BioXcel Therapeutics, Inc. (BTAI) Earnings Call Transcript & Summary

Okay. I think we're ready to get started. So good afternoon. Welcome, everyone, and thank you for attending our BioXcel Key Opinion Leader Day event, either in person or virtually because I know we have about 40 people dialed in at this point. So my name is Dr. Vince O'Neill. I am Head of R&D at OnkosXcel, and I will be moderating the proceedings today. So just a reminder that we may make during discussions or indeed in the slide presentations, forward-looking statements, and these are subject to risks and uncertainty, subject to change depending on market conditions, et cetera. So I'm very excited to say that today over the next 2 hours, we're really going to do a deep dive into BXCL701, actually for the first time. So I'm really excited about that. And talking about the signs behind the molecule and also talk about its potential in the clinic. So to help us do that, we've invited 3 distinguished academic guests to be with us today. Dr. Rahul Aggarwal will actually dial in from California. He wasn't able to be here personally. But we are joined by Dr. Dan Petrylak who is Professor of Medicine and Head of the GU and unit at Yale School of Medicine; Dr. Louis Weiner, who is Director of Georgetown Lombardi Cancer Center; and Dr. Aggarwal, who is Associate Director for the Helen Diller Family Comprehensive Cancer Center and Associate Professor at UCSF. And Dr. Aggarwal is also our PI on the study we will discuss. So in terms of agenda, we'll kick off with Vimal Mehta, our Founder and CEO, giving a corporate overview. Dr. Petrylak will discuss broadly prostate cancer, the challenges in treating prostate cancer, in particular, challenges with immunotherapy today. Dr. Weiner will discuss mechanism of action of BXCL701 and in particular, work that we've jointly published with his Institute. And then Dr. Rahul, Aggarwal again, remotely will discuss really for the second time in a few days, the Phase II trial results from small cell and neuroendocrine. I'd say the second time because he presented these data from the podium Thursday last week at ASCO GU. And then lastly, I'll come in with a discussion of current trials and future direction for BXCL701. And then we will begin an approximately 30-minute open my Q&A session. So with that, I'd like to introduce Dr. Mehta, Founder and CEO, to give a corporate overview.

Thank you, Vince. It's wonderful to be here with you today for our first BXCL501 KOL Day. I'm pleased to share some strategic overview and perspective about our company as well as our immuno-oncology program. We are building a unique biopharmaceutical company. The reason I say that we use AI platform and our goal always is to optimize R&D, accelerate development and enhanced probability of success. Those 2 things -- 3 things are very common when we are looking at any of the programs. And I'm very pleased to stand here and see that we have an approved drug in our neuroscience franchise. And now we have achieved human proof of concept with our immuno-oncology asset, which is BXCL701. Today, for the first time, all focus is going to be on that. I know most of the time we talk about the neuroscience business. So just to give highlight our first drug, IGALMI got approved in about 3.5 years from first in-human all the way to the NDA approval, and it has been launched within a 4-year window. There are multiple opportunities to expand the market potential for this product, and we have upcoming 3 data readouts. One is Alzheimer's-related agitation, TRANQUILITY II; SERENITY III, which is for at-home use. And third is our MDD. So all 3 data readouts are on track, and we are excited to announce that in first half of 2023. Coming back to OnkosXcel. Why did we form OnkosXcel? Because our neuroscience program has moved so fast. And as a result of that, we were not being able to provide right kind of resources, dedicated team, dedicated capital to continue to move our immuno-oncology asset, BXCL701. But we are extremely excited about this because we believe it has a huge potential. And with the recent presentation at ASCO GU and with the help of our distinguished get today, we will get to make a case that how exciting this asset can be. So what have we achieved? We -- it's a unique oral innate immunity activator, designed to turn cold tumors to hot via DPP8 inhibition, which is for the first time it has been done, and we are very happy that our AI platform allowed us to identify this asset. We are doing a combination approach with KEYTRUDA. We believe it can extend the value of immuno-oncology in underserved patient population, which is huge unmet need. And as I mentioned, we are focusing on hard-to-treat tumors or cold tumors. Already, data has been announced for positive data for Phase II trial, which our investigators will discuss today, and we are getting ready to initiate a small cell neuroendocrine Phase IIb trial in second half of 2023. So it's an exciting time for this unit. Innovation. Innovation always shapes the market. We truly believe, and we all know what happened in multiple myeloma with thalidomide, it changed that treatment paradigm for multiple myeloma. The reason it happened is initially, it was being developed from some other indications, and then they figured out that it can be used to treat these tumors. What we are doing with 701 is has some parallels to it. It was developed in early 2000 prior to immunotherapy revolution and was combined with the chemotherapy. And using our AI, we identified this can be immune activator, and we should be combining with checkpoint inhibitors. Not only that, it was also important which tumor type to choose and Vince will discuss how we arrive at that what tumor types to focus in our clinical trials because it's important to succeed to see that your agent or your hypothesis is really working. So having achieved human POC in 2 cold tumor types, and there is obviously a broad application of this agent in multiple cold solid tumors, and we are very excited about that. As I always say, disruption is in our DNA. We brought first [ drug ] to the marketplace and launched within a 4-year window. I truly believe that we were the first company who focused on neuroscience and immuno-oncology becoming a public company in 2018. It's almost 5 years when we became a public company in March of 2018. And I remember coming here at NASDAQ for ringing the bell, opening bell and today, we have a closing bell ceremony this evening at 4. So it's a very gratifying to see in 5 years how the company has evolved and developed. In addition, now human POC has been achieved. We are continuing with our plan, and we were happy that we were able to have a strategic partnership where we were able to secure $260 million that we announced last year with our strategic partners, Oaktree and QIA. All of that is now helping us build 2 business units, neuroscience, which is our core business and BioXcel Therapeutics and our fully owned subsidiary, OnkosXcel, which is poised to potentially impact the cold tumor market. This is a journey that started when we acquired the asset, which is on the left from Point Therapeutics, it's also called as talabostat. And this was acquired and we developed the hypothesis that it should be clinical trials shall be done in adeno as well as SCNC tumors. And Vince will discuss why we chose that tumor. But if you see it's a journey, we've been creating the data, whether it was a safety data, whether it was the efficacy data and developing our confidence whether we are building the confidence in these tumor types, there's 701 can be active. We are utilizing extensive data from 11 prior clinical trials and 700 subjects that we got from Point Therapeutics. We received 21,000 files when we acquired this asset. So our team had a lot of information to go through and see what was working, what is not working, what do we know about this, how to optimize the safety and when we are going for combination therapy with KEYTRUDA. So a lot of learning was done, but all that as said was extremely useful. What you see on the right where we are initiating a Phase II, it has been about 90-plus patients that we have dosed with 701 in combination with KEYTRUDA to get to the human proof of concept. So there is a very strong foundation we had for 701 because of the prior data, and we were able to take advantage of all of that where we are today with this program. We believe that 701 has a very strong value proposition for hard-to-treat tumors. As I mentioned, one of the most advanced oral agents human proof of concept has been established. It's well-tolerated. And we believe there is a scarcity of assets in innate immunity because not that many assets have demonstrated both the safety as well as efficacy. And there are a couple of assets which have been acquired by other because there is such a need or this could be transformative innate immunity activators start turning the cold tumors to hot. On a strategic front, we are looking for strategic options to fund OnkosXcel, one is partnering and/or financing both being pursued in parallel. Now we have data in our hands and it has been presented, we'll continue to pursue those options. And we are extremely excited to build on OnkosXcel Therapeutics. With that, I would like to invite our distinguished guests, Daniel Petrylak from Yale School of Medicine.

Thank you, and thank you for the opportunity to present to you today. My major interest include immunotherapy and prostate and bladder cancer as well as new drug development, particularly ADCs. And we'll be talking about prostate cancer, the overview of the disease and challenges in treating this in terms of immune therapy. So in 2023, approximately [ 208,000 ] men will be diagnosed with prostate cancer in the United States. This will result in 34,700 deaths. The prevalence of the most advanced form of prostate cancer at any given moment in the United States is 100,000 cases. The lifetime risk is 17% are being diagnosed and the lifetime risk of death is 3%. So translating that into other language, every 2 minutes, an Americans diagnosed with prostate cancer and every 18 minutes American dies of prostate cancer. And I think what's most sobering is since 2014, the incidence rate has increased by 3% per year and for localized disease and 5% per year for advance-stage prostate cancer. So as I noted before, there are many paths to prostate cancer. There is the phenotype that a patient will die with and not from. And then there's the lethal phenotype, which is a subject of today's talk. So most men are diagnosed with localized disease or primary prostate cancer. They can undergo surgery or radiation therapy to treat the disease. About 1 in 3 patients will have what's called a biochemical relapse where the PSA goes up after local treatment. This can eventually result in metastatic disease or this can simply remain as a biochemical relapse. In both of these situations, we generally will use androgen deprivation therapy, otherwise known as removing the male sex hormone testosterone. In that situation, prostate cancer will involute and die, but it's not a curative treatment. Eventually, all patients will lead to -- or treatments will lead to something called castration-resistant prostate cancer, which is the most aggressive and lethal form of the disease. So these are different natural histories of each of the disease states that are present in prostate cancer. Of course, we would like to cure the patients initially. So about 1/3 of patients who are cured with local treatment. But the duration of treatment for hormone-sensitive disease when the metastatic is about 1.4 years, when they become castrate-resistant or resistant to that primary hormone therapy, the survival is about 1.5 years overall. And that number has actually improved over the last 30 years. It was only about 10 months in 1991. So we've made some strides with some of the newer drugs. And remember, these are average numbers. There are some men who will live much longer than that 1.6 years and the some men, of course, will live shorter than that period of time. My experience, the longest survival I've seen with any castrate-resistant patients has been 10 years. And again, that's an attribute to the drugs that we've developed for this disease, but he also eventually succumbed to his disease. So how -- what's the landscape and how do we go forth with this? Well, normally, what you'll see on the left on this slide, it shows tumor volume and then, of course, treatment. So initially, we will give surgical or medical castration to a patient. And then there can be a rapid decline in PSA, a rapid improvement in symptoms, bone pain gets better, that patient is able to urinate. But that initial time on hormone therapy is generally about 1 to 2 years and then the patient begins to progress, and we use a [ variety ] of different drugs, which I'll summarize in a moment. The landscape in this disease has shifted. So the drugs that we've approved generally at the end portion of this disease have moved up earlier. And what we have found is that we can get more of a greater therapeutic effect by using these drugs earlier and identifying different forms of the disease. So these are the 4 major classes that we have of drugs for castration resistance. Immunotherapy, Sip-T was approved in 2010 based upon the IMPACT study, randomized trial. Pembrolizumab, we'll talk more about the specific cases that are responsive to pembrolizumab, but the responses have been generally very -- been disappointing. Other hormones can be used. In fact, prostate cancer cells become smart. They eventually make their own testosterone and drugs such as enzalutamide, darolutamide, apalutamide and abiraterone will interfere with that pathway. Cytotoxic therapy, chemotherapy is effective. In fact, I was behind the development of the first chemotherapeutic drug to show a survival benefit, docetaxel. Cabazitaxel also was approved by the FDA. And now we also have DNA-damaging agents like olaparib and rucaparib for specific classes of patients who make something called or have BRCA1 mutation, which is a mutation present in a number of different tumors. Now prostate cancer is plastic. It can change. And this is actually a major problem. And as we become successful with our upfront treatments, this is becoming more and more of an issue for this disease. So prostate cancer can degenerate into something called a small cell or neuroendocrine cancer which is recognized as a separate histologic class of this disease. It can exist right at the beginning of the disease. In fact, I've seen localized patients diagnosed with it. It also can be treatment related. In other words, the treatment can select or induce these changes in the cells and they become neuroendocrine. The characteristics clinically are that patients have low PSA values. They have bulky disease. They have disease in the organs like the lung or the adrenals. And these are very, very difficult to treat. The only drug that has an effect on this course of treatment is a platinum-based compound, and that's generally short and practically all patients will progress on that. So there are small cell, large cell histologies. These are just some pictures of this. You can see on the upper left-hand portion, it's practically all infiltrated with tumor cells. That's the small cell morphology that can be a large cell mixed neuroendocrine tumor. But they also have specific markers. Not everyone has these and these include neuron-specific enolase. The interesting thing is they lose the androgen receptor, which is the target of testosterone. And there can be various forms of this. In fact, it's very common for the neuroendocrine variant to exist along with the adenocarcinoma component. As I mentioned before, this is becoming more readily identified, generally about 10% to 20% of castrate-resistant tumors transformed to this neuroendocrine phenotype of some form. And it's underrecognized, I think, because generally, we don't rebiopsy our patients. And we don't see that particular phenotype unless we do that. But again, the suspicions are if it's a low PSA level and bulky and aggressive disease, that's present. So let's move on to immune therapy for prostate cancer. This has been somewhat problematic. But I think we have to think about diseases in 2 different phenotypes. The first would be the inflamed tumor cell. And this is responsive to checkpoint inhibition therapy, tumors like bladder cancer, like lung cancer, will respond. And you'll see a broad spectrum of cytokines, which are chemicals that are secreted by the immune cells. And type 1 interferon is also classically seen and you'll see upregulation of the PD-L1 molecule. So this inflamed tumor will respond to checkpoint inhibitors. The uninflamed tumor doesn't have these T cells present. They don't have the inflammatory component. You have a lower level of these chemokines overall and also lower levels of tumor-infiltrating lymphocytes. Macrophages and fibroblast will actually be increased in number and these can be activated, but prostate cancer fits more into this category. In fact, a lot of my colleagues will refer to prostate cancer as being the Sahara of the immune desert because they are, in some situations, really no T cells present when you look at a biopsy specimen. So how we try to overcome this particular problem? Well, the first product that was approved by the FDA in the situation with Sipuleucel-T, which is an autologous T cell product, which is made from the patient's own cells, a patient is freezed and they have their lymphocytes removed. These lymphocytes are then activated ex vivo and exposed to a fusion protein consisting of prostatic acid phosphatase and GM-CSF. Then these are reinfused back into the patient. This has done a total of 3x, and these T cells are able to then proliferate and attack the cancer cells. So the IMPACT study was a trial that was designed to evaluate patients with castrate-resistant disease. These were basically patients who had bone-only disease. They did not have disease in the viscera, but again, these will limit the bone. And our patients also who are basically early on. They were minimally symptomatic. And in fact, the patients who do best are those who have PSAs of less than 22. And so this is the survival curve, modest 4-month improvement in overall survival with Sip-T compared to the placebo arm and a reduction in the risk of death by about 25%. Now interestingly, this drug does not generally cause PSA declines. It does not generally cause regression to the soft tissue, but it does cause a survival then we think that they actually [ blunt ] the course of disease and not necessarily causes objective responses. What about the checkpoints? Well, there's dated in checkpoint therapy in prostate cancer. It's actually been fairly disappointing. So we published about 3 years ago, a Phase I trial of atezolizumab in metastatic castration-resistant prostate cancer and found that the response rates are pretty disappointing. No objective tumor shrinkage, a progression-free survival of 3.4 months. Median survival of 18.6 months, which was better than what we would have expected, but a small number of patients that could have easily been patient selection. Pembrolizumab has also been evaluated in castrate-resistant disease, 259 patients overall, response rates of about 3% to 6%, again, very, very low. These are unselected patients, so they're not selected for any phenotype. It's just all patients with castrate-resistant disease. What we found is that we can start identifying patients who are likely to respond to checkpoint therapy. And these are patients who have mutations in DNA repair that allow these tumor cells to make what we call neoantigens. In other words, ways that the immune system can recognize these. So CDK12 mutations, POLE mutations. It's a little bit better with these particular mutations, but it's not great. PD-L1, still objective response rate of 17%, not particularly exciting. Where we do get excited is with a phenotype called microsatellite instability. And here, we have about a 50% PSA decline rate. You can get dramatic progressions in soft tissue. In fact, my clinical experience, I have some patients who have rapid declines. We've actually stopped hormones on some of them, but we've seen regression -- complete regression of metastases with pembrolizumab in this approach. And actually, pembrolizumab is FDA-approved pan tumors for these patients who are microsatellite and stable. What are the thoughts? We can combine chemotherapy with immune therapy, maybe the chemotherapy would cause cellular damage, allow antigens to be shed and then immune stimulation would further improve survival. This is a trial called KEYNOTE-926, which I presented at the ASCO GU meetings last week. And unfortunately, we had no improvement in survival when a patient received docetaxel combined with pembrolizumab compared to pembrolizumab alone. The hazard ratio only showed an 8% reduction in the risk of death and that was not significant, and no difference in the median that was significant either. So how do we improve upon checkpoint therapy and immune therapy in prostate cancer? Well, bring those immune cells in somehow, bring those into the tumor, make them accessible. So cabozantinib is a drug that's approved for kidney cancer and thyroid cancer. It was originally looked at in prostate cancer a number of years ago. Unfortunately, the randomized trials were negative. But cabozantinib has multiple effects. It's tyrosine kinase inhibitor. It can reduce the levels of vascular and [indiscernible] growth factor, which are critical to T cell of regulation. It can inhibit MET, which can also block the mobilization of immunosuppressive neutrophils. It can inhibit [ AXL ], which is involved in Class I recognition of tumor cells and increase the number of circulating tumor cells as infiltrating cells or CD8 cells. So it has an immunostimulatory effect. And when combined with atezolizumab, remember the response rates 0 with atezolizumab in soft tissue. For cabozantinib, it's about 5%. You see here that you got about 30% response rate. So by modulating the immune system, we can actually affect prostate cancer. And this is now being tested in the randomized trial, cabo and atezolizumab compared to second hormones. And this, again, of course, is a registration trial. It's a CONTACT 2 study that's being sponsored by Exelixis. Other agents to bring those T cells into the [ BiTEs ], these actually are very, very exciting. Once T cells are activated BiTE molecule that can proliferate and increase cytokine activity. They can induce apoptosis. They can release cytokines that can cause cell death. The perforins and the [ granulozymes ], they can cause also lysis of multiple cancer cells. And the important thing is you can have sustained activation of the immune system with activated T cells. And the BiTEs are basically -- it's almost like a bridge between an activated T cell and a tumor cell, and it's flexibly linked with a link of region on the protein. And this is sort of a cartoon that looks at pasotuxizumab, which is also a PSMA BiTE, and it has a CD3 area binding on one side and a tumor-specific binding area on the other. There's a peptide [ linker ] between that. And a number of different therapeutic targets that are now being evaluated, [ DLL3 STEP-1 ], TF2, PSA, PSMA and prostate-specific cell antigen as well. So -- or stem cell antigen, excuse me. So there are a number of therapeutic targets that are being done with these BiTEs. J&J has one Regeneron. Also, Amgen is looking at this very, very carefully. The targeted stem -- the CAR T cells. This is also an exciting area, again, trying to move activated T cells into the cancer cells. This recognizes prostate stem cell antigen. This is tiny data from California. She's had responses with this. She has about 20 patients on the study at this particular point. Again, you can see soft tissue responses as well as PSA responses. So again, an engineered approach to the immune system. Same thing with PSMA. [ Susan Slovin and Sloan Kettering ] is looked at a PSMA construct CAR T cells and has a nonviral transposon system, which may actually activate this earlier in the course of T cell maturation. And she also has these same results. In fact, you can see from this particular slide that there is a infiltration of immune cells into the tumor. It kind of [indiscernible] and is pre and then panel -- the other panel is post. So in conclusion, Sip-T Is an FDA-approved agent for castrate-resistant prostate cancer in patients who had minimally symptomatic or asymptomatic prostate cancer with non-hepatic metastases. Checkpoint inhibition therapy is effective in the MSI high subgroup, but the results in unselected patients are extremely disappointing. Further treatment should be designed to convert the cold tumor to a hot tumor. And now it's my pleasure to introduce Dr. Louis Weiner, who is the Director of the Cancer Center at Georgetown, and he's going to be talking about BXCL701 mechanism of action. Dr. Weiner?

Thank you, Dr. Petrylak, and thank you all for joining us today. I'm really excited to be able to share some of our preclinical studies today. A way of introduction, I'm a medical oncologist. I focus on GI cancer. And I've been very involved historically in the development of immunotherapies with a focus on monoclonal antibody engineering and therapy and more recently on manipulating the T cell and NK cell immune responses and share some information with you today. So these are my disclosures. Notably, I'm co-principal investigator of about-to-open clinical trial of BXCL701 plus pembrolizumab in patients with chemotherapy refractory metastatic pancreatic adenocarcinoma. So I've been interest in this drug for a really long time since the early 2000s when it was known as talabostat or Val-boroPro. And it turns out that this is a really a multifunctional molecule with respect to its targets. And you can see here that it has very low IC50s for DPPs 4, 8 and 9. These are dipeptidyl peptidases, and also for a combined dipeptidyl peptidase and endopeptidase noted as fibroblast activation protein, although it's not quite as potent against that particular target. And my interest then back to -- my interest in [ FAP ] at that time, and we participated in clinical trials and led some back in the early mid-2000s, when we were actually focused primarily on thinking about this as a targeted therapy, and we're using high doses which, in retrospect, was not a great idea because this is such an immunologically active molecule. So that's how this molecule works, we think. So at the top here, you see the drug and you see it as 2 primary sets of targets, we think, from the therapy of tumors. On the left, you see it's inhibition of DPPs 8 and 9, dipeptidyl peptidase which leads to activation of the inflammasome and release of a variety of different chemokines and cytokines that are associated with inflammasome activation, one of which is CXCL9. Interestingly, the DPP4 inhibition properties of this molecule shown on the right of the slide, actually stabilize CXCL9, so it doesn't get inactivated. So you have a kind of a double whammy trying to increase the concentration of CXCL9 and that can attract an active -- lead to the activation of CXCR3 positive NK cells and CXCR3 positive T cells. And that's thought to be an important mechanism of action, although I'll talk to you about 2 additional potential mechanisms of action later in my presentation. So the first piece of data I'd like to show you comes from an animal model we've worked with a lot. This is a pancreatic cancer model derived from the MT3 2D cell lines that we received from [ David Tousson ]. This is a KPC-like model, so it has KRAS mutation and P53 mutation. So this tumor behaves as if it was a pancreatic cancer. And we've looked at both subcutaneous and orthotopic tumors. Here's the -- what I'm showing you here are subcutaneous because they seem to be easier to follow, and we just validate with your orthotopic stuff. And here, you're looking simply at what happens when you treat these tumors with BXCL701 alone. And these -- the treatments don't start into the tumors are about 100 milliter cubed in size. So you're treating established macroscopic disease. And what you can see compared to the control, you do get an antitumor effect from BXCL701 as you can see on the left. And on the right, there's a survival advantage that extends beyond the duration of the therapy. So when you combine this with anti-PD-1, you see a synergistic improvement. And our hypothesis going into this was that if, in fact, we were activating CXCL9 and other inflammasome components, you're going to heat up the cold tumor microenvironment in a pancreatic cancer and that, that would then make it more possible for T cells to want to attack the tumor cells, which will then [ erect ] PD-1 as a shield and you'd be able then to use the anti-PD-1 to protect the immune response against the cancer. And that, in fact, is what happens. Shown here, you can see the top line is PBS phosphate buffered saline therapy. So that's basically no therapy. You see that both BXCL701 and PD-1 have modest antitumor activities on their own. And when you combine the 2 agents together, you see an improved outcome and these tumors are quite a bit smaller. And I'll show you other variations of this as we move along. We also found that when we treated these animals with these -- with bearing these tumors with this combination or we could see an increase in circulating inflammasome and TH1-related cytokines in the syngeneic PDAC model. And you can see here, [ UCIL-1-beta ], IL-18, interferon gamma and on the -- CCL2, I couldn't see it is easy. And you can see that the various degrees they all go up as a consequence of therapy. And this is, again, in the circulating blood. If you look at the tumor, you see even more interesting stuff in my view. What you see is that you've actually attracted an accumulation of CXCR3-positive, CD4-positive T cells, as shown on the left panel. And you can see here that there's very little in the way of T cells in the PBS-treated tumors. There's a minor increase with anti-PD-1 therapy, a more significant one with 701 and had a quite significant one with the addition of anti-PD-1 to the 701. And that pattern basically replicates itself throughout these 4 panels where you're looking on the left, the CD4-positive T cells, the CD8-positive T cells, the NK cells was characterized by NK1.1 or the Tbet-positive Th1 CD4 cells, which are the ones that are, we think, driving a lot of the T-cell adaptive immune responses that we see with this combination. So this was really very exciting to us. And -- so I'm going to take you through this slide in some detail because I think it's very interesting. So the question we had is what cell is really important for this in this preclinical model? And -- so if you look here at the -- on the left, you can see on the bottom with that reddish line here or orange, I guess, it is you can see the effect of the therapy with both PD -- anti-PD-1 and BXCL701, and you see quite a substantial improvement compared to the treatment in that green line, which is no therapy at all. You'll see that if you deplete the cells, the animals of their NK cells -- will mitigate the anti-tumor effect some degree. And that's why on the right side, you're looking at day 32, that last set of tumor measurements we had. And you can see that, that third column, which is what happens when you deplete NK cells in these mice, you lose about half of your therapeutic activity. So the NK cells are important for the antitumor effect here. Moreover, if you deplete the CD8 T cells, which you can see, I guess, it's the fourth column over, you can see that there's even a slightly greater aggregation of antitumor effect, which would be sensible given that we expect CD8 T cells are very important here. And when you get rid of both CD8 and NK cells, you actually get more accelerated tumor growth, showing how this tumor -- in this tumor model, you're really modulating the antitumor activity. And we have inferred that the NK cells and a T cells are collaborating together. And there's 2 possibilities here. One is NK cells are directly killing the tumor cells in their own right. And we think there is some evidence, which I don't have time to show you today to suggest that might be the case. But we also think that the NK cells are contributing to the antigen presentation by creating this more inflammatory TME, tumor microenvironment, which is fostering antigen presentation and inducing the ability of these immune responses to initiate long-term host-protected immunity. And so here, we're just looking very briefly here at what happens when you just treat with NK cell with 701 alone. And the same patterns roughly hold true. We do think that the PD-1 therapy in this particular model, mouse, all the caveats that you have to use here, are holding fast here. So NK depletion and T cell depletion do aggregate the antitumor effects that we do see with the 701 alone. So in the course of doing all these experiments, we did have a number of animals that apparently had complete remissions of their cancers. And we didn't know quite what to do with them for a while. So we let them sit for a while. And a few months after we had accumulated 13 animals that had been essentially, as far as we could tell, curative their cancer, we decided to rechallenge those animals with a fresh batch of tumor cells at a fivefold excess compared to what they had originally been challenged with, reasoning that we wanted to see if they can really protect themselves against a more powerful tumor challenge. And we also challenged a group of mice that were naive that had never seen tumor before. So on the top left panel, what you can see is that these tumors, [ T cells ] grew in the tumors just as we expected they would. And on the bottom left, what you can see is you had an early growth of tumor after they were injected. And then in 10 of the 13 mice tumors were disappeared in a pattern that's quite consistent with a T cell response that was highly effective. There were 1 animal never really fully had a disappearance as you can see. And 2 animals had a complete remission, and then they had a bit of a relapse, as you can see. And on the right, the columns are just showing you a numerical representation of what we found. So we take from this that, this combination treatment is inducing a [ host-protective ] T cell immunity that is associated with memory. And in fact, when you actually examine the lymphocytes in these mice that was obtained at the time of sacrifice, you can see that you get an induction of CD4-positive CD44 high positive, CD62 ligand low-positive memory T cells, effective memory T cells. And so we are quite confident that we were inducing a memory response. And we think that this is another potentially important mechanism of action of how this drug combination might help patients when we take it in the clinic. So I've described to you a well-understood mechanism of action. And I'm going to tell you that at this point, what we were talking about was this DPP4 and 8 and 9 inhibition having complementary attributes that lead to the activation of the inflammasome, the release of CXCL9 and the recruitment of CXCR3 positive cells. We showed that this process was expanded when we expose mice to treatment with anti-PD-1. So the combination was more effective than just using 701 alone in this particular setting and work -- I don't have time to show you, but we did also ask the question whether fibroblast activation protein, my old friend, was actually responsible for any of the antitumor effects that we were seeing? And we did get our hands on an FAP-selective inhibitor and tried that in the same model system and it did not work. So we infer from this that the mechanism of action is going to be related more likely to DPP 4, 8 and/or 9 inhibition. And we are -- have active studies ongoing in the laboratory now to tease that out in order to figure out which ones of these mechanisms is most relevant. But then we found an additional mechanism of action. So DPP-4 inhibitors, such as sitagliptin are well known to decrease fibrosis. And so we were wondering whether this drug might have antifibrotic effects as well. So what we did here is we took 22 archived samples from mice that had been treated with either PBS, as you see on the left, PD-1 antibody, BXCL701 or the combination. And we did a Masson's Trichrome stain where the blue stain is collagen. And what you can see on the top 2 for photo micrographs, when there was no BXCL701 being used, there was plenty of fibrosis in these tumor specimens. And that, of course, as many of you might know, is [indiscernible] pancreatic cancer, which is well known to have a very dense fibroblast infiltrate as one of its distinguishing biological features. And if you look at the 2 bottom photomicrographs, what you can see here is that you have far less in the way of blue stain. And when you quantify that using Image J, which is a standard package for analyzing images, you can see that on the fibrosis score that we were able to generate was significantly lower in the tumors of obtained for mice that have been treated with 701 either alone or in combination. And it held up in both of the to 2 subgroups. So we do think that this anti-fibrotic effect could be present. And we do think it could be important because it certainly will change the nature of the migration and activation state various immune effect it into the tumor microenvironment. And we're well aware that specific anti-fibrosis measures that have been tried in pancreatic cancer have not worked very well. And so we're not holding our hats that this is the best way to do it. But we think that the way we are doing it, where we're combining it this fibrosis reduction with an immune activation process with an anti-PD-1 antibody is a different breed of cat than what's been tested in the clinic today. So our lab has studied primarily the PD-1 pathway as the immune checkpoint of choice. Others -- in other laboratories have used the MC38 model and have shown similar types of interaction between 701 plus either OX40 or anti-CTLA-4 suggesting that this notion of heating up a cold tumor microenvironment with an effective activation strategy does appear to be potentially valuable in overcoming some of the host tumor protective mechanisms that exist in many malignancies. So I told you when I began speaking that I'm interested in antibody therapeutics. And one of the areas I've been interested in for many years is the phenomenon of antibody-dependent cell-mediated cytotoxicity, also known as ADCC, where essentially the antibodies Fc domain engages Fc receptors on natural killer cells or mononuclear phagocytes and basically promotes targeted killing of the antibody targeted tumor cell by the Fc domain -- Fc receptor-bearing killer cell. And what you can see here is -- are the results of 2 in vitro experiments that we did, where we use peripheral blood mononuclear cells and expose them to either on the left panel, SKOV3 in ovarian cancer cell line that has amplified HER2 or is very strongly HER2 positive, and on the right, A431 a vulva carcinoma, squamous cell carcinoma that is heavily EGFR overexpressing. And what you can see is that across the BCLA -- BXCL701 concentration spectrum what you can see here is that there is an augmented killing associated with antibody targeting that is maintained throughout the concentration curve here. And we infer that this is not that we're enhancing the efficiency of ADCC as much as we're simply increasing the activation of the killer cells. And in experiment side, I'm not showing you, we have done the same experiments just with isolated human NK cells, and that's what we see as well. We see the same phenomenon. So we think this is primarily an NK cell phenomenon, although we have ongoing studies to determine whether there are other modulators of this process in the peripheral blood mononuclear cells beyond NK cells that might be contributing to this finding. So I've now explained to you that we have this CXCL9 induction by the DPP 4, 8 inhibition and 9 of course. And I've also shown your fibrosis reduction and I've shown you ADCC promotion as another possible mechanism of action. But I got involved with this drug years ago when I thought it was a targeted agent. And the question still remains, is there evidence that it might function like that in some settings? And the answer to that is probably yes. Now this is not work I've done, but it's done in leukemia, where the number of AML lines were tested for their -- the inhibition of their viability in the presence of BXCL701. And it was looked at as a function of DPP 9 copy number in the AML. And as I recall the day precisely about 40% to 50% of AML cell lines have high levels of DPP copy number and as you can see here, the correlation coefficient is quite high, suggest that in some malignancies, when 1 of these 3 targets is being overexpressed at a significant amount, it might be denoting a particular sensitivity to the direct antitumor activity of the molecule. So that's another potential mechanism of action. And so with that, I believe that I have concluded my presentation and I look forward to the next presentation and to the discussion that will follow. Thank you. I hand the button to you.

Great. Thank you so much. Can folks over there hear me okay?

Yes.

Okay. Great. It's -- I'm sorry that I can't be there in person, but I really enjoyed the presentation so far, and I'm really excited to be able to present the results of our combination study of BXCL701 in combination with pembrolizumab and small cell neuroendocrine prostate cancer. I just presented these results at our ASCO GU meeting last week. And just by way of I'm a medical oncologists that UCSF. I specialize in prostate cancer early phase clinical trials developing new therapies and have a particular interest in neuroendocrine prostate cancer and really excited to see novel therapies come forward in this space. So this was our Phase IIa single-arm study that I presented last week. It was with BXCL701 in combination with pembrolizumab and I'll tell you, these are all heavily pretreated patients that enrolled on this study and in total, I'll be presenting the results for 34 patients you could see my fellow co-investigators and co-authors here on this abstract that we presented last week. So I think Dr. Weiner has done an excellent job going through mechanism. I'm not going to reiterate that just to say that we clearly see clinically induction of cytokines and that really flavors both the biomarker work as well as the potential toxicities that we're monitoring for. So clearly, there's stimulation of the immune system, and we see that with patients treated with a combination much more so than we would expect to see with pembrolizumab alone. Just a little bit of background on neuroendocrine prostate cancer. We classically think of this in what we call de novo small cell prostate cancer, which is diagnosed. At the time of diagnosis, it's pretty rare, probably about 1% or less of all prostate cancers, as Dr. Petrylak mentioned. But the more common treatment-emergent neuroendocrine prostate cancer really emerges after in response to -- as a resistance mechanism to androgen receptor-targeting therapies. And we conducted a very large prospective study in which we biopsied men with metastatic castration-resistant prostate cancer and detected small cell neuroendocrine in 17% of all our biopsies. So it's there when we looked for it, and biopsies are really now considered part of the standard of care and part of NCCN guidelines, partly because of the results that we showed that this is a high-risk group of patients we need to be biopsying and looking for this subset because clearly, the outcomes are worse and we need better outcomes. So in our previously reported Phase Ib safety lead-in study, we spent some time trying to figure out what's the right dose and schedule to use of BXCL701 and really turned out that 2 things are really key to mitigate the risk of cytokine release: one was to use step dosing, where we use a lower dose on week 1 of cycle 1 and then going up to the full dose of 0.6 milligrams total daily; and the other was splitting the dose into a bid oral schedule. And those 2 things really help mitigate the effects of excess cytokine release. The most common of those would be things like edema, hypotension, fevers, chills, and those are really mitigated with the use of these 2 techniques. So small cell neuroendocrine prostate cancer, I touched upon this already. It is actually fairly common in the advanced mCRPC setting when it's looked for, and there are multiple targets being evaluated in the neuroendocrine prostate cancer space. Somewhere between 15% to 20% of patients will show this type of dedifferentiation at some point during the course of their treatment. Platinum-based chemotherapy, whether it be platinum etoposide or platinum taxanes are often used. And like in small cell lung cancer, you do see a pretty high initial response. But unfortunately, the responses are short-lived and the median progression-free survival is short, less than 6 months. And second line, there really is no standard of care. We often will use chemotherapy. Response rates are in the 5% to 10% range at best. Checkpoint inhibitors, whether it be single agent or double checkpoint such as IPI-NIVO. Likewise, you can see some activity, but overall, the response rates are 10% or less. And so clearly, there's an unmet need for novel therapies in the post-chemotherapy setting. So these are the inclusion criteria of our current Phase IIa study that I'll talk about. This is a single-arm study. We wanted to -- there have been studies looking at different composite definitions of neuroendocrine prostate cancer. But in this study, we really chose to stay sort of rigorously defined as a histologic confirmation of either the de novo or treatment-emergent small cell neuroendocrine cancer. Patients had to have had at least 1 prior line of systemic therapy. As I'll show you, most of our patients were more heavily pretreated than that. They had to have had progression at the time of study entry using our standard criteria. For patients that had treatment-emergent neuroendocrine prostate cancer but didn't have neuroendocrine cancer at the time of diagnosis, it is important to maintain androgen blockade, and so these patients were required to remain on ADT, whether it's testosterone less than 50 before and during the course of treatment. ECOG performance status is 0 to 2. So we put a cap on the number of prior lines of cytotoxic chemotherapy as 2 or fewer, so more than 2 was an exclusion. And the patients could not have received a prior immune checkpoint inhibitor. You can see the recommended Phase II dose and schedule, and this is what we've implemented in both the neuroendocrine study as well as the adenocarcinoma study, which I'll touch upon as well, really, the standard dose of pembrolizumab, which is 200 milligrams every 3 weeks; and then BioXcel, the BXCL701, the split dose, 0.3 milligrams orally twice daily, days 1 through 14 with that step dosing. So in week 1 -- cycle 1, 0.2 milligrams bid. If patients tolerating well without high-grade cytokine release or immune-related AEs, they would then receive the full dose. And in fact, the vast majority of patients were able to complete the step dosing. It's worth pointing out that unlike other IO regimens that are being tested in neuroendocrine prostate cancer like the bispecific, this is a fully outpatient dosing regimen right from cycle 1, day 1, and that really is a distinguishing feature. The primary objective of our study was really looking at composite response rate. So the vast majority of our patients with measurable disease by RECIST criteria, objective response rate was the primary endpoint, but then a composite of CTC conversion and/or PSA50 for those without measurable disease. And secondary objective endpoints included looking at the median duration of response, further characterization of the safety of the combination and changes in serum cytokines as I'll tell you in a couple of slides from now. The baseline characteristics are shown here. So in total, in this neuroendocrine-specific Phase IIa study, we enrolled 34 patients, all of which had histologically confirmed small cell neuroendocrine prostate cancer, but pretty heavily pretreated group of patients. As you might expect, the median number of prior lines of systemic therapy was 3. And if you look at the bottom row, you can see that over 2/3 of patients have received prior platinum-based chemotherapy. The other thing to point out is that 90% had, had prior androgen signaling inhibitors, which tells you that these were largely treatment-emergent patients that had been on AR-targeted therapies and then developed neuroendocrine prostate cancer during the course of their treatment. The swimmers plot showing the median duration of treatment and follow-up as shown here. So treatment is shown in the dark blue and then the follow-up shown in the light blue. We did allow treatment beyond progression for patients that were clinically benefiting, and you'll see that reflected in the swimmers plot as well. Overall, 5 patients remain on treatment as of the data cutoff back in December, including 3 patients with an objective response, 2 of which have been on treatment for over a year. So really, a subset of very, very durable responses for some of these patients. You can see that overall, the median duration of treatment was 9 weeks, but a wide range, 0.7 to 73 weeks. So the primary endpoint was looking at objective response rate in those with measurable disease as well as composite response. So in the 25 evaluable patients with measurable disease, there was -- objective response rate was 20%, so 5 out of 25, including 4 confirmed partial responses and 1 unconfirmed response. In addition, there were 7 patients with stable disease as best response, so the overall disease control rate was 48%. And median duration response was 6-plus months, the range, from 1.8 to 9.8 months, which is encouraging in this heavily pretreated patient population. There were 3 additional patients that did not have measurable disease by RECIST criteria. And of those, 2 had CTC and PSA50 response, respectively. So when you kind of add all the numbers together in the overall evaluable cohort, the composite response rate was 25%. This is the waterfall plot showing the change from baseline and size of measurable lesions. So this is the 25 patients with measurable disease at baseline. And if you look at the right portion of the curve, amongst those patients with an objective response, of those 5 patients, 4 had, had prior platinum-based chemotherapy, and all of the responders had tumors that were characterized as microsatellite stable and/or a low tumor mutational burden. So this is not a group of patients with cancers where you expect a really high degree of cancer response with pembrolizumab as a single agent. In total, 9 patients experienced tumor regression of any magnitude during the course of study treatment. The summary of the safety is shown here, and this is something that clearly we wanted to look at closely. Overall, you could see that treatment-related Grade 3 or higher adverse events occurred in approximately 20% of patients. There was 1 Grade 5 event, but this was a tumor lysis actually that occurred in cycle 1 in a patient with a very large metastatic disease burden in the liver. Immune-related adverse events, so things like rash or elevated liver enzymes, diarrhea, things that we associate with pembrolizumab were observed in 41% of patients. However, they were all Grade 1 to 2, with the exception of one Grade 3 colitis event, which was reversible with supportive measures. The overall rate of adverse events leading to treatment discontinuation was 18%. And that's about what we would expect for this patient population given how sick they were leading into the course of the study. When we look at specifically adverse events associated with cytokine release, including hypotension, you see that the majority were low grade. There were 2 Grade 3 hypotension events out of 34 patients treated, so pretty manageable cytokine release profile. And the most common treatment-related events of any grade are shown on the figure on the right. You can see that there. This is one of my patients with treatment-emergent neuroendocrine prostate cancer, a classic sequence of therapies. Was diagnosed with metastatic adenocarcinoma. The prostate was treated with AR-targeted therapies, including ADT, followed by abiraterone. Progressed with new liver mets in the setting of an undetectable PSA. We biopsied one of the liver lesions, and it was sure enough, small cell neuroendocrine prostate cancer. Was treated with platinum etoposide without a very good response. Had a tumor that was microsatellite stable, low mutational burden. This is not a patient I would -- probably a checkpoint inhibitor as a single agent. So really enrolled on the study and hoping to see a better response. And after 3 cycles of treatment, you can see he had a significant shrinkage in the size of liver mets, overall, 58% reduction in target lesions following the initiation of treatment. And on the right, you can see some of the biomarker work that we've been doing in him as well as across the study cohort. You can see a significant upregulation of the serum cytokines from baseline, including interferon-gamma, TNF alpha and IL-18, yet clinically, toxicity-wise, really low-grade AE profile without high-grade cytokine release and really was able to complete his treatment fully as an outpatient. And then getting to the DPP9 as a potential biomarker, you can see over fluorescent -- using this immunofluorescent assay in his baseline liver biopsy on the left. And then a representative example from a patient who did not have a response, you can see their tumor was negative for DPP9 expression. So still a lot of work to be done, but I think it's intriguing that essentially we could pull this out as a predictive biomarker response. And then we did have previous data with the adeno cohort. So this is a parallel cohort that was enrolling at the same time as our neuroendocrine study. These are adenocarcinoma patients without histologic evidence of small cell neuroendocrine prostate cancer. And you can see similar response rates as in the neuroendocrine cohort. So the composite response rate was 21%, about 22% with objective response in those with measurable disease. PSA50 response was 17% and CTC conversion rate, about 18%. So there's clearly some activity with the combination in adenocarcinoma as well. So in summary, clearly, in the neuroendocrine cohort, although it's small numbers, this is a sick patient population, really high unmet need. So really encouraging to see these durable responses in a subset of patients that were all MS-stable, low tumor mutational burden, low probability of response to pembrolizumab as a single agent. We do think that safety profile is manageable. And I've treated a fair number of patients at UCSF, and I do think these things like the step and split dosing and careful monitoring at home of patients' blood pressure really does enable a feasible outpatient dosing schedule. We see similar activity in adenocarcinoma. I think clearly, we want to see more work with the DPP9 biomarker, but it is encouraging that this might be able to be eased out as potential predictive marker. And then there is a planned Phase IIb randomized study that Vince, I believe, will be speaking about next. Thank you very much. And I think there'll be time for discussion at the end.

Thanks, Rahul. Okay. Last presentation of the day. So what I'm going to cover here is current trials and future directions for BXCL701. So I'd like to start with a pipeline overview. So as you can see here, we have 2 company-sponsored trials in the blue color here. We have 2 ISTs, or investigator-initiated studies or sponsored trials, in the, call it, mauve, I'm not sure what color that is, but the nonblue color. And again, we'll talk about these as we go through the slides. We will not have time today to do a deep dive into the next-gen DPP8/9 inhibitor, but I do want to call this out. We've just kicked off a discovery program to actually identify and then develop and take to IND an entirely novel, so a new chemical entity, DPP9 inhibitor. This would be a 701 follow-on, but it's important to realize that in oncology anyway, in cancer, the DPP9 space is entirely wide open. So this does give us the opportunity to really lead that space by pursuing this. Okay. So these data, and I'm astonished to actually hear myself say this, were presented 6 years ago at AACR. We will be updating this analysis. Most of it comes from Cancer Genome Atlas data sources, a couple of independent databases. You can see there, we called out, I think, the Broad and then Hopkins. It's a complicated slide, but let me try and simplify. Essentially, what we're showing here are DPP alterations at the genetic level across solid tumors. This is actually a crop of the original picture. And again, it was presented at AACR many years ago. So this picture actually goes way to the right. The upshot is there's probably about 1.5 dozens solid tumor indications where DPP9 alterations exceed 10%, and probably half a dozen where the frequency is between 15% and 20%. It is no accident that the indications that we're pursuing fall into that high DPP8/9 or DPP broadly defined category. Pancreas actually leads the pack there, again, as Dr. Weiner has already mentioned. Small cell neuroendocrine is clearly very high and so a small cell lung. So essentially, we have a rationale to help us pick and identify indications to pursue and prioritize over others, hopefully, ideally increasing probability of technical success. So as Dr. Aggarwal has said, the next step for development of 701 plus KEYTRUDA in small cell neuroendocrine cancer is this study detailed here. This is the so-called IIb. Really only 2 differences between the IIb and the IIa, which Dr. Aggarwal has just presented for us. One, there's an additional arm here. So we do have a 2:1 randomization away from BXCL701 alone. The sole purpose of having this arm is to generate some data to demonstrate or not single-agent activity versus 701 to allow us to tease out individual contribution of the combination. As I say, it is a 2:1 randomization. All the preclinical evidence, as I've said on the phone to many of you many times, does really point us to the expectation that it really is the synergy that's doing the work but has to be empirically demonstrated. And then the second difference versus the IIa is that the primary endpoint is objective response rate by RECIST 1.1. And that is, of course, the only target that the FDA will entertain in discussions. I'll also just mention the biomarkers. We've heard a little bit about biomarkers thus far. We're continuing to pursue biomarker analyses really across all of our studies. We will perform biomarker analyses retrospectively in this trial. So this is really the time line associated with that trial. So we're poised to begin it really fairly soon later this year with a readout first half of 2025 approximately, with a potential submission late in '25. This study was designed with pivotal intent, but it's very -- and I want to be very clear that we have not had our end-of-Phase II meeting yet. We will do that roughly mid this year. So we will go to the FDA with this design, with this study and have a discussion about what type of data would lend itself to an accelerated approval. So our next indication or new indication, and I'm happy to share this with you, I think, for the first time today is small cell lung cancer. And as we've heard, small cell lung and small cell neuroendocrine prostate clearly share clinical, pathological, histological and really, treatment similarities. It is fundamentally a disease of smokers. It used to be about 25% of overall lung cancer. It's now about 15%, but still, unfortunately, a common disease. The vast majority, about 3/4 of patients present with extensive stage disease and essentially, that means the disease has spread beyond the lung. About 60%, so 2/3 approximately, of patients do receive a platinum-based chemotherapy in combination with a checkpoint. So checkpoints are approved here. So this is -- many people will describe this as a cold tumor. At best, it is lukewarm. And despite the approval of these 2 checkpoint inhibitors, the median survival remains about 1 year. So really incremental benefit. And I think it's probably reasonable to say that therapy remains suboptimal. So this is our approach in small cell lung cancer. It will be a Ib/II. So we will have essentially a cohort 1 and then 2 step-up dosing with atezolizumab. This is the Roche molecule. We have no safety data with this checkpoint. We wouldn't expect to see a different side effect profile, but we will be expected to gather some data at a lower dose and then hopefully, to move up the dosing schedule fairly quickly. So the primary endpoint of the study is 6 months PFS rate. We know from the published literature that the 6-month PFS rate having had 6 months of maintenance atezolizumab is only 15%. So that's a low number. Of course, this underscores the fact that this is an underserved disease. Our target is 35%. And with a nano 45 patients, the lower boundary on the confidence band of that 35% will be about 20%, so it separates from the historic control. So this is the associated time line with this study. So the safety really step up to cohort hopefully. Safety experience begins again, second half of this year, should be finished by the end of the year and moving straight into the POC study with a discussion with regulators, depending on results, of course, again, second half of '25. '25 is a busy year. So let me go forward actually to pancreas. We'll come back to AML, but again, just you've clearly heard from Dr. Louis Weiner, who's an authority in this disease. So the data that I showed you -- just starting off this portion of the presentation. So DPP alterations are very, very common in pancreatic cancer. It's unfortunately a pretty common disease, about 65,000 new patients a year, about 20,000 second-line, probably an underestimate, likely a wee bit more, probably 40% to 50% of patients get second-line therapy these days. Again, as Dr. Weiner has shown, we have very compelling preclinical data in this setting. Immunotherapy in the clinic has been thus far a disappointment. Various standards of care in second-line therapy. And I'll give you one example there. This is an irinotecan-based combination with response rates anywhere from the single digits up to the 20-odd percent and a survival figure below 6 months. So clearly, an underserved patient population. So this is our approach. Again, the IST is led by Georgetown University, and Dr. Weiner is a co-PI on this trial. There will be a safety lead-in. We won't do a step-up dose here simply because it's a different indication, although again, I personally wouldn't expect to see a different safety profile for the same combination. So same dosing schedule with a 6-patient safety lead-in, which is a standard approach, and then a classic Simon 2-stage design with the primary objective of 18-week progression-free survival rate. One other point that I think is very important to draw retention to here, all of our patients will be required to consent to baseline biopsy and then biopsy on therapy. That's very difficult to do, and so thank you and kudos to Georgetown for being able to do that with your patients. But that would allow us then to bridge on the mechanism story preclinically to clinically, which we feel is very important. Let me now flip back, sorry for the flow, to AML. Okay. So this is another investigator-sponsored trial. This will be conducted by Dana-Farber, and Dr. Eric Winer out there is our PI. We know, this was published maybe 4 or 5 years ago, that 701 is directly cytotoxic to AML cells. That was published in Nature Medicine in 2018. So it's different from requiring the tumor microenvironment for activity. It's much more akin to cytotoxic chemotherapy essentially. AML, when it presents, tends to be in an elderly population. Many of those patients, in fact, 60%, are simply unfit for standard induction chemotherapy. Your only hope of cure with this disease is induction chemotherapy for a [indiscernible] transplantation. So what those patients who are not fit for said chemotherapy tend to receive is a combination of hypomethylating agents, either decitabine or azacitidine plus venetoclax. That is standard of care. That is what we will combine with once we go through the safety escalation. And we think that a highly active triple oral combination, because decitabine has now been approved with an oral formulation, if it's active, would clearly be of interest to physicians. And then lastly, we've mentioned that based on DPP9, we think about 50% of AML cell lines overexpress that or amplify it. So we have the beginnings of biomarker story there. So this is the design. As I said, Dana-Farber will run this study for us. This is a very complicated slide. The only take-home -- well, actually 2 points to make. One is that the primary objective determine MTD, maximum tolerated dose, and establish a recommended Phase II dose. But very importantly, based on what I've said about 701 in this disease acting really like a cytotoxic, we will attempt to push the dose higher than our current standard dose, which is here, to 0.8 milligrams twice a day, and we will be giving the drug days 1 to 3 in a pulse dose fashion in an attempt to really get high peaks, essentially unlike chemotherapy. Okay. So I think 1 or 2 slides left. So we've heard about small cell neuroendocrine cancer, of course. We've discussed small cell lung cancer as our new indication, pancreatic cancer. Those are 3 cold tumors that we're pursuing. There are, of course, many more. And these are obviously fairly important indications, for example, colorectal cancer, breast cancer, all deemed cold tumors, all potential opportunities for a combination of checkpoint plus 701. And this is my last slide. So what I'm aiming to do here is really conclude and summarize everything you've heard about 701 this afternoon. So 701 is an oral innate immune activator. This we know. Novel mechanism of action now published jointly with Georgetown University and the Journal for ImmunoTherapy of Cancer. 701 has demonstrated clinical POC in combination with KEYTRUDA in actually 2 cold tumor settings. We've spoken a lot about small cell today, but don't forget about adenocarcinoma prostate presented actually a year ago at ASCO GU. We've spoken about our regulatory approach, calling out the fact that we will meet with the FDA in an end of Phase II setting roughly mid this year to firm that up. We have a strong scientific rationale to guide choices of indications going forward. We have a good foundation for a precision medicine strategy. And 701, I hope you'll agree, potentially, really has the possibility of extending value of immunotherapies into much larger unserved patient populations. So with that, I'll ask our speakers to approach the podium, and we'll open it up to question and answer. Thank you.

Okay. Well, I was going to take speaker's privilege and ask the first question, but already, there's plenty. Greg, I'll start with you.

Greg Harrison from Bank of America. Maybe start off with one for Dr. Weiner. What other agents do you think would be promising to combine with 701 instead of or in addition to pembrolizumab?

Well, you asked a very good question. And I think the fundamental observation we're making is that we're heating up the tumor microenvironment. And so what we're doing is either replicating what you can do with in vitro testing, right, when you have complete access to the cells. And presumably, it seems that these cells are [indiscernible] whatever tumor inhibition has been [indiscernible]. So I think that really [ school's out. ] I think that PD-1 [indiscernible] checkpoint theoretically before, right? I think the challenge for us moving forward is really exciting. It's going to be a match in tumor biology. What is it that the tumor was doing to protect itself? And then when you heat up the tumor microenvironment, how do you then deflect the particular host-protective mechanism that was employed? In some cases, it might be a Treg strategy that a tumor was using. In other cases, it might be a LAG-3 or a TIGIT or something like that or an OX40 ligand. I think it's going to depend. And so there will have to be some very significant testing done, I think, preclinically. But I think there are going to be certain cancers -- for example, I think colon cancer, which Vince mentioned, is a spectacular opportunity. We know quite clearly that T cell infiltrates influence prognosis, yet there's no impact except in microsatellite instability that colon cancer is responsive. So something else is blocking it. But if we heat up the tumor microenvironment in colon cancer, it's certainly quite possible. We'll find out a little bit more about it, what defenses are being deployed by colon cancer, then we can develop strategies for combination.

Okay. Great. That's helpful. And then maybe one for the company. In the Phase IIb, what do you think is the appropriate bar for response rate if you were to assume pembro monotherapy would give ORR in single digits or close to 0? Is 20% for the combo the right way to think about what the target should be?

This is, just to clarify, small cell neuroendocrine we're talking, right?

Yes, yes.

Yes. I mean I'll let obviously our experts comment on how relevant a 20% durable response rate is in the clinic. Certainly, I feel comfortable with that. I mean we know -- again, I'm always looking at regulatory interactions and discussions. We know regulators have approved agents with an unmet need with response rates in the teens as a surrogate. But I mean, Dr. Petrylak?

I think 20% is perfect. We know that platinum-based chemotherapy is the first-line treatment for these patients. Generally, you can get a response rate of 40% to 50%, but the duration of response is short, it's about 6 months at best. Practically, everybody does relapse. So once that occurs, there's nothing else you really have that's FDA approved. So 20%, any sort of response rate in that level with acceptable toxicity would be reasonable.

[indiscernible] a Scotsman would ignore an Englishman. Colin, your question?

Colin Bristow, UBS. Just one for Vimal. Just thinking more broadly, I imagine if you -- as you have released more data for 701, it's become an asset you've had more incoming interest on. And so as you think about the path from here to the OnkosXcel potential spin, like to what extent are you running additional processes for this asset? Thinking about potential licensing opportunities, et cetera. Help us frame out that.

So we were waiting for the Phase II data to come out at ASCO GU. Now all the data has been presented. And today, our experts are also talking about the underlying science and the biology of it. So -- and we all understand it's a huge unmet need. So now Vince was at ASCO GU, and there was a lot of interest generated from the strategic partners. So we will now pursue all those opportunities. So we're going to, as I mentioned, pursue both opportunities, strategic partnership, which could be a licensing, co-development or whatever form it will take. We really believe in this mechanism and in this asset. So we want to make sure that it can help patients and we can, with the FDA's help, design a trial and get to the NDA. That will be the goal of the company, whether that happens with a partner or through independent financing.

Yes, Graig?

Graig Suvannavejh at Mizuho. So thanks for that presentation, very thorough. I wanted to ask about the fairly ambitious development plans for 701. You've got 4 trials that you want to start. So do you plan on starting the trials without a partner if you don't have one in place? And I guess a question maybe for Richard in the back there, like what kind of burden is that on the P&L on a go-forward basis if you don't have a partner? So that's question one. And then in the second -- the second question I have talks about the development history of 701 and maybe some additional color on the prior Phase III clinical trial experience in non-small cell lung cancer?

I can take the first question. We are planning -- ISTs are not that much have impact on the P&L. So ISTs are different. So I will say 2 trials. Goal there will be that how can we come up with a plan with the FDA to take this to the registration path. That's our first goal. Second goal is, is it only working in 2 prostate cancer subtype or it works more broadly like inflamed tumors and it has a bigger application. And we have chosen SCLC. To answer your question, it will not have impact on our current cash that we have with BTAI because that's definitely dedicated to what we need to achieve there. We have multiple pivotal trials. We have a product launch. So all capital will be used. These plans will be executed with a partner or with independent financing. Second question?

Yes. I think, Graig -- I think the second part of your question was really around prior experience with talabostat in non-small cell, right? So you were saying. Yes. So to summarize that -- so Point Therapeutics, at least 10 years ago, probably closer to 15, ran 2 potentially pivotal Phase III studies in non-small cell with 2 different chemotherapy partners: one was docetaxel; the other, I think, was Alimta-based, and those studies were closed for futility. We're clearly not pursuing chemotherapy combinations. I think as Dr. Weiner had said, that's probably not the best approach for a drug. Knowing the drug's mechanism at this point, probably not the best approach. We're certainly not going to pursue non-small cell lung cancer. We do believe small cell, because of the really striking similarities clinically, histologically, et cetera, to small cell prostate, that does derisk the approach. And it will be a checkpoint plus 701 combination, not combining -- well, we have the choice to start with chemo, but we're not going to do that. We will come in close to 4 cycles of platinum chemotherapy. Robyn?

Robyn Karnauskas, Truist. So just a couple ones. So for Amgen's DLL3/CD3, where do you see that fit in? Because I think they had some efficacy, if I remember, in this same tumor type. And the second -- and also the correlation with DLL3, I think, and the efficacy. And I was wondering if there's an overlap with like DPP8/9 expression and DLL3 because they may be completely different -- work in different tumor types. That's my first question.

So I can ask Dr. Petrylak and also Dr. Aggarwal, who I think has hands-on experience with DLL bispecific as well. So Dr. Petrylak, did you want to start?

I would think that there would be no cross-reaction. DLL, different antigen and it's a different mechanism using a CAR T cell with -- I'm sorry, bispecific antibody with the Amgen compound. So I would think that they would be complementary.

And then Dr. Aggarwal, just knowing you have experience with DLL3...

Yes. I think that the bispecifics in DLL3 are certainly a worthy avenue investigation. I think one of the distinguishing things with the BXCL701 is the ease of administration and the outpatient dosing schedule. So I think with the bispecifics and this patient population that's already fairly sick and a lot of symptoms, repeated in-patient administrations may be a challenge for the bispecifics.

Okay. Great. And then the second question was around -- I want to clarify what you said, Vimal. The SCLC, is that -- you're going to do that with a partner? I know you said it doesn't impact your cash position, but I just want to make sure I caught you correctly. And third is what is the IP plan for the product? I know with this -- with your AI technology, sometimes the IP can lag as you learn about the biology and the efficacy.

Great questions. So we will execute these if we have a partner or we have independent financing. Currently, we have planned our Phase IIb study as well as SCLC study. So I repeat that we will only conduct these trials once we have a partner or we have independent financing. Coming back to the IP. This is a new chemical entity. So it has a 5-year data exclusivity. We are working in orphan indication. So that gives you 7- and 10-year in U.S. and Europe, respectively. But more important, we have already secured a patent for combining BXCL701 with checkpoint inhibitor. So that patent has been granted in U.S. and other multiple territory. So we'll continue to beef up the IP. That patent expiration is, I believe, 2036.

And I think, Sumant, you had a question?

Sumant Kulkarni from Canaccord Genuity. I have a couple. So as you prepare for the end of Phase II meeting with the FDA, where do you see the most potential for the FDA to have input other than going to the classical RECIST objective response criteria on the primary endpoint?

So that's a good question. So we've obviously spoken to the FDA during the development of BXCL701. And we believe we've really incorporated all their feedback thus far. So it's hard to see -- we don't know until we get there, but it's really hard to see any surprises in terms of feedback on at least the design of this study. I think one point of discussion will be the sample size, and that's a very reasonable conversation to have.

And then my second question is for the experts and also for the company. Given the data we've seen so far on 701, have you seen anything that you might consider to be downsides? Or what would you say might be the key risks that we are still looking out for in 701?

I'm trying to think -- or should I maybe ask our investigators to comment there since you've had hands on -- and also Dr. Weiner, who's had hands-on experience for 10 years of the drug.

Yes. I think that we're beginning to get an appreciation of the importance of the various targets of the drug. And I think that as we move forward, we're probably going to be spending more time focusing on those tumors or even those tumor subpopulations where the relevant targets are being overexpressed. And for example, if you do a TCGA analysis in pancreatic cancer, which is what we study, you can find that DPP-4, 8/9 and FAP are all sky-high compared to corresponding normal tissue. I think that, that's going to be a way of helping to prioritize winners from losers in terms of indication selections. And I think that will be, I think, an important consideration. The downside that I see is really a remembered downside of what happens when you cause cytokine release syndrome in people. And we obviously worry about that. And I think the company has done a great job of figuring out how to make this a more tolerable regimen.

Dr. Petrylak?

Yes, I would agree with the cytokine release syndrome as being an issue, but it's now very well tolerated. Our experience in the clinic has been very positive. Patients have been able to manage their blood pressure and other side effects. It's been very, very manageable. But I think one other opportunity with this drug -- again, it goes along with DPP expression. So we're seeing that, as we saw in the presentation, in the small cell. But as you saw also, in the adenocarcinoma component, there was a 20% response rate as well. And so the next question, is there expression in a population of cells in adenocarcinoma? There clearly is. This may be more applicable to not only small cell but to adenocarcinoma. But also, as I mentioned during the talk, the tumor does dedifferentiate. And that study looked at patients who had extensive prior treatment. You would expect that there's a neuroendocrine component involved, and then perhaps there's a neighborhood effect going on with the other tumor cells that you're bringing in the immune cells. Not only is it recognizing the small cell component, but the adeno cell carcinoma component as well.

So maybe I'd just ask for [indiscernible] Dr. Aggarwal as well. And so Rahul, you and I were very involved in introducing that split dosing and then the step-up dosing. And so had you asked me that question 2.5 years ago, I would have said, yes, we're figuring out the cytokine phenomena. I think now we have addressed that. But again, I'll let our PI comment on that.

Yes. When we treated patients before, we implemented those measures and then after, and it definitely has made a big, big difference. I mean I think as Dan just mentioned, we have many patients we've treated. And the cytokine release, I think, is quite manageable. It does require close monitoring. We check a patient's blood pressure before each dose. We're calling them to make sure that their blood pressure is okay at home. But being able to do it as an outpatient, I think, is very feasible. So I think that, that in terms of a risk, is less now that we have this dosing schedule in place. I do think in terms of opportunity, I mean, clearly, as you've heard the biomarker piece and that this activity does extend beyond small cell. And I do think there's a subset of adenocarcinomas that can clearly have benefit. It's just a matter of identifying those patients.

Great. Any other questions? Greg?

So I know that recently in the second-line small cell lung cancer setting, Zepzelca was approved. Just maybe any overall thoughts on that product as it relates to the specific patient population? And then my second question, as you look to explore higher doses, is it just the cytokine release that you're most worried about? Or is there another element of the potential toxicity profile that we should be looking out for?

So I think given the fact that we are in the IST that we've just described, we are going to give the drug for just 3 days every day. And the -- again, this is empirical so we have to test it. But the expectation is with a short duration, we can get those peaks without the cytokine phenomenon coming back. They tend to occur on a standard days 1 to 14 therapeutic schedule usually at the end of the first week. So I'm hopeful we're going to be able to just avoid seeing that. What was dose-limiting for Point Therapeutics was peripheral edema, right? Will that come back? Again, because of the pulse nature, I don't -- I'm not -- again, I don't know, but the expectation is, no, we really will -- should anyway avoid seeing those adverse events come back. And then your first question, I've forgotten already.

Just Zepzelca in second-line small cell [indiscernible]

Yes. Well, let me comment on -- I mean, in terms of the development path for 701 in small cell lung, we had the option of pursuing first line or second line. We spoke to probably half a dozen opinion leaders in the space, and most recommended that we pursue first line. Not combined with chemotherapy for the reasons that we've touched on, focus on the maintenance, and we can simply add standard of care, pursuing the first-line indication. Any -- yes, [ Brennan? ]

I got a couple of online questions.

Okay.

So some investors online had a couple of questions. Based on your data, do you think there's a potential for combinations with cell therapy like NK cells or CAR T cells?

So probably Dr. Weiner?

Yes. I think there's a strong possibility for that. The idea here would be that -- again, you're heating up the TME. You're attracting CXCR3-positive NK cells and T cells. So it is kind of a conceptual slam dunk to think about trying a CAR NK or CAR T cell strategy. And in fact, in my lab, we've made a mesothelin-targeting CAR NK cell that's a tool, just a tool cell compound or whatever you want to call it, which we're going to be using and ask whether or not 701 alone or 701 with anti-PD-1 would enhance the delivery of CAR NKs into the tumor microenvironment and whether or not that would enhance therapeutic effects compared to any of those modalities alone. And we would certainly want to do the same thing for CAR T cells.

Great. Just a couple more. Would you say 25 -- 20% to 25% response rate is going to excite the field, in your opinion?

Yes. Absolutely. Again, we have nothing at this point. So it clearly would excite it.

And in pancreatic cancer, it's a ticker-tape parade.

Right. And I guess the last question, maybe if you want to touch on this is, can you tell us more about the stable disease patients?

Yes. So we have -- I'm just trying to visualize the RECIST table. We have 7 stable disease patients, 6 of those 7 have duration of stable disease in excess of 4 months. So this seems to be clinically relevant. And the hope is that, that would then parlay itself into better PFS. So yes -- so even -- another way to look at this is even beyond the patients who are getting a response, patients with durable stable disease arguably are also getting some kind of benefit from the drug. So yes. I'll maybe just throw one other question, and maybe to Dr. Petrylak. So you did talk a little bit about MSI-high status in response to pembrolizumab in prostate cancer. Give us a sense of how frequent that genotype is?

It's pretty rare. It's about 2% of all prostate cancer. But again, we always look for it because it's such a dramatic response when we do find it.

Thank you. Yes, Sumant?

Sumant again for Canaccord. Just a quick follow-up, and this might be putting the cart before the horse a little bit. But at this level, how should we on the financial modeling side think about potential pricing for this product?

As Head of R&D, I'm going to duck that one. I'll ask Dr. Mehta to perhaps take that up. And I think it's still early.

So I can say that's why we have our Chief Commercial Officer sitting here. We are exactly working out those details. And as we start our -- like in our Phase IIb trial, we will come back like with real market research data based on comps and how the standard of care is changing, what the real pricing model will be. But in general, if you think of any immuno-oncology drug, they are $100,000 plus per year, yes, yes, yes.

Any other questions? Yes?

[indiscernible] Colin's question earlier. So how do we think about timing of either making a decision to spin out or making a decision to partner? Because those discussions can take like 9 months, right? They take a long time. So just how do we think about that? Because I assume that's a big catalyst outside of these data sets for the company.

Certainly, certainly. Exactly, that's what we have thought about it. And I think you will hear from us pretty shortly what our plans are.

A succinct question -- answer. All right. Any...

We're not going to wait for 9 months.

Any other questions from the audience or online? Okay. So with that, I think I can draw things to a conclusion. Thanks once again to our esteemed guests for joining us. Dr. Weiner, Dr. Petrylak, Dr. Aggarwal, thanks so much. And thanks to the audience for your excellent questions. I enjoyed them. Thank you.