comes from Jeff Jones from Oppenheimer. Please go ahead, Jeff. Thanks, guys, for a great presentation. One just quick follow-up on the nausea question. In the current study, are you allowing anti-nausea agents? Yes. As per standard care. Okay, great. As far as escalating from dose Level 5– 6, can you give us a feel for how long you would expect dose Level 6 to run? You're thinking about escalating to dose beyond dose Level 6. I know you've sort of got a question mark around dose Level 7, and how that impacts the potential timing of the start of phase II. Our goal here really is to fine-tune the dose so that we have the right dose so that when we go forward to the phase II, you know, we maximize the benefits for patients. That's our goal with all of this. You know, it seems like the more we dose higher, the biological activity is, you know, crosses the line more. I don't think it's gonna take very long. I think I'll be surprised if it's tolerated. We do have an intermediate dose, so if 150, for example, is too toxic, if it's not well-tolerated, then we can, we have an intermediate dose of 125 that we can look at, so it's just a few patients. That should be done very rapidly. It's not gonna take a long time. We already expanded the 100 BID to six patients, so we're ready to go if that's our dose. This is not a long period of time till we get to the phase II. Okay. Goal probably getting into phase II early next year. And then I guess, could you touch on the status of the leukemia study as well for Fadra? It's moving. It's leukemia, you know, it's a very—there’s a lot of drugs going there, and it's sometimes takes a little bit longer to get some traction, but we are in the 100 BID dosing. We are, I think we're completing that group. So hopefully, that will start to pick up over time. You know, with leukemia, it's always when there's one response, all of a sudden it just snowballs. All right. Great. Thank you very much. Thanks for the question, Jeff. Our next question comes from Ahu Demir from Ladenburg Thalmann. Please go ahead, Ahu. Good morning. Thank you so much for taking my question and also, the information provided. It was great. My first question is from the PLK1 program. Was the BRD4 inhibition came as a surprise, or was it something that's known, and how was it discovered? And also, if you could put that in perspective in terms of, does it change any of the plans, and what does it mean for the future of this program? No, it was not a surprise. We had, it’s, like I said, the older drug had this property as well. We did full kinase. When we did the full kinase profiling of this drug, this also came up in the profiling, which was a very positive finding. Essentially, that is part of what led to the study that I showed you about the lower dose. I can tell you that what it does impact in our study is that, particularly with this activity that we're already seeing, the lower dose, we're doing pretty extensive correlative studies with our partners at MD Anderson to look at the full epigenetic activity of this drug in the event that that may be something that is contributes greatly. I mean, to me, it's, you know, I did epigenetics in academia before, so, I know one thing that if this is true, then this makes this a great combination partner for many therapies down the line. Does it also make it so different from onvansertib and what we have seen in the other PLK1 programs as well? Does it put you in a very different position in terms of the indication, selection, combinations, and others? I mean, we'll see, but to me, yes. We believe very strongly that there is strong potential for single agent activity with this drug, which differentiates us very, very much from the other agents in the field. That's helpful. My other next question is on the Fadra trial. Mark, you mentioned the duration of response being longer for the higher doses. Could you provide more color on that? Well, there were some patients who went. I can always tell you exact numbers, but, certainly, in the first three patients, we had a patient who went—we had an endometrial patient who had some both decrease in size and went five cycles. Of course, you heard about the PTCL patient, right? Another patient with cervical cancer also had stable disease that went for over three cycles. You know, you start to see this kind of pattern, so it suggests that the dosing schedule are enhanced, you know, as we get to the dose level five. I thought the target engagement study from the poster was very helpful. When you look at the responders, do you see any correlation, the better target engagement resulting in responders, or is there any correlation you have observed? Other than that, you know. What the target engagement tells us is where the dose needs to be, right? The target engagement is not done on the patient's specimens. It's a benchmark for us to dose at. It's a supportive evidence that we are in the right place at this dose level. If I may ask one more question to Dr. Oh. Given your expertise in the BTC field, is there any genetic subset that CDK2/9 might work? Is there any scientific or clinically rational combination for Fadra? Would you say PD-1 combination makes sense in that setting? Can we get some, maybe some of your thoughts on that? Thank you for asking me. Very interesting question. We are trying to find out a biomarker for selecting some patients based on mode of action of the drug. So far we haven't found a good genetic alteration, for example, KRAS. No. Just in the solid cancer, as I showed, the Mcl-1 expression level is the highest well-matched biomarker. We are doing the preclinical research continuously now. Thank you. As a follow-up, the combination of durvalumab or any PD-1, PD-L1 agent, would that make sense? I think, it makes sense hypothetically, but we have to generate some data, for example, immune modulation effect or something like that. Yeah, definitely a combination with immunotherapy might be a very interesting field, I think. Thank you so much for taking my questions. Have a great day. Thank you. Thank you, Ahu, for the questions. Our next question comes from Kemp Dolliver from Brookline. Please go ahead, Kemp. Great. Thank you so much. First question relates to the screen failures and any patterns or things we can take away with regard to generalization of the patient population or results. Yeah, I'd be happy to answer that. You know, this is a phase I study, a phase I center. Usually, the patients that get referred to phase I studies are the patients who have failed, you know, many lines of therapy and don't have standard treatment options available to them. It's obviously a sicker patient population. A number of times, patients were consented and then takes about a month to do the formal screening, they progressed during that time. That was the largest reason for the screen failures in the study. Which is, you know, it's pretty standard. Nothing different than the usual phase I experience, it's fair to say. We've, as you can see from the tempo that we've reached this data, right, the first patient was dosed a year ago in July, and we're already at dose Level 6. All in all, I think compared to most phase I studies, we've accrued very well, even with the screen failures. That's great. Thank you. This is obviously speculative, but looking at a trend toward stable disease in a patient population that has effectively run out of options and where you may have some promising duration, could that end up being where this ends up and, you know, commercially successful? Well, I'm hoping that, when we get to the phase II, where you have less heavily pre-treated patients, when we're at the right dose, this will predict that we'll see more activity. I think, you know, many drugs have long, stable disease as a story. I do think that there are certain disease types, certainly the lymphomas, some other disease types, where we may see formal responses as well. I hope. Understood. Thank you. Thank you for the questions, Kemp. I'll now turn the call over to Spiro to read the written questions. Yes. Hello. I have a question for Dr. Zain. Approximately a year ago, just over a year ago, the accelerated approval of romidepsin in the United States was withdrawn for relapsed or refractory PTCL. Could you please comment on the impact of this withdrawal of this indication on the landscape for PTCL and possible choices for comparative studies in the way forward? You're on mute. You're muted, Dr. Zain. If you don't mind unmuting. Your phone is muted, if you wouldn't mind. There you go. Thank you. Thank you for the question. This was based on a phase III study that was carried out post-marketing with R-CHOP, which was romidepsin with CHOP versus CHOP. The study actually was negative. Based on that, they withdrew the FDA recommendation for romidepsin in PTCL, not cutaneous T-cell lymphoma. The drug is actually still available. In terms of what impact it's had on the landscape, it still continues to be in the NCCN guidelines, so there has been no change in the usage of this drug, if you wanna call it that. We still prescribe it. It's not difficult to get because it's still in the NCCN guidelines. The only issue has been that we have been reluctant to use it in combinations at the moment, in trials of combinations, because it's, we're unsure of the future, whether it will continue to be available. Our feeling within the T-cell community is that because it was based on a upfront study design, they may not be able to, you know, they may not actually withdraw it from the NCCN guidelines. I'm on the NCCN guidelines panel, so I can say that these discussions have happened. We have such limited options for these patients that, you know, we all vote that we should keep it on. So far it has not changed. As I said, it continues to be available for cutaneous T-cell lymphomas, where it's actually used more often anyways because you need this in the long run, this less toxic drug for long periods of time. That's what I can say. Thank you very much for your answer. I have no further questions. Operator. Great. I think we can go with your closing remarks, Spiro. Thank you, Tara. I want to thank our speakers who took time from the busy clinical setting to enrich us with their knowledge in two very important areas of unmet medical need in modern oncology. I want to thank Mark Kirschbaum, who gave an excellent overview of the two programs we are pursuing in the clinic and why we're excited about the stage we have reached. I want to thank all of you for patiently listening to our session and posing your questions. At this time, operator, please conclude the call. Thank you, Spiro. This concludes today's call. You may now disconnect.