O nvansertib in RAS mutated metastatic colorectal cancer and plans to initiate phase three trials next year. Joining me today are Mark Erlander, CEO, and also Dr. Roger Sidhu, who's the Chief Medical Officer. Thanks so much for being with us today.
Thank you, Ted.
Thank you, Ted.
I thought maybe perhaps you could start off by describing PLK1 biology and its role in cancer.
All right, that's great. Let me get us started. PLK1 is a serine-threonine kinase, and it has been known for many years. It was discovered many years ago, and it is integral to the cell cycle. It really is required for cells and tumor cells to really be able to divide. It is a very important enzyme. What happens in tumor cells is that they overexpress it. PLK1 is overexpressed, and that then drives metastasis and also dependency on PLK1. One other thing I'll say about PLK1, it's been known for many years to be involved, like I said, in the cell cycle, really the G2 to mitosis M phase. What has now become much more appreciated in the last 10 years is its role in promoting DNA repair. That's why it has synergy with topoisomerase 1 inhibitors.
What we showed and published in JCO last year was PLK1's role in promoting angiogenesis. It is really a pleiotropic enzyme, and it is a really very interesting and exciting molecule that we are putting forward through the clinic.
That's really helpful background.
Target.
Tell us about, speaking out, tell us about onvansertib, and what are some of the distinguishing characteristics of it?
Yeah, I mean, it's no question, there's been no question in the literature that PLK1 has been a great target for cancer therapy. The problem has been that the molecules that have been generated to inhibit PLK1 have been pretty toxic. Really what we're bringing forward is the first in class, first molecule onvansertib to be able to be, was shown to be very well tolerated and be able to be combined with chemotherapies. Roger will talk about that later today. What's important is that it's because we believe that the reason for that is because of the selectivity. Onvansertib has a 5,000-fold greater selectivity for PLK1, which is the animal that we really want to hit versus other evolutionary related PLKs, PLK2 and PLK3 and PLK4. That is really, we think, a very key reason why we see the tolerability.
A couple other aspects is that onvansertib is an oral drug. Previous ones have been in IV. Third, it has a relatively short half-life, about 24 hours, versus previous PLK1 inhibitors had half-lives of like five days. We think all those things collectively, the specificity, the oral, the half-life, make this really a first in class. That is why we're being able to advance it clinically and combine it with chemotherapies.
That's again, really helpful. Walk us through the positive phase II CRDF-004 data. What did adding onvansertib to standard of care Avastin and FOLFOX, FOLFIRI, and first line RAS mutant colorectal show?
I'm going to pass that to my partner in crime here, Roger Sidhu.
Thanks. In terms of the CRDF-004 study, the goal was really twofold. One was to select a dose to move forward into a phase III study and also to estimate the efficacy and safety in combination with standard of care chemotherapy, and first line being FOLFOX and FOLFIRI with Avastin in the first line RAS mutant CRC population. What we were able to show is a few things. One is, in a very positive way, dose-dependent improvements across different measures of efficacy when adding onvansertib, in particular, objective response rate, confirmed objective response rate, and depth of response and early tumor shrinkage. In particular, with the 30 mg dose as opposed to the other 20 mg dose that's being studied, we observed a 19% difference in the confirmed objective response rate compared to standard of care in the intention to treat population.
In addition, though early, we did see some separation with respect to the PFS benefit with respect to onvansertib versus standard of care. Importantly, in terms of safety, though adding to two different active chemotherapy regimens with bevacizumab or Avastin, we didn't see significant increases in toxicity. Next year in the Q1 timeframe, we look forward to updating the data with a more mature look at durability, specifically PFS and duration of response.
I know it's early, but what did you, maybe you can go into that in a little bit more detail, what gives you confidence there?
I think it's for us really the totality of the data, though in July was an early look at the follow-up. We had about six months of follow-up at that time, given the median PFS in this disease state is anywhere from 10-12 months, depending on the study and the regimen that's used. We did see some signs of early separation, as I mentioned, with respect to, in particular, the 30 mg dose compared to standard of care. We're encouraged that in combination with some of the other metrics that we observed, like early tumor shrinkage and durability and also depth of response, that with more follow-up, we'll see even better durability data.
Was there any difference between FOLFOX and FOLFIRI?
As you know, they have different safety profiles, and we didn't see any significant increase in toxicity when adding to either chemotherapy regimen. Also, we were able to show at the July cutoff that we're adding efficacy to both chemotherapy regimens at this point in terms of objective response rate, early tumor shrinkage, and depth of response.
Yeah. It really speaks well to the benefit of adding onvansertib. Kind of taking our time with this a little bit, because I think this is really where the story is getting important. Obviously, we're going to get the update early next year. What are next steps from here, and what are some of the key components of a potential phase III trial?
Great question. I think for one thing, we do want to take a look at more mature durability data with respect to PFS and duration in the Q1 timeframe to help make those decisions. What we are interested in doing is getting alignment with the FDA on the design of a phase III registrational trial, which the goal is to position a single study that could serve as the basis for both accelerated approval based on a response endpoint and also full approval based on a PFS endpoint and without detriment in OS. We also look forward to getting alignment on, of course, the dose selection through Project Optimus and trying to get alignment on Project FrontRunner through the approval pathway.
How large do you think that trial would need to be, and what kind of follow-up do you anticipate you might need? How long do you think a phase III like that would take?
Those are all great questions. Unfortunately, we're just not able to really provide that guidance yet until we get alignment with the FDA.
Are there other cancers where it makes sense to develop onvansertib?
Absolutely. I think that some of the low-hanging fruit is in mCRC across different lines of therapy, potentially also in RAS wild-type indications. We also have proof of concept data from our investigator-sponsored program, in particular in triple-negative breast cancer, where there was an abstract that was presented just earlier this year at ASCO and also in small cell lung cancer, another indication. There really are a multitude of other opportunities for onvansertib in lung cancer.
Mark, when you look at sort of the development plan going forward, ultimately commercialization, does that make sense to partner onvansertib, or is this a drug that you think you can advance further yourselves? Would a partner potentially be able to help expand into some of these other indications?
I mean, I guess what I'd say is that everything's always on the table when it comes to those types of things. Our plan right now is to go forward independently to really push this forward into a registrational trial. Clearly, partnerships are always something that we evaluate. We're very excited about this program, and we really have got a unique molecule here, onvansertib, and we're looking forward to giving an update on the current trial in Q1.
Great. You guys ended the third quarter with cash of just over $60 million.
Yes.
How long does this fund the company, and what's it enable you to accomplish?
It allows us to be able to have one year of cash while when we put out our data in Q1. We do have cash going into Q1 of 2027. That gives us a whole year prior after putting out that data in Q1 of next year.
Great. In just the time that we have left, what are other mechanisms that might make sense? You talked about earlier on the angiogenesis aspect and obviously the combination with chemo and with BEV. What are other mechanisms that might make sense to combine with PLK1?
I mean, it's a great question. I think PLK1, as you know, is a very pleiotropic enzyme. We do see preclinical models, which we have reported in the last year at AACR. We see synergy with paclitaxel in the breast cancer space. That then led to the trial that Roger mentioned that was reported at ASCO, the investigator-initiated trial in triple-negative breast cancer, where we showed great activity with the addition of onvansertib with paclitaxel. In addition to paclitaxel, another area that we're seeing, we have a lot from preclinical work, a lot of synergy is with Enhertu, these new ADCs, particularly that one in breast cancer, because if you think about it, it makes sense because really the payload there is really a topoisomerase 1 inhibitor.
Just like why we got into colorectal cancer initially with HER2 genesis, we really started in second line, and we added to FOLFIRI, which is the irinotecan. We're seeing once again that same kind of synergy within HER2 and breast cancer in general preclinically. There is another huge area that we can move into. We also have seen single agent activity in small cell lung cancer, which we reported out as well. I think that we're really in the beginnings of what we can accomplish with this molecule, with onvansertib. I think right now, of course, what we want to do is continue to have a focus in colorectal, particularly RAS mutated, and really bring this forward. We look forward to talking about it next quarter.
I guess maybe one additional question. When you're looking at kind of transition from the phase, the next readout in the first quarter to getting up that phase III trial running, what really parts you mentioned speaking with the FDA and getting alignment, what are other aspects that kind of need to happen there to get that phase III operational?
I mean, obviously the FDA, like Roger was talking about, clearly also we would have to raise additional funds to be able to run that. That is the other thing that we're looking at. I think that that's the other step that we need to take.
Okay, great. Very exciting times for the company and really looking forward to the update and seeing the PFS data in the first quarter and then getting the phase III up and running next year. Thank you guys so much for being with us.
Yeah, it's been great. Thanks again.
Thanks, Mark.
Thanks for inviting.
Thanks, Roger.
Thank you.