Thanks so much to everybody joining us here at the second day of Piper Sandler's annual healthcare conference. I'm Joe Catanzaro. I'm one of the biotech analysts here at Piper. It's my pleasure to kick off this next session with Leap Therapeutics joining us as their CEO, Doug Onsi. Doug, as we were just saying, a lot of highly anticipated events in the near future for you guys. Maybe before we dive into some specific questions, I could give you the opportunity a minute or two to kind of just introduce Leap and what you guys have been up to and, of course, what we have to look forward to.
Yeah, no, thanks, Joe, and thank you, everyone at Piper today for hosting the conference and giving us the opportunity to give everyone an update on what's been a tremendous year of progress and execution for the team at Leap Therapeutics. Leap is an oncology-focused drug development company. We've been advancing our lead program, DKN-01, which is a monoclonal antibody that targets the protein DKK1. We're in two large randomized controlled phase two clinical trials. The first is in first-line gastric cancer, and the second is in second-line colorectal cancer. We'll speak a lot more over the course of the chat about the programs, but it's been really exciting to see the team and the studies enroll over the course of the year.
Now, in that very exciting moment of waiting for the patient data to mature and the opportunity to analyze it and share it with all the investors in the coming weeks and months.
Perfect. Maybe a good starting point is just a sort of brief introduction of DKN-01 and its target, DKK1. What's the mechanism? Why it's potentially a great partner for chemo IO, chemo Bev strategies?
No, absolutely. So DKK1 is a secreted protein, and we first got interested in it because it was associated with poor prognosis in several different cancers, including esophagogastric cancer, colorectal cancer, non-small cell lung cancer. And as we learn more about the mechanism of action, we know that DKK1 suppresses the ability DKK1 enhances the immune system's ability sorry, DKK1 suppresses the ability of the immune system to target and clear the tumor. And by giving the antibody DKN-01, we'd like to reverse that in the context of cancer. We know that DKK1 does that by enhancing the activity of myeloid-derived suppressor cells, suppressing NK cell activity. So that immune mechanism makes it a very interesting combination partner for the PD-1 antibodies, the immune checkpoint class that's targeting T cells.
That another mechanism of DKK1 to promote tumor proliferation and growth is through angiogenesis, enhancing the size and number of blood vessels. And so, as we think about a study in colorectal cancer, combining DKN-01, looking to create an angiogenic activity that could complement the anti-angiogenic activity of Avastin, makes it another very interesting combination in an area where the biology of Wnt signaling and of DKK1 is incredibly important. We think about DKK1 also, though, and its impact on signaling through the PI3 kinase and AKT pathway and influencing cell proliferation and metastasis. And we're looking to reverse that as well with DKN-01. So, as we think about that combination potential and the way that the mechanisms could be altered for DKN-01's activity, making it, in our minds, a very exciting, well-tolerated combination partner in gastric cancer and in colorectal cancer.
I want to start with gastric cancer in the DisTinGuish study, and Part C is what we'll get, but we have Part A to look at thus far. When you look back at Part A data from DisTinGuish, what are the data points that give you the most confidence heading into the Part C randomized readout?
Yeah, so when I think about the opportunity in gastric cancer broadly and the development plan that we've executed, it really is the consistency of the data that we've seen across our gastric cancer development. So, we started with monotherapy and saw monotherapy activity with responses in patients who have been heavily pretreated, including treated with a PD-L1 and an IDO inhibitor. We then went to a combination with chemotherapy and paclitaxel and saw a strong response rate, particularly in second-line patients who were treated with chemotherapy and DKN-01. We migrated next to PD-1, Keytruda combining with DKN-01, and saw, particularly in those patients that had high DKK1 expression, very strong response rates, and then we've moved to the current setting of DKN-01, chemotherapy, and immune checkpoint inhibitors.
Being able to see across the endpoints in each of these studies, an improvement in overall response rate translating into an improvement in progression-free survival and ultimately an improvement in overall survival. I think that is a critical and important buildup of this program and understanding the activity of the drug, the patients in which it can benefit the most, and in being able to see that activity across both DKK1 biomarkers, PD-L1 biomarkers in our earlier trials, I think positions us very well to have an exciting set of outcomes ahead.
So, when I think about part A and trying to benchmark it, I think one of the things that's challenging, perhaps for other single-arm data sets when you're benchmarking against standard of care, is sometimes those data sets are quite historical. That's not the case for chemo, PD-1, and front-line gastric cancers. So, as we do that benchmarking exercise, are there any sort of caveats we need to keep in mind about those benchmark data sets relative to part A?
Absolutely. And so, for anyone who'd like to get to know this story better, I really encourage you to dig into the data set that the FDA presented at their ODAC panel at the end of September. So, they took the three large benchmark phase three studies for Keytruda, Opdivo, and Atezolizumab and gave you all of the subgroup data that you want to understand as you try to understand where DKN-01 has shown its best advantage from part A. So, if you think about our part A population, it was a U.S.-based population. And if you look at the publication and from RATIONALE 305 of the patients from North America and Europe that was presented at ASCO GI, you saw that those patients did much worse than the overall study. They had only a 36% response rate and a 5.6-month progression-free survival.
So, understanding that our part A was only in the U.S. and looking for the appropriate comparator data from RATIONALE-305. I think the second is the PD-L1 expression is a very important issue to the FDA today. And they have been articulating a strong perspective about where the PD-1 antibodies plus chemo have the greatest benefit. They're in the patients with the highest PD-L1 expression. So, in that FDA briefing book, they showed you what the data looked like based on PD-L1 expression. And those patients who had PD-L1 expression of 10 or less seemed to have no real clear benefit to adding the PD-1 antibody over chemotherapy. And that if you looked at our data set, there were only two patients with a PD-L1 expression higher than 10.
Of a Part A data where we showed 11.3 months of progression-free survival, 19.5 months on overall survival, a very strong response rate, that was a population that was very heavily PD-L1 low, less than 5%, and I think that's a space where a significant unmet medical need sits and where the potential of adding on DKN-01 is very exciting.
So, moving to part C, the randomized readout, publicly guided towards as a year-end 2024, early 2025 event. Any updates around timelines and expected potential disclosures and sort of where you stand within that timeframe?
We're continuing to be comfortable with the guidance that we've given. Late this year, early part of next year is consistently what we've said since April. It's an event-driven outcome, so it is still not something that is known to us today. We continue the teams executing extremely well. We continue to follow the patients and make sure that we can do the turnaround as rapidly as we can. I think it's very important that we have a chance to have a good mature readout and that the patient events will take their own time.
So, maybe irrespective of the actual timeline, as we think to a top-line readout, what are your expectations and what you might be able to disclose versus maybe withholding anything for a sort of future medical meeting presentation?
So, certainly the progression-free survival and overall response rates are the data that should be the most mature at that time. Overall survival is likely to still be immature. The understanding how the full population looks, but the key subgroups based on DKK1 expression and PD-L1 expression, I think it's critical to understanding what that top-line data set means. As you looked at the FDA analysis, it is clear that not all subgroups behave the same way and that the FDA and patients want you to provide as much context as you can for if your top line has a certain benefit, where did that come from? Did it come from each subgroup equally, or were there groups that significantly contributed to what that overall outcome was?
Yeah, so I want to go to that FDA conversation on PD-L1 expression levels a little bit and ask you whether that whole question that's being asked there complicates in any way the readout here, or is it simply a matter you will have all the data? It's just a matter of cutting it and analyzing it in those appropriate ways.
Yeah, absolutely. I think it points out that there's a very high unmet medical need still in first-line gastric cancer. That the FDA, we expect over the next few weeks, is likely to restrict the use, the approval for PD-1 antibodies plus chemotherapy to PD-L1 greater than 1 based on the advisory council vote. So, there is a group of patients that will not be indicated for PD-1 that could be a very interesting opportunity if our data suggests improvement in that patient population. The 1- 10 PD-L1 range was one where it was questionable, and so you'd like to see and understand how the patient populations performed there.
A disease in which overall survival is still just over a year tells you we need new medicines for these patients, and the best way to use the backbone of PD-1 + chemo is to find new mechanisms of action, ideally new biomarkers in addition to PD-L1 that can help you get the right drug to the right patient at the right time, and we will have all that data. We stratified on the basis of PD-L1 expression in addition to DKK1 expression, and we're excited to see where it leads us.
So, you've just mentioned DKK1, PD-L1 as sort of different subgroups you may look at. Any other notable subgroups that you're interested in? I know you mentioned, right, geographies may be one. Anything else of note that you're particularly worth taking a look at?
No, I think those are the key ones for us as we understand this data set and think about how it could fit into patient care.
Then maybe last one on this DisTinGuish Part C is what do you think the physician community deems as sort of clinically meaningful PFS benefit in this setting? I guess when you go and look at sort of the benchmark studies, what did they show, and is that something that is a good reference point for DisTinGuish Part C?
I do think that's really important that the three large benchmark studies each had progression-free survival advantages of less than one month, and they were practice-changing. People immediately moved to adding PD-1 on top of chemotherapy on a progression-free survival of less than a month and overall survival of around two months of improvement. You'd like to show more than a month of benefit in our study over the control arm. I think that anything over a month is clearly meaningful to patients. You'd like to be at a month and a half to two months. But most importantly, you're going to want to understand if that's what the overall population or a larger population looked like, did you get there by certain subgroups kind of overperforming that, where other groups sort of held water?
What does that mean in terms of if you were choosing a drug for a patient, what would you want to know, and when would you want to add DKN-01 to make a difference for that patient?
Actually, I had a couple more questions here. So, as we think about part A, part C, and potential differences in the baseline and features, again, I know part A was just U.S., part C expanded globally. Anything else you think we should keep in mind?
I think that's the major one was that part A was all in the U.S. , and I think it's important as you compare it to benchmarks to take that into consideration. There'll be 100 of the 170 patients from Korea. So, I think it gives us a good representative sample to make phase 3 planning decisions around. I think part A was very low PD-L1 expression. Only a few patients, two patients were higher than a 10. So, it'll be interesting to see how that plays out when you have more patients with higher PD-L1 expression. The U.S. population tends to be more gastroesophageal junction than gastric as you add more patients with lower gastric disease to see if there are differences there too.
So, I think it's such an important trial for us to understand how DKN-01 and immune checkpoint inhibitors can work together, and that as you think about how you use DKN-01 going forward and the other opportunities that we could build off of if there is success in the gastric cancer DisTinGuish study into endometrial cancer, into triple-negative breast or lung cancer, other areas where there's been a role for DKK1 or data around the area, and that PD-1 chemo is currently standard of care.
So, you mentioned phase three planning. So, maybe as we think towards the future, potential phase three program here, is that something you think you guys can tackle on your own, or is ultimately a partner necessary to take on the scope of that potential trial?
Yeah, so I think if people look at the deal that Olema announced just on Monday in terms of the ability to find ways to collaborate to get to a phase three, I think that becomes more of an option than I would have presumed when you wrote the question sort of two weeks ago. Our assumption has always been that a PD-1 partner is critical for us in the gastric cancer program because it's a critical strategic opportunity for us as a company. While the FDA may have treated each of the PD-1 antibodies as being effectively interchangeable, they did a meta-analysis of putting them all together. You'll likely only get the approval for the PD-1 antibody you use in phase three.
And so, the pitch to us, to a pharma company, that you participate as the PD-1 antibody in our trial, contribute to it financially, support it from a regulatory perspective, gives you the additional revenue opportunity for having longer progression-free survival. It can give you a competitive advantage by having a combination that's better than the PD-1 + chemos that exist today. It can allow you to reach into patient populations that either may not be indicated anymore, like PD-L1 negatives or might be underpenetrated, like the 1 to 10s. It gives you a gateway to other PD-1, DKK1 combinations. And if the ultimate IP and commercial strategy is co-formulation, the time to make a co-formulation decision is before phase three, you need to have somebody who's truly on board to do that. So, I think the strategic rationale to a pharma partner is really high to come in sooner.
Yeah, great. So, maybe with that, we can move to CRC and the DeFianCe trial and maybe start there with just sort of refreshing our memory on what you've been able to show in part A of that trial when you combine DKN-01 with chemo plus BEV in a second-line CRC population.
Absolutely. So, we're incredibly excited by the CRC opportunity. It has been the field that doctors have asked us about. Every time that we would begin to speak about gastric cancer, they come back to, well, why not CRC? You've got mutations in APC, CTNMB1 that are in the Wnt signaling pathway. They're activating mutations of Wnt signaling that in our own preclinical data and in even the consensus molecular subtypes, Wnt activation, very prominent feature in colorectal cancer. And so, as we looked at our own part A data, DKK1 being a potential resistance mechanism to chemotherapy led us to a second-line setting for this trial.
The 33% response rate that we saw in the overall population exceeded what we had set as a hurdle based on our understanding from investigators as to the standard of care of Avastin + chemo in the second line, particularly as we looked at left-sided patients and rectal patients, areas where we think there is more DKK1 involvement, a higher percentage of patients that have the Wnt activated CMS subtype 2 and saw higher response rates, longer progression-free survival in those patient populations, made us very excited to get into the randomized portion of this trial and explore those other mechanisms of DKN-01's activity and set us up to the part B randomized trial that just completed enrollment in September.
You may have answered this question, but this goes back to my question kind of earlier about benchmarking versus historical data sets and chemo PD-1 and gastric cancer being very contemporary. I mean, I've gone through this exercise in CRC with chemo BEV, and that's very much not the case. They go back maybe 10, even 15 years. When you talk to physicians, and again, I think you answered, what are their current expectations for what chemo BEV does in a second-line CRC population as it relates to response rate and maybe even PFS?
Yeah, so I think you're exactly right, which is that this is a heterogeneous population without current recent randomized trials that hit the exact population that's today's real-world second-line patient population. So, the expectation we got was that you would expect a 10%-15% response rate in less than six months of progression-free survival was broadly what they would see. You have to take into account, as you'd said, whether the patients had prior BEV experience, KRAS mutations, liver metastases, sidedness of the tumor all play into none of the clinical trials that you look at in the benchmarks feeling like a great representation of the more heterogeneous population.
As we were setting the target and going into part B, talking to pharmaceutical companies, talking to the investigators, the things that stood out to them were the strong response rate, the depth of responses, very few patients having immediate progressive disease. You weren't seeing a significant number of patients bouncing, or even you were having stable disease, but with large growth. You were seeing the vast majority of your patients having tumor reductions in a well-tolerated profile where the areas of biology where you were expecting to see greater activity were playing out, that there was such a significant unmet medical need for new mechanisms to come into colorectal cancer targeting more than just niche mutation populations.
So, for part B, you mentioned enrollment just completed at the end of September. Talk us through sort of timelines from here, a top-line readout, and maybe how you'd go about sort of teasing out these sort of different subpopulations that maybe line up with Wnt signaling biology.
No, absolutely. This is a tremendous effort out of our biomarkers group to be thinking about how the mechanism of action plays into CRC. We expect that that data will mature in the middle part of next year. That's been our kind of consistent guidance from when we finished enrollment. We're very interested in DKK1 protein levels in colorectal cancer. We know DKK1 can come from the bone in addition to from the tumor. And so, we're very interested in following that. The CMS subtype 2, as we had said, is the Wnt activated subtype. That would be very supportive biology as we look at left-sided and rectal patients. CMS subtype 4 will be interesting as well. That's the angiogenic subpopulation.
Being able to present both the overall data outcome, but the subgroups that explain why you saw the activity you saw, which were the ones most enriched for the activity that led to a hopefully successful trial, being able to communicate that all at the same time as you make the announcement is really important. We are making sure that all of that data is together so that as the clinical outcomes become available, you can tell a full story.
So, we'll get Distinguish first, presumably, and then Defiance part B. Any read-through you see to what we see in Distinguish and what it might mean for what we could see in Defiance?
So, probably not. We really do think about them as non-correlated study outcomes as you think about DisTinGuish really playing to the immune mechanisms, the PD-L1 upregulation driving synergy, the innate immune system targeting with the adaptive immune system. It's very different than you may be thinking about adding an immune component or additional anti-angiogenic component to Avastin and chemo and colorectal or helping to the extent, I guess, that you get the chemo making the chemo more successful by removing DKK1 that's different in a second line than in the first-line population. So, we do think they give us two really important insights into the drug and a reason why they both make a lot of sense to us.
As we think about potential opportunities for collaborations and partnerships, how do you think those discussions sort of weigh in the opportunity in gastric versus an opportunity in colorectal and how you sort of balance those two opportunities?
Yeah, so I mean, colorectal is of interest to every single pharmaceutical company. They know it is a very substantial U.S. and European market and stands on its own. Gastric cancer is important to some companies and not to others, but I think people look at the gastric opportunity as a PD-1 combination opportunity and the opportunity to take it beyond gastric to other PD-1 combinations. So, I think it gives us a broad landscape of companies that can be strategically interested in what we're doing and will be all about what do we see in the underlying data to help us understand how you can get this drug to phase three into the market.
In these last two minutes, maybe we could cover FL-501 and maybe first start with sort of the growing burgeoning interest in GDF and give it a little bit of an intro there and maybe where your program stands.
Yeah, absolutely, and this was a molecule we got from the acquisition of Flame Biosciences. It is a molecule made by Adimab. So, you've got a used Ponsegromab and others as the target to try to have a differentiated best-in-class molecule. The Pfizer data for Ponsegromab at ESMO combined with a couple of financings generated a lot of interest in cachexia as an indication first in cancer, but also in heart failure, COPD, other tumor types, or other disease indications where cachexia is a real driver of health outcomes and quality of life. This molecule was engineered to have a greater affinity for GDF15 than the existing benchmark molecules, engineered to have a longer half-life so that you could then hopefully drive more patient convenience, the ability to self-administer at home with a patient-friendly, longer-acting molecule. It's been moved into formal preclinical development, so cell line development and process development.
Hopefully, over the course of the year, we'll be in a position to more rapidly move it towards the clinic. I think it's got a lot of excitement for the program internally. We're even looking at GDF15 levels in our colorectal cancer and gastric cancer studies as part of the panel to see, is there something there where we see impacts of that on weight or other outcomes. You're trying to learn everything you can from these studies to put ourselves in the best position possible going forward.
Great. Well, Doug, with that, we're out of time. Thanks so much for your time. Obviously, looking forward to what can be a potentially transformative next six to nine months for the company. So, thanks for that and thanks to everybody for tuning in. Take care.