Hi, and welcome to our next session. I'm Robert Burns, a Managing Director and Senior Biotech Analyst at H.C. Wainwright. I'm joined today by the CEO of Cardiff Oncology. Mani, thank you for joining us today.
Thank you, Robert, and I also have my colleague, Josh Muntner, our CFO here with us, and thank you for inviting us, and we look forward to the discussion.
Awesome. Sounds good. I think I'm going to rejigger the question list now, given the major news that you released this morning. Why don't you provide an overview of that press release, and maybe go into the structure of this rejiggered agreement with Nerviano?
Yes. We are quite pleased that we have reached a settlement with our licensor, our partner, Nerviano Medical Sciences, out of Italy. We had licensed the molecule from them back in 2017, and we had some dispute that we were litigating in the courts, but I'm pleased that that is over. We have an out-of-court settlement, and the two parties will mutually resolve each other of all claims. Some of the key highlights about this settlement are, number one, that we will collaboratively focus on taking onvansertib forward in phase III for patients. I think that is the most important thing. We retain exclusive worldwide rights to the molecule and its development and all decision-making. We maintain our inventorship. There has been no changes to the patents. They continue to be Cardiff patents. The royalty rates remain the same.
There has been some extension in terms of the period of royalty, and we have filed an 8-K, so if anyone's interested, they should look into additional details about this resolution in the 8-K. We would continue to work collaboratively, seek their input, but final decision-making remains with us, and they have a board observer seat that they will also get as part of it, an observer seat.
Okay. Maybe you could go into that little royalty modification a little bit more. So you said there's an extension in the period with which Nerviano will be able to receive royalties. What was it previously, and what is it now?
The royalties are generally tied to valid claims, or patents. The prior agreement obviously was tied around the composition of matter patents that we had licensed back in 2017. With patent term extension, that term was to go to 2035. Without going into specific details, which we have not disclosed, that term has been extended.
Okay.
It wasn't a term set in stone, but I'm saying that the patent term extension would have taken this to 2035, and now it's definitely been extended.
Okay. We know that you had an end of phase II meeting with the FDA, where you aligned on key elements for the planned registrational trial, evaluating onvansertib 30 mg, plus FOLFIRI/bev, in that first-line RAS mutated metastatic colorectal cancer setting. Maybe you can walk us through the trial design with regards specifically to primary and secondary endpoints, patient enrollment size, and what you expect that to be, as well as the control arm agreed upon with the agency.
Yes. There are quite a few questions in one. I do want to start by just summarizing the promising data that we released at ASCO earlier, and especially in RAS mutated first- line colorectal cancer, an indication which hasn't seen any new therapies come in for the last couple decades, almost. It's pretty much the standard of care has been chemo combinations with bevacizumab, which is an anti-angiogenic agent. As our data showed, that was a randomized controlled study with two different doses of onvansertib, our PLK1 inhibitor, along with two predominant standard of care regimens that are used. One is FOLFIRI/bev, and the other one is FOLFOX/bev. Our benefit was predominantly in FOLFIRI/bev.
Not for the first time, but this is the second time we showed that the drug, onvansertib, works best when combined with FOLFIRI and bevacizumab in first- line. So, where we had reached an overall response rate of 72% versus 42% or so in the standard of care arms. Based on that, our discussions with the agency have been very productive. We have a dose that we would take forward. That is the 30 mg dose, which showed the most benefit in combination with FOLFIRI/bev. We have agreed on the regimen to take forward with the FDA, FOLFIRI/bev, and they gave us guidance for a simplified trial design based on which we came back and have now designed the study as a one-to-one randomization to FOLFIRI/bev, which is one of the standard of cares.
The second arm is 30 mg of onvansertib to be combined with FOLFIRI and bevacizumab in patients with first- line prospectively selected for RAS mutations and all RAS mutations. That is the key. Our phase III design is currently designed to enroll around 640 patients between those two arms. The agency did allow us to go for accelerated approval should the data be compelling, which is based on overall response rate, as well as some durability. The same study can continue for full approval based on PFS too.
Okay. Maybe talk to me a little bit about the statistical analysis assumptions you are using for PFS. Right? Obviously, we saw that 72.2% objective response rate at ASCO. Based on that analysis, where do you think that the PFS will come in? How are you designing that statistical analysis there?
We have obviously not disclosed the entire statistical plan. However, I again want to remind you that in the data that we released at ASCO, by the way, our phase II is still ongoing, the PFS in the two standard of care arms was what has been previously reported between 11 to 12 months, and we have not reached median PFS in the onvansertib arm in combination with FOLFIRI/bev. As of the time of ASCO results, we had not reached median PFS. It is difficult for me to go into all the details at this point to reveal that. But I will say that we have powered the study well for PFS. There is greater than 90% power that we should be able to show a difference in PFS that is clinically meaningful.
Okay
along with overall response rate.
All right. Well, when we think about the first-line RAS mutated CRC competitive landscape, obviously it remains highly underserved. We have seen a few data sets for these specifically targeted RAS variant molecules, so KRAS G12C and KRAS G12D. How does a broader pan-RAS downstream approach via PLK1 inhibition position onvansertib to capture a dominant market share relative to those specific allele-targeted inhibitors that only narrowly target a small subset of these patients?
Yes. As you said, they target a small subset of these patients, and the ones that approved right now is G12C specific, and the G12Ds are in development. Beyond that, G12C is just for your reference, it is around 4% or so of the mCRC first-line indication. They do have to be combined, by the way. Now, there are pan-RAS inhibitors in development, and we are going for pan-RAS indication, by the way. But it is not as easy to bring pan-RAS, which by the way, it has been an amazing advancement in PDAC, pancreatic cancers, with the pan-RAS inhibitors. But the biology of the two cancers is very different. For colon cancer, it is not so straightforward to bring a pan-RAS inhibitor because they have to be combined with an anti-EGFR-based therapy because there is an escape mechanism or a feedback loop through EGFR and wild-type RAS.
PLK1, and again, this is going into too much of a scientific details, is not a downstream molecule. It is a parallel path. There is synthetic lethality between PLK1 inhibition in cancers that have RAS mutations. So it is a very parallel path, and hopefully, the potential for mutations and all are not there, or resistance is not there. So we think it synergizes very well in cancer, where there are RAS mutations, irrespective of the allele-specific mutations.
Okay. So, in your 2Q update, you stated plans that you plan on initiating the registrational trial in 1Q, subject to additional financing. Maybe talk to us a little bit about what sort of financial mechanisms that are currently on the table in order to fully capitalize on that phase III trial, whether that be strategic partnerships, royalty monetizations, or even secondary offerings. How are you thinking about funding this trial and sort of, given the size of the expected enrollment, what sort of funds do you think you would need in order to complete that trial?
Yes. So one, let us start with the last part first. How much money do we need? I think that is the biggest question on everyone's minds. We have not given specific guidance as to how much money is needed, but again, if you do the math, anywhere from $200,000-$275,000-ish or so per patient costs are what is industry standard. So you can come to some conclusion as to what would the trial cost. Now, in terms of mechanisms of getting the study funded, we have said that our goal is to get the study up and running in first quarter of next year, pending funding, and we still stand by that. We are spending a lot of this time preparing for this global phase III study. This is going to be a global phase III study with global registrational intent. We have talked to the FDA.
We are going to start up on. We are already in conversations with the European agency, a regulatory agency, and there's a lot that needs to get done. There are just like for any other biotech, we are going to pursue multiple ways of making sure that we get the company capitalized and the trial financed, be it by tapping the capital markets or looking into non-dilutive funding, be it by collaborations, regional collaborations, and any other mechanism that companies like us seek.
When we think about the opportunity for onvansertib outside of colorectal cancer, how do you see the evolution of onvansertib's clinical trial development sort of evolving over time into other sorts of indications?
One of the mechanisms that we at Cardiff have sort of gone into to look at into life cycle management or pipeline expansion, so to speak, is by mechanism of investigator-initiated studies. We have a number of investigator-initiated studies that allow us to pick should there be any promising signals in any of the other cancer types, and the few that are ongoing are in CMML, chronic myelomonocytic leukemia, small cell lung cancer, pancreatic, and triple- negative breast. The one that I actually will sort of want to highlight is CMML, chronic myelomonocytic leukemia, relapsed refractory setting. Nothing is approved for patients in that setting. We have started seeing some promising signals there from this investigator-initiated study from Mayo Clinic. Here we are using onvansertib in monotherapy.
It is not combined with any other agent in a patient population where overall survival is less than a year. The drug is showing some clinical benefit, and these data were actually presented at ASH last year, 2025, by the investigator. This trial is still ongoing. You see benefits. This was MPN like CMML. There were benefits in thrombocytopenia, spleen size reduction, even marrow blast control. They are promising signals, so I just sort of wanted to highlight that between the various investigator-initiated studies, we are already seeing some that are showing more promise than others.
Okay. Maybe you could walk us through the market opportunity here and patient sizes, other potential treatment-eligible patient population sizes for both CRC. I am curious about the CMML as well.
CRC, it is a big market. There are 150,000+ patients who are diagnosed with colon cancer, and as you may know, more and more younger patients are getting diagnosed. I do want to say, if you go back to the data, we have done some forest plot analysis. Despite a small number of patients, we do see that our drug shows benefit irrespective of the age of the patients. We had patients who were on liver meds, multi-organ involvement, and across many of these baseline characteristics, our drug candidate did show benefit. But out of the 150,000 patients, a good size, a good proportion, a fourth or so of those patients become metastatic. The drug that we are using is for RAS mutated, which is approximately 45%-50% of the frontline patients who have RAS mutations, KRAS and RAS.
Mm-hmm. Okay.
CMML, it is a rare disease. It is a rare orphan kind of disease. The numbers are still out there, but certainly less than 250,000 or so. However, the numbers are less because these patients are misdiagnosed. They are either diagnosed as MDS or MPN because there are no therapies available, and especially in relapsed refractory setting, the HMAs, the hypomethylating agents are approved in the first-line setting. There has not been great deal of diagnosis. What we hear anecdotally from experts in the field, that there are more patients than we think that is out there.
Okay. Going back to the trial design for your phase III in colorectal cancer, you say that there is an interim analysis which could support accelerated approval, and then PFS would eventually, potentially support full approval. Talk to me a little bit about the timings with which you think that you could get to that interim ORR analysis for accelerated approval, and ultimately for the PFS as well.
You have to wait for the trial to initiate to help us give you full guidance, given there is a lot more math involved in figuring out worldwide enrollment. It is not just in the U.S., depending on the countries we choose, so stay tuned for that. However, it is not really an interim analysis. We will wait for all patients to be enrolled in the study to get to an ORR analysis.
Which could support an accelerated approval should the data hold. It is not really an interim analysis in that way, however, the study continues for full PFS assessment down the road. Typically, it takes, again, without giving very specific guidance, but industry-wise, could it take between 18 to 24 months in enrollment and whatever other time is needed for PFS.
I guess the last question from me, since we are coming up on time. What other calls can investors expect over the next, let us say, 12 to 18 months? I know that you said that we have not really seen what the mPFS is as of yet for CRDF-004, so I am curious when we might be able to sort of get a glimmer as to that data point specifically.
Yes. As of the ASCO data, the mPFS in onvansertib plus FOLFIRI/bev had not been reached. When we released our quarterly results, we mentioned that there were 12 patients still on study, out of which eight patients were on either 20 mg or 30 mg onvansertib plus FOLFIRI/bev. We didn't give any guidance on median PFS, but we will continue to follow these patients, and depending on when the data emerge, whether it's in conjunction with a medical meeting or otherwise, we will release those data.
Okay. That's really all the questions I have. Are there any questions from the audience today? All right. Well, Mani, thank you for joining us today.
Thank you.