Decoy Therapeutics Inc. (DCOY) Earnings Call Transcript & Summary

Ladies and gentlemen, thank you for standing by, and welcome to the Salarius Pharmaceuticals KOL, an investor event conference call. [Operator Instructions] Please be advised that today's conference may be recorded. [Operator Instructions] I would now like to hand the conference over to your speaker today, Jason Rando at Tiberend Strategic Advisors. Please go ahead.

Good afternoon, everyone, and thank you for joining Salarius Pharmaceuticals virtual key opinion leader and investor event. Before we begin, I would like to remind our listeners that remarks made during this call may contain certain forward-looking statements about operating metrics, future expectations, plans, events and circumstances, including statements about our strategy, future operations and the development and potential effectiveness of our lead investigational drug candidate, seclidemstat. Forward-looking statements are made pursuant to the safe harbor provisions of the federal securities laws and represent management's current expectations. These statements are based on our current expectations and should not place undue reliance on these statements. Actual results may differ materially due to our risks and uncertainties, including those detailed in the Risk Factors section of Salarius Pharmaceuticals' 10-K filed with the SEC and other filings you make with the SEC from time to time. Salarius Pharmaceuticals disclaims any obligation to update information contained in these forward-looking statements, whether as a result of new information, future events or otherwise. Presenting on today's webcast will be David Arthur, Director and CEO of Salarius Pharmaceuticals; Dr. Nadeem Mirza, Senior Vice President, Clinical Development, Salarius Pharmaceuticals; Dr. Johnathan Whetstine, Director of Cancer Epigenetics Institute at Fox Chase Cancer Center; Dr. Sant Chawla, Director, Sarcoma Oncology Center, and Adjunct Associate Professor MD Anderson Cancer Center; and Dr.Kapil Bhalla, Professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center. Following each of the presentations, there will be a question-and-answer session that will be moderated by Dr. Daniela Santiesteban, Director, Corporate Development at Salarius. Questions may be submitted at any time during the event via the "Ask a Question" option at the top right of the webcast screen. With that, it is my pleasure to introduce David Arthur. David, please go ahead.

Thank you, Jason, and welcome, everyone, to this discussion, which I'm sure will be an exciting event and very informative to all those who are attending. The timing is very beneficial. We have recently announced a strong first quarter earnings report that puts -- we feel put Salarius in the strongest financial position we have ever been in with as of March 31, $36 million in the bank and funding to complete all of our ongoing clinical studies. We've also recently announced the completion of dose escalation in our lead clinical trial in Ewing sarcoma and the expansion of that trial to enroll patients in addition to Ewing sarcoma with myxoid liposarcoma and other FET-rearranged sarcomas, all cancers that share biology similar to Ewing sarcoma. In addition, last Tuesday, we announced a collaboration with the MD Anderson Cancer Center to target patients with myelodysplastic syndromes and chronic myelomonocytic leukemia, both cancers that can progress into acute myeloid leukemia. And we're fortunate today to have a group of premier key opinion leaders to discuss a variety of topics and to answer your questions. Dr. John Whetstine was part of Dr. Yang Shi's lab and the team that originally discovered LSD1. He continued investigating subsequent methylases and is a true expert in the field of epigenetics and demethylases. Dr. Whetstine is now Director of a Cancer Epigenetics Institute at the Fox Chase Cancer Center that is focused on bringing discovery to the clinic. Dr. Sant Chawla is a pioneering physician whose work in sarcoma oncology has brought him several accolades and recognition as one of the world's leading authorities in medical treatment and clinical research for bone and soft tissue sarcomas and sarcoma therapy. Dr. Bhalla is a nationally and internationally recognized physician, scientist for his original basic and translational research findings that have led to the clinical testing of many novel-targeted agents in combinations for the therapy of leukemia and myeloproliferative neoplasms. We're incredibly fortunate to have this distinguished group of global opinion leaders speaking on a variety of topics today. And with that, I will turn it over to Dr. Whetstine, please take it away.

Thank you very much. So the first part we're going to talk about is the background epigenetics and its link to cancer and disease, then a focus on LSD1, the demethylase, also known as KDM1A. It's really important to think about epigenetics in the context of a very dense nucleic acid rich environment that contains these kinase both DNA, RNA, chromosomal proteins in key histones. Histones that allow you to get that beads on the strain that you see on the right side and the schematic. This is what allows you to take 6 feet of DNA and compress it into a unique structure, the chromosome those are uniquely placed in cells. This is important for regulating both gene expression as well as chromosomal integrity, which facilitates proper cell division, cell fates and tissue generation. However, at the same time, we know that in the context of cancer, what can happen is you can actually destabilize your genome. This means that you can alter the chromatin structure, you can alter the way the nucleosomes are holding the DNA and the information that's packaged. And what does this do? This does affect genes, but it also impacts the infrastructure. The way the chromosomes are assembled and held together, the stability of the genome, proper expression and coordination, this can help promote cancer cells, tumors and, of course, lead to poor patient outcome and responses. When thinking of this macro molecule or thinking of a chromosome or thinking of a chromogenesis environment, it's important to realize that there's one small functional subunit that's assembled together for this to occur, and that's the DNA wrapped around your histones. Histones are key because they have these tails that extend out beyond the DNA. Think of them like whiskers or antenna for insects, they pick up signals and then they get modified. Examples shown here are phosphorylation in blue, methylation in red, or acetylation in the triangles in green. These serve as kind of recognition sequences. They serve as like this bar code that can be seen. They then orchestrate a series of events that happen downstream. Now these modifications don't just appear out of nowhere, they're actually coordinated through a panel of enzymes and orchestrated in the genome in a very specific way. Shown in this picture is just kind of a more gross overview. There's writers, erasers, readers and remodelers. They orchestrate both the adding of the post-translational modifications to the tails of the histones as well as erasing them, their enzymes are proteins that read them, they can see them and they allow them to be targeted to them, as well as remodelers, which are important for moving these packages of information around on the DNA. What we're going to talk about, in particular, relates to the erasers. In this case, we're talking about the demethylases, and they're important for removing those methyl marks. And they're -- by removing them, they can impact transcription or transcripts, they can impact genome stability, they can affect cell cycle progression, and all these downstream consequences are coordinated through the plus or the minus or combinations of these modifications. In the context of cancer, what you can see in the circle is in all categories. You can see that there's been links to enzymes or epigenetic factors or readers, the writers, the erasers, the remodelers that are impacting cancer. There are misregulation or mutations influencing. You can see LSD1, the demethylase KDM1A is as highlighted here as one such example. It's also important to realize that histones themselves can be mutated, these acetyl-CoA histones, demonstrating the importance of the chromatin environment. And you can see it there versus KDM. Those mutations then have consequence, illustrating that the direct manipulation of the chromatin environment itself is critical. And it's also true that various other enzymes, demethylases, KDMs as well as other methyltransferases, they carry a lot of various mutations or genomic alternations, which then allow the cell to have altered epigenome, altered modifications, altered post-translational control. Where did this fit in the context of thinking about therapy and treatment and long-term goals? Well, a major question is, why is it that people can have an initial response and then progress? Our ultimate goal, no matter how we think about this, is we would like to have durability and understand what are those selective pressures that allow response versus no response or then durable response. I believe that epigenetic abnormalities as well as many people in the field that abnormalities in the regulation of that microenvironment, how the DNA itself is controlled ultimately will facilitate both the development of the cancer and a lack of response or responses. So the ultimate goal is to identify novel therapies, novel drug targets, such as LSD1 that one could take advantage of that opportunity to tweak how the genome is packaged and regulated so you get durability. Another option, which is a long-term future here, is epigenetics and combination therapy, applying them with other therapies to achieve this maximum goal in the patients. It's important to think about how this all works. These enzymes, these epigenetic enzymes are attractive targets, and it's because of how they control it. So the nucleus has that 6-feet material that's well compartmentalized, organized in a high degree of structure. These regulators are able to go in and modify in this case histones and change whether the genome is more closed, which means it would be less permissive for transcription or is, in fact, more open, allowing permissibility of gene expression. In many cases, this can also impact does the cell replicate early? Does the cell replicate later? Is the genome more stable or not? So that degree of going from close to open is key. In the context of cancer disruption of these enzymes, disruptions of who they interact with and how they function can tip the balance. You can have tumor growth genes be turned on because the target of interest is upregulated and allowing things to be expressed or can be downregulated allowing them to be is miscontrolled. You can have tumor suppressor genes being suppressed. So the orchestration of those modifications and how this is put together facilitates imbalanced. This is where these epigenetic inhibitors come in. They can be used to reset the balance, reset so that the proper genes are under the proper control and properly regulate. So when targeting these modulators for therapeutic benefit, our goal, like I said, is to achieve this longitudinal effect duration. We need novel biomarkers and stratification tools. We need novel targets. We need new combinations with traditional and new therapies. The key is to target drug resistance and impact tumor heterogeneity. This particular target LSD1 kind of fits the bill for novel target, the idea of novel combinations and what it can do and impacting resistance and so on. I'll cover that in a few moments. It's important to realize that this target is being pursued by many for various applications across a wide range of cancer. So who is LSD1 or KDM1A? First realize that this enzyme was discovered in 2004 in Yan Shi's laboratory. It demethylates mono and di-H3K4 methylation. It's been shown in conjunction with the antigen receptor noted as human AR down below. It can then facilitate H3K9 demethylation. To believe that, that interaction is fundamental for that switch in enzymatic activity, in vitro, you can see a demethylate beautifully, H3K4. It uses a metabolic substrate, FAD. And it uses as an amine oxidase that I noted here. This crystal structure shows you something very unique. You have your enzyme domain there, the oxidate domain, you have a swarm domain that other kind of structures in yellow off to the right and the tower domain sticking up. The swarm and the tower are key. The reason they're key is they help facilitate interactions with numerous proteins, they facilitate these interactions, and it's important to realize something about LSD1, which is true for many others, if not all, of these epigenetic enzymes or these regulators. They don't work in isolation. They have a network of proteins they work with. They have key primary complexes and then subcomplexes and understanding these complexes or thinking about how they become misregulated in cancer opens up opportunity. So for example, your repressive complexes can interact with various components versus if you look at the activating components like ER or AR, they've been shown to potentially interact with the tower domain. And all of these will ultimately alter or help facilitate the enzymatic activity and function of an LSD1. LSD1 in association with all these various interactions and with its own enzymatic function, actually its ability to interact with proteins, plays a key role in normal development as well as disease. It's required for hematopoiesis, it functions and stems in differentiation, and there are other functions such as motility and epithelia mesenchymal transition or EMT as well as autophagy. It has this key kind of relationship because of when it's used, how it's used, how it's targeted and how it's facilitating the output. As one might imagine, having such a key node like this, when disregulated, can propagate or generate disease. When thinking about this in the context of cancer, often LSD1 is overexpressed and associated with poor prognosis and this isn't just one cancer, it's across a variety of cancer types as shown here in this review. On the right, you see that this shows a box plot, which basically shows the level of expression of LSD1 across a range of tumors. And the ones that are on the left, the most highest that we're expressed, you're going to hear in subsequent talks relationships to this high expression and targeting and using and targeting for disease and treatment. But the take-home point is the misregulation, the inappropriate overexpression is what's creating this opportunity. Therefore, with inhibition, you can restack that and control it. So LSD1 overexpression promotes tumor development in general. Shown here, Seclidemstat or SP-2577, and I'll refer to it as S-2577 throughout, is a reversible demethylase inhibitor. It's also been shown to impact that other scaffolding function that I was mentioning, which would interfere with interactions, protein-protein interactions. So this provides 2 opportunities for this molecule to achieve its goal. Here are kind of 2 examples to highlight this. On the left, the 2577, it's shown that if you treat cells, you can increase the level of the methylation that it would be involved in demethylating in cells. On the right, you see that it would -- it interferes with an interactor, the anti-receptor because it's prohibiting or reducing association. So what this highlights is this is kind of hitting 2 aspects of the enzyme simultaneously. It's interfering with interactions and it's regulating or impacting the demethylase function, which provides an opportunity. It also emphasizes the importance of thinking about how one targets epigenetic factors because they do not work in isolation, as I mentioned earlier. Here's an example of where this plays a key role in castrate-resistance prostate cancer. You can see in CRPC that LSD1 by immunohistochemistry, IHC, is very highly expressed and is associated with advanced disease. It's important to realize that when you purify interactors, what they found in this study is that there's interactors with proteins that are key in CRPC such as ZNF217. Do ZNF217 has also been found in many of the core complexes related to LSD1. So it's a key component, and it's a key factor that's been implicated in prostate cancer. So what they show using a first-generation molecule, SP-2509, is that when you add this to cells, it disrupts the association between ZNF217 and LSD1. There are 3 different cancer cell lines that are showing in the data for this, once again, illustrating that this molecule not only can hit the enzyme as a possibility, but it's actually hitting the structure in the sense of how it interacts in forms its interaction complex. And what they showed in the study is that it actually results in reduced tumor volume. So LSD1 is not just unique in the context of solid tumors. It's also been shown to be important in heme malignancies as you just heard in the very beginning from David. But there are not just one type of solid malignancy that's important. There's a range, and there's proof-of-concept data shown in vitro and in vivo showing here, the use of 2577 or the first generation 2509 and their impact on a number of solid malignancies. It's also important to note that Salarius is showing their data here whereas what they've shown is that there's a whole slew of cells under different cancer subtypes or types that show increased sensitivity or lack of response to 2577, which opens an opportunity to start to understand why would that be, what's going on? And it's also important to realize that not only do you need to be looking at cell death or what's going on, but since LSD1 impacts EMT, epithelial mesenchymal transition, this is a phenotype to be thinking about and looking at -- as well as suffer new liability in the context of cancer stem cells. So there's a key thing about future studies and considerations. Epigenetic enzymes have had preliminary success of cancer therapeutics, in fact, seen by our recent FDA approval. There remains significant unlocked potential that could increase the patient benefit as seen with this -- with LSD1 inhibition. It's important to realize that epigenetic factors are in complexes, their role and response and resistance is key. Understanding that dynamic, understanding how their interaction partners, who -- just like in humans, whom we interact with determines much of our faith. It's the same thing with these enzymes. Who they interact with and how can have huge consequence. Genetic factors contribute as well. This has recently been shown by a study where they showed the 2 mutations, the ones that affect the DNA methylation, can actually determine when to use LSD1 inhibition as well as DNA methylation inhibitors. So thinking about how genetic factors and predisposition influences. Third, how do extrinsic factors or cell stresses change the epigenome or how these factors are modified and then turn of responses. And fourth, we must consider that different inhibitors may have different access to different tissues, that's the pharmacology as well as their different toxicities and how they may be affecting what's going on. And last, we must consider the role of proliferative potential since cell division is key, replication and chromatin work together, age because of increased mutations or susceptibilities and also tissue development. These are all areas that need to be considered about once thinking of optimal therapeutic windows and opportunities for epigenetic control. Thanks. I'll take any questions.

Great. Thank you, Dr. Whetstine. Hi, everyone. Thank you for joining. This is Dr. Daniela Santiesteban. I'm the Director of Corporate Development at Salarius. And as mentioned, I'll be moderating the Q&A portion of the call. So thank you, again, Dr. Whetstine for that great overview. It's so wonderful to have him here with us and especially exciting as he was part of the original team that discovered LSD1. And with your current focus on translating your research into the clinic to have a positive impact on patients, a goal which is very much aligned with ours here at Salarius. Again, we appreciate your time and presentation.

To the audience, please feel free to typing your questions into the chat. I can see that we already have some coming in. So I'll start with those, and we'll see how many we can get to. Dr. Whetstine, the first question that's come in is what are some recent findings that make you excited about epigenetics research and then specifically with LSD1 inhibition?

Yes. No, this is a great question. I think we're in this new era for epigenetics in many ways. We're beginning to realize that it's not just -- only just the idea of the tumor and the gene, but it's also how epigenetics is being programmed in the surrounding microenvironment around the tumor. And then an area that I think is quite exciting and has huge potential associated for like this type of [indiscernible] to be thinking about is the role in immunotherapy because epigenetics is involved in fate determination, cell proliferation capacity and this impacts not just the tumor but also the immune compartment and the cell fates of the immune compartment. There's been a lot of work that's been shown to play a key role there, and LSD1 has turned out to be a central figure in this. There are a number of different studies from a number of different groups. So understanding how targeting LSD1 in this space will be very important as potentially immune modulatory or potentially regulating the -- just the normal cells in the body and how this would play out based on what's in the literature. I think this is a very exciting area. But what's important to realize is it's not just unique to LSD1, there are a number of other epigenetic factors, whether it be enzymes or readers or regulators that are now also being noted to pay rolls in this process, which opens up a whole new opportunity to think about a novel combination therapy, and that therapy is taken the world by storm. It's doing so well and impacting a number of individuals. So that combination, I think, is quite exciting. The other part that I think is really interesting literature is the role of epigenetic factors and resistance. There's senescence studies where cells go into the senescent state and regulating them and controlling them and figuring out how you control that -- those spaces. There's this idea of using genetics, as I mentioned in my top, targeting 2 mutations and taking advantage of dysregulating LSD1 and DNA methylation to turn on the promoter, enhancer interactions to facilitate sensitivities. And at the same time, there's these other studies that are showing, including work-from-home group about how epigenetic factors, other demethylases control, copy number adaptation, amplification of extrachromosomal DNA elements, this makes this another major area by which the epigenome controls your cells. So I think these are kind of key areas that I think have huge implications, not just for combination therapies, but also thinking about how we could control or regulate these resistant selection over time.

Great. Thank you. And yes, we agree with you here that Salarius is an area that we're actively exploring with SP-2577. Seeing some other questions pop up. So let's see. How can epigenetics focus companies optimize for patient selection, the next question?

I think that's a really good question. I think what -- there's a couple of areas in particular that I'm very fond of and that have become a major focus of kind of our efforts and things that we're doing is, I think we really need to have proper tools to look at the actual protein themselves because the transcript or the transcript levels of an enzyme is not the only answer. We have to remember that since these proteins work in complexes, and they are modified and it can affect where they go, not only in the nucleus, but when they shuttled out of the nucleus to the cytoplasm or they targeted for degradation and control. So I think building proper immunochemistry panels with reliable reagents is a critical one, and that's something that's a big focus here for people like myself and the institute is to develop those kind of tools. The other one is to not -- to make sure we relate genetic information to epigenetics. And to really start to bridge the gap between what we know genetically about genetic drivers or even potentially passengers that can become drivers. They may -- that may be happen through Crosstalk with epigenetic dysregulation. So I think those are kind of areas that -- when I look at it and I think of how do I want to help facilitate the basic lab discovery to the clinic, those are the kind of things that I think become important. And I think industry partners should be considering those because that may allow that stratification to be identified.

Great. And last question I'm seeing coming through is somewhat related to what you discussed earlier. If you could elaborate on how we should think about epigenetic enzyme inhibition in terms of its enzymatic activity versus protein-protein interactions? And what making the impact of inhibiting those?

Yes. I think this is quite exciting in this area because you might be able to get selectivity for function because in one context, you might have an enzyme like LSD1 that has it's enzyme dependent role. And in another context, as I mentioned earlier, it interacts with so many other proteins or sub complexes or interactions that it may be those interactions that are key at other sites. So one might envision that depending on which part of it you'd perturb, you can press certain buttons. So if it's only an enzyme inhibitor, you might get one consequence. But if you're hitting -- if you're bifunctional inhibitor, you might get a slightly different one. And I also think it becomes important to think about how are they targeted because if you can disrupt targeting, you might be able to harness or control that specific attribute or function of the enzyme. And then the latter one that I think is really important to pursue long-term is the degradation tools. When you basically obliterate all the complexes together, whether the consequences and how did that play out. So these are kinds of areas that I think are really important and it's just important for everybody to walk away with the following. Enzyme is not just an enzyme, it works as a hub. And it can have its enzyme roles, but it can have the non-enzyme roles as well. Think of it, it can have a support role to a larger compass doing something else. So I think thinking about how molecules target that and how one can dissect that apart, that's a very important area for future development, in my opinion.

Great. Thank you, Dr. Whetstine. Yes, it's fascinating how much has been recently discovered in terms of the many functions these epigenetic enzymes have. So once again, very, very appreciative of you joining us today and going through that great overview and for taking these questions. Thank you, Dr. Whetstine.

It's my pleasure. Thank you.

All right. For the next portion, we are going to move on to SP-2577 treatment for select sarcoma. This session will be led by Dr. Sant Chawla. Dr. Chawla, please go ahead whenever you're ready.

Thank you very much. I sincerely appreciate being -- speaking on this important topic, and this promising drug SP-2577, which was detailed mechanism given by Dr. Whetstine. As we generally say, cancer is a very smart disease, plays number of roles and mechanism, and we have been working out for last 50, 100 years to cure. And the treatments with surgery and radiation is obviously done and chemotherapy, targeted therapy, and all these have been in the last 50 years. As Dr. Whetstine very beautifully shown all the detailed mechanism of how cancer works, but finally, as Biden said, recently proof is in the pudding. And the proof all these mechanisms just like we need flour, sugar, water to make pudding and the detailed description of water as hydrogen and oxygen, sugar, carbon and oxygen and carbohydrates, proteins, all these details have been told by Dr. Whetstine. My role is I take the drugs and give to the patient and see how it works. I have been involved for last 25 to 30 years in sarcomas. And sarcomas make 1% of all the cancers, while 99% of cancers are carcinomas. Sarcoma arise from the connective tissue or wall, and half of them are soft tissues sarcoma and there are 95 types of histological subtypes, like liposarcoma and leiomyosarcoma, GIST sarcoma. While bone sarcomas, which usually happen in younger people, are like Ewing sarcoma, osteosarcoma and chondrosarcoma. In '70s and '80 before that Ewing sarcoma and osteosarcoma are basically incurable disease, and these tumors occur in the legs and we usually amputated the patients and majority or almost 90% or over 90% died of metastatic disease. And that's when the standard chemotherapy like doxorubicin, Adriamycin, cisplatin, methotrexate, all came in, and we cured with those standard treatment about 50% to 70%. But since then, we have reached the plateau, and we have not been able to cure the remainder of the 30% to 40% of the patients. We have had success in small steps, like GIST sarcoma we could cure with the targeted drugs like Gleevec. And only in last 20 years only a smaller number of the drugs approved like trabectedin, which is the marine-derived chemotherapy, but overall cure rate is small, the response rate is low, and it controls the disease only a few months. Similarly, in soft tissue sarcoma, Pazopanib is a tyrosine kinase inhibitor drug, again, approved and only controls -- median control is 4.6 months. Eribulin for liposarcoma and tazemetostat which is only approved for a very rare sarcoma called epithelioid sarcoma, but, again, response rate is 15 -- I mean, 15%. So these drugs control the disease very briefly, and we need some promising drugs, hopefully, based on that mechanism, demethylation, epigenetics and other things. Sarcomas, specially number of sarcomas are derived and played with the translocation -- translocated chromosomes, and these are FET family rearrangements. As stated previously, the LSD1 or demethylase enzyme may play an important role in this kind of sarcoma, which include Ewing, myxoid lipo, clear cell, desmoplastic small round cell and myxoid liposarcoma. As stated before, this demethylase or LSD1 specifically may be effective in the preclinical setting, as shown before. This was also shown as an oncoprotein inhibitor in the Ewing sarcoma as shown in this preclinical study in this slide. Further inhibition was shown with the additional studies by this antiprolific activity across FET rearranged sarcoma types in multiple subtypes in the DSCRT on the left side, clear cell and myxoid liposarcoma on the right side. Based on this, we initiated a Phase I clinical trial of SP-2577. This is a dose escalation trial and it's an oral drug given twice a day. And we have been advancing the dose up to 600 milligram BID, and we may have additional doses beyond these dose limits. Pharmacokinetics data are shown here, these data showed that there's a long half-life and the dosage have been given from 300 milligram to 1,200 milligram BID in the patient shown 610, 3 and 3. AUC is shown in the left hand panel. So far, by -- in April, we had 27 patients given in the Ewing sarcoma. Although we did not see any objective response, about 10% of the patients had a long-term disease control. This is one of the patients who showed some response although counted as a stable disease because there nontargeted lesions were still not decreasing and some of them increased. But the control of the disease at 600 milligram BID was over 6 months. These are the monotherapy efficacy data in other rearranged FET sarcoma. This extraskeletal myxoid chondrosarcoma, which is a very difficult disease to treat, do not respond to chemotherapy and the patient has a diffuse disease in the bone, liver, lung and is still under study over a year. There is a patient with a myxoid liposarcoma, 5 patients treated. And again, median duration of control of the disease is 7 months, and he has received over 7 months. And there's another patient with the desmoplastic round cell sarcoma. And so, based on this preliminary study mechanism as elucidated before, there are 2 planned therapy in the refractory Ewing sarcoma, we will be giving LSD1 combining with the second or third line study with topotecan and cyclophosphamide, which are the second, third line NCCN approved therapy. And we hope to increase the response as well as duration of response, and this rationale of combining is there are no overlapping toxicity as this drug only causes mild to moderate GI toxicity, but no myelosuppression neuropathy or other side effects of the chemotherapy. And we hope to increase the efficacy based on the mechanism elucidated by previous speaker. The second study will be the myxoid liposarcoma and other translocated sarcoma. And again, after the frontline drug failure, hopefully, this drug we will get. As shown here, there will be a standard inclusion criteria in the Ewing sarcoma. Patients will get the drug 600-milligram BID. In some patients, we'll increase the dose up to 900-milligram BID and additional cyclophosphamide and topotecan will be added as a standard drug. And myxoid liposarcoma and myxoid chondrosarcoma will be used as a single drug and 900-milligram BID. And in conclusion, sarcomas are rare. They make less than 1%. Predominantly, they affect the young people. Initial 50% to 60% patient have been cured by standard chemotherapy, surgery and radiation. We need more promising drugs. Recently, except Gleevec in 2000 for GIST sarcoma, we have not had any major good drug, although drugs like top -- like [indiscernible], trabectedin, eribulin, pazopanib and tazemetostat have been approved, their efficacy is limited. We are hoping that LSD1 will play a role as a single agent as well as in combination in these rare sarcomas. And thank you so much. And if you have any questions, I'll be happy to answer.

Thank you, Dr. Chawla for that wonderful overview and for discussing our preliminary clinical data and our trial design. The [indiscernible] was quite evident throughout the talk, and we really value your participation and support of our ongoing trial. So thank you once again. And like last time, audience members, if you have any questions, please feel free to submit them using the button and chat feature, and we'll try to get to you as many as we can.

So Dr. Chawla, one question I'm seeing here is specifically about the FET sarcoma patients. Are they easy to identify in clinic and how are they identified?

This is a histopathologic diagnosis, and it's very easy. It's not complicated. And most people -- most pathologists will name these sarcomas as the name required.

Okay. Wonderful. Great. So another question that's coming through is regarding your comment on sarcomas being challenging to treat. In your opinion, what makes them challenging to treat?

G-O-K, that means God only knows. Or Dr. Whetstine may come out with a different mechanism. We truly don't know why they are so difficult and complicated to be treated.

Do you think that SP-2577 can address this or by going after those genetically defined sarcomas?

This is my hope and pray that this single drug may help us. But again, I'm expecting realistically to be the small step success. I don't expect that it will cure all sarcomas by itself, but it will certainly, by mechanism elucidated by itself as well as with our drugs and demethylation, it will be helpful and a good armamentarium against sarcomas.

Great. Yes. Yes, like you mentioned, these are challenging. So I think that is partly why we are so excited for those 3 patients enrolled in the trial to have seen such promising time to progression. And like you, we're also hoping that we can continue to see that kind of impact as we enter the dose expansion portion of the trial. So we will see how that goes, but early data suggests that there is promise, and we might be able to make a significant step forward as we continue to develop SP-2577. All right. And then I see one more question, which you touched on briefly, but if you could elaborate if there's any concern with combining SP-2577 and topotecan and cyclophosphamide or other agents based off the dose escalation data that we've reviewed so far?

Excellent question. As we know that most chemotherapy we use combination chemotherapy, and we use combinations different chemotherapy, different targeted drug and different immunotherapy. We want to sort of put the cancer in control from all direction with the all modes where it does not escape. And when we use these drugs, we want to use with a different mechanism and different side effects. So LSD1 inhibitor is an enzyme protein-to-protein scaffolding, and that is the mechanism unlike chemotherapy. Number two, this drug has only side effect nausea and vomiting, and we have excellent drugs to counteract those side effect. The chemotherapy, on the other hand, has side effect of like myelosuppression, drop in the hemoglobin platelets, white cells or cardiac toxicity or nephrotoxicity or neurotoxicity, and we do not want to aggravate those side effects. So there is no overlap toxicity of this LSD1 with other chemotherapy or immunotherapy drugs. So it's an ideal drug to combine with other agents. At this point, I do not have any concern of combining with cyclophosphamide and topotecan. And I think it is an excellent idea, and we are hoping it will be more effective than chemotherapy alone.

Wonderful. Thank you, Dr. Chawla. One more question that I'm seeing here is, if you could provide your criteria on progression-free survival and overall survival benefit that a new drug would need to show for you to use it as second-line treatment or later in Ewing sarcoma and then also some of the other FET sarcomas that you described.

Standard has been, and this is a very low standard for median progression-free survival, if any drug has -- controls the disease 4 to 6 months, I think it's reasonable to be approved, although it's a very low bar. Unfortunately, we have not had many drugs and only selected drug, which could reach this low bar in last 20 years. And again, survival beyond 1.5, 2 years, it will be excellent. Of course, we want to cure. But at this level of the regulatory approval and with the FDA, if any drug can keep the PFS more than 4 to 6 months, survival beyond 1.5 years is likely to get approved.

Thank you, Dr. Chawla. One more question I'm seeing is someone asking about myxoid liposarcoma seeming to be benefiting from seclidemstat in current preliminary data. Do you have any thoughts on why myxoid liposarcoma may be more sensitive to LSD1 inhibition? Or is this something that we'll have to explore during the expansion portion?

Myxoid liposarcoma has a fusion protein translocated sarcoma. And it's unusual that besides the standard chemotherapy, it also has been shown to be extremely responsive to a marine-derived chemotherapy called trabectedin or Yondelis. And so we are seeing, similarly, the response with this drug. Actual mechanism, we do not know, but all the mechanisms, which Dr. Whetstine touched, may be one of the mechanism.

Great. Great. Thank you so much, Dr. Chawla. Those are all the questions that came through. Once again, thanks for providing your expertise and for going through our preliminary data and trial design. We really appreciate it. Thank you for your time.

Thank you.

All right. So our next session will be kicked off by Dr. Kapil Bhalla. He will be discussing LSD1 inhibition with SP-2577 for hematologic malignancies. Dr. Bhalla, please go ahead if you're ready.

Thank you, Daniela. Yes. Let me start with an overview of hematologic malignancies. These malignancies are cancers that affect the blood, bone marrow and lymph nodes. And they're broadly classified, as listed on the slide, leukemias, such as acute lymphoplastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia; and myeloproliferative neoplasms. These are mostly chronic diseases such as chronic myeloid leukemia, primary myelofibrosis, essential thrombocythemia. There are other related hematologic malignancies, such as myelodysplastic syndrome, which is a precursor or pre-leukemia to acute myeloid leukemia; and chronic myelomonocytic leukemia, which also transforms into acute leukemia. Then there are the lymphomas, including Hodgkin's disease and non-Hodgkin's lymphoma, which can be both B- or T-cell lineage-derived. And then multiple myeloma, which is a malignancy of differentiated B-cells, plasma cells. So what's the mechanistic basis of these common -- of the common hematologic malignancies? Well, they are driven by more or less similar biologic mechanisms, namely genetic and epigenetic alterations or aberrancies. These disrupt the normal blood cell differentiation process and effect cell proliferation and self-renewal of stem progenitor cells of these malignancies. In the case of AML, as shown below in the right-hand panel, the disease is caused by changes in the myeloid stem progenitor cells, the genetic and epigenetic alterations, resulting in differentiation arrest of leukemia stem progenitor cells as well as uncontrolled clonal proliferation of malignant myeloid progenitor cells. The left-hand panel here is a bone marrow aspirate morphology showing normal differentiation of myeloid progenitor cells into mature lineages. Now what's the role of LSD1 in normal hematopoiesis? Well, the main function is to support the self-renewal of hematopoietic stem cells. This regulates the differentiation of progenitor cells in mature lineages, mature common myeloid progenitors first and then also common lymphoid progenitors, which then further differentiate into lineage specific cells such as megacaryocytes, red cells, erythrocytes, mass cells and myeloid lineage cells differentiating eventually to granulocytes and monocytes or macrophages. The common lymphoid progenitor cells further differentiate into lymphocytes, T- and B-cells and then eventually B cells into plasma cells. Now you heard about the fact that LSD1 is part of many corepressor complexes that function in a context-dependent manner. In the case of myeloid lineages, LSD1 has been shown to be -- to partner [indiscernible] to a repressor -- transcriptional repressor called GFI1b to control or rather repress gene expression of genes involved in differentiation and self-renewal. And seclidemstat actually disrupts the binding of LSD1 from GFI1B and thereby reversing this repression of gene expression and promoting differentiation of myeloid genes. So overall, because of this prominent role in linear-specific differentiation of normal hematopoiesis, LSD1 over-expression and disregulation of its function can lead to hematologic malignancy development and progression. And thus, it's a -- this makes LSD1 an attractive therapeutic target. Now so what's the pattern of expression of LSD1 in various cancer cell types? So this slide shows that LSD1 is over-expressed, particularly in leukemias, myeloid leukemias as well as in B- and T-cell leukemias. This expression is shown here as log2-fold increase, which is a significant increase in expression in leukemias, particularly myeloid leukemias. So what is the effect of seclidemstat in hematologic malignancies? And this study was conducted in a variety of cell lines. Cells were exposed to -- for 96 hours to seclidemstat. And as shown here, virtually all cells showed some level of inhibition. The 50% inhibition concentration that was observed for seclidemstat ranged between 100 nanomole or 0.1 micromole to as high as 5 micromoles. So there's a range of activity inhibitors -- growth inhibitory activity of seclidemstat against cancer cell lines. As a snapshot of its activity in leukemia cell lines, this slide shows 4 different leukemia cell lines and the effect of seclidemstat exposure for 96 hours. As shown here, seclidemstat inhibits the growth of all 4 cell lines over this time period and at this concentration. Important to note that MOLM13, MV4-11 and THP1 cells are -- contain genetic alteration, MLL gene rearrangement. And in the case of MOLM13 and MV4-11 cells, they also contain mutation in a tyrosine kinase receptor gene called FLT3. And THP1 cells, which have also MLL gene rearrangement also had p53 loss, which makes them highly resistant to standard chemotherapy. OCI-AML5 cells express RUNX1 mutation, which also make them somewhat resistant to standard treatments for AML. So LSD1 treatment is -- induces growth inhibition in all these cell types. So seclidemstat is clearly showing growth inhibition in vitro and, as I will go over a little later, also inhibits in vivo growth of leukemia cells. But what's the potential basis of this activity? As shown here, in -- for example, in AML, OCI-AML5 cells exposure to seclidemstat for 16 hours in this immunoblot analysis in the far left panel, LSD1 treatment caused induction of a differentiation marker, CD11b, reduced the expression of Myc and Myb. These are genes that -- or gene expressions that are pro-growth and pro-survival for leukemia cells without affecting the levels of LSD1. Treatment with seclidemstat also induced increased expression of differentiation markers like CD86 and CD11b in leukemia OCI-AML5 cells. And in 20 samples from -- derived from patients with AML, this panel in the right-hand extreme, shows that exposure to seclidemstat significantly inhibited the survival, increasing the percentage of non-viable cells. In the far right hand, as the panels show the effect of seclidemstat on the leukemia growth and survival of immune-depleted mice that had been engrafted with human AML cell, i.e., PDX model of AML cells that contained a common nucleophosmin 1 mutation as well as FLT3 mutation, an aggressive AML subtype. And as shown here, this is oral treatment for 3 weeks with 100 mg per kilogram of seclidemstat significantly induced the -- reduced the spleen mass as well as significantly improved the overall survival of these mice. So what about myelodysplastic syndrome, as I described earlier in the introductory slide? And this is a MDS, or myelodysplastic syndromes, are a group of clonal disorders characterized by defective hematopoiesis, which leads to cytopenias and often transforms into acute myeloid leukemia. So it's sort of a precursor to AML. In preclinical studies, seclidemstat demonstrated, as in Panel A, increase in percentage of differentiated cells in a cell line that was derived or developed, grown in culture from a patient who had presented with myelodysplastic syndrome, cell line called GMR-AML1 cells. And these cells, following treatment with seclidemstat, showed increased expression of the differentiation marker CD11b, and again in Panel C, seclidemstat induced cell death in these cells. And in the immunoblot analysis, treatment with seclidemstat increased the expression of the repressor GFI1b as well as CD11b, which made service biomarker of activity of seclidemstat in AML cells. Now as we know azacitidine, a DNA hypomethylating agent, is approved for treatment of patients with myelodysplastic syndromes, particularly advanced ones. Azacitidine is, as I mentioned, DNA hypomethylating agent reduces cytosine methylation of DNA. In cell studies, co-treatment with seclidemstat increased azacitidine-induced apoptosis in 2 MDS-derived cell lines, MDS1 and GMR-AML1. And combination of seclidemstat with azacitidine was synergistically lethal in vitro in culture against both MDS cell types, showing combination indices less than 1.0, which denotes synergy of activity. I'll stop here and be happy to answer questions.

Thank you, Dr. Bhalla. Great presentation. That data that you just reviewed is a key example of how you are a leader in translating basic research into the clinic, as it was one of the principal sectors in Salarius initiating our own trial in the hematologic space. So thank you. Thank you again. To the audience, once again, a reminder that you can submit questions via the platform. I do see some questions already in queue.

Dr. Bhalla, the first question is, is LSD1 often mutated or how is it driving these hematologic malignancies?

So as I showed in one of the slides, LSD1 is over-expressed as compared to normal tissues in myeloid malignancies, particularly AML and myelodysplastic syndrome. So it's not found to be mutated in myeloid hematologic malignancies, but over-expressed. But that suggests that the stem progenitor cells of these myeloid malignancies may be addicted to the repressive effects of LSD1. And if inhibited by seclidemstat, these stem progenitor cells may be susceptible to differentiations and then lethality.

Great. Thank you, Dr. Bhalla. Another question. In your opinion, what are the most promising hematologic malignancies for an LSD1 inhibitor?

I think the hematologists are particularly interested in interrogating the activity of LSD1 inhibitors, but specifically seclidemstat. The team at MD Anderson Cancer Center is very excited about studying this drug in patients with myelodysplastic syndrome to see if this would induce in combination with azacitidine to see: a, it would have a superior activity than azacitidine alone, but also whether it would work where patients have start responding to azacitidine or don't respond to azacitidine. And as a combination, it would improve the activity of azacitidine. So that's one situation. But I think the exciting possibility is to study it in chronic myelomonocytic leukemia, which is a type of myelodysplastic syndrome, where, again, its expression is high. Also in acute myeloid leukemia. As I showed you in the preclinical studies, seclidemstat seems to have very significant differentiation inducing and growth inhibition. And so that's inducing activity, both in vitro as well as in vivo in patient-derived leukemia cell xenograft model, i.e., PDX model. So I think myeloid malignancies, in general, are a very exciting area to study the role or activity of seclidemstat alone and in potential combination in future.

Yes. And that is in line with what we heard from Dr. Whetstine and Dr. Chawla about the benefit of combining LSD1 inhibitors like seclidemstat with those that are approved and seeing an improved benefit in these patients. So yes, we are also excited to start that trial with MD Anderson soon. The last question, Dr. Bhalla, that I'm seeing is if there is a way to assess the impact of seclidemstat on leukemia in the setting of a clinical trial. Can you speak to that?

Yes. I think there are very exciting advances in assessing responses to novel agents in leukemia. Most leukemic patients now undergo a next-gen sequencing to define the mutations that are present in the leukemia cells. But more recently, there are studies now done, which are not yet -- still at the research level to define the clonal architecture of the different clones in leukemia along with their surface protein expression, which allows you to then see whether LSD1 inhibitor like seclidemstat would be able to particularly eliminate specific clones that are ancestral or stem cell variety that have specific mutations. So these kind of studies will allow us to particularly define activity of seclidemstat against leukemia clones. So next-gen sequencing is one way to find out where seclidemstat activity would be particularly very prominent. Second ways to assess what is routinely done is a flow cytometry-based assessment of minimal residual disease that one looks for in patients who do achieve remission with novel treatments like seclidemstat. So again, it would be important to see whether seclidemstat increases the percentage of patients that are negative for minimal residual disease status. And patients who are treated with other treatments for leukemia and end up having a positive minimal residual disease status, it would be very important to see if seclidemstat can convert these patients from a positive MRD state to a negative MRD state, i.e., be lethal against leukemia stem progenitor cells that escape the activity of standard treatments of leukemia and myelodysplastic syndrome.

Thank you, Dr. Bhalla. Very good points and something to consider as we start this new trial with MD Anderson. Those are all the questions I see for you, Dr. Bhalla. So thank you once again for that great overview and for answering those questions so nicely.

My pleasure.

All right. So to round out the session and the event, Dr. Nadeem Mirza, who is Senior Vice President of Clinical Development at Salarius, will provide an overview of the trial that Dr. Bhalla was referring to and discuss SP-2577 in these hematologic malignancies. Dr. Nadeem Mirza, whenever you're ready, please go ahead.

Thank you, Daniela, for the introduction. As mentioned by Dr. Whetstine and also by Dr. Bhalla about the role of LSD1 inhibitor in a variety of tumors, including solid tumors and hematologic malignancies, I will give a high-level overview of the trial that was mentioned earlier by David Arthur and also by Dr. Kapil Bhalla, the trial that is ongoing at MD Anderson Cancer Center. As a reminder, there are other companies that are also investigating the role of LSD1 inhibitors in hematologic malignancies. Some of these are shown here. The 2 companies, both Oryzon and Celgene, have focused on acute myeloleukemia in combination with the standard azacytidine or combination with venetoclax and azacitidine, which is a standard therapy given to these patients as a front-line in AML. Imago, a company, is investigating role of single-agent LSD1 inhibitor, and they are focused more on myeloproliferative disease such as myelofibrosis, essential thrombocytopenia and polycythemia vera. We, as Dr. Bhalla showed a very elegant preclinical data on the combination with -- and the role of seclidemstat in AML and also in combination with azacitidine, based on his elegant work, MD Anderson has currently activated a trial, which is investigating seclidemstat in combination with azacitidine. This is a Phase I with expansion phase trial, investigating combination of azacitidine with seclidemstat in myelodysplastic syndromes and chronic myelomonocytic leukemia, both as mentioned earlier, are a precursor to acute myelogenous leukemia. As I mentioned, this is a dose escalation trial, which will determine the recommended Phase II dose or also investigate maximum tolerated dose for the combination. Patients that are enrolled in the trial with the diagnosis of MDS or CMML with intermediate 1 or 2 or higher risk disease with either patients who have relapsed or refractory disease or patients who have received hypomethylating agent saw 6 cycles and have not responded well to those therapies. As you know that these patients, once they've -- not -- are unresponsive to hypomethylating agents, their prognosis is quite poor. Patients will be enrolled in the 3 plus 3 design where they'll use a standard dose of azacitidine, given 75-milligram per meter square daily for 7 days, either intravenous or subcu. Both are FDA-approved dosing schedule and route of administration. Seclidemstat will be given as a dose escalation from a BID dose for -- continuous BID dosing as a 28-day cycle. The primary objective of the study is to determine safety, tolerability, maximum tolerated dose and also to look at overall response rate. And in these patients, as I mentioned earlier, they typically have a very poor overall response rate and they also have a poor overall survival. Secondary objectives include overall survival, duration of response, leukemia-free survival and relapse-free survival. We will be conducting some correlative studies to further define the subtype of patients that benefit from this combination. This trial is currently listed on clinicaltrials.gov and has been -- is active -- has been activated at MD Anderson recently. So with that, I will end my presentation.

Thank you, Dr. Mirza. Thank you for the nice overview. And we're all, at Salarius, excited to get that trial activated and look forward to enrolling and treating patients soon. To the audience, if you have any questions regarding this trial, please feel free, once again, to submit them via the platform.

I do see one question already in queue. Dr. Mirza, the question is, is Salarius planning on expanding into other hematologic malignancies like AML?

That's an excellent question. Based on what Dr. Whetstine and Dr. Kapil Bhalla showed, the role and -- of LSD1 in a variety of tumors, including AML, we definitely are investigating or considering looking at which specific hematologic malignancy to pursue, and AML comes to the top of that list. Our current study with MDS and CMML will give us an earlier signal for patients who are precursor to AML or these patients, if they're not -- if they don't respond to current standard treatment, they will progress to AML. So by conducting this trial, we will get an early signal. In addition, we are looking at other hematologic malignancies based on mechanism either as a single agent or in combination where we find synergistic combinations for the hematologic cancers.

Great. Thank you, Dr. Mirza. Those are all the questions we have for your session. Once again, thank you for the overview. With that, I will turn it back over to David Arthur to close out the event. Thank you, David.

Daniela, thank you for the moderation. And thank you to our 3 guests, Dr. Whetstine, Dr. Chawla and Dr. Bhalla. I really appreciate the time you've taken out of your busy schedule to help share some of the information not only about LSD1 and the potential of -- for patient outcomes on developing medications to target that enzyme, and then to Dr. Chawla and Dr. Bhalla to talk about the clinical opportunity that presents itself. Hopefully, what you heard today is an overview of our plan to treat patients with refractory and relapsed Ewing sarcoma in combination with topotecan and cyclophosphamide, a combination that has demonstrated synergy in, in vitro studies. We are hoping to extend the progression-free survival from the currently accepted 6 months and perhaps even show other outcomes that could benefit these patients. We've also talked a little bit about the potential for treating patients with myxoid liposarcoma and other FET rearranged sarcomas that share biology similar to Ewing sarcoma. And then in this patient population, the devastating impact of the disease only provides about 1.6 months of progression-free survival. And we believe and we are certainly going to try and beat that and provide even better patient outcome. And finally, I won't go into this in great deal because you've heard from 2 experts in the field. This recently announced collaboration and trial in myelodysplastic syndrome and chronic myelocytic leukemia, both of which can lead to AML. This collaboration with MD Anderson could give us the information we're looking for to help us expand the use of seclidemstat into just some additional devastating cancers. As a takeaway, by the end of this year and in the very near future, we hope to be treating 5 patient segments with seclidemstat, both as single agent and in up to 3 different combination therapies. Cancer is a devastating disease. And we believe that while each individual single agent should show benefit, patients deserve to be treated with the best medicines possible, and that can be multiple combinations of drugs. And that's what we want to ensure we do when developing seclidemstat. So once again, thank you to our esteemed thought leaders, and Dr. Santiesteban for moderating this event. And I wish everyone listening to be safe and stay safe. Take care.

Thank you. Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.