Okay. Hi, everyone. My name is Maury Raycroft, and I'm one of the biotech analysts at Jefferies. I'm happy to introduce and welcome Mani Mohindru, CEO, and Josh Muntner, CFO of Cardiff. We're doing a fireside chat format. Thanks so much for joining us today. Thank you, Maury. Great to be here. For those who are less familiar with the company, can you give a brief overview of the company and your pipeline? Sure. Pleasure. We are focused on a target known as polo-like kinase 1, PLK1 inhibitor. It is an oral molecule. Interestingly, we are one of the few companies where we are ready to take this molecule into phase III. We've had some amazing data coming out at ASCO earlier this week. Phase II randomized control data in frontline RAS- mutated metastatic colorectal cancer. We have been investigating this molecule in a number of solid tumors as well as heme malignancies. Of note is chronic myelo monocytic leukemia, CMML, where our investigator has shown some single-agent activity, pretty dramatic single-agent activity in the relapsed refractory setting. It's an orphan disease with very poor outcomes. From a company perspective, our focus is on frontline metastatic RAS- mutated colorectal cancer, where clearly there hasn't been any innovation in the last 20 years or so, and chemo and bevacizumab seems to be the regimen of choice for most patients. Got it. Yeah, it's a great overview and intro to the company. You mentioned ASCO, where you're just there. You had data. Maybe quickly recap the latest you've seen on efficacy and safety from the program. Yes. As I said, we've been lucky that we had randomized control data where our molecule, known as onvansertib, was combined with the two known regimens in the frontline setting, FOLFOX/ bev or FOLFIRI/ bev, and compared to each of these control arms alone. We saw activity predominantly in the FOLFIRI/ bev combination arm, and this is the second time we have seen activity with this chemo regimen. There had been a prior study where we also saw great activity here. It's great to see. It increases our confidence in the molecule and the regimen. We saw overall response rates in the order of 70%+, 72% to be precise. If you look at the comparator arms, whether it's FOLFIRI/ bev or FOLFOX/be v, the ORR there was what has been reported historically in the range of 42% or so. More importantly, we have not reached median PFS in either of the two doses we tested, 20 or 30 milligrams. Both doses seem to be active. 30 is clearly the dose of choice taking forward. Median PFS has been reached in both comparator arms, FOLFIRI/ bev as well as FOLFOX/ bev, similar to what has been reported by investigator assessment. They're in the range of 11 months or so. It's great to see that patients on onvansertib combination with FOLFIRI specifically continue to do well. We are monitoring them. More importantly, the hazard ratios have been very promising and encouraging, in the order of 0.55 or so, approximately for any of the arms. That is a pretty remarkable hazard ratio in RAS -mutated disease in the frontline setting. Yeah, we're looking forward to continuing to monitor these patients and see where we end up with the study finally. A lot of enthusiasm from U.S. and ex-U.S. investigators. I mean, ex-U.S. clinicians, because the study was just U.S.-based. We did a call yesterday with two of those KOLs, so we've been very encouraged with what we see, and we are ready to take the program forward into phase III development. Got it. That was a great summary of the data that you've shown. You're seeing this difference between FOLFIRI and FOLFOX. You said the second time you've seen the benefit with FOLFIRI. Maybe just talk about what could explain the difference in efficacy, the stronger responses you're seeing with the FOLFIRI combination. Yes, maybe before I address this, I also want to note that we did complete our end of phase II meeting with the FDA earlier this quarter, and based on our interactions with the agency, we are taking the 30 milligrams with the FOLFIRI/bev combination forward in phase III. Regarding the differential outcomes in FOLFOX and the FOLFIRI arm, this is the second time we've seen the responses. Let me start back up a little bit and start from the efficacy perspective. Both FOLFIRI and FOLFOX are quite similar in their efficacy in the first-line setting, even in NCCN guidelines, and physicians use it interchangeably, albeit that their toxicity profiles are quite different. Regarding their combination with onvansertib, there are certain mechanistic differences the way irinotecan, a component in FOLFIRI, and oxaliplatin, a component in FOLFOX, work. Specifically, we have data, internal data, where irinotecan, along with onvansertib, inhibits a pathway that's involved in angiogenesis or new vessel formation through a molecule known as HIF1alpha. It is interesting that both irinotecan, oxaliplatin, have an anti-angiogenic effect. Put it on top of bevacizumad, which is anti-VEGF, another anti-angiogenic effect. Three punches coming to the tumor that way we think is responsible for the outcomes we see in this combination. In contrast, oxaliplatin, a component of FOLFOX, does not have the same effect on HIF1alpha at the doses that are used. The other one is that irinotecan actually causes DNA damage, which is very distinct from the way oxaliplatin causes DNA damage. I won't go into the molecular details, they have different ways of killing the cells through DNA damage. PLK1 is involved in DNA damage repair pathways in the way that irinotecan causes DNA damage. If you have irinotecan-induced DNA damage, and on top of that, you put a PLK1 inhibitor that inhibits the repair of the DNA damage, so you get synergism there, which is not seen because PLK1 is not involved in oxaliplatin-induced DNA damage pathway. There are a couple of different ways, and this is published in the literature. We're generating data there as well. These are really mechanistic differences. Patients who were on oxaliplatin did have dose discontinuations of oxaliplatin specifically, which is again, not unusual. It is a toxic regimen. You get neuropathies and other toxicities, and patients do come off this pretty frequently. That could be another reason contributing to the lack of similar efficacy that we saw with FOLFIRI combination versus the FOLFOX combination and nivolumab. Got it. Very long answer, but grounded in science and repeated in two of our studies. I think a lot of details there. It seems like there's a decent amount of evidence supporting the different mechanisms- Yes. Between FOLFOX, FOLFIRI, and presumably this was discussed with FDA in your meeting as well. Yes. Of course, FDA goes by evidence-based science. They saw the efficacy in FOLFIRI. In fact, they guided us to keep our phase III pretty simplistic. We did release our phase III design that we have come up with after getting guidance from the agency. They were fine with taking the molecule forward with FOLFIRI combination. Our phase III looks at one-to-one randomization of the 30 milligram arm given with FOLFIRI/bev versus FOLFIRI/bev alone. They did tell us that FOLFOX and FOLFIRI are very similar in efficacy. If we are able to repeat and show the kind of efficacy we showed in our phase III, there's no reason why physicians wouldn't switch patients from the FOLFOX to FOLFIRI plus nivolumab combination should our phase III be positive. Got it. Interesting. Okay. You reported several cases of 100% lesion reduction in the 30 milligram cohort. Have those patients shown more durable responses than the broader population? Yes. 100% reduction in the target lesion. Yes, because some of them we identified as complete responders, some of them are partial responders, even though there was 100% reduction in target, maybe because there was a non-target lesion or something. We haven't commented on case-by-case, patient-by-patient specifics around durability, but we did say that some of the patients went on curative surgery. The number of patients who went on curative surgery were the largest in the 30 milligram nivolumab plus FOLFIRI/bev arm. Without going into the specifics, it's possible some of the patients went into curative surgery, and some of them contributed to the lack of median PFS we have seen thus far. We will see if we can release patient-by-patient data in- Yeah. The months to come. Yeah. Okay. That's something that you're continuing to do more work on. Yes. I guess, are there patients who are super responders or more likely to respond, and could you potentially enrich for that? Yeah. Generally, what you see is deeper responses do contribute to better durability. Again, not trying to evade it, I don't remember at the top of my head, but yes. That is generally the case if you have very deep responses. In our case, we even saw deeper responses much early on, and in totality, they contribute to the PFS benefit overall. Got it. Okay. As a note, four patients on the 30 milligram, nine patients out of the 14 that are still on treatment are on nivolumab plus FOLFIRI/bev arm, and out of that, four patients are on the 30 milligram arm. There are quite a few patients still on treatment with nivolumab and FOLFIRI/bev regimen. Got it. Okay. The hazard ratio in the 30 milligram cohorts, it's compelling, but you could argue that the confidence intervals are wide. What gives you confidence you can reproduce a similar magnitude of benefit in the phase III? I mentioned we've looked at many different ways, the confidence intervals, they all sort of point in the hazard ratios in multiple ways. Very compelling around 0.5. We did not share the 20 milligram arm, but I do want to say that the 20 milligram arm is pretty active as well in terms of durability of responses. We didn't share that specific data, but I think it's around some 0.67 or something like that, the hazard ratio. Your question was the confidence intervals are wide, which is true because this is a phase II study with limited number of patients, so this is not unexpected. However, we showed two ways of looking at PFS benefit and two ways of Kaplan-Meier curves. One was looking at combined 20 and 30 milligram doses, which gets us to a decent number of 36 patients or so versus comparator FOLFOX and FOLFIRI combined. That's a good number. If you look at that, again, the hazard ratio combining an active arm with a suboptimal arm was still 0.5. That gives us a lot of confidence in the activity of onvansertib as a strong active agent. In the 30 milligram arm, the number of patients were around 17 or so. There the confidence intervals are wider, but not as unexpected. I think if you look at the totality of the data, we feel pretty confident that even combining a suboptimal dose of 20 milligram, getting to a hazard ratio of 0.5-ish is a very strong place to start going into phase III. In phase III, you don't have to get to a 0.5 hazard ratio. Of course, we build some conservative estimates in designing the study. The success is not just 0.5. There's many other things between 0.5 and beyond. You can get higher than 0.5 and still meet success. Got it. Okay. Overall, no matter how you slice and dice, the hazard ratios give you confidence then? Yes. Hazard ratio combining with the suboptimal dose and still getting compelling hazard ratio, yes, all of that in the totality of the data. Two studies, actually, we keep forgetting that. There's a prior study which had PFS benefit also in the same range that we see. There the PFS had been reached. Here we haven't, but ORR was very similar, so yes. Okay. There are differences between the BICR and investigator's PFS. We talked about this. Yes. It seems like it's probably driven by a small number of patients. Can you just talk about the discrepancy there and what data set best informs your phase III assumptions? Yes. I'll start by saying that there is a reason that there's BICR analysis and investigator analysis, mostly confined to phase III registrational studies because there is always a discordance between local reads and central reads. We also had it. It is unusual to have BICR as a read in phase II studies, but we are lucky, and that gives us more confidence and conviction in our data. Discordance is not unexpected. It shouldn't be too much. Ours is pretty concurrent. There's a lot of concordance in our readings. We've done analysis of patient by patient. The slight difference that you see in median PFS in the control arm, because only median PFS has been only reached in the control arm, is driven by patients who were assessed as progressors by investigators and were taken off study. BICR really didn't get to see the subsequent reads of radiographic analysis from patients who were taken off study by investigators. They got captured as events in the investigator assessment arms, whereas by BICR, they were not deemed progressors because they just didn't get the read. That was inherently there. When we get to the phase III, you generally make sure that the local sites make decisions after getting the BICR to see the data. Got it. Okay. Yeah, that makes sense. For OS, what's your early read for the 30 milligram versus control, and are you starting to see any differentiation, and when could you expect an update for the KM curve? Yes. Still early days. This was a first-line study. We are monitoring patients who continue on the study or have come off. However, just to set expectations straight, this is a small study, not really designed for seeing any statistically significant differences in survival or anything like that. The survival was not a formal endpoint. It's early days, but we will continue to monitor and see if over time we start seeing a survival difference. Got it. Okay. Certainly more patients came off because of progressive disease in other arms versus the 30 milligram arm. Okay. How are you thinking about the control arm recruitment and compliance? Are you seeing any physician preference for FOLFOX/b in the frontline that could make FOLFIRI/bev less attractive in this setting, specifically in the U.S.? Great question. Just as a background, FOLFOX/bev as a regimen is more used in the U.S. Both FOLFIRI and FOLFOX/bev are considered equivalent, as I said, even in NCCN guidelines for efficacy, not for safety. In ex-U.S. and Europe especially, FOLFIRI is the regimen of choice by most physicians and patients versus FOLFOX, they're both used. As you can see, our first study, a phase II study, which is 110-patient study, decent number, we were able to enroll without any issues in the U.S., despite FOLFOX, FOLFIRI differential preference. The phase III study is going to be a global study. We do have the benefit of going into countries where FOLFIRI is the treatment of choice. That said, I am coming from ASCO, I can tell you firsthand, there's a lot of excitement. We had breakfast with KOLs from U.S. and ex-U.S. investigators as well as clinicians because the current study was not open outside. They are more than happy to open a study with FOLFIRI in the U.S. based on the strength of the data that we have. They anticipate no issues whatsoever in the U.S. and ex-U.S., of course. FOLFIRI is the regimen of choice. Oncologists are very data-driven, unfortunately, because of still poor outcomes with current therapy. They would follow where the data is, and the patients are willing to participate. Got it. Okay. That's helpful. Maybe let's jump to the phase III design. Can you walk through just key assumptions, including study size, powering, blinding, and expected enrollment timeline? All right. Quite a few questions rolled into one. No, we're very fortunate that from an ongoing phase II study, we got enough strong signals that we were able to go to the FDA and have a formal end of phase II meeting, a type B end of phase II meeting, and be able to share data from an ongoing study and get their feedback. They did agree with the FOLFIRI regimen. They had no objections to the 30 milligram dose that we proposed to take forward in phase III. The regimen dose were selected. The comparator arm is FOLFIRI/bev, which is based on the feedback that we received from the agency. We took the data that we had in hand to design the statistical powering. Based on the statistical powering, both in terms of ORR and in terms of the hazard ratio that we saw in the ongoing study, we have powered the study with more than 90% power to see a difference in PFS as well as ORR. We have the ability. The study is well powered to show differences both in ORR, PFS, and that got us to a total sample size of 640 or so patients. Also, the study is so designed that we have the ability to go for accelerated approval based on the strength of the ORR data plus durability. Of course, the same study can be used for PFS being the basis for full approval. This is going to be a global study with global registrational intent. There could be slight modifications in the study. I want to put it out there because we have sought FDA guidance but haven't received EMA guidance yet. We are working towards that. Got it. Just to clarify for the PFS assumptions, are you saying with anything more specific on that for the control arm versus treatment arms? We went with the hazard ratios we have in hand and built some conservatism into it. That's why we feel very, very confident of the numbers here. Got it. Okay. Worldwide study, 640 patients. How should we think about the cost study? Again, an excellent question. This is what keeps us working every day towards getting this to phase III. It is not a trivial size. It is one study for global registrational intent. The market is huge in terms of both U.S. and ex-U.S. patient numbers. The commercial opportunity is huge. We haven't quite given guidance on the total cost of the study, but since we've given the numbers, you can do your own math, anywhere from $200,000-$300,000 per patient, and then you have the number there. You know what? We are making sure that we get the company capitalized to support this. Like any biotechs, we continue to explore all options, dilutive as well as non-dilutive capital to bring in. Makes sense. For the study designs, PFS is going to be the approvable endpoint. With ORR potential for accelerated approval. Got it. Yeah. Okay. Would crossover be allowed in the study? How should we think about enrollment timelines? On the crossover side, I don't want to comment because we are going to be working with the European regulators as well, so I just want to make sure that we get all regulatory endpoints to get to that level. Your second one was enrollment timelines, right? A little too early to say. That said, we have been talking to global CROs, so that activities have been ongoing for the past few months. We're just coming out of ASCO. We had more such conversations. Lot of excitement both on the ex-U.S. side and within U.S. to open the study. I would wait till we select the CROs, do some site feasibility, deeper dive into it to give more guidance on how quickly we can get up and running. We're going to have many, many sites across the world to do this, so stay tuned as we get there. Got it. Going back to the FOLFOX versus FOLFIRI, we talked about this earlier where basically FDA thinks it could be fine for doctors to switch patients from FOLFOX to FOLFIRI. For the U.S. clinicians, do you think that could be an issue enrolling in the study in the front line? Yes. I sort of touched on that. One is, yes, the FDA strongly felt that way, and I can say that because I was in part of those conversations. Second, we have done some independent analysis, market assessment of our own. We have robust data there as well that suggests that based on the evidence that we would present with our current study, there is, even from our current study, that we don't anticipate any issues if we show that there is significant benefit added on top of FOLFIRI, that patients would switch from the FOLFOX regimen. From our coming out of ASCO, that is a third data point, having met with a lot of U.S. oncologists, GI oncologists. We hear nothing but that they're ready to open sites and get started with the study. Got it. Yeah. Okay. They don't anticipate issues that physicians wouldn't want to put patients with a FOLFIRI, bevacizumad, and onvansertib combination on study. Pretty good enthusiasm from- Yes. The doctors. I think driven by the strength of the data. Keep in mind, first line RAS- mutated population in metastatic colon cancer has not seen anything new. Forget about that. In non-EGFR, non-BRAF, there has been absolutely, RAS or wild type, there has been nothing new that has been approved in two decades. This section of patient population really needs innovative therapies, and we have evidence to show that this agent has potential to transform care there. This has treatment changing paradigm potential here. Yeah. It's really interesting, and there's been a lot of debate and discussion around RAS inhibitors- Yes. In the space. This could be a differentiated approach. As the RAS treatment landscape evolves, how do you position onvansertib primarily as a broad RAS agent, and how durable is that positioning over time? Yes, I'm glad that you asked that question because for those of us who came from ASCO, it was pretty transformative to see the kind of benefit pan-RAS inhibitors have provided in pancreatic disease. I also want to note, since I didn't, that in the metastatic colon cancer setting, an allele specific RAS inhibitor is approved, the G12C RAS inhibitor is approved, and it works. I want to acknowledge that. That said, based on our discussions with GI oncologists, they really don't see those pan-RAS, the current generation of pan-RAS inhibitors, having the same kind of benefit or having the same kind of outcomes in the colon cancer setting, primarily because of toxicities. In colon cancer, from what I understand, is you really need to add these pan-RAS inhibitors on top of anti-EGFR therapies and chemo, and those toxicities could be limiting. That could be the limitation. At least in the first generation of RAS inhibitors, and this is not my assessment, this is based on my personal discussions with GI oncologists, jury is still out whether they will be able to provide the same kind of benefit as pancreatic, given the toxicity limitations of combining with EGFR. I hope for the sake of patients that there are more second-generation, third-generation pan-RAS inhibitors emerge that have better tox profile. It's going to be great for patients to have more than one option, even in the RAS- mutated space in frontline. Got it. I do want to comment. Yeah. One underappreciated aspect of onvansertib, our PLK1 inhibitor, is the tolerability. Right. The reason we could move into first-line RAS- mutated space as our first indication is because of the tolerability of this agent when given with chemo, which is generally not the case. It's extremely unusual to go for a first-line indication as your first indication. Right. Yeah. Makes sense. Wanted you guys to comment on the current status of the Nerviano related IP situation. Any key highlights there? Yes. Again, I was waiting for that question. Just again, from a level setting perspective, we have proactively filed a lawsuit in the U.S. Federal Court of the Southern District of California. This emerged when we realized that our discussions with Nerviano, our licensor, from whom onvansertib was licensed a few years ago, had some dispute regarding inventorship on a Cardiff owned patent, a patent that emerged out of our clinical work, which extends our IP to 2043. There's certainly financial reasons involved here, and they asserted that they were an inventor, which we absolutely disagree and would fight our patents. We have proactively reached out to the courts to settle this and let us perform our obligations within the confines of the current agreement. Subsequently, Nerviano came back and terminated the license saying that there was a material breach. We absolutely disagree. We feel there is no breach, and we are performing within the confines of the current license agreement. Forget about a material breach. However, we already are in the courts, and we hope that the legal system would intervene and resolve this very quickly and so we can focus on our business at hand. Got it. That makes sense. We're out of time, so maybe in closing, between starting the phase III study and I guess how should we think about key catalysts ahead for the company? Yes. I think our focus single-handedly is to keep moving the program forward. We have initiated activities to start our phase III. In the meantime, ASCO was a big event for us, showcasing our data, engaging with the GI oncologists, U.S., ex-U.S., our CROs, and getting the company capitalized to support the phase III program. In the meantime, looking at indications beyond this current RAS- mutated colorectal cancer. As I said, something that we're looking closely at is CMML because it's a monotherapy relapsed refractory indication that we will continue to look at and see. Nothing approved there as well. Nothing at all in that setting. Got it. Mani and Josh, thanks so much for joining us today. Yeah. Thank you, Maury.