Good afternoon and welcome to the 43rd Annual JP Morgan healthcare conference. My name is Dave Praharaj, and I'm part of the Healthcare Investment and Banking team here at JP Morgan. Today, I have the pleasure of introducing our speaker, Doug Onsi, President and CEO of Leap Therapeutics. And also here on the podium, we have CMO Cyndi Sirard and CSO Jay Baum, who will be participating in Q&A. With that, take it away Doug.
Thank you very much. It's a pleasure to be here at the JP Morgan Healthcare Conference, and I'm also pleased to be joined, in addition to Cyndi and Jay, by other members of the Leap team: Jonathan Miller from Business Development, Gus Lawler, our Chief Operating Officer, and Patty Martin from our Board of Directors, and as Leap heads into an incredibly exciting year of clinical trial readouts, I'm proud to be able to give you a corporate overview and update and discuss the milestones that are ahead. My presentation will include forward-looking statements, so we remind you to review the risks and uncertainties discussed in our SEC filings. Leap Therapeutics is a biomarker-focused oncology drug development company, and we are very excited in this presentation to be able to announce the generic name for our lead antibody, DKN-01, sirexatamab.
It's always been a tongue twister at Leap to say that it's DKN-01 that binds DKK1. It was even a bit worse. Originally, the company name was DKN, DKK1. And so you had DKN developing DKN-01 to remove DKK1. So excuse us, we slip up occasionally, but we'll get used to rolling sirexatamab out, and there's an internal hot debate over what the appropriate short version of that is. Is it Sirexa, Sirex? But it's an exciting thing to be able to talk about. And Leap was formed to combine diagnostics and therapeutics with the goal of bringing the right drug to the right patient at the right time. And patient selection strategies, whether based on biomarkers or patient tumor or treatment characteristics, have always been central to our approach to allow cancer patients to live longer and have better outcomes with high quality of life.
Last year, we completed enrollment in two randomized controlled trials for sirexatamab, one in first-line gastric cancer patients in combination with a PD-1 antibody and chemotherapy, and one in second-line colorectal cancer in combination with bevacizumab and chemotherapy. Patient follow-up is continuing in both trials, and to allow us to make strategic decisions about the populations to move forward into phase III, we intend to provide initial data from both trials in the first quarter of this year. We had previously guided to that timeframe in our gastric cancer study, but now we're accelerating the analysis of the colorectal cancer data so that we can have a comprehensive, even if not final, look for ourselves, regulators, our investigators, investors, and pharma in both data sets. Our cash runway remains solid.
Thanks to a $40 million financing last April led by Gilead, we finished the third quarter with over $62 million in cash and a cash runway into the second quarter of 2026. We believe that sirexatamab has exciting potential in multiple clinical indications. As I mentioned, we have the two randomized controlled clinical trials that are company-sponsored. And as I spent most of my last fireside chat in December talking about the gastric cancer indication, I'll spend most of this presentation talking about the opportunity and data for sirexatamab in colorectal cancer patients. But in addition to this, as many of you know, sirexatamab demonstrated single-agent activity, including a complete response in patients with endometrial cancer, and we're happy to be able to support an investigator-sponsored trial of sirexatamab in combination with Keytruda in women with second-line endometrial cancer.
As part of our effort to build a pipeline of antibody therapies with the potential to treat patients with serious unmet medical needs, last year we announced the advancement of FL-501, our anti-GDF15 antibody, into formal preclinical development and manufacturing development. I'll talk at the end about the FL-501 program and our objectives to share initial preclinical data from the program at the beginning of the second quarter, and we'll work towards moving the program into the clinic next year. Before I dive into the clinical data, let me remind everyone of the role of DKK1 in cancer. DKK1 is a protein that plays a critical role in the development of cancer, where it's often overexpressed, leading to worse outcomes for patients. It is able to promote cancer development through the induction of proliferation, metastasis, and angiogenesis.
DKK1, see, that's how we got stuck and needed to call it sirexatamab. DKK1 has four main effects in promoting the growth and proliferation of cancer. First, DKK1 signals directly to myeloid-derived suppressor cells and M2 macrophages to enhance their ability to suppress the anti-tumor immune response. Second, DKK1 decreases the activity and number of natural killer cells, further establishing an immunosuppressive tumor microenvironment and preventing the immune system from targeting and clearing cancerous cells. In addition, DKK1 promotes angiogenesis through increased number and size of blood vessels. Finally, DKK1 can directly activate the PI3K/AKT signaling pathway by binding to the CKAP4 receptor and promote tumor growth and proliferation. These mechanisms explain why when DKK1 is expressed or present in the context of cancer, those patients often have shorter overall survival and faster time to treatment progression on standard therapies.
In all people, DKK1 is produced by the bone. If you look for early papers on DKK1, you'll find its important role in embryonic development that led to the name Dickkopf-1 or big head, and to its role in the differentiation of osteoblasts and osteoclasts in the development and treatment of bone. In a patient with cancer, such as a colorectal cancer patient, that DKK1 that can be produced by bone or other sources can travel to the tumor microenvironment, and depending on the other cells in the TME and the mutational profile of the tumor, can have a pro-tumorigenic effect. In other cancers, such as gastric cancer, DKK1 can be produced directly by the tumor cells and is part of the tumor strategy to evade detection from the immune system.
As a result, Jay and our biomarkers team are busy developing two assays to allow us to measure DKK1. One to measure DKK1 in plasma in the circulation, and the one you've heard us talk most about, which is measuring DKK1 RNA from the tumor. We believe that both could be very important to our understanding of the role of DKK1 in cancer patients and the effectiveness of sirexatamab therapy. Sirexatamab is designed to reverse those harmful pro-tumorigenic effects of DKK1. Sirexatamab specifically targets and removes free DKK1 from the tumor microenvironment, blocking the signaling of DKK1 and causing a pro-tumorigenic effect. It also is expected to be able to reduce angiogenesis, which could lead to potentially beneficial combinations with other VEGF inhibitors that also have an anti-angiogenic effect.
Another main mechanism of sirexatamab involves creating a more favorable immune response to attack and clear the tumor. Preclinical data suggest that by reducing that harmful activity of suppressive myeloid-derived suppressor cells, converting M2 to M1 macrophages, and promoting the activity of NK cells, sirexatamab can drive an increased immune system effect. Let me talk about colorectal cancer and provide a little bit of background on the disease as I get into our studies and our data. Colorectal cancer is a highly prevalent and impactful disease. Most of us probably know someone who has dealt with this disease. Hopefully, everyone who's over the age of 40 has had a colonoscopy and is doing their part for prevention of colorectal cancer.
It's the third most frequently occurring cancer globally, the second leading cause of cancer-related deaths, with over 2 million cases worldwide and nearly 1 million deaths worldwide. Colorectal cancer can arise on the left or the right side of the colon, and I highlight this difference because there can be differences in the molecular features and the treatment paradigms depending on where the colorectal cancer arises from. Various mutations can occur with different frequencies, and the most frequently targeted mutations relate around BRAF and KRAS. So national guidelines do recommend screening, but however, many patients will present symptomatically with issues such as rectal bleeding, anemia, abdominal pain, at which time they've already had advanced stage disease. Generally, at that stage, these patients are treated when the disease is metastatic, and it's typically incurable.
So as we think about colorectal cancer and its application to sirexatamab, it's a cancer with high activity of Wnt signaling, which is modulated by DKK1. It is approximately 80%-90% of tumors include mutations in the DKK1, the Wnt signaling pathway, such as APC. And Wnt pathway activation is enriched significantly and is part of the definition of the consensus molecular subtype 2, which is commonly found in left-sided tumors. My apologies for not advancing that slide quite quickly enough for those here in the room. But what we hear from physicians is that second-line colorectal cancer is an extremely heterogeneous disease, that their decisions around therapy and their expectations for outcomes are significantly impacted by whether the cancer is on the left or the right side, the sites of metastasis, such as liver or lung, and how well a patient did on their first-line therapy.
As a result, there are divergent outcomes from the historical, often 10-year-old phase III trials that led to the approval of bevacizumab, depending on the mix of patients that are included in the study. The two main trials that were used to support the approval of bevacizumab in second-line patients are listed here, ML18147 and E3200 in Bev experienced and Bev naive patients, respectively. Overall response rates for the combination of bevacizumab and chemotherapy can range from 5.7% to just over 20% or almost 23%. PFS ranges from 5.7- 7.3 months, and OS ranges around a year. So within the Bev naive population includes left-sided KRAS wild-type patients who may receive an EGFR therapy in the first line.
And so in a retrospective analysis of how those patients did on bevacizumab as second-line therapy, we have the Sclafani analysis where there was a 25% response rate, so roughly equivalent to what you saw in the Bev naive population overall. And as we evaluate our data in colorectal cancer, we'll be focused on understanding and presenting the activity in these different subgroups in order to identify the strongest activity of the sirexatamab-based combinations in the optimal population for phase III development. So with this foundation, we launched a company-sponsored clinical trial, the DeFiance study, to evaluate the addition of sirexatamab in patients who progressed on front-line therapy in combination with bevacizumab and either FOLFIRI or FOLFOX chemotherapy, which is the standard of care for second-line metastatic disease. Part A of the study was designed as a single-arm run-in.
In addition to safety review, we wanted to ensure that there was strong enough efficacy signal to support a randomized controlled clinical trial. Part A of the DeFiance study included significant numbers of patients who had previous exposure to bevacizumab, tumors with KRAS mutations, liver metastasis, and early progression on first-line therapy. And our view is this heterogeneous population reflects the real-world second-line therapy that physicians see in the clinic and includes subgroups where there are poor expected outcomes. As I was preparing for this presentation, I got a few questions from investors about whether there was any update on the Part A data, that run-in that we presented earlier last year. And so we did have a data cut that was available from October, and I thought there were some interesting developments as part of this initial follow-up, additional follow-up.
The best overall response for the evaluable population remained as it had been disclosed over the summer, with nine patients achieving a partial response, yielding an overall response rate in the response-evaluable population of 33%, with a disease control rate of 93%. This exceeded the 20% response rate target and was overall deemed by the investigators as very encouraging in the context of their practices with second-line patients. With additional follow-up, we have a more mature duration of response for the nine responding patients at 9.92 months, with three of the responding patients who appear to be still on therapy. Next, I'll break down the two categories that we are using to stratify patients in the randomized Part B portion of the trial: tumor-sidedness and prior bevacizumab exposure.
Overall, we've seen a greater activity in the patients with left-sided tumors in this combination than in the right-sided patients. The overall response rate of 38% on the left and disease control rate of 100%, which we believe reflects a population enriched with higher DKK1 levels and activated Wnt signaling. In the right-sided group, the response rate is lower, and with only six patients that were right-sided, we're trying not to draw too many conclusions from that until we see the randomized study. The median progression-free survival on the patients with left-sided tumors remained at 8.6 months, which we believe is very favorable compared to the benchmark studies. The element of the updated Part A analysis that was most striking to me was the activity in patients without prior bevacizumab exposure. We noted a very high overall response rate in those patients who were naive to bevacizumab.
This population included patients who were rapid progressors on first-line therapy, one patient who was EGFR experienced. And in particular, many of these patients had received adjuvant therapy for resected disease, a setting in which bevacizumab is not used, and they progressed either very quickly or while on treatment, indicating an aggressive cancer. So in this population, the response rate was 53%, now with a disease control rate of 93%. In terms of differences from our earlier presentation, during the data cleaning and follow-up, we did note one patient who was initially included in the bevacizumab experienced population was now correctly characterized here and had a partial response as bevacizumab naive.
With the additional follow-up, the median progression-free survival for the bevacizumab naive group now exceeds eight months, which we believe is very favorable considering the mix of patients included in today's second-line patients population and this study enrollment. And so this all leads us to our randomized control trial. We completed enrollment of 188 patients at the end of September. Patients are stratified, as I said, on the basis of tumor-sidedness and prior bevacizumab exposure. And while the primary endpoint is progression-free survival, our first look at the data will focus on overall response rate while the progression-free survival continues to mature. And as we've described several times previously, we're also conducting a randomized control trial of Sirexatamab in combination with tislelizumab and chemotherapy in first-line HER2-negative gastric cancer patients. We enrolled 170 patients in the United States, South Korea, and Germany, equally balanced between the two arms.
Patients were stratified on the basis of DKK1 tumor expression and PD-L1 expression, and the primary endpoint of this study is median progression-free survival, which we'll be evaluating in the overall population as well as the DKK1 high subpopulation. The goal is to be able to identify the treatment effect and optimal populations for a future phase III study in gastric cancer, but also for future development of sirexatamab with a PD-1 antibody in other tumor indications where DKK1 is expressed. From a benchmark perspective, there have been three large randomized studies for PD-1 antibodies plus chemotherapy in this same HER2-negative first-line population. In our view, these studies are quite consistent in their outcomes.
This slide represents the data for tislelizumab in their phase III trial, RATIONALE-305, which was the basis for the approval of the drug in patients with PD-L1 expression greater than or equal to one. The median PFS in this trial of 1,000 patients was 6.9 months, with 95% confidence intervals of 5.7- 7.2 months. The hazard ratio in the full population was 0.78. ORR was 47.3%. And interestingly, the data in patients from North America and Europe was poorer than the population as a whole, with only 5.6 months of progression-free survival and a 36% overall response rate. We also note that tislelizumab was not approved in the United States for patients with PD-L1 less than one, likely due to the 0.98 hazard ratio on overall survival. ORR was also lower in these patients than in those with higher PD-L1 expression.
As a result, there remains a very high unmet medical need in patients with low or negative PD-L1 expression. As those patients did very well on our single-arm Part A of the DisTinGuish study, we're very interested in seeing how these groups perform in our randomized trial. Now let me turn to the FL-501 program targeting GDF15. GDF15 has recently been established as a clinically actionable target in cancer cachexia. This represents a large and unmet medical need. We know that patients in the clinic that have cachexia. It's a key element of the morbidity and mortality associated with their cancer diagnosis and their cancer effect. We know that there are many other indications where GDF15 and that cachexia that's associated with it leads to significant decreases of quality of life, of morbidity and mortality.
And being able to look at the opportunity for this to be a very interesting targetable program that's very consistent with our experience in the development of sirexatamab is something you'll hear us talk more about over the course of the coming year. FL-501, the antibody that we have that's targeting GDF15, was developed to be a best-in-class inhibitor of GDF15 with extended half-life and high affinity. In preclinical models, FL-501 demonstrated key indicators of anti-cachexia activity, including reversal of body weight loss and rescue of cardiac muscle, skeletal muscle, and fat mass. And we're very much looking forward to our first public presentations of the preclinical data for FL-501 over the next few months. So let me go find our conclusion slide. There we go. Corporate milestones on. Yeah, perfect. So let me conclude before we take a few questions.
By laying out the corporate milestones for 2025, which is on track to be a transformational year for us at Leap, as I mentioned, in order to make strategic decisions for the sirexatamab program about the populations that should move forward into phase III, we intend to provide initial data from both trials in the first quarter of this year. We're very excited to be able to see that analysis of the data from both studies so that we can make a real important allocation and strategic decisions for ourselves and in collaboration with our investors and investigators and pharma. I'm looking at both data sets and then on the FL-501 side, we're looking forward to that first presentation and to continue to advance the program forward towards clinical trials.
So before we take a few questions, I just want to thank all of our investigators, the clinical staff, and the patients who participated in our clinical trials. Everything that we do at Leap is designed and focused around patients. And I want to thank all of my fellow Leap sters for their tremendous work in 2024 and in executing these two clinical trials and to all of our shareholders and supporters for their support. And with that, I'm happy to take a few questions.
Thanks, Doug. That was a great presentation. So my first question is for Cyndi. Just keeping it broad here right now. So just in terms of your conversations with KOLs, what do physicians tell you are the main unmet needs for colorectal cancer patients?
Yeah, so that's a great question. I mean, when speaking with investigators, it is clear that there is a need for new therapies in colorectal cancer. As Doug mentioned, there haven't been many approvals in any real broad-based therapies in more than a decade. There have been some approvals in first and second line for some targeted populations, although those targeted populations, such as BRAF or KRAS mutated patients, represent a relatively small proportion of the patients with colorectal cancer. So we're hoping that we can devise something that meets a good population of this colorectal cancer group in first and second line, as there are very few therapies available to those patients. And unfortunately, the majority of those subjects do succumb to their disease.
Thank you. And Jay, this is for you. Can you discuss the different ways of measuring DKK1 in patients and what you believe the clinical impact of that might be?
Sure. So we know based on our past experience that when DKK1 is highly expressed locally at the site of the tumor, that the cancer uses that to promote proliferation, metastasis, and angiogenesis. The team has done a great job in creating an assay that's able to measure that local DKK1 at the site of the messenger RNA with high sensitivity and specificity. We've also seen in our past trials that when that DKK1 is high at tumoral expression, those patients typically respond to DKN-01-based therapies. But I think it's important to note, as Doug showed, that tumor DKK1 is not the only source of DKK1 expression. It can be produced from other sources and put into circulation.
And now we're fortunate to be able to measure that also with high sensitivity and specificity assays. Those have been implemented into our current clinical trials, so we're excited to see the results from those. We do believe that it really doesn't matter where the DKK1 is made or comes from. As long as we can measure it and it's very high in the patient's system, we expect those patients are going to be the most likely to respond to DKN-01.
Great. Cyndi, so for Part A of the CRC data, what gives you confidence about the potential for success in Part B?
Right, so as Doug has described, with the continued follow-up and the more mature data that's evolving, even with Part A, we've been fortunate to identify several subgroups in general who appear to be doing better when given DKN-01. In particular, we're very excited about looking at the Bev naive population. That bevacizumab naive population would be a population that you could potentially even consider moving into earlier lines of therapy with this agent because those subjects typically receive a bevacizumab-based regimen in the front line. We're also, as Doug has mentioned, we're also interested in looking at additional populations such as the EGFR group as well, whereas we didn't have many of those patients in Part A. It's something we'll continue to follow in Part B.
We also, as Doug mentioned, look at across a variety of patients with different locations of tumors, such as liver or lung mets. And I think importantly, the response rate of 33% in Part A does improve upon what you would expect, as Doug mentioned on the benchmark slide. But I think what was really noticeable to me is the duration of response, really being around nine months, that almost parallels the expected overall survival of that population in second line.
By the way, you guys are committed to sticking with DKN-01 despite the.
No, I did.
Sorry, I was about to follow up. Like, you guys weren't even close to getting.
Didn't even try.
You have to put $1 in the jar.
Exactly. Yeah. And I guess following up on that, why develop into 2L CRC and not move into 1L?
Into first line? Yeah, so I think we have to still see the maturity of the second line study, and then we will have to consider and make determination about what the best population to advance into would be. As we've discussed, the second line has a true unmet medical need. It's a faster development path because, unfortunately, the patients live shorter than developing in front line, but I do think that there is potential opportunity if we are successful in a bevacizumab-naive population to advance to a front line setting.
Got it. Jay, for you, can you discuss DKK1 as a target and its mechanism and why it's a good potential partner for chemo or IO or any VEGF combination?
Yeah. So I think, as Doug nicely showed, we know that DKK1 is associated with an immunosuppressive tumor microenvironment with those more immunosuppressive immune cells like M2 macrophages or MDSCs and sort of a reduction in cells like NK or T cells. Sirexatamab, we believe, can reverse that and create a more favorable tumor microenvironment. And I think that really sets up a nice partner for many IO therapies where we often focus on their PDL1 expression, but the checkpoint only really matters if you have a favorable tumor microenvironment as well. So I think that synergy between the two will be really nice. I also think we have evidence, at least preclinically and some in the clinic, showing that sirexatamab is able to upregulate the expression of PDL1.
And that may add an additional boost to many of the anti-PD-1s that just aren't effective in a low PD-L1 setting. In terms of other potential partners like angiogenesis factors, you mentioned VEGF like bevacizumab. We have quite a lot of preclinical data now that shows additive effect when you combine sirexatamab with an anti-VEGF like bevacizumab, where you see greater tumor reductions with both in combination as compared to either one as a monotherapy. We also know that DKK1 promotes larger and more blood vessels. And we have evidence as well that sirexatamab is able to reverse that, creating fewer and smaller blood vessels.
So I think that's a really important mechanism that we'll continue to look at. And then finally, you mentioned chemotherapies. So DKK1 is a known resistance mechanism to chemotherapies like oxaliplatin and 5FU. And we also have a lot of preclinical evidence suggesting that sirexatamab can overcome that resistance and reverse it. So I think it really sets up nicely for the molecule to combine with a wide range of different combination partners and standard of care in the clinic.
Thank you. I guess shifting gears a little bit, can you tell us more about what you expect to show in the GDF15 preclinical update and how it might differentiate from the other drugs in development?
Absolutely. I'll try to keep it short because I could probably do the last hour or next hour or so on GDF15. It's a molecule I'm really excited about. I think we all are. Obviously, Doug talked a little bit about the recent clinical data from Pfizer in their cancer cachexia study with ponsegromab. I think that data was very encouraging for proof of concept of the target. But I think it was also somewhat modest and leaves room for improvement. And that's where FL-501 comes in. This was designed to be a potential best-in-class molecule in terms of some of the aspects that Doug touched on from high affinity to optimized PK properties. And so I think that's really what we're looking forward to showing, especially the enhanced PK properties.
We hope that that will translate into the patient experience, a better patient quality of life, and optimizing their dosing, and so when we look forward to presenting that preclinical data in a few months, I think it will largely be based on why we believe this is a potential best-in-class molecule in terms of some of those affinity and PK properties I mentioned, as well as looking across a range of different cancer cachexia molecules, how we reverse some of the key aspects of cancer cachexia from body weight loss to bone loss, muscle loss, potentially even functional outputs, so the team is really hard at work at putting that data package together, and we're excited to show it to everyone.
Thank you so much. This was a great presentation, and thank you for answering all my questions.
Can I ask a question? Is that okay?
Sure.
Sorry. Can you see FL-501 in settings? Sorry.
I can hear you.
Do you see FL-501 in settings beyond cancer?
Yes. Okay. Absolutely. I think we know right now Pfizer is in a heart disease study. I think that'll be interesting to continue to monitor. We've had discussions with key opinion leaders about an unmet need in chronic kidney disease and respiratory diseases such as COPD. Obviously, there are some companies that are interested in the link between GDF15 and morning sickness. So I do think that there are a number of opportunities, especially where cachexia plays a role, not just in cancer. And that could be a wide range of indications.
Thank you so much. It was a great presentation. Have a good one.
Okay.