All right, welcome back to the 45th Annual TD Cowen Healthcare Conference. I'm Marc Frahm from the TD Cowen Biotech team. Next session, we're really happy to have the team from Cardiff Oncology. The plan is to have about 20 minutes of presentation, kind of higher level program updates, and then we'll have about 10 minutes of Q&A. With that, I'll turn it over to the CEO, Mark Erlander, to do the presentation.
Thank you, Marc. I really appreciate it and really great to have an opportunity to speak at your conference here. Let me get started. Today I want to talk to you about onvansertib and the opportunity that there is in onvansertib here at Cardiff Oncology. Onvansertib is a small molecule. It's oral. As you can see here, onvansertib inhibits a serine-threonine kinase called PLK1. PLK1 is overexpressed in a lot of different tumor types. It's actually a way that tumors actually hijack PLK1 because PLK1 is involved in the cell cycle. It allows tumors to have a higher proliferative rate and that sort of thing, and also metastasis. That's really the origins and why it is considered a great target for cancer therapy. On the right-hand side, you can see that at PLK1, we have a high specificity to just PLK1.
There are other evolutionarily related PLKs, but we have, as you can see there with the IC50s on the right side, about 5,000-fold greater specificity. So very specific for just PLK1. You know, when I first started the first two slides, I'm really just going to tell you the journey and how this is the genesis of this program. And then I'm going to jump to the most recent data that we released on December 10th of last year. Really, this whole program started with an unexpected but exciting finding in a second-line trial we were doing in KRAS mutated metastatic colorectal cancer in second line. And what we found there was that there was a patient population that did extremely well. And I'll talk a little bit more about that later. It was called the bev-naive patients.
They were patients who had not received bevacizumab or bev in first line when they came into our second-line trial. Now, because of that finding, we then had to really go into understanding the background of that from a preclinical point of view, the mechanism. That actually turned out to we found a new mechanism of action for onvansertib that not only led to the issuance of now a patent from the USPTO that's very important for us, but also that one and two here was actually published in Journal of Clinical Oncology, the ASCO flagship journal back in October of last year as well. Just as a sidebar, it's free. So enjoy. Now, once we had that finding, we went to the FDA.
With the FDA meeting in June, a Type C meeting in June of 2023, we really ended up pivoting our trial, our whole clinical development plan into first line. On top of that, also Pfizer was very interested in being through their Pfizer Ignite program to run that first line trial. That is the data that I'm going to talk to you about right now. We did put out initial data on December 10th of last year. That is the data that you're going to see today. What was the, we had a shift then. Our shift was really from a second-line clinical development path to a first line. Talk a little bit about that. Most of you already probably know this, but on the left-hand side, colorectal cancer is the fourth most diagnosed cancer in the United States.
On the right side, it is the number two killer in the United States. The reason I bring that up is because when you look at the patients that we are targeting, which are the RAS mutated patients within first line colorectal cancer, which is about half the population, there really has been nothing new since 2004 when Avastin or bevacizumab or what people just call bev was approved back in 2004. Over 20 years have gone by for these patients with no new therapies. I think some of you probably know about the fact that there have been some G12C inhibitors. There was one recently approved in second line, the Amgen KRAS G12C inhibitor. As I point out here in the pie chart, it really represents a very small sliver of the RAS mutated tumors in colorectal cancer.
The reason that's important is because onvansertib on the right side really goes after all of the RAS mutations. The reason for that is that PLK1 is downstream of the RAS pathway. We're able to really affect all the different mutations of RAS. With that, let me move into this trial. This is the trial that we reported our initial look on December 10th. Left side, you can see that the enrollment is first line. It's all RAS mutated, unresectable, and of course, no prior bev. In the middle of it, you see that we actually have six arms it was randomized to. Within that six, they can really group those into three groups. The three groups, of course, are standard of care, which is either FOLFIRI + bev or FOLFOX + bev. Both of those chemo regimens are approved for first line.
That's why we did that. Then you're looking at the 20 and the 30 mg on top of that. Importantly, on the bottom of this slide is two things. One, ORR is the primary endpoint. Two, all the data you're going to see is through blinded independent central review or what we call BICR. This is really important because we do have 41 sites across the United States where this trial is currently being run. On the right side, you can see that really what the dosing is. We overlay onvansertib on top as an oral drug on top of the existing standard of care, which is really the chemotherapy plus bev, which is every 14 days, two 14 days equal one cycle. Now, the objectives of this trial on the right side were pretty straightforward.
First of all, we wanted to look at efficacy because it is a randomized trial. Secondly, and really the point of this trial was through Project Optimist with the FDA, was to really confirm a dose, 20 mg or 30 mg. Finally, really, of course, looking at safety as well. Now, one of the things that we show here is just simply, I'm not going to go into it, but we're really showing that even though it's just 30 patients, they're relatively balanced between the three different major arms. That's important because that allows us then to compare between these three different groups. This is an initial look at the data. This is a standard waterfall plot where you see that once a tumor shrinks to 30% or greater, it turns to a teal color, which then is an objective response.
You can see here that in the control arm, we had a 33% versus experimental arms. That's combining both the 20 mg and the 30 mg together with 57%. What I'm going to do now in the next two slides is I'm going to parse this data two different ways. I'm going to first ask, is there a difference in the chemo backbones? The more important question is, is there a difference in dose? First, when we looked at the backbones of the chemotherapy, you can see on the left, these are obviously small numbers of patients. What we have taken from this and really what the takeaway from this slide is really that when you add onvansertib on top of either FOLFIRI + bev or FOLFOX + bev, you are seeing an increase in signal.
That is really what we take away from this at this point. We think that that is good news because that means that potentially in a registrational trial, we'll be able to have more of an investigator choice as far as the chemo backbone. The second way to look at this data is, of course, by dose. What you're seeing here is the control on the left and then 20 mg and 30 mg. One of the things that we noticed right away with this was that there does appear to be potentially a dose effect when you see this data. When you go from a 20 mg to a 30 mg, there are a greater number of responses and also they appear deeper. A way to really look at this, I think in a better way, is with the traditional spider plots.
The spider plot, as you can see on the X axis, you're looking at the cadence of the scans. Standard of care, we get for these patients, and the standard of care is a scan every eight weeks or every two months. You can see on the X axis, two, four, six, eight corresponding to months. You can look at the depth of the change in the tumor size or the targeted lesions by looking at each one of these lines. Each line here represents a patient. If the line has turned to teal, that means that that patient now has an objective response. What you can see right away with this is that there are deeper and greater numbers in the 30 mg versus the 20 mg and the control arm.
Another way to look at this is in the actual swimmer plots where you can see that each lane here is a patient. I don't expect you to be looking at this from where you are right now, but this is on our corporate, on our website. What you'll like about this, I think, is that we actually put in the % of decrease of the tumor at each scan. You can see those numbers there that you can maybe barely make out. Those are the actual number versus baseline. It allows you to really look at every single patient here. One thing I will point out is that two patients have already gone off trial for surgery with the curative intent. One at the 20 mg and one at the 30 mg. Excited for those patients.
We do expect more of that to happen, but already seeing two patients have left the trial because of that. The other question really is this is the numbers. I mean, our number 33% is a little lower than what the historical controls are. Historical controls for RAS mutated is 38%-44%. So in the 40s would be appropriate. We are at 33%, which is a little lower, but it's not too far off from it at this point. The other what we also the demographics and characteristics I won't go into, but we're not seeing anything here that's unusual. The safety slide, very busy slide, but the bottom line here is that we're not really seeing any increase in neutropenia with onvansertib being added, which is neutropenia would be an on-target toxicity of a PLK1 inhibitor.
We're not seeing that added amount of neutropenia with the chemotherapies. Where are we going with this? This on the left-hand side is 004. That is a trial that we're talking about today. As you know, as I mentioned, we did have a meeting with the FDA, a Type C meeting where we came out of that, excuse me, was really not only the Project Optimus for the 004, but then also we agreed with the FDA, agreed with us that we would have a seamless one trial, the 005, for the registrational where ORR and duration of response would be the primary endpoint for the accelerated approval. PFS and OS showing no detriment would be the primary endpoint for full approval all in one trial. I'm looking at our time. Is that 13 minutes? Is that like for the whole 30 minutes?
Yeah.
Okay.
Let me just hit a couple of things here. One thing that from this shift was we went into a deep dive into the science. It was very exciting what came out of it. As I mentioned, we had this unexpected finding. That came from this second line trial. Really the bottom line here was that we did not know at the time we were doing this second line trial that we had two different types of patients coming in. There were those that were bev-naive and bev exposed. In fact, that made a big difference when you looked at the bev-naive on the left side, response rates were much higher, 73% versus 16% with the bev exposed. Also, we saw the median PFS was at 15 months versus really around seven to eight. That really led us to preclinical research.
We did the obvious experiment. We said, okay, there's something going on between a tumor that has not seen bev and has not seen onvansertib. We did the obvious experiment, looked and showed that onvansertib plus bev did have an effect that was greater than either agent alone. We decided, okay, let's do a couple more models and see if we see the same thing. We saw the same thing. In those last two models, we said to the CRO that was doing it, look, why don't you do a gross dissection of their tumors and take a photo of it and send it to us. They did. What you can see here is that in the control, very vascular, your eyes go down to the bottom.
You can see that when you have the onvansertib and bev together, they're the most pale tumors. They're obviously smaller, but a lot more pale. That was what we call a hint and a clue of what was really going on. What was really going on? We all know that tumors on the left side here, that they get hypoxic because they outpace the vascularization of the tumor. The way they adapt is they turn on a whole new set of genes through a transcriptional factor called HIF-1 alpha. HIF-1 alpha is really a master switch, turns on over 200 genes that increases not only your angiogenesis of secretes VEGF, but also survival and proliferation. We know how bev works, and that is really well known. What we didn't know is that onvansertib inhibits the inducibility of HIF-1 alpha.
It's a one-two punch is what we discovered. And this, as I said earlier, was all published in JCO. It's really a great way to, if you want to know the background story of this whole program, this article really lays it all out for you. With that, what I'd say is that we do have other programs in PDAC, small cell, and triple negative breast cancer ongoing. These are all investigator-initiated trials. We hope to give updates on those at some point. They're a little slower because they are investigator-initiated and not sponsored. We also do have two different types of relationship with Pfizer. On the left-hand side, they did do an equity investment through the Breakthrough Growth Initiative. Like I said earlier, they are really in essence acting as our CRO.
We have a great relationship with them, of them running our current trial. With that, I will just end with the classic slide on the bottom. How much cash do we have? As of the end of the year, we had a little over $90 million or almost $92 million. We burn around $10 million a quarter. We have cash into Q1 of 2027. With that, I have, I think, finished actually really on time. Perfect. That was 20 minutes. That was blasting through. All right. Thank you.
Great. Thanks for that, Mark. I have some questions, but obviously anybody in the audience, feel free to raise your hand if you want to ask yours as well. We will try to get those answered. Maybe to start off with, Mark, in the presentation, you touched on this idea.
One of the pushbacks I've heard on your data is that control arm potentially having somewhat underperformed expectations. When you look at baseline factors and stuff, is there anything that kind of jumps out that maybe explains why it might be at the low end or maybe even slightly below the low end of that expected range?
Yeah, there's nothing that jumps out at us. I think what we're talking about here is just really a low number of patients. You do have variability because of that. I think that's what it's attributed to.
Okay. On the differences in FOLFIRI and FOLFOX, again, I know it's small numbers, but when you've done some of those preclinical experiences, is there any rationale for why this might, the combo with FOLFIRI might underperform FOLFOX, the FOLFOX combo a bit?
Yeah, preclinical in vivo models, we see a synergy with both the FOLFOX and the FOLFIRI, the Arena Tecan , and as well as the 5-FU. We do not have any basis preclinically to think that we would see a difference clinically. Obviously, we have to, it is early days on this trial, so we will see how things pan out.
Okay. You will be updating data later with half, right, from the trial. I think the other day on your earnings call, you mentioned that enrollment has obviously picked up. Yes. It has accelerated as you have got this trial going. You are up at the 90 now or about to, I guess, you have stopped screening, but.
We have actually...
Yeah, we need to update that.
We have stopped screening for patients in this trial. The goal of this trial was to have 90 available patients. We have stopped screening.
We project that we'll have full enrollment by the end of this month.
Yep. What's triggering to make to the next kind of disclosure of efficacy? Is it getting initial scans on all those 90 patients? Is it waiting for confirmatory scans for everyone? What type of follow-up do you think is necessary?
At a minimum, what we're looking at is that, as we mentioned in December 10th disclosure, we had 60 patients dosed with 30 of them with at least one post-baseline scan. That's why we had 30 patients in the disclosure as far as data. We've noticed so far in the trial that the responses, the PRs that occur, they occur either in the first scan or the second scan. There's one patient that had a third in the six-month scan, but most of them are two-month and four-month.
We think at a bare minimum, we would like to see at least those 60 patients with at least two scans. We like to maybe see a little bit more than that, but that is at least what we think is a bare minimum as far as having another release that would be substantive. Okay. I know it certainly will not be fully mature, but would you expect to start talking a bit about PFS with that or just keep it? I do not think so, but I mean, I never say never, right? I think that the median PFS for this patient population is 9-10 months with standard of care historical data. Our first patient dosed was in February of 2024. As you know, enrollment is slow in the beginning. We will have to see how things pan out.
As the PFS, whether it is with this next update or the subsequent one, but as PFS matures, you mentioned that benchmark. What type of separation do you think you want to be able to show to maintain confidence for the 05 trial?
We just had an ad board where we had seven KOLs really commenting about the whole registrational trial. The consensus among them was that they want to see a delta of three months or greater in the PFS. That is kind of what they are looking for.
Low to mid double digits. I mean, obviously, it depends a little bit on the control. Right. Okay. I guess, do you think this update in the first half, is that enough maturity to kind of pull the trigger on starting to start the process of opening 05?
Do you need some of that PFS data before you?
Yeah, I mean, it's a great question, Marc. I think as we sit here today, what we're thinking is that as we've promised, we will put out an update in the first half of this year, so really essentially Q2. We also then really the gate to the registrational trial is the meeting with the FDA. The question there comes down to is how much data do they want to see as far as confirmation of the dose? When we met with them, they said run a 90-patient trial. Now, we would like to go sooner than that if we can, obviously.
I think, though, that realistically, as far as an update on what we plan to have an update on in the first half with efficacy and safety of 004, the next update would be in the second half of this year. That is the time that we would have to be able to communicate our FDA feedback. We want to be able to put that out there to the community and say, look, this is what we learned from the FDA. This is the final trial design. This is the powering. This is all the assumptions. We want to lay all that out. We do not think that we will have that until the second half is when we think we will have that data.
Okay.
For that FDA meeting, you mentioned confirming with them which of the two doses are going to go forward. What are the other kind of key topics that you want to? Yeah, there's really two objectives. Objective one is what you just said, dose. Second objective is for them to, in essence, sign off on the protocol for the registrational trial. Those are really we want to get those two things done and accomplish at that meeting. Okay. I think it is the kind of seamless design that you've laid out with the 05 of response rate followed by PFS is, I mean, certainly things that we've heard from the FDA, but it is a little bit new of an approach. You want to discuss some of the regulatory precedents around there and some of the guidance documents.
Right.
I mean, on December 20th of last year, it was announced that the Breakwater Trial, which was the first-line BRAF mutated tumors and first-line CRC, that they got accelerated approval. They were running a seamless trial, which was really both ORR for the accelerated and then PFS and OS, showing no detriment for OS as the full approval. We think that that's a great template for us. I mean, obviously, we are in RAS mutated, which really are mutually exclusive of BRAF mutated patients in general. We think it's a great template for us. This is really, I mean, the FDA did suggest to us when we met with them in June of 2023 that of doing this seamless trial where you had both accelerated and full-in-one trial. It was great to see Pfizer's BRAF inhibitor getting that approval and using that mechanism for accelerated.
We just heard, I think it was in January, they press released that they were stat-sig on their PFS endpoint and that they'd be reporting more details at a medical meeting.
Okay. Maybe I guess that they're run by IC, so you don't have full control of them. Those other indications, does it make sense when we may see some updates there? I think a couple of those have reported some very early data historically.
Yeah, small cell lung cancer. I mean, at this point, I can't really give you any more guidance. I mean, we would like to, with the small cell lung cancer, the PI moved to another institute. That slowed that down for small cell lung cancer. Triple negative breast cancer, we may be able to report something out this year. We think we might be able to.
I can't tell you specifically until I have more details from the investigator. The third one is actually the first-line PDAC, pancreatic. We have started that trial with the investigator-initiated trial on that. We'll have to wait and see how that goes.
If the board continues kind of on the trajectory it is now, when's the right time to start thinking about more corporate trials and other indications? Is it just off of 04, or is it waiting for 05 to read out for accelerated approval? Just how do you approach kind of expanding the program?
Right now, we're open to going after another with a sponsored trial. We have not decided yet. We are exploring signal finding with these three investigator-initiated trials. We are looking at the RAS wild-type group in colorectal cancer. We have reported at AACR in 2024 activity there as well.
It's a very interesting story. We just have to wait and see. Our primary objective is this program that we have in RAS mutated CRC.
Yeah. Okay. Unfortunately, it's all the time we have, so we're going to have to cut it off there. Thanks a lot, Marc, for the presentation.
Thank you, Marc. Really appreciate it. Thank you for your time.