CRDF - NASDAQ

Welcome to the Cardiff Oncology Fourth Quarter and Full-Year 2023 Financial Results and Corporate Update Conference Call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question-and-answer session. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to turn the conference call over to Laurence Watts, Gilmartin Group. Please go ahead.

Thank you, Operator. Joining us on the call today from Cardiff Oncology are Chief Executive Officer, Mark Erlander; Chief Medical Officer, Dr. Fairooz Kabbinavar; and Chief Financial Officer, Jamie Levine. During this conference call, management will make forward-looking statements including, without limitations, statements related to guidance, results, and the timing of the data readouts for onvansertib clinical trials. These forward-looking statements are based on the Company's current expectations and inherently involve significant risks and uncertainties. Our actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of these risks and uncertainties. Factors that could cause results to be different from these statements include factors the Company describes in the section entitled Risk Factors in our annual report on Form 10-K for the year ended December 31, 2023, filed with the SEC earlier today. Cardiff Oncology undertakes no duty or obligation to update any forward-looking statements as a result of new information, future events, or changes in its expectations. Slides for today's investor call can be found on the homepage and the Events and Presentations tab on the Cardiff Oncology Web site at www.cardiffoncology.com. With that, I will turn the call over to Chief Executive Officer, Mark Erlander. Mark?

Thank you, Laurence. Good afternoon, everyone, and thank you for joining the call. We have some very important new clinical data to share on the call today while we -- which we think is highly relevant to our current first-line metastatic colorectal cancer program. As you may be aware, last year, we made a highly consequential decision to shift our mCRC program from the second-line to the first-line setting. There were three factors that drove our decision. The first was the clinical signal from our second-line mCRC trial. The second was the new mechanism of action we discovered for onvansertib. And the third was the strong support from the FDA for the first-line clinical development plan. What's new today is that, for the first time, we are releasing data from our ONSEMBLE trial, adding powerful support to our first-line strategy. And as we'll discuss, what's different with the ONSEMBLE clinical data is that it's independent, it's randomized, and its perspective. You'll hear more about each of these attributes today. And by the end, I hope you'll agree that ONSEMBLE data adds substantial support to our first-line program. Slide three shows the three topics we'll cover in today's call. First, we'll talk briefly about 2023 and what a transformational year it has been for Cardiff Oncology and for the clinical development of our drug, onvansertib. Secondly, as I mentioned, we'll share clinical data from our randomized second-line ONSEMBLE trial. And then, finally, we'll talk about our financial position that we disclosed today in our Form 10-K. On slide four, we show the highlights of the significant announcements we made in 2023. In August, we provided our mCRC clinical update, where we announced the discovery of a novel mechanism of action for onvansertib which was previously unknown, and the clinical level that it plays in the HIF1α pathway exhibiting fast utilization. The data we presented, showing evidence for complementary mechanisms of action for onvansertib and bevacizumab, which we will refer to as bev, for explaining the strength of our clinical data in the mCRC. And after discussing the clinical and underlying mechanism with the FDA, in June of last year, we received strong support for the decision to move our program to the first-line setting. Further, we announced the Pfizer Ignite program that is providing chief clinical execution for the CRDF-004 trial. At the time we made all these decisions, we were already enrolling patients in the ONSEMBLE trial in the second-line setting. So, in August, we announced we would discontinue the trial to focus our efforts and resources from the larger patient population and the significant unmet need in the first-line setting. In September of last year, we held a second update call to announce data for our programs outside of the mCRC in our second-line pancreatic cancer trial; we announced four initial partial responses from the 21 patients. And today, we can provide an update and on those four patients by sharing that three of the four initial responses were confirmed on a substantive scan. We also announced our decision to shift our pancreatic program to a first-line setting with an investigator-initiated trial combining onvansertib with standard-of-care bevacizumab. Finally, we announced new data from our refractory extensive-stage small lung cancer investigator-initiated trial where we observed that the confirmed PR among the first seven patients. Importantly, this is the first clinical data generated using onvansertib as a single agent. Looking at the range of our announcement in 2023, you can -- we believe that the year was a truly transformational for Cardiff Oncology. I just have to break for a second. I'm sorry. I believe I'm losing my voice. So, I'm passing the light to my CFO, Jamie, to continue the remarks on the call. I'll be available for Q&A at the end of the call. Thank you.

Thanks, Mark. On slide five, we transitioned to our second item on the agenda, the new clinical data we're announcing today. Recall that our mCRC program includes three clinical trials, and we want to very clearly discuss what's significant in each one. The Phase 1b/2 trial in KRAS-mutated mCRC generated the initial signal of efficacy on which we based our mCRC clinical development program. And the trial is now complete. Based on the strength of the preliminary data from the single arm Phase 1b/2 trial, we proceeded with our originally designed next step of our clinical development program by implementing the second-line ONSEMBLE trial which would provide randomized data comparing onvansertib plus standard of care to standard of care alone. However, as the Phase 1b/2 data matured, we saw a powerful and unexpected positive signal from the data. We identified a subgroup of patients, specifically those who had not had prior treatment with bev in the first-line setting, but achieved higher response rates than what would have been expected. As we state on slide eight, we discussed our findings, including both the Phase 1b/2 clinical data and the new mechanism of action I mentioned at the start of the call, with the FDA, which led to their strong support for us to discontinue to ONSEMBLE trial and shift our clinical program to the first-line setting. CRDF-004 is our randomized first-line RAS-mutated mCRC trial for which we just announced the first patient was dosed. And Pfizer Ignite is providing clinical execution. As you see on slide nine, today we are sharing new clinical data in the CRDF-003 ONSEMBLE trial. We had enrolled 23 patients in ONSEMBLE prior to making the decision to discontinue this trial. While we closed the trial to new enrollment, those patients who are already enrolled continue treatment for protocol. And the majority of the patients enrolled remain on the trial today. As you'll see, there are important findings in the ONSEMBLE clinical data that validate our decision to shift to the first-line. I'll now turn the call over to Dr. Fairooz Kabbinavar, our Chief Medical Officer, to review our clinical data. As a reminder, Dr. Kabbinavar is a medical oncologist with 35 years of experience, who led the colorectal cancer program at UCLA, and was heavily involved in the registrational trial that led to the approval of bev in metastatic colorectal cancer.

Thank you, Jamie, and thank you, Mark. It's my pleasure to present the new randomized clinical data from our CRDF-003 ONSEMBLE trial. On slide 10, you can see the ONSEMBLE trial design. This trial enrolled second-line RAS-mutated metastatic colorectal cancer patients with unresectable but measurable disease. Patients were randomized across three arms. One was a control arm, where patients received standard of care chemotherapy consisting of FOLFIRI plus bev. In the two experimental arms, patients received a dose of onvansertib in each of the first five days, following the FOLFIRI plus bev infusion. One arm included a 20 milligram daily dose of onvansertib; the other arm included a 30 milligram daily dose of onvansertib. The primary endpoint was objective response rate. And the dosing schedule will be the same as in our Phase 1b/2 trial. Looking at the enrollment at the top of slide 11, you can see that [indiscernible] 23 patients had been randomized across the three arms. Importantly, one patient was never treated because the patient withdrew consent and left the trial prior to receiving any therapy. This reduced the treated patient population evaluable for safety to 22 patients only. Also, one additional patient withdrew consent and left the trial before receiving any post-baseline scan. So, 21 of the 23 patients are now available for efficacy. Both patients who left the trial were randomized to the control arm and both were bev exposed. So, their withdrawal from the trial does not impact any of the conclusions drawn from the data on the following slides. On slide 12, I'd like to define exactly what we mean by bev naïve and bev exposed. In our second line, mCRC patients, trials, and role patients would have already received first-line therapy that may or may not have included bev. A bev naïve patient is simply a patient whose prior therapy did not include bev. So, these patients would have received only FOLFOX chemotherapy in their first-line treatment before coming into our second-line trial. In our second-line ONSEMBLE trial, seven of our 21 patients evaluable for efficacy were bev naïve. We refer to the other 14 evaluable patients in our trial as bev exposed, meaning that prior first-line therapy included bev in addition to FOLFOX chemotherapy. So, the critical question we had as we watched the ONSEMBLE trial data mature over the past six months is, will the high response rates we saw for bev naïve patients in our Phase 1b/2 for single-arm trial continue to be observed in the ONSEMBLE randomized trial. And I'm excited to show you the results of the next slide. Slide 13 is the waterfall plot, which shows each patient's best response to therapy over the course of their treatment. As you can see, the answer to my question, the bev naïve patients receiving onvansertib with FOLFIRI/bev once again had the most robust response to treatment. Now allow me to walk you through what this slide is showing. Starting from the top of the slide, you can see that we have segregated the 21 evaluable patients into two groups. So, the seven bev naïve patients are on the left, the 14 bev exposed patients are on the right. Within each of these cohorts, we further divide the data into experimental arm patients who received on one-sided plus standard of care FOLFIRI/bev, and the control arm patients on FOLFIRI/bev without onvansertib. Looking at the graph, the bars above the midline represent tumor growth, and the bars below the midline represent tumor shrinkage. A teal-colored bar represents an objective partial response, meaning the patient had 30 percent or greater reduction in the tumor size. A light red bar represents progressive disease, which is an increase of more than 20 percent in the tumor size. And a yellow bar represents stable disease, which is between these two numbers. At the bottom of the slide, you can see the dose of onvansertib received by each experimental arm patient, either 20 milligrams or 30 milligrams, shown in blue boxes above the patient number. And the first three digits of the patient number is the clinical trial site number. As you scan from left to right on the waterfall plot, you can see that the three patients with the greatest tumor shrinkage observed are bev naïve patients receiving onvansertib plus standard of care. This is highly encouraging and consistent with what we would have expected based on our prior Phase 1/b2 trial data. On the next few slides, we'll parse this waterfall plot into sections and draw additional conclusions. As you call out on slide 14, you can see that for the bev naïve patients, the only objective responses were observed, we observed, were in patients that received standard of care plus onvansertib. Given this is a randomized trial, it's also important to point out that we did not see any responses in the control arm of bev naïve patients that received standard of care alone without onvansertib. In addition, by looking at the first three digits of each patient number, you can see that each bev naïve patient was enrolled at a different trial site, so that the bev naïve finding is not the result of any bias coming out of a single trial site. Specifically in the bev naïve patients that did respond, one patient received onvansertib, demonstrated a 44% reduction in the tumor size, and the second patient had a 43% reduction. Importantly, both these patients have confirmed partial responses. And we see these partial responses at both 20 milligram and 30 milligram dose of onvansertib. The third bev naïve patient who received onvansertib had a 20% reduction in the tumor size, which is very close to the 30% threshold to qualify for a partial response. I would like you to keep this patient in your mind as I'll provide more details in the next few slides. On slide 15, we focus on the 14 patients in the bev exposed cohort. And you can see that in both the experimental and control arms, there were no objective responses observed. And certainly the size of the effect appears to be less than what we see in the bev naïve cohort. And on slide 16 you can see that the bev naïve and bev exposed control arm patients appear to have very similar responses to the standard of care therapy. On slide 17, we are looking at the spider plots for the bev naïve patients. You can see that on the left are patients in the experimental arm. The teal lines in the plot allow you to see the trajectory of the two patients with confirmed partial responses. The plot on the right shows the bev naïve control arm patients who did not receive onvansertib. Importantly, the two control arm patients with tumor shrinkage at their two-month scan both subsequently progressed at their four-month scan and left the trial. Now on slide 18, I'd like to provide some context around the patient I mentioned earlier, who had a 27% reduction in the tumor size at their six month scan. On this six month scan, a suspiciously metastatic lesion was noted in the patient's lung. So, the treating physician decided to discontinue onvansertib, but continued treating the patient with standard of care FOLFIRI/bev. The lung lesion was later confirmed by biopsy to be a Valley fever of fungal infection, unrelated to the patient's cancer and not a new tumor lesion. At the patient's eight-month scan, the tumors increased sufficiently for it to be considered progressive disease. But more importantly, during this two-month period between the six-month and eight-month scan when the tumor progressed the patient was not receiving any onvansertib, but was only on FOLFIRI/bev. In summary, on slide 19, I'd like to reiterate the three attributes of the ONSEMBLE data that Mark and Jamie mentioned at the start of the call now that you have seen all the data. First, the ONSEMBLE trial was independent because it's a second clinical trial at a different point in time than our earlier Phase 1/b2 trial, showing once again that bev naïve patients have a strong response to therapy that includes onvansertib with FOLFIRI and bev. Second, the ONSEMBLE trial was a randomized trial, thereby removing all clinical bias, where we see that bev naïve patients in the control arm of FOLFIRI/bev without onvansertib had no objective responses. And finally, the ONSEMBLE trial was prospectively designed. The original bev naïve finding in the Phase I/b2 trial was from a retrospective look back at the data. However, we had seen the bev naïve signal before enrolling the ONSEMBLE trial and had prospectively planned to evaluate the differences in response rates between the bev naïve and bev exposed post patients in a randomized fashion. And importantly, when we look at the safety data that is included in the appendix of this material, we see that onvansertib when combined with chemotherapy plus bev is well-tolerated with no major unexpected toxicity that was observed. On slide 20, I'll conclude my remarks reminding you of the new mechanism of action we discovered for onvansertib, and that Mark mentioned at the start of the call. This mechanism of action explains why we believe we are seeing this clear efficacy signal in bev naïve patients. As we discussed in detail in August, we believe that the robust responses we are seeing are due to a novel mechanism of action that we have discovered for onvansertib's role in the hypoxia response pathway. It is well known that tumors outgrow their blood supply and become hypoxic, meaning they become starved of oxygen and nutrients. Tumors respond to this hypoxic stress by producing the HIF1 alpha protein. HIF stands for Hypoxia-inducible Factor 1 alpha protein, which turns on hundreds of genes that allow the tumor to survive in the hypoxic environment. One of those mechanisms involves the tumor secreting vascular endothelial growth factor A or VEGF-A, promote the formation of creation of new blood vessels to bring oxygen and nutrients to the cancer cell. As you can see on slide 21, bev works by neutralizing VEGF-A, inhibiting the creation of new vasculature, but onvansertib plays a role upstream of VEGF by inhibiting HIF1 alpha directly, and thereby, blocking all its downstream effects. This shows why onvansertib and bev are complementary in a bev naïve setting, by deploying two separate hits on the tumor angiogenic pathway and its survival mechanisms. In conclusion, in my 35 years as a medical oncologist, I've never been as excited as I am now to see the kind of efficacy signal we are observing across our clinical trials. Now, I'm going to hand this call back over to Jamie to continue the discussion further. Jamie?

Thank you, Fairooz. We'll conclude the call with a few comments about CRDF-004. Turning now to slide 23, you can see that colorectal cancer is a major public health issue. It's both a highly prevalent form of cancer and it is challenging to treat. And recently, there have been a number of reports that CRC is becoming more common in younger adults, thus increasing our responsibility to develop more effective therapies beyond the current standard of care. And on the right side of the slide, you can see how our decision to move from second line to first line substantially increases the number of metastatic colorectal cancer patients who may benefit from adding onvansertib to the current standard of care. On slide 24, you can see that the first-line standard of care for RAS-mutated mCRC consists only of chemotherapy with bev, a regimen that hasn't changed in 20 years. So, this large patient population is in need of new therapies directed at all RAS mutations. Slide 25 provides the study design for a CRDF-004 trial. Similar to the ONSEMBLE trial, CRDF-004 includes mCRC patients whose tumors have a RAS mutation and are unresectable. A key difference for CRDF-004 is that all patients are first-line and therefore have not previously been exposed to bev. The trial will randomize 90 patients across three arms. First, a control arm consisting of standard of care with FOLFIRI/bev or FOLFOX/bev, and then two experimental arms looking at standard of care chemotherapy plus bev and a 20-milligram or a 30-milligram daily dose of onvansertib, the same doses as in the ONSEMBLE trial. Our primary endpoint for the trial will be objective response rate, and the secondary endpoints are duration of response and progression-free survival. Let me provide a few additional details about the CRDF-004 enrollment. Our clinical operations efforts, together with Pfizer Ignite, are going well, with a critical mass of 20 clinical trial sites activated as of today. And as we announced, we've dosed our first patient. Based on the current robust screening activity observed and our current enrollment projections, we expect to meet our goal of releasing data from the trial in mid-2024. And we anticipate this initial release will include objective response rate data for approximately half the patients we expect to enroll on the trial. On slide 26, I'll cover our third agenda item, our financial position as of December 31, 2023. As we disclosed today in our Form 10-K filing, we had $74.8 million in cash and investments as of December 31, 2023, and our cash used in operating activities was $7.1 million in Q4 '23. Today, we have greater clarity on our expected future expenses, and so we can be more precise about our forecasted cash runway. Specifically, we believe that our current cash resources provide us with cash runway into the third quarter of 2025, which is beyond the expected readout from the CRDF-004 trial. Finally, on slide 27, we summarize why the ONSEMBLE data we released today is so relevant for our first-line mCRC strategy, and our ongoing CRDF-004 trial. First, ONSEMBLE is the second independent and randomized dataset reproducing the robust efficacy signal for onvansertib plus standard of care in bev naïve patients. And this supports our currently enrolling first-line trial where all patients are bev naïve. Secondly, no bev naïve patients in the ONSEMBLE control arm showed an objective response to treatment without onvansertib, suggesting onvansertib is critical to the robust responses observed in the experimental arm. And finally, both of two onvansertib doses appear to be active, which suggests the two experimental arms of the CRDF-004 trial could be combined when evaluating the trial data for efficacy. For all these reasons, we continue to believe our shift to the first-line setting is the best strategy for all of our stakeholders, particularly the large number of patients, 48,000 per year in the U.S. with RAS-mutated mCRC that may benefit from a new approach to treating their disease. With that, we'll open the call up for questions. Operator?

Thank you. [Operator Instructions] Our first question comes from Mark Frahm with TD Cowen. Your line is open.

Thanks for taking my questions, and congrats on the data that you were able to release. But -- and maybe first off just -- obviously, you've dosed the first patient today, but any sense for how much data you'll be able to release in the middle of the year from the 004 trial? And then for the data today from ONSEMBLE, any characteristics you can provide on the baseline, like were there any differences in left and right-sidedness, and things like that that might explain a little bit of the difference in response rate?

I can start. And first of all, and like we said and on the call, we're going to be putting data out when we have approximately about half the patients enrolled in the trial. And the second thing was regarding the ONSEMBLE data, we have looked at that. We haven't seen any differences, but we [indiscernible] come from the side of this, but we do not present that here.

Okay. And sorry, just on that update, is it once you've enrolled or it -- that you have mature response data on one half, that's the question?

Where we've been looking is at least one scan after the baseline.

Okay. Okay, thanks. That's helpful.

Thank you. Our next question comes from Joseph Catanzaro with Piper Sandler. Your line is open.

Hey, everybody, thanks for taking the questions and update here. But maybe first on the ONSEMBLE data, I'm wondering if you guys performed a PFS analysis. So, I'm looking at the swimmers plot, and even sort of considering both bev naïve and bev exposed, and it feels like there's a pretty good, even maybe emerging PFS signal that you're seeing in this randomized data. So, wondering if you did that analysis and maybe what it's saying? Thanks. And I have maybe one follow-up.

Thanks, Joe, for that question. We have not done it rigorously, we were waiting for more follow-up for us to look at that [indiscernible] led to small number of patients. But we agree with you, that there looks like there is an emergent signal.

Okay, thanks. And then for the frontline trial, was there any -- is there any safety run-in on the backbone of FOLFOX, just trying to get a sense of maybe, historically, how the neutropenia compares with FOLFOX relative to FOLFIRI? And then maybe relatedly, the expected split between FOLFIRI and FOLFOX as a backbone. I'm thinking back to some earlier preclinical data from a couple years back that suggested onvansertib and irinotecan, that there is some [cooperativity] (ph) there. So, hopefully that question makes sense.

Yes. And, evening, Joe. Let me first start by talking about the preclinical data. We actually have shown publicly that we have synergy with both oxaliplatin as well as irinotecan in [indiscernible] model pre-clinically. And we have not any toxicity as well. For your questions regarding the FOLFOX in the first -- in our first-line trial, I'm going to turn it over to Fairooz, our CMO here.

Hi, Joe. So, the question about regarding any safety run-in for the FOLFOX bev plus onvansertib, yes, for the first nine patients, we'll be -- after the first nine patients have been dosed and those patients will be evaluated by the safety [indiscernible] committee. And once the -- it is determined that FOLFOX plus onvansertib plus bev, there's no additional toxicity beyond what is expected of FOLFOX bev, then they're -- that arm will continue to accrual to its full completion of the full complement of the patients. So, yes, there is a safety valve built into this trial. And we don't expect, based on how onvansertib partners with other chemotherapy drugs. We don't expect any major toxicity issues. And even the -- and giving you a lot more detailed information even though there were two patients with neutropenia that was seen in this -- in the ONSEMBLE trial, those was at the lower-end -- lower dosage, 20 milligrams, not at the 30, and then these patients got neutropenia resolved just by holding the treatment or delaying the treatment for seven -- in one patient seven days, and another patient 10 days. And those patients still continue on treatment without any dose reductions.

Okay, thank you. That's all very helpful. Thanks again for taking my questions.

Thank you. Our next question comes from Andy Hsieh with William Blair. Your line is open.

Great, thanks for taking our questions. Mark, I hope you feel better soon.

Thank you.

I just want to dig a little -- just to dig a little deeper into the ONSEMBLE top line results, maybe on two topics. So, one is on liver metastases, and maybe second on dose response. Maybe I'll go first on the dose response. Maybe -- perhaps you can comment on whether you see is there a dose response or both are active, and how do you think about the both doses going forward. Typically on the liver metastases, I think if I did the calculation right, it's about 77% of patients have some sort of liver metastases. And that's kind of on the higher side. Have you looked at the two responders, do they have liver metastases? And I think the emerging data is suggesting that these patients are particularly hard to treat, and maybe there is a potential hypothesis on the mechanistic side of onvansertib that's active in this population. And I have a couple of follow-ups.

Okay, well, thanks, Andy, for the dose response. If I understood your question correctly, we are seeing similar activity, albeit small data numbers. But we are seeing similar activity between the two doses, the 20mg and 30mg, if that's what you're asking. And so --

Yes, [indiscernible] that right.

And from that, that's why we're concluding that we can combine those arms together to look at efficacy in the 004 trial. As far as the liver [met] (ph), we have not analyzed that robustly yet. But I would say that in our Phase 1b/2 trial, that we've shown that there was no difference in the response in bev naïve patients that had a liver met, which is those that didn't -- that there was no division of response there, irrespective of livers, but --

Yes, so, Andy, just building up on what Mark just said, in the Phase 1b/2 trial we looked at multiple other factors trying to see were there any other features that would impact these responses that we're seeing in bev naïve patients. And to give you a very short answer, absolutely no clinical feature appeared to play a role in significant robust responses that were seen in the bev naïve patients. So, we looked at laterality of the tumors, right and left tumors, both responded equally. We looked at patients with liver met, without liver met, they all seem to respond well. We looked at patients who had gender did not impact the outcome. So, we think that this point, based on what we have seen in the Phase 1b/2 trial and that if the bev naivety, if you will, that there is a significant role in the dramatic synergy that you're seeing between bev and onvansertib plus chemotherapies.

I see. That's very helpful. So, maybe moving out of the -- sorry, actually before we move on, so in terms of managing neutropenia for the ongoing 004 study, are you considering doing growth factor prophylaxis for patients?

Well, the three things that we normally would use, hold the dose or delay the next dose, allow the bone marrow to recover. If it doesn't recover, then we use growth factors according to ASCO guidelines. And then, subsequently, I mean, we also have the option of doing dose reduction depending on which drug is the culprit. But again, going back to 1/b2 trial and others, we have not found a reason for us to dose decrease. So, we have all the options that will standard of -- that we would normally use in managing these patients. But at this point, we don't think it's going to be a big issue.

Got it. That's helpful. And then, so outside of CRC, I believe small cell lung cancer in the September update was 1 PR3, stable disease patients. Do you have any updates on that cohort or that's kind of the latest data?

I can say that we don't have any updates. The PI has moved to another academic institution and so that has somewhat slowed down the accrual in that particular trial.

I see. Great. Thank you so much for taking all of our questions and congratulations on the progress.

Thank you. Thank you, Andy.

Thank you. There are no further questions at this time. I'd like to turn the call back over to Jamie Levine for closing remarks. Thank you, Operator.

Thank you, Operator. This concludes our conference call and thanks again for joining us this afternoon. Bye-bye.