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.
And for those who are less familiar with the company, can you give a brief overview of the company and your pipeline?
Sure. Pleasure. You know, we are focused on a target known as pololikinase 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 3. We've had some amazing data coming out at ASCO earlier this week, phase 2 randomized control data in frontline RAS-mutated metastatic colorectal cancer. Beyond that, we have been investigating this molecule in a number of solid tumors as well as heme malignancies, and of note is chronic myeloid 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 rasmidated colorectal cancer, where clearly there hasn't been any innovation in the last 20 years or so. And chemo and BEV seems to be the regimen of choice for most patients.
Yeah, it's a great overview and intro to the company. You mentioned ESCO, 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, you know, we've been lucky that we had randomized control data where our molecule known as unvancetib 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. and we saw activity predominantly in the full theory 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 so this is 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 plus percent 72% to be precise if you look at the comparator arms, whether it's Folfiri, Bev, or Folfox, Bev, the ORR there was what has been reported historically in the range of 42% or so. But 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. So it's great to see that patients on advanced combination with Folfiri specifically continue to do well. We are monitoring them. More importantly, the hazard ratios have been very, very promising and encouraging in the order of 0.55 or so, you know, approximately for any of the arms. That is a pretty remarkable hazard ratio in RAS-mutated disease in the frontline setting. And, yeah, we're looking forward to continuing to monitor these patients and see where we end up with the study finally. But 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. So we did a call yesterday with two of those, you know, KOLs. So we've been very encouraged with what we see, and we are ready to take the program forward into phase three development.
Got it. And that's a great summary of the data that you've shown. You're seeing this difference between FullFury and FullFox. You said this is the second time you've seen the benefit with FullFury. Maybe just talk about what could explain the difference in efficacy, the stronger responses you're seeing with the Folfuri combination.
Yes. And maybe before I address this, I also want to sort of note that we did complete our end of phase two meeting with the FDA earlier this quarter. And based on our interactions with the agency, we are taking the 30 milligram with the Folfuri BEV combination forward in phase three. regarding the differential outcomes in Folfox and the Folfiri arm. You know, Folfiri, this is the second time we've seen the responses. Mechanistically, 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, changeably, albeit that their toxicity profiles are quite different. Regarding their combination with unvancetib, there are certain mechanistic differences the way irenotecan, a component in Folfiri, and oxaliplatin, a component in Folfox work. Specifically, we have data, internal data, where irenotecan, along with unvancetib, inhibits a pathway that's involved in angiogenesis or new vessel formation through a molecule known as HIF-1-alpha. So it is interesting that both irinotecan and oxaliplatin have an anti-angiogenic effect. Put it on top of BEV, which is anti-VEGF, another anti-angiogenic effect. So 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 HIF-1-alpha at the doses that are used. So that's one differential. 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, but they have different ways of killing the cells through DNA damage. and plk1 is involved in dna damage repair pathways in the way that irenotecan causes dna damage so there itself you know so if you have irenotecan 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 so there are a couple different ways. And this is published in the literature. It's, you know, we're generating data there as well. So these are like really mechanistic differences. And also, you know, 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. So that could be another reason contributing to the lack of similar efficacy that we saw with full theory combination versus the full fox combination and advanced chip. So very long answer, but grounded in science and repeated
in two of our studies. Yeah. Yeah. I think a lot of details there. It seems like there's a decent amount of evidence supporting the different mechanisms between full fox, full theory. And presumably this was discussed with FDA in your meeting as well. Yes. You know,
of course, FDA goes by evidence-based, you know, science. They saw the efficacy in Folfuri. In fact, they guided us to keep our phase three pretty simplistic. So we did release our, you know, phase three design that we have come up with after getting guidance from the agency. They were fine with taking the molecule forward with Folfuri combination. And our phase three looks at one-to-one randomization of the 30-milligram arm given with Folfuri Bev versus Folfuri Bev alone. And they did tell us that Folfox and Folfuri are very similar in efficacy. So if we are able to repeat and show the kind of efficacy we showed in our phase 3, there is no reason why patients wouldn't switch where there's no reason why physicians wouldn't switch patients from the Folfox to Folfuri plus on Vansative combination should our phase 3 be positive.
Got it. Interesting. Okay. And you reported several cases of 100% lesion reduction in the 30-mig cohort. Have those patients shown more durable responses than the broader population?
Yes. So 100% reduction in the target lesion, you know, 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, and the number of patients who went on curative surgery were the largest in the 30-milligram advanced plus-fold-fury-bev arms. So 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. But we will see if we can release patient-by-patient data in the months to come, yeah.
Okay, so that's something that you're continuing to do more work on. I guess, are there patients who are, like, super responders or more likely to respond, and could you potentially enrich for that?
Yeah, so generally what you see is deeper responses do contribute to better durability. You know, again, not trying to evade it. You know, I don't remember at the top of my head, but yes, I mean, that is generally the case if you have very deep responses. And in our case, we even saw deeper responses much early on, and in totality, they contribute to the BFS benefit overall.
Got it.
Okay. And as a note, you know, four patients on the 30 milligram, nine patients out of the 14 that are still on treatment are on unbancetib plus folferi bev arm. And out of that, four patients are on the 30-milligram arm. So there are quite a few patients still on treatment with invansative and full-fury-bev regimen.
Got it. And the hazard ratio in the 30-mig cohorts, it's compelling, but you could argue that confidence intervals are wide. What gives you confidence you can reproduce a similar magnitude of benefit in the phase three?
So, I mentioned, you know, we've looked at many different ways, the confidence intervals, they all sort of point in the hazard rate, I mean, sorry, the hazard ratios in multiple ways. Very, 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. So your question was the confidence intervals are wide, which is true because this is a phase two 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 Folfuri combined. So 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. So that gives us a lot of confidence in the activity of an vansative as a strong active agent. And in the 30 milligram arm, the number of patients were around 17 or so. There, the confidence intervals are wider, but not as, I mean, unexpected. So 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 three. Now, in phase three, you don't have to get to a 0.5 interval, a 0.5 hazard ratio. You know, of course, we build some conservative estimates, you know, in designing the study. the success is not just 0.5. You know, there's many other things between 0.5 and beyond. You know, you can get higher than 0.5 and still meet success.
Got it. Okay, so overall, no matter how you slice and dice, the hazard ratios give you confidence that...
Yes. Hazard ratio combining with the suboptimal dose and still getting compelling hazard ratio, yes, all of that in the totality of the data. And two studies, actually. we keep forgetting that, you know, there's a prior study which had PFS benefit also in the same range that we see. I mean, there the PFS had been reached. Here we haven't. But ORR was very
similar. So, yes. Okay. And there's our differences between the BICR and investigators as PFS. We talked about this. 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 three assumptions?
Yes, I'll start by saying that there is a reason that, you know, there's bicker analysis and investigator analysis, mostly confined to phase three registrational studies because there is always a discordant between local reads and central reads. We also had it. It is unusual to have bickers as a read in phase two studies, but we are lucky, and that gives us more confidence and conviction in our data. And 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. So Bicker really didn't get to see the read of, you know, the subsequent reads of radiographic analysis from patients who were taken off study by investigators. So they got captured as, you know, as events in the investigator assessment arms, whereas by Bickr, they were not deemed progressives because they just didn't get the read. So that was inherently, you know, there. And when we get to the phase three, you know, you generally make sure that the local sites make decisions after getting the Bickr to see the data.
Got it. Okay. Yeah, that makes sense. And for OS, what's your early read for the 30-mig versus control? And are you starting to see any differentiation? And when could you expect an update for the KM curve?
Yes. So still early days. This was a first-line study. So we are monitoring patients who have either 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, you know, statistically significant differences in survival or anything like that. You know, the survival was not a formal endpoint, but we will – it's early days, but we will continue to monitor and see if over time we start seeing a survival difference.
Got it. Okay.
But certainly more patients came off because of progressive disease in other arms versus the 30-milligram arms.
Okay. And how are you thinking about the control arm recruitment and compliance? Are you seeing any physician preference for full FOX BEV in the front line that could make full fury BEV less attractive in this setting, specifically in the U.S.?
Great question. Actually, just as a background, FOLFOX BEV as a regimen is more used in the U.S. Both FOLFERI 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, FOLFERI is the regimen of choice by most physicians and patients versus FOLFOX, but they're both used. As you can see, our first study, a phase two study, which is a 110 patient study, decent number, we were able to enroll without any issues in the U.S., despite Folfox-Folfiri differential preference. The phase three study is going to be a global study, so we do have the benefit of going into countries where Folfiri is the treatment of choice. That said, I am coming from ASCO, so 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 our study with full fury 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, you know, Folfiri is the regimen of choice, you know. Oncologists are very, very data-driven, unfortunately, because of still poor outcomes with current therapies, so they would follow where the data is and the patients are willing to participate.
Got it. Okay. Yeah. That's helpful. And maybe let's jump to the phase three design. So 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. But, no, you know, we're very fortunate that from an ongoing phase two study, we got enough strong signals that we were able to go to the FDA and have a formal end of phase two meeting, a type B end of phase two meeting, and be able to share data from an ongoing study and get their feedback. So they did agree. They did agree with the full FD regimen. They had no objections to the 30 milligram dose that we proposed to take forward in phase three. So the regimen dose were, you know, selected. And 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. and 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. So we have the ability, so 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 and 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 and of course the same study can be used for PFS being the basis for full approval. And 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. So we are working towards that.
Got it. And just to clarify for the PFS assumptions, are you saying anything more specific on that for the control arm versus treatment arms?
so um we we went with the hazard ratios we have in hand and built some convert uh conservatism into it um so so that's why we feel very very confident of the numbers here got it okay and um
worldwide study uh 640 patients how should we think about the cost study again an excellent
question this is what keeps us um you know working every day towards getting this to phase three it is not a trivial size you know it is one study for global you know global registrational intent the market is huge in terms of both US and ex-US 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 make your own you can do your own math anywhere from 200,000 to 300,000 per patient and then you have the number there and you know what we are making sure that we get the company capitalized to support this and like any biotechs we continue to explore all options dilutive as well as non dilutive capital to bring
in makes sense and for the study designs PFS is going to be the
approvable endpoint um or our potential for accelerated approval got it yeah okay and um
would crossover be allowed in the study and how should you how do you how should we think about
enrollment timelines so on the crossover side you know 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 um and uh 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, a lot of excitement, both on the ex-US side and within US to open the study. But 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. But we're going to have many, many sites across the world to do this. So stay tuned as we get there.
Got it. And going back to the full Fox versus full Fury, we talked about this earlier where basically FDA thinks it could be fine for doctors to switch patients from full Fox to full Fury. For the U.S. clinicians, do you think that could be an issue enrolling in the study in the front line?
So I sort of touched on that. So one is, yes, the FDA strongly felt that way. And I can say that because I wasn't part of those conversations. Second, we have done some independent analysis, market assessment of our own. So 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 FOLD theory, that patients would switch from the FOLD FOX regimen, But, you know, from our coming out of ASCO, that is the 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.
They don't anticipate issues that physicians wouldn't want to, you know, put patients with the full theory, Bev, an advanced combination on study. So pretty good
enthusiasm from the doctors. Yes.
I think driven by, I think, the strength of the data. And 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. So this section of patient population really needs innovative therapies, and we have evidence to show that this agent has potential to transform care there. So this has, you know, treatment-changing paradigm potential here.
Yeah. Yeah, it's really interesting, and there's been a lot of debate and discussion around RAS inhibitors in the space. This could be a differentiated approach. As the RAS treatment landscape evolves, how do you position on Vincertiv primarily as a broad RAS agent, and how durable is that positioning over time?
Yes, so 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. And 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. So 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. Because 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. You know, that could be the limitation. So 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, you know, jury is still out whether they will be able to provide the same kind of benefit as pancreatic, given the limit, the toxicity limitations of combining with EGFR. You know, I hope for the sake of patience that there are more, you know, second generation, and third-generation PAN-RAS inhibitors emerge that have better tox profile. So it's going to be great for patients to have more than one option, even in the RAS-mutated space and frontline.
Got it.
And I do want to comment. One underappreciated aspect of an Vansetip RPLK1 inhibitor is the tolerability. 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 first-line indication as your first indication.
Right. Yeah. Makes sense. And I wanted you guys to comment on the current status of the Nerviano-related IP situation. Any key highlights there?
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, and this emerged when we realized that our discussions with Narviano, our licensor, from whom Onvancetive 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, so there's certainly financial reasons involved here, and they asserted that they were an inventor which we absolutely disagree and would fight our patents. So 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, Narviano came back and terminated the licensing 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 And we hope that the legal system would intervene and resolve this very, very quickly. And so we can focus on our business at hand.
Got it. That makes sense. And we're out of time. So maybe in closing, between starting the phase three study and I guess how should we think about key catalysts ahead for the company?
Yes. So I think our focus single-handedly is to keep moving the program forward. we have initiated activities to start our phase three. You know, in the meantime, you know, ASCO was a big event for us, showcasing our data, engaging with the GI oncologists, USXUS, CROs, and, you know, getting the company capitalized to support the phase three program. And in the meantime, looking at indications beyond phase, you know, beyond this current RAS-mutated colorectal cancer and 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. Thank you, Mari.