Welcome to our next Fireside Chat. Again, I'm Robert Burns, a Managing Director and Senior Biotech Analyst at H.C. Wainwright, and I'm joined today by the CEO of Cardiff Oncology, Mark Erlander. For those who don't know, we cover Cardiff with a buy rating and a $14 price target. Mark, thank you for joining us today.
Well, thank you, Robert, and thank you for inviting me to your conference. It's exciting. I love the venue, I love the opportunity to talk to you all about what we're doing at Cardiff Oncology.
Awesome. So, so for those who may be unfamiliar with Cardiff, could you provide a brief, high-level overview of the company and your main asset onvansertib?
Yeah, absolutely, and I'm gonna use some slides as props as I go through, just to facilitate that. I do have some forward-looking statements. So really, if you look at Cardiff Oncology at a high level, we've got a small molecule oral drug called onvansertib. It targets a very specific enzyme, if you go from left to right up behind me. It targets a very specific enzyme that is hijacked by tumors and enables tumors to have uncontrolled growth. That's what this story is all about. If you go to the second, you can see that we are coming off some really exciting data, very high response rates for second line, and I'm gonna talk a little bit more about that in the next couple minutes.
And also, the FDA, we went to the FDA, and they saw the data we had. We went in with a proposal of a second-line clinical development plan for accelerated approval and full approval. They countered by saying they really recommended that we think about pivoting and going to first-line. So that really was exciting meeting with the FDA, and then finally, Pfizer has made an equity investment in us, as well as their Pfizer Ignite group is actually acting as our CRO in running the first-line trial that is ongoing as we speak. That data, the initial release of that data, we are planning to release that in Q3, Q4 of this year, so and we believe that's a significant inflection point for the company. And finally, we have cash into Q3 of 2025.
At a very high level, that's really Cardiff Oncology, based in San Diego.
You know, one of the things that you mentioned just now is that you were initially looking at the second-line setting, and that was in the ENSEMBLE trial, but the decision was ultimately made to pivot into the first-line setting, and that was with a little bit of FDA input. So could you provide some background and context for our investors as to why the FDA recommended that, why you concurred with it, and how it compared, that data you saw in the ENSEMBLE trial, to standard of care?
Right. Yeah, it's yes, absolutely, and, you know, we're gonna talk about three trial, three trials today. The first trial is the one that is here on the left, right here, but we have three trials. The first one is the Phase Ib/II, which was the genesis of our program in RAS mutated colorectal cancer, metastatic colorectal cancer. But you also we will talk about a trial that was a randomized trial that we actually discontinued based on the recommendation from the FDA to pivot to first-line. But we do have, we did have randomized data from that, that was actually very exciting data. And then finally, the showing at the top is CRDF-004, and that's the current ongoing trial in first-line. So let's talk a little bit about this.
You know, the Phase Ib/II trial was a single-arm trial. It was 66 evaluable patients. All the patients had to have a KRAS mutation. They all had to be unresectable, and in this trial, this is really the first time that we saw this kind of data. This was the data here. It's this waterfall plot that you're looking at might look a little complicated, but on the left side of the waterfall, you see what we call BEV-naive, and on the right side, Bev exposed. What that meant, and we didn't know at the time when we did the trial, but in our second-line trial, we allowed patients to come in that had either received a Bev or bevacizumab or Avastin in first line, or they didn't have to. They could have not had it.
We didn't know at the time that that actually made a big difference, and I'll go a little bit into the scientific findings from this. But what you can see right away is your eyes go to the left, and you say, "Yes, much greater response rate in patients that were coming into our trial and receiving Bev and onvansertib in FOLFIRI, but they were, had not been exposed to Bev. If you look on the left-hand side of this slide, you can actually see the numbers, 73% response rate in the BEV-naive, and also, if you go down to the bottom, you can see that the st- you know, really historical data for second line patients was in about the 25% response rates.
So we were seeing in a single-arm trial, a, this huge response, rate. And, you know, the question we had at the time was, "Okay, did we do this trial? Was it just skewed somehow? The trial was biased? Is that why we're seeing this kind of data that's such huge response rates?" And we looked at all the different patient characteristics.
We looked, you know, in essence, we looked at the different characteristics that would have considered to be different prognosis and maybe could have explained it, and we did not find anything that, any patient characteristic, that would tell you that that was the reason. It really was- came down to the fact that these patients had not received Bev before, and that was why we were seeing this huge response. So that was really the first, the first trial, and then in the, and then in the second trial, where this was this randomized trial that we had started, and then after we talked to the FDA, we decided to discontinue it, but we continued to treat the patients and follow the patients that had already been enrolled....
and there we had 21 patients that were evaluable, and in this trial, now, this was a randomized trial. Now, this trial, actually, patients got either standard of care or they got standard of care plus our drug at 20 mg or at 30 mg. So it was a three-arm trial. And what was interesting about this data was the fact that if you're looking at the slide and the waterfall plot, your eyes go, immediately go to the left. That's where all the activity is, and where is that activity? There are four patients that were BEV-naive, but they also received onvansertib on top of the FOLFIRI BEV.
We had two confirmed PRs when one patient who actually had a -27, and that in comparison to the, right next to it, to the right of it, were the three patients that had received just the standard of care. So there was a really big difference there, and then BEV exposed, we didn't see any objective responses. Now, what was interesting about this data was the fact that we were seeing activity also in both the 20 mg and the 30 mg doses, and also the patients that were in BEV-naive that you're seeing here. All BEV-naive patients, all seven of them, came from different clinical sites, and so there was really no bias as far as that was concerned as well.
So this was really, Robert, where we had seen not only the single-arm trial, where we had this finding of the BEV-naive, and then, yes, it's a small randomized trial that we had truncated. However, having said that, you can see it was a very stark difference in response whether you got onvansertib with the standard care versus standard care alone in the BEV-naive patients.
Yeah. No, these two data sets I find, I find really interesting, especially when you see the difference between that BEV-naive versus BEV-experienced patients. One of the things that's not apparent, however, at least it wasn't before, was how PLK1 inhibition induced such a profound efficacy impact in this BEV-naive patient population. I know you did a little translational work to really, you know, elucidate, the scientific underpinning as to what actually is going on here. So can you provide some color for those who aren't, are not familiar with PLK1 for this setting?
It was really, this finding was unexpected, and there really was nothing in the literature to suggest, there's something going on here. 'Cause clearly what was happening was that if a patient's tumor had not been exposed to BEV, and came into our trial, and they got onvansertib and the BEV plus the FOLFIRI, this is where we saw these huge responses. So something was going on mechanistically that was not known before. This really caused us to do what would be considered a reversal of what you normally do. We went back to the bench and spent about a year, our R&D groups, had about a year dissecting this. We just went to AACR, you know, as you know, last month. We have an entire poster on the mechanism.
I'm just gonna give you a very high level here. We also have all the slides and everything, all with the on our website. If you have more you wanna dig in, you can also give me a call, but I mean, just saying that. If you're an investor.
No, I'm not.
I'm just kidding. But we're certainly available as well. But, let me just talk a little bit more about this. So we did the obvious thing. We went back and said, "What's going on here?" So let's go back preclinical. Let's get some in vivo models. Three different in vivo models here, where we treated the mice with either onvansertib or BEV or the combination, and you can see right away that the gold line on the bottom, when you had the combination, that had a much greater significant impact on tumor growth across all three of these RAS mutated in vivo models of CRC.
So what was interesting is that we called up the CRO that was doing the experiments for us, and we said, "Hey, by the way, before you sacrifice these, or after you sacrifice them, but before you know, they go away, do a gross dissection of the tumor, 'cause we wanna look at it visually," because... And what I was talking about here is that, and then we said, "Take a photograph of it and send it to us." So what you can see on the top is that in this experiment, control, vehicle, really pretty vascularized but bloody tumors, right? But then when you look at BEV, you can see that, yeah, we know BEV is basically binds G, VEGF.
It should inhibit angiogenesis, it should inhibit vascularization, and it does. You can see that they are less red. On onvansertib to a certain extent as well, but what was really compelling to us was the bottom row there, where the combination, yes, much smaller, but really what was striking to us was that they were a lot more pale. So that meant that something was going on here that was not known before, that was, in essence, causing there to be a decrease in vascularization.
This was really a watershed moment was looking at these tumors at a gross dissection. We obviously went back and did. We've done IHC, and at the AACR, our poster, we show that the vascularization by CD31 staining is significantly decreased. But just even by your naked eye, you can see that there is a difference. And really what it came down to was a hallmark of cancer that is very well known. In cancer, as you know, tumors outgrow, outpace the vascularization required the nutrients, the oxygen, and so what happens is tumors have become hypoxic, particularly in the middle, in this, on the left-hand side of the cartoon that Robert's head is blocking. There you can see that you know, they're hypoxic in the middle.
Normal cells would die, but tumor cells survive by adapting, and what they do—how do they adapt? They turn on HIF-1 alpha, which is a transcription factor that turns on a whole plethora of a new genetic program of gene expression that allows these tumor cells to now survive. And part of how they survive, as you can see, I can see right behind me, is they secrete VEGF, which is a growth factor for, obviously, angiogenesis. And so what we realized was there's probably something going on here that was going to explain the clinical findings, where this would be the underpinnings. And you can see that we're showing you here. I'm not going to get into all the data, but at the high level, what we show is that onvansertib inhibits the inducibility of HIF-1 alpha.
At a very high level, it's a one-two punch to the tumor. You got one where you're knocking down HIF-1 alpha, and then you've got Bev that's mopping up the VEGF. So that was really... Is that all the time we have left?
No, no, we're, we're go-
Okay, all right. Then something, 'cause I, I was going to have to curtail some things.
No, we've got it.
All right, thank you. So that's really how we've unraveled this, and I think that that's the last of that part.
Okay. So, you know, when we think about the frontline development program, obviously, it consists of two trials: CRDF, the Phase II CRDF-004 and Phase III, CRDF-005. Could we discuss, could you discuss the trial designs for both- trials, as well as what the benchmark for success is in CRDF-004? 'Cause that's the gaining factor.
Yeah, that's right, that's right. And then, you know, so what we're going to be doing now is we're going to be really now talking about what are we doing now. And it's the CRDF-004 behind me, that is a trial that's ongoing today. But actually, to step back, as Robert's asking me to, to step back and just really lay out the clinical development plan that the FDA agreed to, is really this slide here. So on the left-hand side is the CRDF-004. This is the trial we're doing right now. This is a 90-patient trial. It's going to have two different doses in it. This is the trial that we will be giving an initial readout of, later this year.
The reason why this is so important is because it's really the first time we're looking at randomized data in the first line. But to talk a little bit further about this, so when we met with the FDA, they also agreed to the clinical path to the accelerated approval and full approval, which is the trial behind me on the right, which is 005. Now, 005, they agreed to—we asked, and they agreed to us having ORR, or objective response rates, to be the primary endpoint for accelerated approval. And you'll notice in this slide that actually, it's one trial. It's a seamless trial for registrational.
It's going to give an interim readout for accelerated approval and for full approval in the same trial, where we'll be using median PFS, or PFS, and trend and OS for full approval. So it was really exciting for us. We came out of the meeting with the FDA very, very pleased because we were able to, in essence, have a clinical path that enabled us to look at ORR for accelerated approval. I think that's covered. I think I covered that. I didn't go into. Let me see, yeah, I can let me talk a little bit about that and the and where we're going with that.
So this is the trial today that we're doing, which is this, to remind you, is this trial on the left. It's CRDF-004. It's a 90-patient trial. It's randomized. You can see their standard of care, and then standard care with 20 mg and 30 mg of onvansertib. This trial is really to confirm a dose. This is really part of now, I think most of you know, sponsors all have to go through the Project Optimus of the FDA's Project Optimus, where you identify the lowest, most efficacious dose. So with this also, the question, though, that Robert's asking is, well, what's the bogey here for seeing a significant difference?
We're looking at with the treatment arms with the study drug, onvansertib, about a 20, an absolute 20% difference. So the standard of care in first line is in the 40% range of expected response rates. We're looking for something that's approximately 20% greater, which would be in the 60% range. That's kind of where we are with this trial right now.
You know, obviously, when you announce that you're shifting over into the frontline setting, you know, and calling the ENSEMBLE trial, the stock took a hit, right? But from my perspective, it's a much larger market opportunity going from second line to the frontline setting. So can you help frame the market expectations around the, you know, patient population size?
Yeah, so this really speaks to it on the left-hand side of this slide. So in second line, there's really about 9,500 patients per year that are BEV-naive in the United States. And you can see from the slide that when you go to first line, you're at 48,000. All patients are BEV-naive in first line. So you have a really significant increase in the number of patients that could benefit from onvansertib, and obviously, it's much, a much bigger market.
You know, one of the things that you announced during your 1Q earnings was that, you know, the initial readout for 004 was pushed back into the second half. You know, help frame the rationale and the reasonings behind that, as well as, you know, what are the expectations now for that data set in the second half?
Yeah, I mean, when we first made the forecast for this trial, CRDF-004, the one we're talking about that's ongoing, that was back in August of last year, 2023. And so at that time, we did not really have any enrollment data at that point. So it was really a forecast, and we in essence said mid or Q2, Q3 of this year. Now, earlier this year, we started to see enrollment trends, and so we were able to make, we believe, a much more prudent, accurate forecast.
And so that's where we came in and said, "Well, look, we're, we're, we're looking at this a nd it looks like we will have initial readout in the Q3-Q4 timeframe. Now, what we are looking at, our plan is to release data on approximately half the patients in the trial. So 40, 45 patients, and all of them would have at least one post-baseline scan. So at least 1. So that's kind of where we are today. And that's what we're planning to do.
Okay. You know, one of the impressive things from my perspective regarding onvansertib, is that the objective responses you've seen is across the RAS mutation spectrum. It's not isolated to one individual A type of mutation. You know, so we, you know, we've seen some relatively encouraging data in CRC for KRAS G12C inhibitors in combination. Right? But we're also starting to see data now from these pan-RAS approaches, and I'm really thinking about the Revolution Medicines compound. But obviously, we got BridgeBio and Erasca just in line with something else.
So I wanted to get your thoughts as to the potential competition from these pan-RAS inhibitors in colorectal cancer, 'cause that, obviously, that's a target you know, given the magnitude of mutation frequency with the companies you're mentioning, the trial data they've been putting out has been in PDAC and has not been in CRC. Part of the reason for that is because, in CRC, it's already known that with the G12C inhibitors, they know they have to combine it with EGFR inhibitor. We at this point in time, as we sit here today, we are... we don't really see it as competitive. We are in first line. None of these are in first line. And so we do feel like we have a big leg up, as we, as we move forward, today.
Okay. Beyond colorectal cancer, obviously, there are a bunch of investigator-sponsored trials. Give us a flavor as to what we can expect, you know, from onvansertib in these other tumor types.
Well, yeah, Robert, we haven't put out a guidance yet on when we would be releasing data for that. We do have investigator-initiated trials both in pancreatic and small cell lung cancer and triple-negative breast cancer. Once we have a little... You know, as you know, investigator-initiated trials do move at their own pace. And so we will be, when we have a better idea of when we can we will put out more data. We have already reported in the small cell lung cancer, seven patients, and within the seven, and this is monotherapy of onvansertib. In monotherapy in small cell, we had one, a confirmed partial response of greater than 50% reduction, in the first seven patients, which is very exciting 'cause it's a refractory small cell lung cancer.
Yeah. Obviously, we've seen data in pancreatic cancer as well. You know, is this something that you, you want to pursue further?
Yes, we do, and we are... We, you know, we were in second line. We had very promising data from there. But as we made clear in one of our recent PRs, public relations statements, we are going into first line with investigator-initiated trials in pancreatic.
Okay. You know, outside of CRDF-004's readout later this year, what can investors expect over the next 12 months, let's say?
Yeah, I mean, right now, our focus is 004. You know, so we haven't really put out a guidance on the investigator-initiated trials, but really, our entire focus is to really execute and produce the data for the 004 and first-line CRC.
Well, that's really all the questions from me. Are there any questions from the room? No. Mark, it was a pleasure.
Robert, as always-
… so much
... a pleasure to talk with you.
Awesome.
Thank you for your attention.