Good day, and thank you for standing by. Welcome to the Leap Therapeutics R&D Day. At this time, all participants are in listen-only mode. After the presentation, there will be a question and answer session. To ask a question during the session, you'll need to press star one on your telephone. Please be advised today's conference is being recorded. I would now like to hand the conference over to your speaker today, Dr. Cynthia Sirard, Chief Medical Officer for Leap Therapeutics. Please go ahead. Operator. Welcome, and thank you to those of you joining us today for an update on Leap Therapeutics' DKN-01 development program. This call is being accompanied by a slide deck, so I will ask that you please turn to our forward-looking statement on slide two. I would like to remind you that any statements made during this call that are not historical are considered to be forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these statements as a result of various important factors, including those discussed in the Risk Factors section of the company's most recent annual report on Form 10-K, as well as other reports filed with the SEC. Any forward-looking statements represent our views as of today only. A replay of this call will be available on the company's website, www.leaptx.com, following this call. With that, please turn to slide three. I am Cynthia Sirard, the Chief Medical Officer for Leap Therapeutics, and with me today are Dr. Samuel Klempner, Associate Professor at Massachusetts General Hospital and Harvard Medical School in Boston, Massachusetts, Dr. Zev Wainberg, Professor of Medicine at UCLA and Co-director of the UCLA GI Oncology Program in Los Angeles, California, Dr. Rebecca Arend, Assistant Professor and an Associate Scientist at the O'Neal Comprehensive Cancer Center Experimental Therapeutics Program in Birmingham, Alabama, Dr. David Wise, Assistant Professor, Department of Urology at NYU Grossman School of Medicine in New York, New York, and Jay Baum, Vice President and Head of Translational Research at Leap Therapeutics. Now turning to slide four. Leap Therapeutics is an oncology drug development company focused on developing our DKN-01 monoclonal antibody. DKN-01 targets DKK1, a protein produced by cancer cells that modulates important cell signaling pathways and plays a key role in maintaining an immunosuppressive tumor microenvironment. Leap is committed to biomarker-targeted development that links to the underlying biology of DKK1 in order to better identify patients who may benefit from DKN-01. DKN-01 has demonstrated single-agent activity in three tumor types, including esophageal gastric cancer, non-small cell lung cancer, and endometrial cancer, including an ongoing single-agent complete response with Dr. Arend, we'll discuss later in the presentation. Our development strategy has been to identify specific biomarkers that will predict which patients are more likely to respond and have better survival outcomes. We have shown that gastric cancer and endometrial cancer in patients with high DKK1 expression have better outcomes with DKN-01 therapy, whether as a single agent or in combination with an anti-PD-1 antibody and chemotherapy. We have a strategic partnership with BeiGene, the premier oncology development company in China and an emerging global leader to develop DKN-01 in Asia, excluding Japan, Australia, and New Zealand. Recently, BeiGene has been very engaged and supportive in the development of a randomized controlled trial in first-line gastric cancer, which is due to start later this year. We come into the next two years with a focused development plan and a mission to bring new therapies to cancer patients. There are many catalyst events over the next 24 months. Turning to slide five. I'm Jay Baum, Head of Translational Medicine at Leap. Slide five illustrates the critical role that DKK1 plays in the development of cancer, where it's often overexpressed, leading to worse outcomes for patients. DKK1 is secreted in part by tumor cells that signal to several different cell types, including tumor, immune, and endothelial cells. As a result, DKK1 promotes cancer development through an induction of proliferation, metastasis, and angiogenesis. This occurs through several contributing mechanisms shown here. First, evidence suggests that DKK1 can promote angiogenesis through increased VEGFR2 expression in the blood vessels. In addition, DKK1 can also bind to the CKAP4 receptor on tumor cells, causing the activation of the PI3K AKT pathway to drive cancer cell proliferation. Importantly, DKK1 also has a significant impact on the immune cells in the tumor microenvironment. It signals directly to myeloid-derived suppressor cells, or MDSCs, to enhance their activity while also decreasing the activity in the number of natural killer cells. This creates an immunosuppressive tumor microenvironment, which helps to promote growth of the tumor. As illustrated on slide six, DKN-01 was designed to inhibit the function of DKK1 and is able to reverse the pro-tumorigenic effects of DKK1 through a combination of mechanisms. This includes blocking the binding of DKK1 to CKAP4, causing a downregulation of the AKT/ PI3K signaling on tumor cells, which in turn leads to reduced proliferation. In addition, DKN-01 is able to decrease angiogenesis, resulting in fewer and smaller blood vessels. Importantly, DKN-01 is able to remodel the tumor microenvironment, creating a more favorable immune response to attack the tumor. This occurs in part by reducing the activity of MDSCs and promoting the release of cytokines to activate NK cells. Each of these combines to create a multi-pronged attack on the cancer cells, the microenvironment around them, and the blood vessels running through them, which we believe all contributes to DKN-01's activity. In addition to its direct impact on tumorigenesis, the mechanism of DKN-01 also allows to synergize well with other agents, including anti-PD-1s, as shown on slide seven. As I mentioned, DKN-01 helps to create a more favorable tumor microenvironment, in part due to the activation of NK and dendritic cells, as well as the inhibition of suppressive MDSCs. In addition, we've seen across multiple studies that DKN-01 increases the expression of PD-L1 and results in T-cell infiltration into the tumors. This mechanism sets up the tumor microenvironment well for combination with an anti-PD-1 to then stimulate adaptive immunity. This may be especially impactful in patients where anti-PD-1s are normally ineffective, such as in PD-L1 low settings or cold tumors. Today, we'll show some examples of this synergy as we walk through the different preclinical and clinical data sets. Now advancing to slide eight. DKN-01 has been tested in seven company-sponsored clinical trials and a number of investigator-initiated studies across a broad range of cancers. Our lead indication is gastric cancer, where DKN-01 has shown single-agent activity and additive activity in combination with paclitaxel, anti-PD-1 antibodies, and most recently, an anti-PD-1 plus chemotherapy. As Dr. Klempner will describe today, in collaboration with BeiGene, we are expanding the ongoing DisTinGuish study to include a randomized controlled clinical trial in first-line patients of DKN-01 plus tislelizumab and chemotherapy, compared to tislelizumab and chemotherapy. This study part is expected to initiate enrollment in the fourth quarter of 2022. DKN-01 has also demonstrated single-agent activity in endometrial cancer. We are pleased to have Dr. Arend with us today to announce a new investigator-initiated study in endometrial cancer, which will combine DKN-01 with pembrolizumab. That is being provided by Merck. Colorectal cancer is yet another indication in which Wnt signaling plays a major role in tumorigenesis. Jay will present new preclinical data for DKN-01 in colon cancer before Dr. Wainberg provides an overview of the randomized controlled study in second-line patients in combination with standard of care bevacizumab and chemotherapy. This study is expected to initiate in the third quarter of 2022. Lastly, Dr. Wise will provide an update of the data presented at ASCO from his investigator-initiated study in prostate cancer, where DKN-01 is being evaluated as both a monotherapy and in combination with docetaxel in previously treated patients. We hope that today's presentation will give you all a deeper appreciation of the progress here at Leap as we move into this exciting new phase in the development of DKN-01, the transition into randomized clinical trials, and the initiation of new indications and therapeutic combinations. Please turn to slide 10 as we begin with the development of DKN-01 in gastric cancer. As mentioned earlier, DKK1 is often associated with worse clinical outcome, including rapid progression of disease and poor survival. If you look across cancers in the TCGA database, patients with high DKK1 demonstrate approximately 2.5 years shorter survival than those with low DKK1 expression. The prognostic impact of DKK1 is especially true in gastric cancer, as shown on the top left. This data was taken from the stomach adenocarcinoma dataset, where patients with high DKK1 in green have a shorter overall survival than those with low DKK1 in blue. In addition to being an overall poor prognostic marker, DKK1 is also believed to be a key resistance mechanism to standard of care therapies. To examine this closer, we've been working with Tempus, who has one of the world's largest databases of real-world evidence containing clinical outcome and molecular data. Using Tempus's data, we've looked at common treatment regimens in gastric and GEJ cancer, such as platinum and fluoropyrimidine-based therapies typically used in frontline gastric cancer patients. On the bottom left, you can see a similar trend towards high DKK1 patients discontinuing treatment faster compared to those with low DKK1. It's important to note that DKK1 is a widely expressed marker with high levels of tumoral DKK1 seen across indications. We'll discuss several of these different cancers today. However, even in those indications with lower median levels, there is still a subset of patients with very high DKK1 expression. We believe that if DKK1 is present at very high levels in a tumor, it's likely critical for driving the growth of that cancer. However, it's also important to recognize that there are other non-tumoral sources of DKK1, and thus a patient with low DKK1 expression in a tumor can still have a significant level of DKK1 circulating in the body and promoting development of their cancer. Given the important role of DKK1 as a prognostic and potential predictive marker, it's critical that we have a robust and reproducible way to detect it in patients. As often the case for small soluble proteins, there are currently no good antibodies with sufficient specificity and sensitivity to measure DKK1. As a result, we explored alternative options, including RNA in situ hybridization using the RNAscope technology shown on slide 11. This is a method that uses FFPE tissue similar to IHC, but focuses on RNA expression rather than protein. A DKK1 specific probe binds the RNA sequence of interest. Then, through a series of amplification reactions, the signal is visualized as a dot, with each dot representing an individual transcript of RNA, so it's extremely sensitive and specific. We believe RNAscope has several key advantages over alternative methods of detection. For example, it's fully automated, so it can be run routinely in any pathology lab. It's amenable to small samples requiring only about 100 tumor cells. It allows you to collect spatial information regarding tumor versus stromal DKK1 expression, and it lends itself well to the use of digital pathology. With this assay, we're currently focusing on tumor cell expression, where a substantial amount of DKK1 is produced, and we've been using an H-score to quantify DKK1, which is calculated on a scale of zero to 300 based on the cumulative DKK1 expression across cells. Here are a few examples of what a pathologist may see when scoring the assay. With the DKK1 staining shown in red, you have one patient who has very high DKK1 staining at an H-score of 108 and another with significantly lower DKK1 expression of four. The H-score cut-off shown here of greater than or equal to 35, which separates high versus low expression, was previously identified in our gastric study with Keytruda and then prospectively defined in the subsequent DisTinGuish study. This assay is currently validated in Flagship Biosciences CLIA lab for prospective clinical use, and in parallel we've also initiated companion diagnostic development with Leica Biosystems. Okay, so you just recently heard about some of the rationale for DKK1 as a target and the expression across gastroesophageal adenocarcinomas. Now I'm going to walk you through some of the clinical data leading up to the recent randomized phase II design. What you're looking at here is early monotherapy activity, which we always are interested to see in any biologic target. What is being shown here is a single agent's response in a refractory patient to DKN-01 monotherapy. This is from the previously published data set, which you can see this is later line patients. Moving on to the next slide, there's also a substantial body of literature suggesting cooperative activity with standard of care agents such as paclitaxel. Here we're looking at some late line patients looking at DKN-01 with paclitaxel, that's shown on the left panel. On the right panel you see the combination with pembrolizumab, which laid some of the foundational data for the frontline cohorts that you'll be talking about in a minute. What you can see here is that in a reasonable size cohort of patients where we have a historically good benchmark for the activity of paclitaxel in this patient population, we see that there was substantial activity for the combination with the response rates across the entire cohort of 25%, and a disease control rate of 60%. Just as a context, the single-agent activity for paclitaxel in gastric cancer is generally around 15%-16% of a response rate. If you try to make a more accurate comparison, look at the second line population specifically. The numbers are smaller here. You see 15 patients, but you can see an encouraging improvement in the response rate to 46.7% with a disease control rate of 73%, suggesting that there is some cooperativity there beyond what you would expect to see for paclitaxel alone. Similarly, when you move to the second-line population, and here's the 31 patients that we observed in the prior trial, you see that now is where some of the support for potential biomarker selection comes into play, where you're looking at the DKK1 high versus the DKK1 low population. Again, caveat with relatively small numbers, but what you see here is that in a biomarker-selected population, the response rate was 50% in a chemo-free regimen, which is highly encouraging and with some of the data that led to interest in further development. Now I'm on slide 14, moving into the bulk of the data and the more recent data. This is data from the DisTinGuish trial, which is a study in advanced gastroesophageal and GEJ adenocarcinomas with two parts. Part one or Part A is a frontline cohort looking at DKN-01 plus the anti-PD-1 agent tislelizumab in combination with standard of care 5-FU/ platinum, in this case XELOX, with a primary endpoint of overall response rate and additional endpoints of progression-free survival and duration of response. Part B is a DKK1 high selected PD-1 naive population looking at the chemo-free combination of DKN-01 plus tislelizumab. Essentially building on that DKN-01 plus pembro data I just showed you, again looking at similar endpoints. Part A, this is the consort diagram, so you can see the patient disposition. It's a relatively small cohort of 25 patients enrolled in the intent-to-treat population. You see the breakdown of the biomarker testing. The takeaway from my end here is you see a relatively high prevalence of the biomarker, 12 of 25 patients here testing positive, and then there's four unknown, so 12 of 21 known. This is an encouraging prevalence of a biomarker that can potentially be used to select patients. You see the disposition within those cohorts. In the lower panel is just the actual dosing regimen for this combination, where on day one of a cycle all agents are given together and then capecitabine continues per standard of care. There's the day 15 DKN-01 dosing. Getting into the meat of the trial, here is the overall response by DKK1 expression. What you're looking at here is green is DKK1 high, and I think visually on this waterfall plot, immediately what you see is, one, an encouraging waterfall plot in that there is no patients with primary progression here. Two, the vast majority of the bars which stretch past the 30% RECIST response cutoff are green. If you add everyone together, the modified ITT population, we see the overall response rate of 68.2%. Then importantly, when we get into the biomarker selective, we see what we would hope to see, which is an improved biologic activity translated in form of response rate in the biomarker selective population. Here, among the 10 DKK1 high patients, the response rate was 90% with one non-evaluable patient. In the DKK1 low patients, we see an encouraging response rate of 44%, and then the unknown patients are shown in the far right. Looking at the durability of response, which is important for any frontline combination, we see this spider plot here. What you can see across the horizontal axis is time in months. There you see the majority of the green lines going down and extending out, showing the best durability. You see there are several patients here, ongoing with durable responses. Again, this is highlighting the durability and that 90% response rate in the DKK1 high patients. Here we see now on slide 18, looking at progression-free survival in the overall population and then the DKK1 high patients. The historical reference here is CheckMate- 649, which we can try to put a little bit more context to this data as we go forward. 25 patients, progression-free survival for reference is around 7.5 months. What we're seeing here is that in the all patients, we see a progression-free survival of 10.7 and a numerically longer, progression-free survival for the DKK1 high patients, quite close to a 12-month, median PFS here, which is very encouraging and was presented at, ASCO GI in January of 2022. Of course, with many patients, several patients go on study, and duration of follow-up, the overall survival here is not yet reached. With median PFS, they're approaching, you know, 11.9 months, and the overall survival from CheckMate- 649 of 13.8 months in the experimental arms, it certainly compares favorably with the caveats of different sample sizes and slightly different trial populations. An important question that comes up throughout this data set is. Of course, if we have a response, a combination that is biologically active in this patient population, we also have to know if it's tolerable. This is getting at some of the safety and AE profile highlights of the combination. DKN-01 plus tislelizumab appears to be relatively well-tolerated. I can speak from personal experience that this is very similar to giving standard 5-FU/ platinum with or without a PD-1. Most of the events are G rade 1 and 2, related to typical chemotherapy side effects in my own opinion. There are patients here who experience, Grade 3 or higher DKN-01 related adverse events, and I can certainly speak, in my own opinion, about some of these events if there's questions. There were no Grade 4 events, and there are some, treatment-emergent adverse events, leading to death, which is prominent one PE that was assessed by an investigator as probably related to the regimen, and an aspiration pneumonia and hepatic failure, which unfortunately are common within this patient population, and possibly related to disease progression. Looking at the upcoming Part C randomized study, here we see the broad schema. Again, this is a similar patient population to Part A. These are previously untreated, locally advanced unresectable or metastatic patients with measurable disease, HER2-negative. You see the important stratification factors here, DKK1 expression, in this case, TPS, and certainly the team has done due diligence to correlate TPS and RNAscope expression and PD-L1 status. This will further validate the biomarker and the relationship between the two. The 160 patients randomized 1: 1 to DKN-01 plus tislelizumab plus standard of care chemotherapy, so very similar to the Part A regimen that I just showed you. Then a control arm, which essentially mimics the CheckMate- 649 experimental arm of 5-FU/ platinum plus an anti-PD-1 agent. Take homes from this data in gastroesophageal adenocarcinomas. Certainly, as someone who deals with this every day, I would say that DKK1 does appear to be an important emerging therapeutic target in gastroesophageal adenocarcinomas. It is associated with aggressive biology, poor response to 5-FU and shorter survival. Suggesting that this is a relatively aggressive population, which perhaps suggests that the results that we're seeing in Part A are perhaps even more encouraging. What we did see from Part A was significant biologic activity with an overall response rate of close to 70% and an encouragingly high response rate in the biomarker-enriched population of 90%, with a historically very favorable median PFS period of 11.9 months. It's notable that even in the DKK1 low population, the response rate is still good and the median progression-free survival also looks encouraging. It may be that there is some DKK1 modulation of the microenvironment even in patients with relatively low expression of the biomarker DKK1. That's certainly an area of ongoing investigation and thinking for myself as well. There does not appear to be a clear relationship between PD-L1 and DKK1, suggesting that this is a independent biologic activity and the response does appear correlated with the biomarker, which is what we would hope to see. I will turn it back over to the Leap team and look forward to questions. Thanks, Sam. Can you tell us a little bit about treating a gastric cancer patient? How do they first realize that they have gastric cancer, what their symptoms are, and what your current initial treatment options and decisions are for those patients? Yeah, sure. Good question. It's unfortunately a high morbidity disease. These patients present quite symptomatic, usually with weight loss from difficulty swallowing or dietary modifications over the preceding months, sometimes GI bleeds related to the presence of the primary tumor, often fatigue and discomfort. Those are symptoms which need to be palliated, otherwise these patients will continue to feel unwell. The current approach is based on some standard of care biomarker testing, which is mismatch repair testing, HER2 testing, and PD-L1 testing. The results of those biomarkers are used to inform our treatments. Perhaps the most common therapeutic approach is chemotherapy. Most patients get chemo. That's 5-FU and oxaliplatin, usually in FOLFOX or XELOX in the United States and across most of the world. Then the addition of targeted agents is based on biomarker testing. At our institution and at many other academic institutions, we have somewhat adopted the evidence-based approach that patients with low PD-L1 scoring or CPS less than five, we are not currently adding routine immunotherapy outside of a trial. In patients with CPS greater than five, we consider that to be standard of care. Great. Thanks. How many patients have you personally treated with DKN-01 across the different studies? Are there any observations that you could make about how your patients have done on this agent in particular, and the tolerability or quality of life while on DKN-01? Yeah, sure. I don't keep a tally exactly, but I would say over 10 patients I've treated with DKN-01 across different DKN-01 studies. Observations, you know, this is a monoclonal antibody, and it's been my experience that it's been similar to other biologic agents, such as checkpoint inhibitors and drugs like ramucirumab, which are antibodies. That the actual patient experience is they barely notice they're getting anything at all. The safety experience in my own patients has been quite good. I'd say, you know, it's always hard to deconvolute what side effects are coming from what contribution, especially when combined with chemotherapy. I would, in my own attribution, consider most of the effects that I've seen are more consistent with chemotherapy side effects or just complications related to the underlying disease. Perhaps in some of the monotherapy experience, I would say that there is some mild GI upset and that may be DKN-01 related. But in general, this has been a quite tolerable agent in terms of combining with multiple other approaches, whether it's other IO or chemotherapy-based approaches. I have yet to see any situations where I could say that this was potentiating the side effects of another combination or that there was synergistic toxicity in the combination of this agent with immunotherapy or chemotherapy. I think it's a readily combinable agent, and that's certainly an attractive feature. Okay, thanks. Maybe we can shift gears a little bit. You had talked a little bit about your standard practice in biomarkers that were used in patient selection for different therapies. How interested do you think that the field is in continuing to explore new biomarkers to assist in patient selection for different therapies? Extremely interested, like my entire career, and career of many friends. The need to select patients for, you know, the best therapy is the goal of oncologists across tumor sites. Certainly, you know, our lung cancer colleagues have been leading the way in selecting and dividing up the pie in terms of identify target matched to an effective therapy and prove that that's an effective strategy. In gastric cancer, disease is more heterogeneous, but we are increasingly learning about biomarker selection and things like FGFR2b, CLDN 18.2, perhaps some of the other checkpoint expressions are of course interest, and I would put DKK1 expression right in there with those other biomarkers. I think this is an attractive approach in terms of potentially modulating the microenvironment and sort of remodeling in a favorable way to develop a cooperative effect with checkpoint and chemotherapy. To me, one of the most attractive aspects of any given biomarker is the prevalence and things like FGFR2 and CLDN 18.2 are relatively lower frequency. Some of the things like MSI-high are of course very low frequency. It was interesting to see in the patients who were going into Part A and Part B in the poster that we presented. You know, the biomarker prevalence here is pretty high, like + 50% of patients testing as DKK1 high in Part A. I think this is really encouraging to see a biomarker that may offer a therapy to a large portion of our patients, because obviously we wanna ultimately direct biomarkers and certainly historically when we've had a biomarker that reflects biology and the drug that can target that biology, it's generally translated into an effective therapy. Yeah, thanks. I guess that leads me right into the next question, which is, you know, obviously as someone who has been instrumental in helping us design the randomized controlled study, how did you think about including all patients regardless of DKK1 expression, as compared to focusing on that roughly 50% of patients, as you described, who appear to have the higher levels of DKK1 expression? Yeah. I think this is really kind of two ways to develop a biomarker and a drug, but I think that the best way to validate a biomarker in my own opinion is to look at enrolling people both with and without that biomarker and then further understanding the impact of the biomarker on the outcome. That will give you a really granular understanding of is your patient population with the biomarker really driving the magnitude of benefit with the drug. It's also interesting to note that no biomarker is perfect, and DKK1 expression appears to be a robust biomarker for identifying benefit as predictive biomarker, also prognostic for this aggressive disease. But there may be an interesting interaction in my own opinion between modulating DKK1 even in a DKK1-low tumor microenvironment. I think we're still learning a lot about the biology of this disease across stages and therapeutic areas. I would be very interested to get more understanding in terms of are we potentially even helping patients with lower DKK1 expression? Might there be a subset in there that we can learn some from more? I think a randomized design, including all comers, allows you to do two things. One is to validate your biomarker in a real world population and understand the predictability and performance. Two, potentially even gain some insight into what might be happening in this DKK1-low population where the response rate was still encouraging in the Part A patients. Great. My last question. What kind of outcomes are you hoping to see in the randomized clinical trial? What improvement in progression-free survival would you view to be clinically relevant? It's a good question. I think we often think about in terms of hazard ratios and magnitude of benefit. If I see a hazard ratio that's less than 0.7, I'm very interested in an agent, especially with randomized data. If we see hazard ratios in the 0.68, 0.67, 0.69 range, I think the field will be very enthusiastic. If we see in the range from 0.7 to 0.75, it suggests, you know, there's something real there and may warrant further study in a larger trial. Those are sort of the broad strokes of how I would look at it. In terms of absolute magnitude of what is clinically relevant in terms of an improvement, we have, you know, CheckMate- 649 and ATTRACTION-4 and 590 as sort of reference data sets of survivals. There, as you've shown, survival is around 13, 14, 13.8, around 14 months. If you have an absolute magnitude of improvement of an additional, you know, three months or so, that's a clinically meaningful improvement. I think those are sort of the magnitude of benefit that I'd be looking for in the hazard ratio. In terms of absolute magnitude, somewhere in the three months range or better would be ideal. Response rate is another variable that's important to consider. One of the reasons that patients are able to stay on trial is if they feel better and they're able to, you know, maintain their performance status, then response rate is important there. This is a patient population who comes in with often a lot of disease, a lot of symptoms, that are impacting quality of life, and certainly combinations that have high response rates. If the response rate that we're seeing in Part A holds up in the randomized data, then I think that will be very encouraging because patients will feel that literally. They will know that they are having response and that their disease-related symptoms will improve, and that often will translate into patients being able to remain on our trial, longer and undergo additional lines of therapy, as well. I think response rate is important. It's certainly not a harder clinical outcome as progression-free survival or overall survival. In this patient population, high response rate is a clinically meaningful point. I'll be certainly looking at response rate across the subset of patients. We would now like to turn your attention to colorectal cancer, which we believe represents another strong opportunity for the development of DKN-01. As shown on slide 26, CRC is an indication with high activity of Wnt signaling pathway, which is modulated by DKK1. APC mutations, for example, are very frequent in CRC, with up to 80% of these tumors containing alterations in APC. As we've done in other indications, we worked with Tempus to better understand the role of Wnt signaling in DKK1 expression in CRC. Real-world evidence demonstrates significant elevation in DKK1 in later-stage CRC patients as compared to those with earlier-stage disease. This increase in DKK1 is also observed in microsatellite stable or MSS CRC patients. In terms of the treatment landscape, 5-FU is commonly used in early lines of colorectal cancer, and we know from our gastric cancer experience that DKN-01 synergizes well with 5-FU-based therapies. Pre-clinically, DKN-01 has shown activity across different CRC models, both alone and in combination. This includes settings where tumors are no longer responsive to 5-FU, as demonstrated on slide 27. We've been working with Ajay Goel's lab at the City of Hope to look at preclinical models of CRC. Dr. Goel's lab has previously published data demonstrating DKK1 overexpression as a key factor in the resistance to 5-FU in CRC patients. As part of this work, they created 5-FU-resistant CRC cell lines that have elevated levels of DKK1 expression. The lab took both the parental and the resistant cell lines and inoculated them into mice, treating with either an isotype control, DKN-01, 5-FU, or the combination. On the left is a xenograft HCT116 colon cancer model that's still sensitive to 5-FU treatment. Modest tumor growth is observed. Tumor growth inhibition is observed upon treatment with either DKN-01 or 5-FU, but the greatest effect is seen in the combination group, illustrating the additivity between DKN-01 and this chemotherapy. On the right is the 5-FU-resistant version of the HCT116 model, and here it's clear that 5-FU treatment on its own no longer has any effect. However, upon treatment with DKN-01, even as a monotherapy, these tumors are almost completely ablated. The 5-FU-resistant model is one that we believe is reflective of a second-line CRC setting, where patients will have already seen and are no longer responsive to 5-FU. The deep tumor regressions induced by DKN-01 in this model, especially in comparison to the chemotherapy alone, are quite striking here. In order to ensure that this effect was not cell line dependent, the lab also utilized SW480 cells isolated from a colorectal cancer patient, as shown on slide 28. Again, they created a 5-FU-resistant version of these cells, implanting both the parental and the resistant cells into mice. Similar to the effects seen with HCT116, the SW480 parental xenografts on the left showed modest monotherapy activity and additivity with the combination of 5-FU and DKN-01. Again, in the 5-FU-resistant model, which is reflective of a second-line setting with prior exposure to 5-FU, DKN-01 was able to induce significant tumor regressions. Treatment with DKN-01 almost completely eliminated the tumors by day 13 when the study was ended. Again, in stark contrast to 5-FU, which was unable to prevent tumor growth. In addition to our key academic collaborations, we've also generated our own pre-clinical data in CRC models at Leap. While anti-PD-1s typically are not used in CRC outside of MSI-high patients, based on our mechanism of action, we feel that there's an opportunity to induce synergy between DKN-01 and anti-PD-1s. As discussed earlier, we know that DKN-01 increases PD-L1 expression and brings T-cells into the tumor. Here we use the CT26 syngeneic model and treat it with DKN-01, anti-PD-1, or the combination. Unlike the anti-PD-1, which had very little effect and was unable to prevent tumor growth, DKN-01 monotherapy treatment significantly slowed and then began to regress tumor growth by day 21. This effect of DKN-01 was even further enhanced by combination with the anti-PD-1. These results are especially interesting as unlike the previous two models I showed which expressed tumoral DKK1 expression, CT26 has essentially no expression of DKK1 in the tumor cells. As a result, the dramatic effect of DKN-01 and the synergy in combination with anti-PD-1 are likely due to DKK1 expression from sources outside the tumor, such as from the immune cells or the bone. Finally, we also want to explore DKN-01's effectiveness in a PIK3CA mutant model as shown on slide 30. This interest was based largely on the findings from our previous gynecologic study, where each of our responding patients were noted to have PIK3CA mutations. We conducted this again in that colon HCT116 model using both the parental cell line and one in which we engineered in a PIK3CA mutation. Each of the two models was treated with DKN-01, the PIK3CA inhibitor, BYL719, and the combination of the two. In both the wild type and the PIK3CA mutant models, we observed good tumor inhibition with either DKN-01 on its own or the PIK3CA inhibitor as a monotherapy, which was even further enhanced when using the two in combination. Based on the high activity of Wnt signaling in CRC and the substantial preclinical efficacy across different CRC models and combinations, particularly in the 5-FU setting, we've decided to initiate a randomized phase II study in second-line colorectal cancer, which Dr. Wainberg will now describe. Hi, my name is Dr. Zev Wainberg, and I'm a medical oncologist with a specialty in GI oncology at UCLA, and I am going to go over the DKN-01 colorectal cancer study, that we'll be launching in patients with metastatic colorectal cancer. The purpose of the study is to study the addition of DKN-01 to standard of care chemotherapy regimens in patients with what we call second-line metastatic colorectal cancer. The study will be enrolling patients who have progressed on front line and are now in second line with either FOLFIRI or FOLFOX and bevacizumab, which is, the de facto standard of care for patients with second-line metastatic disease. The study will require eligibility of having progressed on 1 line of therapy, having RECIST-evaluable disease that is microsatellite stable and that does not have evidence of a BRAF V600E mutation. The main stratification factor will be DKK1 expression, and initially there will be a safety run-in of standard of care chemotherapy, which is either FOLFOX, FOLFIRI, bevacizumab and DKN-01, followed by a safety review. If, as expected, there are no unusual safety complications, which we do not expect based on prior studies, the patients will be randomized 1:1 to either chemotherapy and bevacizumab alone or chemotherapy bevacizumab plus DKN-01. The primary objectives of the study are to improve progression-free survival with secondary objectives, including overall response rate, duration of response, overall survival. Of course, there will also be, as mentioned, investigation as to the role of DKK1 expression on efficacy outcomes of the DKN-01 combination platform. We look forward to participating in the study once it launches. Great. Thank you, Dr. Wainberg. Can you tell us a little bit about treating a colorectal cancer patient? How do they first realize that they have this cancer and what their symptoms are like and what your current initial treatment options and decisions are? Sure. When we face patients with metastatic colorectal cancer, which is the most common GI cancer we have, the majority of patients are in fact, or 40%-50% present with metastatic disease. Generally speaking, we would start with chemotherapy with rare exception. The majority of their symptoms that they present to medical attention tend to be vague, but can include weight loss, abdominal pain, sometimes changes in bowel habits. I just saw a patient today with that exact presentation, and they are started on chemotherapy after they've completed staging. The standard of care chemotherapy is either FOLFOX or FOLFIRI or in some patients FOLFOXIRI. While treatment is sometimes dependent on specific biomarkers, the only circumstance where we don't start with chemotherapy is in microsatellite unstable or MSI-high metastatic colorectal cancer in which patients are usually started on a PD-1 inhibitor or a PD-1 CTLA-4 combination. Great. I think you also spoke a bit about this, but how effective have anti-PD-1 antibodies been in clinical trials to date, in particular in colorectal cancer? I know you touched on that it's typically used in MSI-high disease, but how about microsatellite stable patients or other biomarker specifics in colorectal cancer? Right. This is probably the most common question we get from our patients and, after this year's ASCO especially in 2022 where we saw, very nice results of a small trial in rectal cancer. Essentially the role of PD-1 antibodies is only in patients with metastatic colon cancer as microsatellite unstable or MSI-high. There's really no role for these drugs in microsatellite stable colon cancer. They've been studied. Multiple different drugs, multiple different combinations with multiple different companies, and they've all essentially shown no improvement over standard treatment. There is no role for, in my opinion, for these drugs outside of the context of microsatellite unstable MSI-high colon cancer. Okay. What sort of outcome in the clinical trial that you described are you hoping to see or what would you determine to be clinically effective? I mean, the standard response rates in second-line colon cancer is actually quite low, so it's only 10%. We'd hope to achieve at least a 20% response rate, which would make us feel sufficiently comfortable that this is an active combination. More importantly, forget perhaps progression-free survival, which the standard there is of course, as we mentioned, a median PFS of 5.7 months. It would be great to improve that by a few months to 7.7 or 8 months. That would, to me, indicate a real active regimen. Combination treatments in second-line colon cancer have not, unfortunately, changed the landscape for many years of most colon cancer, with the exception of BRAF-mutated disease, which does have an FDA approval there of a BRAF inhibitor. In the other 85% of patients, there really hasn't been a change for many years. So we hope that we see both a statistically significant and a clinically impactful improvement with the addition of DKN-01. I'm Rebecca Arend from University of Alabama at Birmingham, and I'm gonna talk a little bit about DKN01 and how it is being developed in the endometrial cancer space. A little background on endometrial cancer and looking at the five-year overall and relative survival based on stage. You can see in metastatic disease only about 17%. It is vastly increasing in incidence and prevalence. It's the most common gynecological cancer in the Western world. There's about 66,000 annual cases in the United States, and the incidence continues to increase. It's the fourth most common cancer in women in the United States. Clinical risk factors include estrogen replacement therapy, obesity, chronic anovulation, tamoxifen, null parity, early menopause, and late menopause. I want to point out that what I'm going to be addressing is the relationship between DKN-01 and the expression of DKK1 on endometrial cancer. Cancers that express DKK1, or otherwise known as high DKK1, have been associated with poor response to anti-VEGF therapy in endometrial cancer patients, as you can see in this diagram. If you look at historic single agent activity in endometrial cancer, it's pretty abysmal. If you look at the overall response rates and the disease control rates, bevacizumab actually has the highest disease control rate. But as you can see in the prior slides, bevacizumab is an anti-VEGF, and patients who have high DKK1 have a poor response. The other response rates, overall response rates on the order of 10%-15%. Single agent activity is very low, ranging from about 3%-20%. I want to bring you to the phase II study design that was evaluating DKN-01 monotherapy and in combination with weekly paclitaxel in advanced gynecological malignancies that has been completed. The primary objective of our study was overall response rates, and patients either received DKN-01 monotherapy or they received DKN-01 plus weekly paclitaxel. Patients had recurrent endometrial cancer. We also did include ovarian cancer and carcinosarcoma, but we're focusing today on the endometrial cancer patients. It's important to note that 50% of patients in each group had a Wnt signaling alteration, and they needed to have measurable disease. If you look at the DKN-01 monotherapy and the overall response based on DKK1 tumoral expression, patients that had high DKK1 had an overall response rate of 25% and a disease control rate of 63%. When you compare that to historical controls, that is an extremely impressive number. Additionally, it leads to the idea that we are developing more and more biomarkers in the endometrial cancer space, such as DKK1. DKK1 high tumors have better overall response rates, 25% versus those who do not express DKK1 and better clinical benefit. If you look at the right-hand slide, that shows you the spider plot showing that DKK1 high patients have longer progression-free survival, so 4.3 versus 1.8. I'm going to point out that bottom patient to you on the next slide of this spider plot. This patient had a complete response with DKN-01 monotherapy. As you can see, she's a 60-year-old female with recurrent endometrial cancer. She had prior radiation, prior chemotherapy. She was DKK1 high, and she received DKN-01 monotherapy and had a complete response after 14 months and now remains on single agent therapy in complete remission, which is pretty remarkable in her circumstance. If you look at other agents that are being utilized in this space with endometrial or recurrent endometrial cancer. Pembrolizumab plus lenvatinib is the second-line treatment for endometrial cancer in patients that are biomarker negative. You can see the significant toxicity grade greater than or equal to three treatment-related AEs is almost as high as 90%. Any grade treatment emergent AEs are 100%, and actually fatal adverse reactions were as high as 6%. If you look at the LENVIMA discontinuation rate, it's about 31%. The majority of us as clinicians actually don't start at the recommended dose based on the high toxicity. LENVIMA and KEYTRUDA do have some impressive response rates, with an overall response rate of 31% in the post platinum-based therapy in all comers, so regardless of your biomarker. In MMR-proficient patients, so patients that are not eligible for KEYTRUDA alone, the response rates are 30%, which is also higher than our historical controls. This brings us to our new study design, which is DKN-01 plus pembrolizumab in recurrent endometrial cancer patients. This study is going to be looking at DKN-01, 300 mg IV day one and 15 in combination with pembrolizumab, 200 mg IV day one. The goal of this is to further identify this biomarker of DKK1. Stage I of the design is going to break them into DKK1 high and DKK1 and look at the response rates to those two combinations. The objective response rate is the primary objective and the secondary objective is clinical benefit, progression-free survival, overall survival, and duration of response. We will continue to develop this biomarker of DKK1, and our goal is to further prove that not only is this regimen efficacious, but it's also extremely well-tolerated. I can tell you from experience in patients who receive DKK1, there is very, very minimal toxicity. Thank you. Thank you. Rebecca, can you tell us a little bit about treating an endometrial cancer patient? How does she first realize that she has endometrial cancer? What are her symptoms like? What are your current initial treatment options, and how do you come to those decisions? Yeah. Most patients with endometrial cancer present with post-menopausal bleeding, and then that gets followed up by a biopsy. The majority of patients undergo surgery with a hysterectomy and staging initially, and then depending on what stage they are and what their risk factors are, will determine their adjuvant treatment. If they have if they're high risk, your options are either chemotherapy alone or radiation alone, or actually a combination of chemotherapy and radiation. If you're low risk, observation, you don't need any additional therapy after your treatment. There's some debate about sort of this high intermediate risk category and whether or not they need treatment. Some of us observe them and some of us do give them treatment. More commonly, we give brachytherapy alone. Oh, that's very helpful. Overall, you had mentioned the tolerability of DKN-01 in a clinical setting. How many patients have you treated with DKN-01 in the prior study with DKN-01 as a monotherapy in combination with paclitaxel? In particular, are there any observations that you could make about how your patients have done on DKN-01 and the tolerability or quality of life? And perhaps expand a little bit further on that. Yeah, absolutely. We have 15 patients here at UAB who I've treated with DKN-01. Two patients remain on monotherapy. One patient with a complete response, another patient with carcinosarcoma who has stable disease, and they remain on single agent chemotherapy right now, and neither one of them have had any side effects. The side effects that I saw were really in the combination arm and likely secondary to the weekly Taxol. In my experience, there have been really almost zero. We actually sort of joke about it and say, "You know, is that patient just taking some water?" In my experience, this is an extremely well-tolerated drug. You referenced your patient with a complete response. I guess, just to put this into perspective, how often do you actually see complete response in patients who are second line or later, especially where it has been sustained for so many years, and in particular, your patient with a CR has been in a CR for a while. It's been on therapy for four years at this point in time. What do you think that this overall means to the patient? You know, we always discuss with our patients at the time of recurrence that our goal is to keep you from having progressive disease and stable disease is a win because we almost never see complete responses. Now, we have started to see some in the IO space with patients who are microsatellite instability high or mismatch repair deficient. I do have one patient who had a complete response to nivolumab as a single agent, but they're very, very far and few between. Even in the beginning of this trial, I never would have said my goal for you is to get you into complete response, especially with this patient who has received many prior lines of therapy. To me, it almost feels like a true miracle. She feels that way. We recently celebrated it with a big, you know, she was on TV, she came to a basketball game. The cancer center director was there, and we talked about, you know, individualized treatment and the importance of clinical trials because she probably would not be alive today and is now in complete remission. Yeah, that's great. In the P204 study, what stood out to you as the most compelling reason to continue development of this monoclonal antibody DKN-01 for your patients? To me, I would also say the patients who had beta-catenin mutations. I have continued to see beta-catenin mutations on a lot of my next-gen sequencing, and I continue to mourn the fact that I do not have this drug as an option for those patients, given how well it's tolerated, and the response that I have seen in patients who either have a beta-catenin mutation or who are DKK1 high. You know, I think we also have more and more data suggesting that these patients, without any therapy or with our standard of care therapy, actually do worse than patients who do not have any alterations in the Wnt pathway. The Wnt pathway upregulation or beta-catenin mutation is actually a poor prognostic factor. Some of us are debating about, are those the patients in the high and intermediate risk category that we should be making sure that we offer adjuvant treatment to because they are more likely to recur and more likely to die of their disease. If we also have an option for them in terms of a targeted agent in a space where they could benefit, that's even more compelling. Yeah. I guess that leads me to my next question, which is: What have you seen that suggests a combination, perhaps, with an anti-PD-1 and DKN-01 that may be beneficial? I think, for one, I think in the individual space, most patients are going to want to receive immunotherapy, whether it's they're MMR deficient and they can receive pembrolizumab alone or whether they're not and they, you know, have seen and know about the data with lenvatinib. I do think, additionally, we did look at some of the tissues in the monotherapy arm of the P204 study and saw some upregulation of PD-L1 in the tumors that were treated. I've also done a lot of preclinical stuff in my lab, mainly looking in ovarian cancer, but the role of the Wnt pathway in creating more of a cold phenotype in tumors. If we could potentially target this pathway or target DKK1, which we know has some factors in contributing to this cold signature, could that make some patient more responsive to KEYTRUDA or pembrolizumab? My hypothesis is that it can, and that it will lead to a sustained benefit, potentially just the same as lenvatinib and pembrolizumab in all comers, but particularly in patients with a beta-catenin mutation or who have high DKK1. Great. I have two final questions, and one you just kind of started to address. Is it right for us to think of pembro plus lenvatinib as the benchmark for assessing the tolerability and efficacy of DKN-01 plus pembro? What are the aspects of the len/pem profile that you would like to improve upon? Is the study population being enrolled in the investigator-initiated study compared to the population enrolled in the lenvatinib pembrolizumab study? Yes, I would say that this is the appropriate design. I do think that it's similar patients. You know, we are limiting it in our investigator-initiated trial to no more than two prior chemotherapy regimens. I would say that a lot of patients are receiving len/pem as second-line. You know, patients do not have mismatch repair deficiency, and they are MSS who receive len/pem. That's also the population that we're enrolling here. I think, you know, based on patients who are admitted with hypertension, diarrhea, fatigue, mucositis, anemia, all of those factors in the lenvatinib patients, I've never seen any of those side effects with single-agent DKN-01. Even with lenvatinib alone, you can see a substantial amount of those side effects, which I think we have a real area that can be improved upon, specifically in this biomarker population. That's exciting to me. We may see that it's more effective or it's equally as effective as len/pem in the all comers, but I'm particularly excited to see what it does in the patients with DKK1 high. Because I do think that those patients also warrant the opportunity to receive pembrolizumab at some point in the trajectory of their cancer. If they could do that in combination with DKN-01 and never have to see lenvatinib and potentially get a durable response and potentially a complete response, then that is a home run for our patients. That's great. I guess lastly, what sort of outcomes do you hope to see in the study to support moving into a head-to-head against lenvatinib plus pembrolizumab? I would say equivalent efficacy and response rates. My hope is that there will be a difference, and I think there will be in the DKK1 high and low. Really continuing to see the lack of dose reduction and needing to discontinue treatment and the low amounts of side effects is really what I think our benchmark is gonna be. That's all I have, so thank you very much for your time, Dr. Arend. Thank you. Okay, great. Today I'm gonna be talking about our experience using DKN-01 in prostate cancer. I'm gonna start with some of the preclinical data that provided the justification for our investigator-initiated trial. I'm gonna review the phase one experience we've had thus far. Beginning with the preclinical data, we came across DKK1 in our search for genes upregulated in prostate cancers with low androgen receptor expression. These prostate cancers that present in the context of metastatic castration-resistant prostate cancer with low AR expression tend to be quite aggressive and tend to poorly respond to standard of care therapies. That's why we focus on this subtype. You can see in the first panel on the left, when we subdivided prostate cancers by AR or androgen receptor expression, you can see that we clearly see a difference in DKK1 expression. When you further subdivide by neuroendocrine status, and that's labeled NE, what you can see clearly is that it is really the prostate cancers that are non-neuroendocrine and with low AR expression that have the highest levels of DKK1. Now, what was really interesting from some of the other studies that were reported about the impact of DKK1 in the tumor immune microenvironment is the potential that DKK1 could be a suppressive molecule in the context of the prostate cancer tumor immune microenvironment. In order to investigate that, what we did is we looked at the published cohort of metastatic castration-resistant prostate cancer biopsies in the Stand Up to Cancer public consortium and that's the middle panel. What we did is we subdivided all approximately 120 biopsies by DKK1 expression quartile. What we found not surprisingly, based on some other published data, was that the biopsies with highest DKK1 expression actually had the lowest levels of CD8 + T cells. But what was also really interesting, consistent with some of the data from Memorial Sloan Kettering from the Massagué Lab, was that there was also a relationship between DKK1 and NK cell composition, and actually an inverse relationship. The tumors with highest DKK1 expression actually had the lowest composition of active NK cells. Whereas higher levels of quiescent NK cells were observed in biopsies with higher DKK1 expression. To validate these findings in a preclinical model, we chose an established prostate cancer xenograft model, the PC3 model, which actually has high DKK1 expression and concomitant low AR expression, as you would expect from our clinical sample analysis, and found that in fact, DKN-01 treatment of these mice did significantly slow tumor growth. Actually this was dependent upon the presence of NK cells in a separate study that is not shown here. When we deplete NK cells, we are able to completely or almost completely reverse the effect. Let's go to the next slide. This really provided the justification for an investigator-initiated trial in mCRPC targeting DKK1 in patients in this disease context. We focused on the patient population that is both representing the greatest unmet need as well as patients that we felt were likely to be best treated with this therapeutic strategy. I'll explain a little bit more what I mean by that. In order to be eligible, patients had to have progressed on one AR signaling inhibitor, typically either enzalutamide or abiraterone. This was a non-randomized study. There were two cohorts. One cohort to get a better sense of the monotherapy signal with DKN-01, and the other cohort in a patient population that has had no prior taxane exposure in combination with DKN-01 and docetaxel. Principally because these patients do have aggressive disease, as I mentioned, and we felt that a chemotherapy backbone would provide some disease control at least in the early part of the patient's treatment and which would give time for the DKK1 inhibitory effect to take hold. Here are the baseline characteristics, and here we're showing the phase I experience. The trial did expand into phase II, but we are here really focused on what was recently presented at ASCO. Here's the phase I experience with two dose levels of 300 mg and 600 mg, DKN-01 dose level in the monotherapy as well, as in the combination cohort. You can see here a typical age distribution for metastatic castration-resistant prostate cancer. These patients had a predominantly adenocarcinoma, although we did allow neuroendocrine carcinoma as long as patients had progressed on platinum or were platinum ineligible. Again, that's based on some of our preclinical work showing a subset of those patients do have elevated DKK1 expression. We did also include patients with aggressive variant prostate cancer, and that's a clinical definition that overlaps with neuroendocrine carcinoma, but essentially represents a constellation of clinical findings that correlate with a low AR expression and are enriched with multiple tumor suppressor losses, most commonly TP53, PTEN, and RB1. We also did pay attention to Wnt signaling gene mutations because in our work we did also find a correlation between Wnt mutation and upregulated DKK1. In our safety data, we actually had an experience similar to other DKN-01 studies in that we found that DKN-01 was very well tolerated. There were no DKN-01-related Grade 3 or higher adverse events in either cohort. Actually, the response from the standpoint of safety with docetaxel was really very comparable to the experience with docetaxel given as a monotherapy. In terms of the DKK1 expression of the samples that we were able to analyze, we found that there was at least some expression in approximately 42% of cases. You can see here the distribution with about 12% having that, you know, really high DKK1 expression with an H-score of greater than 35. Pushing gears to the next slide, looking at the activity, which was a secondary endpoint, in the phase I experience here. What we can see here for the five evaluable patients in the monotherapy cohort, there was a best response of stable disease. We see three patients at the higher dose level and two patients at the lower dose level, so no clear signal correlating dose with response. In the combination experience with five evaluable patients for RECIST, all five patients did have a PR, three of those being confirmed and two of those being unconfirmed. One of those patients was non-evaluable because of bone-only disease, which was allowed on the phase I portion of the study. To put it this in another way, in our patients with aggressive variant prostate cancer, there were three patients, two of which had a confirmed response. We'll talk about this a bit more, but you know, our anticipated response rate with docetaxel, although there were no randomized studies to guide that, most of the historical data supported a response rate of approximately 20% with docetaxel alone. In the KEYNOTE-365 trial combining pembrolizumab plus docetaxel, there was actually a 23% confirmed overall response rate, which is pretty consistent with some of the prior non-randomized trials. When looking at biomarker response, we look at PSA response in addition to RECIST clinically, and we reported the data as well here, and we saw concordant excellent PSA responses in actually all patients. When looking at the progression-free survival, which was radiographic progression-free survival, that was 6.4 months. Again, comparing you know, quite reasonably, with docetaxel monotherapy, where we would expect a, you know, anywhere between a 30%-50% PSA response rate with docetaxel monotherapy. The progression-free survival again varies, but approximately six months is what you'd expect from docetaxel monotherapy alone. Looking at a particular patient vignette, which we thought was particularly promising, this was a 69-year-old man with mCRPC who had previously been treated with multiple therapies, including radical prostatectomy when he presented with localized disease, salvage radiation therapy and enzalutamide, a prior vaccine clinical trial, as well as abiraterone and darolutamide. What we see here is that he initially did respond while on combination with docetaxel and DKN-01, but he really couldn't tolerate much more than five cycles of docetaxel. We continued him on DKN-01 alone per protocol, and he actually did continue to have ongoing tumor regression in the setting of DKN-01 monotherapy alone. He actually remains on study to this day. Putting this all together, our preclinical data really identified DKN-01 as a promising therapeutic to target DKK1 in this prostate cancer subtype with low androgen receptor expression and high DKK1. We launched a trial in collaboration with Leap to really focus this strategy in mCRPC, where we've seen activity clearly in combination and even in patients with a particularly aggressive subtype known as aggressive variant prostate cancer. We're continuing to look at the samples that we've collected to better understand the mechanism of action here in our clinical samples and to guide our path forward. As you have heard today, we have a focused and aggressive strategy for the next stage of development of DKN-01 over the next two years across three indications and three separate combinations, including our first randomized controlled studies. Throughout this timeframe, we will have several important clinical milestones where we will be able to report our preliminary data, as you can see demonstrated on this slide. In gastric cancer, in collaboration with BeiGene, we are expected to present final mature progression-free survival and overall survival data from our ongoing first-line Part A group in the latter part of quarter three of 2022. Present final data from the full second line Part B cohort in late 2022. We expect to begin enrolling the new phase II randomized controlled Part C study group in first-line patients in the fourth quarter of this year, with overall response rate data becoming available in 2023 and progression-free survival data maturing in the first half of 2024. In our new indication of colorectal cancer, we have been hard at work at study start-up activities and are on track to enroll our first subject in the second half of 2022, with the initial data from the leading cohort of 20 patients in mid-2023. In order to advance development in endometrial cancer in a cost-effective way, building on our prior successful company sponsored study, we are advancing DKN-01 in combination with pembrolizumab in an investigator-initiated study at MD Anderson and University of Alabama, with the first patients planned to be enrolled before year-end and preliminary data becoming available in the second half of 2023. In prostate cancer, the required steps to build on the exciting signal seen for DKN-01 in combination with docetaxel in the initial group of patients would be to initiate a larger company-sponsored study. However, given the evolving changes in the treatment landscape in prostate cancer and the current market environment, we are going to prioritize our other three indications for now and hope that we will be able to return to prostate cancer in the future. We are excited to leap into the next stage of DKN-01 development, and we appreciate the support of all of our investigators, our shareholders, and the patients who participate in our clinical trials as we work together to bring this important new drug forward for cancer patients. Now, we will be happy to open the line to questions to Dr. Klempner or any of us here at the company. As a reminder, to ask a question, you'll need to press star one on your telephone. Again, that is star one to ask a question. Please stand by while we compile the Q&A roster. Our first question comes from Timur Ivannikov with Raymond James. Questions. So first question from us, in G/GEJ cancer, so in terms of your decision to initiate the study now, I think in the past you were talking about potentially disclosing PFS data to BeiGene and then based on that, them sort of buying in. So just a question, have they seen additional data, you know, past the January disclosure that you've provided? And if they have seen it, you know, what drove them to agree to initiate the study now? And, you know, what is their level of buy-in in this study? Obviously, they're supplying tislelizumab, but beyond that, if you could provide any other information, that would be great. Sure. Thanks, Timur, for the question. BeiGene has seen all of the clinical data from the DisTinGuish study on an ongoing basis, including updates with respect to progression-free survival and the maturation of data both for PFS as well as for overall survival. The design of the randomized study that we're announcing today has been done in collaboration with BeiGene, consistent with their input and their view of the, you know, clinical and future competitive landscape in gastric cancer, and a view for how best to understand the additional activity of DKN-01 on top of tislelizumab and chemotherapy in the DKK1 high population as well as in the overall population. All of the study preparation work that we've described has been as a result of a close collaboration with them. With respect to the contractual relationship between Leap and BeiGene, as we've mentioned, it's an option structure where BeiGene's option term extends until a period of time after they receive the final data in Part A and Part B of the DisTinGuish study. That's not impacted by sort of this announcement of beginning Part C in the randomized data. I think that you know, we can't comment on what their ultimate decision will be, but as you point out, they are providing tislelizumab here. We are aggressively moving the program forward together and you know, in our view, hoping to put them in a position where you know, it's an exciting program that they want to continue to be a part of at the time when they contractually are required to make their opt-in decision. Okay. Got it. Thanks. Then maybe just a broader question sort of about triplet therapies and oncology because, you know, DKN-01 is used on top of chemo and tislelizumab. So how receptive do you think? Obviously, the treating physicians are, you know, sound very receptive, but how receptive do you think payers could be if you add, you know, another therapy on top of an existing, you know, relatively expensive therapy? Yeah. I'll answer just kind of briefly a commercial question. It's, you know, ultimately it comes down to the magnitude of clinical benefit, the side effect profile and quality of life for these patients while they're on a study, and does it extend survival? Does it do it in a way that is consistent with the patient's goals? Our overall attempt to make a higher quality of life and a longer life for patients with cancer. We believe that strong data and profiles that are consistent with what we've shown so far is what payers, patients, and physicians want to see. Pharmaceutical companies will continue to be, you know, compensated appropriately for it. Sam, perhaps maybe from a physician's perspective or as you all talk to, do. Yeah. Does it cause you not to wanna combine additional agents? Sure. Happy to weigh in. Good question. First of all, there's actually been a reasonable number of analyses that people who are responding. It costs less to take care of them, especially in GI cancers, because they're not visiting the ERs and the hospital where most of the healthcare dollars happen. It is actually probably cost-effective in the long run to have more biologically active combinations. Of course, data drives practice. As Doug said, survival and PFS will ultimately define coverage. I don't have any concerns clinically about triplet or quadruplet regimens. I mean, if you look at every ongoing phase III trial in gastroesophageal cancer and phase II. Let's take FGFR2, for example. You have FOLFOX plus bemarituzumab plus PD-1. You have FOLFOX plus CLDN 18.2 plus PD-1. You're gonna have CAPOX, FOLFOX, plus tis plus DKN-01. Everyone is trying to leverage the improved biologic understanding of cooperativity with PD-1 and potentially other mechanisms. I don't have any concerns. The places where I do have concerns with triplets and quadruplets is where there are potential synergistic toxicities. For example, combining an antibody drug conjugate like T-DXd with chemotherapy, where they both have chemotherapy-like side effects. Combining T-DXd with PD-1, where there's both have potential lung toxicity, whether it's ILD or pneumonitis. Combining tucatinib with paclitaxel and ramucirumab, where tucatinib can have some GI effects. I think if it's thoughtfully done, I don't have any clinical concerns. I think this triplet, in my opinion, I have zero clinical concerns. Okay. Thank you very much. Just one last quick question for me. In terms of again, in terms of the study design for Part C study, just can you help us understand the DKK1 expression stratification? I think, you know, I think you used H-score of 35, and now it looks like there's a TPS of 20, above 20. Can you just talk about what, you know, how that changed over time? Thank you. Sure. I'll mention it briefly, but the TPS score of 20 is intended to equate to the H-score of 35, and we've done a lot of work to confirm that and ensure that there is, you know, consistent reproducibility and validation to that scoring system. That was a move to TPS is something that was encouraged as part of our FDA discussions in terms of being a preferred method for taking this biomarker forward. I think it's a bit easier for the pathologist, and I think will lead to a, you know, a consistent set of outputs for driving the program forward and analyzing DKK1 expression going forward. Jay, does anything you wanna add? The only thing I'll add is TPS is a tumor percentage score, so the percentage of positive tumor cells is a scoring system that pathologists are already very familiar with. It's a scoring system that's used in other pathology assays, such as PD-L1 across different indications. As Doug said, I think it'll make for a very easy integration into the current landscape. Okay, great. Thanks for the questions. Thank you. Our next question comes from Joel Beatty with Baird. Hey. Hi. Thanks for the detailed presentation today and for taking the questions. The first one is for gastric cancer, for the randomized controlled trial, is that designed to support approval, or would there be another trial potentially needed? Yeah. No, we are not designing this as a pivotal study from the start. You know, it is intended to allow us to answer some of the most important questions to designing that pivotal study, which is, should we move forward in the biomarker high population only or in the full population by better understanding with a control group, the additive benefit of DKN-01 on top of tislelizumab and chemotherapy. Our design here is to put us in a position to execute, you know, a study for approval that's informed by this randomized control design. That's in part why we're doing it as part of the existing protocol, is to speed its ability to get up and running as a study, from an efficiency and timing point of view, so that we can, you know, continue the development program while we're doing regulatory conversations and strategy for a registrational study in parallel. Got it. Yeah, that makes sense. Roughly how many patient data could we see when the trial reads out for the gastric study as well as the other two? Are you talking about this year or are you looking into sort of 2023 and 2024? Yeah. Thinking ahead over the course of the next two years. Yeah. Our hope is to enroll these 160 patients over a period of about one year to be able to be looking at overall response rates early. You know, we've seen responses being at end of cycle two, end of cycle four. You know, progression-free survival obviously will follow into 2024 as we hope to continue to show improvement over the 7.7-month PFS that you would expect from the nivolumab chemotherapy study, but truly understand how much shorter that progression-free survival could be in the control group that are DKK1 high. It's a little early to be able to look at numbers of patients, but it was certainly a study designed with the statistics in mind to, you know, demonstrate statistical significance for adding DKN-01 in the biomarker high population and potentially the full population. Yeah, that makes sense. For Dr. Klempner, can you discuss the safety experience more of this agent? You know, it sounds like overall you've characterized it as quite safe. I know it's on the safety slide. There's a couple of Grade 5 adverse events, including a PE assessed as related to the regimen. Curious just for your thoughts on that. Yeah, it's a good question, and this has come up a few times when the data is presented as abstract format. I think, as you heard, the experience across tumor types, the tolerability has quite good and that's been my clinical experience as well. PEs are, you know, in adenocarcinomas, not uncommon and in, you know, GI cancers particularly are some have the highest rates of disease-related PEs. It's very unless there's a clear mechanistic tie, you know, bevacizumab for example, where there's some direct mechanistic evidence for prothrombotic events, it's a little bit hard to make the attribution. That patient was not mine, so I can't speak for the investigator who made that attribution. But I can say that for me, mechanistically it's hard to tie how this would increase the risk of PE. In a patient population where venous thromboembolic events are common, probably in the 10%-15%, maybe even higher% range across someone's, you know, disease course, my general thinking is that this is probably more related to underlying disease. Again, I can't speak for the specific clinical situation that led that investigator to think that this was potentially related. Got it. Thank you. Thank you. As a reminder, if you'd like to ask a question at this time, that is star then one. Our next question comes from Supawat Thongthip with Mizuho. Hi, hi. Congrats on the new study and data. My first question is on the relationship with BeiGene, you know, specifically on the Part C study. Is there any economics involved? In regards to the potential opt-in decision, would that change the dynamics of that relationship? Yeah. Great question. You know, we certainly know that we designed this study and built it in a way that was done in collaboration with BeiGene to reflect what they want to see and what we all want to have for the program going forward. You know, I can't comment on more than that with respect to BeiGene's disposition. You know, certainly, you know, we're very enthusiastic here about BeiGene as a partner and the working relationship that got this study up and running together and understand that BeiGene has their contractually allowed timeframe to make their final opt-in decision. In the short term, they are not paying for this study during this phase before the opt-in decision. After the opt-in decision, you know, there would be their opt-in exercise fee and, you know, the rest of participating in development costs. Got it. Thank you. Any other questions on the colorectal cancer? I mean, I think the preclinical data looks pretty compelling. I was wondering if you have performed any mechanistic study, you know, just to see if the antitumor effect was manifested through Wnt signaling or some other, you know, potential function of DKK1 inhibition. I'll give this to Jay. On the PR. Yeah, in terms of this, as you think about mechanism of action in colorectal cancer specifically, as you know look back, what would you attribute to the antitumor effects you might see in some of the different models or some of the different combinations? Yeah. I think again, it's worth reiterating that CRC is an indication that's largely driven by Wnt signaling. We know, for example, one of the four Consensus Molecular Subtypes makes up about a third of patients in CRC, and that's characterized by the activation of the Wnt signaling pathway, but high expression of beta-catenin. I think there's a lot of rationale there for Wnt signaling pathway to really play a significant role in this. In terms of the potential synergy with PD-L1, I think, you know, we've now seen across each of these models that we've looked at, you know, we have an effect both on our own but in combination with the various partners, including the anti-PD-1. We've seen an upregulation of PD-L1 activity as a result of DKN-01 treatment. I think we continue to have that rationale mechanistically. There's both the, you know, the Wnt beta-catenin pathway rationale, I think that drives CRC, but also that upregulation of PD-L1 that we see when we treat these models. We will continue to explore this further as we go through this study with our biomarker samples. Got it. That's very helpful. If you may sneak in one more question. In terms of the DKK1 expression cutoff, is the strategy going to be consistent among different tumor types? You know, can you speak a little bit on this? Yeah. I think our view has been that you will need to identify the cutoff in each indication by enrolling patients and really understanding the distribution of DKK1 expression and the outcomes for patients, you know, that we see in the study. You know, we would point out that in endometrial cancer, you know, the DKK1 expression has been a bit lower than in gastric cancer. Our cutoff where we had the complete response and single agent activity was lower than the cutoff we've used in gastric cancer. I do think the colorectal cancer study starts in a similar way. You enroll all comers, understand more about expression and distribution, and then make a good clinical and scientific decision for how you know, understand and balance that to drive the best outcome for patients. Maybe just to add to that. You know, I think it's important to keep in mind that if a patient has low DKK1, that doesn't necessarily mean they have no DKK1. You know, I think that is why a lot of patients that have fallen in that low DKK1 bucket across some of our studies do respond well, in addition to having other sources of DKK1. If it is present in the tumor and made by the tumor, typically we've seen majority of those patients respond, in accordance with the data that you've seen today. There is DKK1 produced by other sources such as the bone, such as platelets in the blood, that we are continuing to explore the role there to see the effect about that DKK1 travel to the tumor and really play a role there as well. Thank you. That's very helpful. Thank you again. Thank you. This concludes today's conference call. Thank you for participating. You may now disconnect.