Hi, everyone. Good afternoon. Glad you all are here today to join us. My name is Lalitha Sundararajan, and it's my pleasure to introduce Leap Therapeutics' speaker for today, CEO Doug Onsi. He's joined on stage by Chief Medical Officer Cyndi Sirard, and Chief Scientific Officer Jason Baum. With that, Doug, I'll turn it over to you.
Thank you very much. Thank you, everybody. It's a pleasure to be here to ring in Leap Year 2024 at the 42nd annual JP Morgan Healthcare Conference. I'm Doug Onsi, and I'm pleased to be joined by other members of the Leap management team, Cyndi, Jay, Gus Lawlor, Jonathan Miller, and one of our board members, Patty Martin. And to be able to talk to you about what is gonna be an extremely, extremely exciting year for Leap, as our lead program, DKN-01, heads into some very important data readouts from two randomized controlled clinical trials. My presentation includes some forward-looking statements. So as a proud graduate of the University of Michigan Law School, I encourage you to read the risks and uncertainties affiliated and found in our SEC filings and in the rest of our corporate filings.
So with that, Leap Therapeutics is a biomarker-focused oncology drug development company with a focus on gastrointestinal cancers and looking for the opportunity to combine diagnostics with therapeutics to generate a personalized medicine approach for patients. To be able to allow patients and physicians to run a panel of diagnostic tests, to identify the appropriate therapies, for their particular cancer. And at Leap, we have two drugs that are in active clinical trials right now, and our lead program, DKN-01, is in two randomized controlled studies, and which we'll be reading out over the course of this year. As a company, we've had a real focus on GI cancers, and we're seeing in this area there's a strong desire to add new therapies to improve what have been very poor outcomes for patients with gastric cancer and colorectal cancer.
We ended the year with $70 million in cash, and that provides us with a runway into the second quarter of 2025, so beyond the two very important clinical readouts that we have from our randomized controlled studies. As we head into a, you know, a very important year, we're really looking forward to the opportunity to position DKN-01 as a late-stage, first-in-class program, for patients with GI cancers. I'll spend the majority of the presentation describing that lead program, DKN-01. It's our antibody that targets the protein DKK1, and reviewing with you some of the results of the clinical trials and the designs of the two randomized studies, along with some of the data that led to the execution of those trials.
For the first of the studies, we did announce last week that we completed enrollment at 170 patients in the randomized controlled clinical trial of DKN-01 in combination with tislelizumab and chemotherapy in first-line gastric cancer. We're very excited to, to be seeing strong enrollment in our second clinical trial, which is DKN-01 in combination with bevacizumab and chemotherapy in second-line colorectal cancer. We'll be presenting the Part A data from that study, the single-arm run-in at ASCO GI next week. As DKN-01 transitions into later stages of development and potential strategic partnering, we've sought to enhance the pipeline with some additional biomarker-focused antibody programs.
Through the acquisition of Flame Biosciences last year, we brought into the pipeline, some, what we think is potentially best-in-class programs in the claudin 18.2 and the GDF-15, antibody field, and I think you'll be hearing more about those, over the next, year or so. But before I dive into the clinical data, let me remind everyone about the role of DKK-1 in cancer. DKK-1 is a protein that plays a critical role in the development of cancer, where it's often overexpressed, leading to poor outcomes, for patients. It's secreted largely by tumor cells and is able to promote cancer development through an induction of proliferation, metastasis, and angiogenesis. As we think about DKK-1 biology, it has four main effects in the growth and proliferation of cancer.
First, DKK-1 signals directly to myeloid-derived suppressor cells and M2 macrophages to inhibit their ability or to encourage them to be able to suppress the immune system from targeting and clearing cancer. Second, DKK-1 decreases the activity and number of natural killer cells, so further establishing an immunosuppressive tumor microenvironment and further preventing the immune system from being able to target and remove cancer. In addition, DKK-1 promotes angiogenesis through the increased number and size of blood vessels. Finally, DKK-1 can directly signal on the cancer cell through CKAP4 and activate the AKT/PI3K signaling pathway. So these multiple mechanisms describe why when DKK-1 is expressed in a tumor, those patients have shorter overall survival and faster time to treatment progression on standard therapies. DKN-01 is designed to reverse the harmful pro-tumorigenic effects of DKK-1.
DKN-01 targets and removes free DKK1 from the tumor microenvironment. DKN-01 blocks the signaling of DKK1 through CKAP4, causing the downregulation of the AKT/PI3K signaling pathway on tumor cells and reduces proliferation. In addition, it can reduce angiogenesis, resulting in fewer and smaller blood vessels, and potentially contributing to the benefit of combinations with anti-VEGF inhibitors and anti-angiogenic agents like bevacizumab... However, the key mechanism of action of DKN-01 is really involves creating a more favorable tumor microenvironment to attack the tumor. Preclinical data suggests that this is characterized by really reprogramming the tumor microenvironment, in part by reducing the activity of those suppressive myeloid-derived suppressor cells, yeah, correcting M2 to M1 macrophages, and promoting the activity of NK cells. The immune modulatory mechanisms of DKN-01 allow it to synergize extremely well with immune checkpoint inhibitors and other immune mechanisms.
You know, we see that anti-PD-1 antibodies, such as tislelizumab or pembrolizumab, are known to take that brake off the immune system. They act through the activation of T-cells, and when you combine that with a DKN-01, they can activate NK cells and impact the tumor microenvironment from the innate immune system. You know, we see very exciting and synergistic results. One of the other things we see about DKN-01 is it upregulates the expression of PD-L1, also contributing to what we see as very interesting activity in PD-L1-low tumors by making them more favorable for PD-L1 or PD-1 combinations. And when DKN-01 and PD-1 antibodies, while they each have their own single agent activity, the complementary mechanisms of action, we believe, is a real one-two punch in the war on cancer.
So we initially became interested in DKK1 and the DKK1 target on the basis of data in the literature that patients with higher DKK1 expression had shorter overall survival. If you look across the TCGA database, you see that it's about 2.5 years of shorter overall survival if you have high DKK1 versus low DKK1 expression. If you look solely at gastric cancer, and that's the top panel here, the patients who, in their database, who have high DKK1, as shown in the green, have shorter overall survival than those patients who have low DKK1 in blue.
Then we collaborated with Tempus, which has a very large repository of real-world outcomes, and we're able to identify in patients who were treated with first-line, standard of care regimens, that patients who have high DKK1 expression, as shown in green on the lower panel, discontinue that first-line therapy faster. They come off and they have, as we view, a more aggressive prognosis to their disease. Our DKN-01 development program has gone through, monotherapy, chemotherapy combinations, as we've led into the current first-line combination with tislelizumab, and I thought I'd review, some of that data just briefly with you. As a monotherapy, DKN-01 did demonstrate single-agent activity.
We had two patients with responses as a monotherapy, one of whom had had a prior PD-L1 and IDO inhibitor combination in a clinical trial and was able to benefit for a year on DKN-01 by itself. We had about a 40% stable disease rate in monotherapy, and this is very consistent with the activity that we see for other active agents in their monotherapy studies in esophageal gastric cancer. And then DKN-01 demonstrated what we thought was very exciting activity on the left panel in combination with paclitaxel, which was in the second-line patient setting, a 47% response rate and a median PFS of four and a half months.
As you compared that to paclitaxel alone in the second-line setting in esophageal gastric cancer, it was usually about a 16% response rate and a 2.9-month PFS in the Rainbow study. On the right-hand side, we've also done PD-1 combinations without the chemotherapy. In the first study in which we were able to use a diagnostic test to measure DKK1 expression in patients, we saw that if you combine DKN-01 with Keytruda in patients whose tumors expressed higher levels of DKK1, we had very strong results with a 50% response rate and a, you know, a much stronger improved signal of activity than in patients who had lower DKK1 expression. So these studies then led to the DisTinGuish trial that has been the focus of the company over the last few years.
So we put all the pieces together, the checkpoint inhibitor, chemotherapy, and DKN-01, now in first-line patients. And in our part A of the study was a single-arm run-in, and in the patients that were able to receive a full cycle of two doses of the DKN-01 in that first cycle, that we saw very strong results in this trial with over 70% overall response rate in the MITT population, with particularly strong results in those patients whose tumors expressed high levels of DKK1, who are represented there in green. It was definitely encouraging that all patients who were evaluable did have a tumor reduction, and that even those patients with lower DKK1 expression, as you see in the blue bars, still had a very strong response rate, including a patient who had had a complete response.
These response rates overall exceed the approximately 50% response rate benchmark that you would expect from PD-1 antibody and chemotherapy alone. And this. As we looked and understood more about the DKK1 expression data, we're always asked about PD-L1 expression. And so, as you look at the same waterfall, but this time color-coded, based on the expression of PD-L1 being high in the purple or lower in the orange, what you see is that you have still very strong response rates in those PD-L1 low patients, the ones you would expect to have had poor outcomes on a PD-1 antibody and chemotherapy alone.
and with, you know, an 86% response rate in those PD-L1 low patients, and importantly, in that double biomarker group who have high DKK1 expression and low PD-L1 expression, the group that has both unfavorable, prognostic factors, we had 6 of the 6 patients all have partial responses.... In terms of the survival outcomes in the study, and importantly, as we think about the randomized trial that we are running right now, we were very pleased with the progression-free survival and the overall survival, in this 25 patient cohort. We had 11.3 months of progression-free survival and 19.5 months of overall survival. So we had what we believed was very strong response rates, turning into compelling progression-free survival and overall survival.
As we, particularly, as we compare it to the three very large benchmark studies of PD-1 antibodies plus chemotherapy in this first-line HER2 negative population. You know, as you look across the studies for nivolumab, pembrolizumab, or tislelizumab, you see very consistent results in an approximately 50% response rate, 6.9-7.5 months of progression-free survival. And so while this is an improvement over chemotherapy alone, you still see that nearly half, that half of the patients don't have a response on therapy, and that overall survival, at only a little over a year, still leaves much to be desired. And so based upon that single-arm data, we're conducting a randomized controlled trial of DKN-01 in combination with tislelizumab and chemotherapy in these first-line HER2 negative gastric cancer patients.
We ultimately enrolled 170 patients, so even higher than our expectations for the trial in the United States, the Republic of Korea and Germany, equally balanced between the DKN-01, tislelizumab and chemotherapy arm and the control arm. Patients were stratified on the basis of DKK1 and PD-L1 expression, and the primary endpoint of the study is median progression-free survival, which will be evaluating in both the DKK1 high biomarker population as well as the entire population. The goal overall is to be able to identify the treatment effect in the patient population, where there is the strongest overall activity as you start planning ahead for phase 3.
With the completion of enrollment at the end of December, you know, we would expect that initial response rate data with three scans on all patients would be available in the middle of the year, and that progression-free survival data would mature in the second half of the year. But whenever we shared our gastric cancer data with GI oncologists or pharma companies, they always asked what our plans were to move into colorectal cancer. Colorectal cancer is a cancer that has high activity of WNT signaling, which is modulated by DKK-1. Approximately 80%-90% of CRC tumors contain alterations in the WNT pathway, genes such as APC. WNT pathway activation is enriched in the CMS 2 subtype, which is more pro-focused on left-sided tumors and typically characterized by APC mutations, advanced mutations in KRAS, and a loss of TP53.
Real-world evidence from Tempus demonstrated that DKK1 is elevated in late-stage CRC patients and is the highest in the metastatic rectal. As a result, we'd anticipate that the activity of DKK1 inhibition would be strongest in left-sided tumors, those that have the greatest WNT activation, and particularly in rectal cancers, where you'd have the most DKK1 biology associated with the disease progression. In terms of the treatment landscapes, you know, the foundation of first- and second-line therapies consists of a 5-FU-based regimen. We've seen from our gastric cancer studies that DKN-01 can synergize safely and with a lot of activity in those 5-FU combinations. Preclinically, we've seen that DKN-01 can have activity in settings where the animals are not responsive to 5-FU-based chemotherapy.
So just to show just a little bit of that preclinical data as we head in towards clinical data next week. On the left side is DKN-01 in combination with bevacizumab, and separately in a model of colorectal cancer in the. On the left panel, you see is each of DKN-01 and bevacizumab have modest single activity, single agent activity on their own, but have stronger activity when you put them together. On the right side, in a model that's generated same cell line but has resistance to 5-FU based chemotherapy, you see the very strong activity of DKN-01 as a single agent, and additional activity when you combine in a 5-FU based chemotherapy, creating a second line setting that is very similar to what we plan to be enrolling in this clinical trial.
As we talk to physicians, what we hear is that second-line colorectal cancer is an extremely heterogeneous disease, that the decisions around therapy and expectations for outcomes are heavily influenced by a patient's characteristics, including tumor characteristics such as their genetic profile, the sidedness of the tumor, the consensus molecular subtype, the sites of metastases, and particularly liver, and whether the patient had rapid progression in first-line therapy. They routinely select the therapy based upon those factors, whether a tumor is right-sided or left-sided, whether it has KRAS mutations or is wild type, has a BRAF mutation, is MSI-high. So as a result, there are widely divergent outcomes in a collection of historical, often ten-year-old phase 3 studies, depending on the mix of patients included in the study, as some groups deliver poor or better outcomes than others.
Unlike in gastric cancer, we had three contemporaneous large phase III trials. It is much more difficult, as we look at the range of studies that have led to the use of bevacizumab and chemotherapy in second-line colorectal cancer. We've seen response rates that range from 4% up to 22%, disease control rate from 62%-78%, and PFS from 2.5- 6.9 months. So as we evaluate our data, we'll be focused on understanding and presenting the activity in these different subgroups in order to identify the strongest activity for the DKN-01 combination and the optimal population for phase III development. We know the physicians want to use a personalized medicine approach to treat their CRC patients and have new therapeutic options based on that patient's tumor location, CMS subtype, and genetic profile.
And so with this foundation, we launched the second company-sponsored study, the DeFianCe study, to evaluate the addition of DKN-01 to bevacizumab and chemo and chemotherapy in the second-line setting. Patients receive FOLFOX or FOLFIRI, depending on what they received in the first line. So they'll receive the opposite in second line of the 5-FU-based combination they received in first line, and that's the standard of care for second-line patients. Part A of the study was designed as a single-arm safety run-in. And in addition to safety review, though, we wanted to ensure that there was a strong enough efficacy signal to support a successful randomized clinical trial. Part A of the DeFianCe study included significant numbers of patients who had previous exposure to bevacizumab, tumors with KRAS mutations, liver metastases, and rapid progression on their first-line therapy.
This population represents the true second-line population that our physicians see in the clinic and includes subgroups with poor expected outcomes. Part A was originally planned for 20 patients, but as a result of significant investigator enthusiasm and the momentum in running the study, wound up enrolling a total of 33 patients. Based on the advice of our investigators, we set 20% as the ORR benchmark to advance into the randomized Part B. This Part A data is the data that will be presented at ASCO GI next week. From a timing perspective, the abstracts for ASCO GI become available on Tuesday at 5 P.M. Eastern time next week, at which point we'll be able to issue a press release to describe the data in more detail and provide a first look at that to everyone.
The poster itself becomes available on Saturday over the weekend, and then, we intend to conduct a webcast for the investment population, investment public, to have some of our investigators be able to present that data and their experiences using DKN-01 in colorectal cancer with you all. You know, we're very excited about the Part A data as it's come together, and really looking forward to sharing that data with all of you over the next two weeks. The enthusiasm of the investigators and of the company in that led us to opening the randomized control Part B study in August and September of last year. It...
The primary objective there is to have that look at progression-free survival and with, you know, the bevacizumab and chemotherapy control arm, and enrollment is off to a very strong start in this study. We expect to be able to complete enrollment mid-year, which will allow us to have initial data from this study, overall response rate, you know, near the end of the year. And we're always asked questions about other indications for DKN-01 and other evidence of single-agent activity. And I'll remind people that there was, you know, a very strong and exciting signal in endometrial cancer for DKN-01 as a monotherapy.
You know, we have a patient who's now at 5.5 years in a complete response on monotherapy with endometrial cancer on DKN-01, and I think it is, you know, particularly since we look at where the strongest single agent signal was in two of the patients where we did not know their DKK1 expression, they had activating mutations in the Wnt pathway. And that, in this study, led to higher DKK1 expression and is very similar to some of the activated Wnt pathway activity that we see in colorectal cancer patients. So we're seeing some very important and interesting ties between our different indications in the role of DKK1 biology in mutations in the Wnt pathway and the activation of the Wnt pathway.
Investigators from MD Anderson and University of Alabama at Birmingham approached us with the concept for an investigator-sponsored study of DKN-01 in combination with a PD-1 antibody to build upon that second, that single-agent activity in endometrial cancer. This study is now open for enrollment, and our goal is to be able to have, some data late in the year as proof of concept for additional PD-1 combinations outside of gastric cancer. You know, we have had very strong investigator interest and very strong biological rationale for being able to combine DKN-01 with PD-1 antibodies in indications such as triple-negative breast cancer, head and neck cancer, biliary tract cancer, and, even pancreatic cancer, which has some of the highest expression of, of DKK1. So 2023 was a very strong year of development, execution at Leap.
And now we're heading into, an incredibly exciting period, very data-rich period over the course of, Leap year 2024. You know, with the completion of enrollment in the randomized controlled gastric cancer study, you know, we're now set to have that initial data on response rate in the, middle of the year and then watch progression-free survival data mature over the course of the second half of the year.
With the rapid enrollment that we're seeing in the colorectal cancer study, we fully expect to be able to complete that enrollment at 130 patients, in the middle of the year, begin to see that, second randomized dataset readout, but also be able to kick off the year with, ASCO GI and be able to show the first look at the Part A colorectal cancer data over the next couple of weeks. So I'd like to thank all of you, and before we take a few questions, just, do a big shout-out to all of our Leapsters who are back in the office. We've got a fantastic team at the company that's executed extremely well.
You know, we head into, you know, an incredibly important year, and I'm proud of all of the execution and hard development work that's been done by this team. I'd be remiss if we didn't thank the patients and medical staff who participate in our clinical trials. You know, it's really their commitment and understanding of the drug and how they treat their patients that is incredibly motivational to all of us as we seek to improve the outcomes for their patients. So with that, we can take a few questions.
Thanks so much, Doug, for running through that. I guess, a couple of questions here. The first one is, as you had kind of mentioned earlier, both of your clinical trials seem to have enrolled very rapidly, and even over-enrolled is kind of what you had mentioned. What are you hearing from your investigators, or what is it about current treatment options in gastric cancer as well as CRC, that's generated such interest in DKN-01?
Sure. Cyndi, you want me to take that?
Sure. So I believe that the investigators who have been participating on our clinical trials over a number of years have been very committed to the development of this agent, principally because of the complexity of DKK-1 biology and really how it drives many cancers. There is, you know, both gastric cancer and colorectal cancer are significant unmet medical needs, and while we've made some advances in gastric cancer over the recent years, as Doug has described with the three randomized studies, there are still half of the patients that are not deriving any clinical benefit from or advantage to the use of those therapies. So we still need novel therapies to complement the existing therapies, and I think CRC is a little bit different. Like, so with colorectal cancer, there has been limited advances over the past decade.
Many of them have been older drugs that have been used in, you know, in different maintenance settings or continued treatment settings that really haven't advanced the field. So colorectal cancer really is in need of some novel agents to come in, and again, once again, complement the existing standard of care chemotherapies. Our investigators, you know, I think they believe in the drug. The drug is extraordinarily safe to administer. The safety profile, you know, has been very easy to combine with any variety of agents, and they continue to enroll quite strongly for us.
And then drilling down just a little bit. In the DisTinGuish part A, you showed there was a 90% ORR in the DKN-01 high patients. Kind of a two-part question, but one, are you planning to use the same cutoff to define DKN-01 high in part C and going forward? And then, secondly, what do we know about other sources of DKK1 or the amount of DKK1 protein that might impact the tumor microenvironment and cancer progression?
Sure, I can take that, and I'll start with the first question on the cutoff. So, going into the DisTinGuish study, we predefined the cutoff for DKK-1 high to correspond to at least 20% of tumor cells staining positive for DKK-1. We determined this largely based on our previous study with Keytruda, and I think you saw today it held strong in part A of our DisTinGuish study. So this is the cutoff that was used for both stratification and will be used for the primary objective in part C, the randomized portion of the study. With that said, I think we've seen that patients with lower expression of DKK-1 can also benefit.
So retrospectively, we will be looking at other cutoffs of DKN-01, potentially allowing us to modify the cutoff for future studies, phase III and beyond, and also potentially allowing us to enlarge the patient population that may benefit. In terms of your second question on the source of DKN-01, you know, you saw today, both in endometrial as well as in gastric, that if the tumor makes high DKN-01, the patients seem to respond very well to treatment. I think that's very clear. But there are other sources of DKN-01 as well, including the bone. And what our preclinical data shows us is that it's also important to neutralize those sources of DKN-01. And so that also allows us to open it up into not only tumors that may express high levels of DKN-01, but also those that...
where it may come from another source, where we can definitely neutralize it with DKN-01.
Thank you. And then I guess taking a bigger, you know, step back, can you comment on your strategic partnering strategy and the positioning of DKN-01 as the randomized clinical trials mature this year?
That's really important. I mean, if you look at the combination with PD-1 antibodies that we've done, we've done studies with pembrolizumab, nivolumab, atezolizumab, tislelizumab. You know, it is for us, you know, the PD-1 antibodies behave relatively similarly with each other, and in each case, across particularly those three large trials, you still see very significant improvements that need to be made for patients. And so, you know, we believe you could combine DKN-01 with any of the PD-1 antibodies to improve those overall outcomes. And it's gonna be important for us that we are able to find and work with a PD-1 partner that is really committed to exploring the broad range of opportunities that DKN-01 and a PD-1 combination would have.
We're not locked into needing to use the same PD-1 antibody in phase as we're using in the phase II study. I think for any of the companies that have a PD-1 antibody, they're all searching for additional combinations that will give them a marketing advantage compared to their peers in terms of having a differentiated profile for that combination. They would obviously, if we have three or four months of additional progression-free survival, they'll have additional revenue for the PD-1 antibody versus what they would have had if that patient had come off earlier. And that maybe it'll help them reach into populations where the PD-1 antibody isn't reaching today.
So patients with low PD-L1 expression who might find that PD-L1 expression increased by DKN-01, and be able to have stronger outcomes in PD-L1 low patients than they're currently having today, gives them an additional source of opportunity for patients and differentiation against the other PD-1 antibodies that don't have that connection. As we look at colorectal cancer, you know, this is an indication where there hasn't been a lot of additional progress in the base therapeutic regimens, outside of some small mutational or wild KRAS wild type. Even KRAS wild type was 10 years ago. So many of these trials are still using the same vemurafenib and switch chemotherapy that they've been using for a long time.
As you look at the opportunities to be tying into really important areas of colorectal cancer biology with a new mechanism, that can, you know, reach a broader market opportunity, for the pharma companies that have a GI profile, have a GI presence, leverage that call point better, I think creates a very strong, you know, kind of additional set of partnering opportunities as a first-in-class novel drug, positioned to be a late-stage asset that could be revenue for any one of the pharma companies in the back half of the decade.
Got it. Well, thank you very much for that and for running through the presentation. I think with that, this concludes our session, and thank you all for attending.