Good morning, everyone. Welcome to the second day of Wells Fargo Healthcare Conference. I'm Adam Vogel, one of the mid-cap biotech analysts here, and this morning, we have the pleasure of hosting ORIC Pharmaceuticals. And with us today, we have CFO Dominic Piscitelli and CBO Matthew Panuwat. Gentlemen, welcome back.
Yeah, thanks for having us at the conference, Adam. We appreciate it.
Absolutely. So maybe for those who are new to the story, we can start off with, like, high-level overview of the company and then dig into some more detailed questions from there.
Sure, that'd be great. ORIC Pharmaceuticals is a clinical-stage oncology company. Our name really encapsulates our mission, which is to overcome resistance in cancer. Given the team that we've assembled, our strategy is really focused on three therapeutic areas, which is prostate, lung, and breast cancer. And again, given the team and the capabilities that we've built out in-house, we do have kind of a two-prong approach to building out the pipeline. We have full internal research and development capabilities, and we complement that with opportunistic business development opportunities, which Matt leads for us.
Right now, we have two lead programs in the clinic. Our first program is ORIC-114. This is a brain-penetrant EGFR/HER2 exon 20 program that we'll talk about a little bit later, and the second is ORIC-944. This is an allosteric PRC2 inhibitor that we actually in-licensed from Mirati, and here we're pursuing it in prostate cancer, which is currently in a combination study with the AR inhibitors. So let me stop there, and we can dive deep into the questions.
Absolutely. So let's start off with ORIC-114. Maybe we can revisit the data that you shared at ESMO last year. Maybe walk through, you know, what you presented there and any additional data you can provide us with since then-
Yeah
What supports this advancement? Yeah.
Sure, I'll take that one. So, just a reminder, ORIC-114 is our EGFR exon 20, inhibitor that we in-licensed a few years ago. What we actually really liked about the program was a couple things. I think, one, it was prospectively designed to be an exon 20 inhibitor, so it was very specific to those types of mutations, when at the time we in-licensed the program, there wasn't any other ones like it. The second distinguishing feature is that it was designed to be brain-penetrant, and so the preclinical data, that supported that was compelling in our view, and so that we felt was also missing in the exon 20 landscape, which there are a number of programs out there. There have been many before, that haven't advanced, and there are now some that are actually approved.
And so those were the two differentiating features. Our clinical study that we designed is actually different than everybody else's. One is we allowed patients that were previously treated with anything else, and so patients that had previously been treated with an exon 20 inhibitor were allowed in our study. And over 80% of those patients actually had a prior EGFR exon 20 regimen. Secondly, we allowed patients with brain metastases into our study. That's typically a pretty significant exclusion criteria to other studies. Most notably, we allow active brain mets, and so you're able to come into our study not having prior radiation if you actually have, you know, progressing brain mets. And so those are distinguishing features.
We mostly designed that study, again, a very difficult study, enrolling very difficult patients, really because we wanted to make sure that our program was differentiated. You know, we were not the first EGFR exon 20 inhibitor, so we wanted to make sure it was doing exactly what it was doing. We presented the initial data at ESMO last year, and in our view, you know, we showed exactly what we wanted to see. We saw confirmed responses in patients that were previously treated with amivantamab, which is the approved therapy, as well as chemotherapy, as well as mobocertinib, which was an approved therapy before, is now withdrawn from the market. And secondly, we saw really compelling brain activity as well.
You know, one of the case studies that we reviewed during ESMO last year was a patient that had failed amivantamab and had failed chemotherapy, was progressing with active brain metastases. The brain metastases has not yet been treated. We saw a confirmed complete response in the brain. We saw a confirmed systemic response, and that patient was still on therapy and responding, you know, at nine months at the time of presentation. So we thought that that was kind of the perfect case study for our molecule that really shows the differentiation. That was type of data that we haven't seen yet from another EGFR exon 20 inhibitor, so we're very excited by that.
We have also seen some activity in HER2 exon 20, a closely related mutation, and since then, we have been looking at our molecule in atypical EGFR mutations as well, and so we thought that the initial data that we presented at ESMO last year was supportive of advancement of the program. We announced earlier this year we are moving forward in expansion cohorts in all three of those different mutation types.
Yeah, and just to add to that, I think right now, when you look at the current landscape, there's two things that we think we differentiate ourselves on, right? It's the safety aspect of it, and the safety really is sub two subgroups. I'd say that's kind of on-target tox in the form of rash and GI issues, and then kind of the off-target tox, where you see some of these other agents have, you know, elevated liver enzymes, prolonged QTc, and other off-target tox. If you look at the kinome screens that we have on our deck, you can see that, again, it's specifically designed to be selective, and they were really clean kinome screens.
The second thing on the CNS activity, we think this is super important, and the reason for that, if you look at the data, you know, 35-40% of these patients do present with baseline brain mets. And again, if you look at the data, the point of first progression for a number of these patients, even if they did not have baseline brain mets, is the brain. So we do think this is a severe unmet medical need, so hopefully, this is what we're looking to show in our current study as well.
Wonderful. Have you provided any updates on the patients that had complete responses? Are they still on drug? Have you seen additional complete responses or partial responses since ESMO?
Yeah, we haven't provided any further update on that study. Again, that was dose escalation data. What we did say is we'll provide an update in the first half of next year. That update will really be focused on the expansion cohorts that we started first half of this year. So in the first half of this year, we did announce that we selected two provisional RP2Ds. Those doses were 80 milligrams and 120 milligrams once a day.
Again, this is really to satisfy Project Optimist, and we're enrolling three groups of patients, so the EGFR exon 20. Here, we're actually, these patients have not seen a prior exon 20 inhibitor, so this is more comparable to what others have shown previously. We have HER2 exon 20, and then the atypical EGFR as well. So these are the three cohorts of patients we're enrolling, and we said we'd provide an update in the first half of next year, on that study.
Okay, perfect. So maybe, if you don't mind, can you elaborate more on provisional phase two recommended dose? Like, what flexibility you have there? Like, what data do you need to see convincing that's going to let you move forward with either the 80 or 100
Yeah
daily dose, or like, you know-
Yeah, yeah.
Potentially dosing up?
Yes. I think at the time of ESMO, we showed up to, I think, it was 75 or 90 mg once a day. Again, the drug was well tolerated. We had no grade three rash and, you know, low rate of grade three diarrhea. We were able to push the dose to 120, so the FDA does require you to kind of test two doses. Basically, what they're looking to see, that you can see if you can see the same level of efficacy at a lower dose. So we do believe out of those two doses, we should be able to select RP2D in 2025. And assuming it's a go decision, we would start a registrational study in the second half of next year. Now, given the unmet medical need with CNS.
With not being a CNS active agent out there, we do think there's an accelerated approval path forward there as well. So that could be a single arm study, looking for a surrogate endpoint there, as well. So again, we could see. Now, that could be, you know, could be one of those cohorts, could be two of those cohorts, could be three of those cohorts, or could be none of those cohorts. So we'll have to look at the data and determine whether it's a go or no go in 2025 , and then we're going to move forward with that program as well. We do take a very objective approach on this. Obviously, we understand the competitive landscape. So far, we believe we have a differentiated program. Obviously, we need to show that in this data set as well.
Great. So safety is not holding you back to dose up to 120 if that's, yeah-
That's right.
where the data is pointing you?
That's right.
Okay, great to know. And then maybe on those cohorts, right now, you are phase I-B, patients that have active metastases in the brain. That's an inclusion criteria. Is this like, is this going to be a patient population or inclusion criteria for advanced trials, too, and potentially registrational trials?
Yeah. Matt, you want to take that one?
I think that's a great question, and so that's you know maybe just a quick step back where we you know look at the other targeted lung cancer therapies. You know we really felt that to have a best-in-class molecule in lung cancer you really have to have brain activity. And I think we've seen that with other targeted therapies in the EGFR classical mutations osimertinib for example. We've seen that in the RET inhibitor space in the ROS inhibitor space, and so we felt that that was always missing in the EGFR exon 20 space. It's not necessarily that you're just targeting the patients with brain mets but it's also important that you actually have you know comparable hopefully improved systemic response as well. And I think that's really what we're looking for.
What we've seen with other molecules, you know, the early generation ones, amivantamab and mobocertinib, for example, they have published this in their data. They actually see a lot of their patients progress with brain mets. And so that was the site of first progression with the mobocertinib data, which doesn't have brain penetration. And even though they had pretty extensive exclusion criteria on what types of brain mets were allowed, that was the first site of progression. And so we think that having a brain-penetrant molecule will actually give you more durable, you know, responses in the long term. And so that's kind of what we're hoping for. There are potential registrational strategies, we believe, to enrich for, you know, brain metastases and things like that, given that the current approved therapy, you know, excluded that from their label.
We estimate that that's at least a third of the patients. So there's a pretty significant group of patients that aren't well served from the approved therapy. And from a vast majority, if not almost all, of the currently ongoing clinical studies, they exclude those types of patients. And so what's interesting, what we saw from phase I data that we presented last year, over 80% of our patients in our study actually had you know some form of brain metastases. Not all of them were active. That was a pretty significant percentage of patients, mostly because they didn't really have another study to enroll in. And so we did see you know probably a higher percentage of those patients. So that's something that you know will be interesting to see in our later data sets.
But it does give us flexibility to, you know, one, enroll patients. There could be some, you know, unique development strategies, you know, based on that as well.
Gotcha. Thank you for the color on the market opportunity, too. One third of the patients, that's significant, yeah, upside there.
We think so, yes.
Yes, so then ultimately, where are you looking to position 944 in the treatment algorithm? Is this, you know, going to be a frontline therapy? Is it going to be in combination with chemo, or is it going to be reserved more for, like, patients that are intolerant or post-chemo?
Yeah, that's a great question. So the current expansion cohort patient base, this is monotherapy, single-agent studies, and again, this is more of a mix of patients. I'd say more second-line patients. If you look at EGFR exon 20, a large majority of those have failed chemo, probably in that study, since we're not allowing prior EGFR exon 20 inhibitors. When we think about the first-line strategy, I think there's a couple options that are open to us, and you know, there's a chemo combination, which you've seen amivantamab do, and I think that's what Cullinan is doing as well, where you're combining with chemotherapy, and the control arm there is chemotherapy as well. That's where, you know, amivantamab currently has its label based on the PAPILLON study, as well. The second strategy that people are doing is monotherapy.
That's what mobocertinib did. Unfortunately, that study did not read out positive, but there are other companies like Dizal and ArriVent that are doing, you know, single agent versus chemo as kind of their first-line strategy. A third option that we're kind of contemplating thinking through is a potential combination with amivantamab. The beauty of that is, amivantamab is obviously approved in chemo and first line. If you look at the New England Journal of Medicine that was published just last year at the time that they presented their PAPILLON study, if you look at it, it is a subset analysis, and you can, it's clear that patients with baseline brain mets do less well on the combination, so it is an unmet need.
So that could be an interesting combination, where you combine an EGFR inhibitor, TKI, with an antibody, as well as it has the MET component, which could be a benefit of certain resistance to EGFR inhibitors as well. So that's an option. Obviously, we'd have to test that in the clinic. We'd have to see the combination wasn't too toxic, but that is something that we think could be an option that's available to us because of the differentiation on the CNS activity.
Gotcha. Okay. So we have expansion cohort data coming in first half of 2025 with the recommended phase II dose, potentially. Are there other key milestones to the program, that we should be keeping an eye out for in?
No, I think again, that those are the key milestones that we've kind of talked to. Again, the goal, assuming a goal scenario, would be that we'd start the registrational studies in the second half of next year. We are prepared to do that. You know, the team that we've assembled does come from, the clinical team in particular, comes from Ignyta, so they've got a lot of experience in developing, you know, TKIs, CNS penetration TKIs in oncology. So that's, that's the current baseline, assumptions that we're using right now in our, in our runway, as well as our overall strategy.
Gotcha. Okay. So, maybe we can then segue into your other molecule, ORIC-944, your... Sorry, your PRC2 inhibitor. Could you maybe just walk us through the biologic rationale of this molecule and why it makes sense to go after prostate cancer?
Yeah, I'll start that. Matt, feel free to chime in. So if you look at the PRC2 complex, it's got two druggable subunits. One is EZH2, and the second is EED. Most people are familiar with EZH2. If you go back to GSK, Constellation, Epizyme, they've been exploring the EZH2 inhibitor in prostate cancer, both as a monotherapy and in combination for many, many years, a strong biological rationale. What we really like around this program is this program was in-licensed from Mirati Therapeutics back in, I think it was August of twenty twenty, and what Mirati did is really take an objective approach, and they profiled a number of PRC2 inhibitors, both EZH2 inhibitors as well as EED inhibitors, and what they discovered was basically based on the preclinical data profiling they've done, what is now ORIC-944, was the best compound.
Now, if you go back and you look at their first-generation EZH2 inhibitors, they were really plagued by two key issues, one being drug properties, so they had very short half-life, and the second one, also drug properties, is they had this CYP autoinduction issue, and what I mean by that is, if you look at some of the first-generation EZH2 inhibitors, as they increase dose, they have less exposure as well. So these are issues that they've had. Obviously, Pfizer has an EZH2 inhibitor that I'm sure we'll talk about a little bit later, but they seem to have solved kind of one of the two issues. They don't seem to have the CYP autoinduction, and they have slightly improved the half-life as well. The clinical rationale here, the biological rationale is obviously complex here. It's all about combinations.
So if you know about the AR inhibitors like enzalutamide, apalutamide, and darolutamide, and it's a great treatment options for patients with prostate cancer. Over time, however, these patients do gain resistance to the AR inhibitors, and they progress. What the logic here is basically that these prostate cells become more AR-dependent, and they transition to more an independent state. With these epigenetic modifiers like ORIC-944, like Pfizer's Mevo, what basically is happening is we're pushing these cells to a more AR-dependent state, and basically synergizing with the AR inhibitors.
Gotcha. Okay. Thank you. So maybe then we can walk phase I-B trial design in the data that you presented earlier this year, and how that supports the advancement of the ORIC-944.
Yeah, I'll start that as well. So early this year, we did present the early POC data from the dose escalation study. This was single agent. Now, again, given what we've seen with the first generation PRC2 inhibitors, what we really wanted to demonstrate here is potential best-in-class profile. So we showed here, we showed good synergy with AR inhibitors across different models. We showed good drug properties. Again, we showed that we do not have any CYP autoinduction, and we have a long half-life. Our clinical half-life is estimated at about twenty hours, which is very different than, you know, tazemetostat, let's say, that was around three hours.
We showed good target engagement. We saw a maximal decrease in H3K27 methylation assays with very little interpatient variability. And then from a safety profile, we didn't see any grade 3 events at doses less than 900 milligrams. Based on that, we've checked the boxes we wanted to check as a monotherapy, and again, we're moving forward into combinations with AR inhibitors.
Gotcha. Okay, that makes sense. Then maybe we can revisit Pfizer's data stream this year, where they presented beginning at the Innovation Day in February, and then at ASCO, and then later in the ClinicalTrials.gov website. Just your thoughts on the data and any potential readthrough to nine four four.
Yeah, we actually find the data to be pretty interesting. You know, it's single arm data. It's a very small data set, but, you know, what they have shown, we think is very encouraging. It's something that we just haven't seen before with the PRC2 inhibitor yet, but essentially what they did is just their PRC2 inhibitor, which they're referring to as mevorametostat, in combination with their AR inhibitor, enzalutamide. And based on their data, I think others, ours as well, is when you look at those, that combination preclinically, you see pretty significant synergy with the two, and so that has kind of always been the front runner strategy. So they went into a combination study as quickly as possible, essentially just enrolling relatively late-line prostate cancer patients.
So it was required that, all the patients had failed at least one AR pathway inhibitor, either abiraterone or enzalutamide. Many of their patients had failed both of them. They allowed chemotherapy. What we saw from ASCO, a majority of the patients also had chemotherapy, so it is a pretty treatment-refractory type patient population. Within that, what they saw is that, the median progression-free survival, which is kind of the regulatory endpoint, in patients that had already failed these therapies, their median progression-free survival is 11.7 months. And so that's a pretty dramatic PFS. It is in an uncontrolled study, so that. There is that caveat, but that median progression-free survival is, at least three times kind of what you would expect from a patient population that had already failed an AR inhibitor, before.
So that is encouraging. The other dataset that they looked at was in patients that had failed abiraterone, and had not yet experienced enzalutamide. Those patients had a median progression-free survival of 17.1 months. Again, uncontrolled, and it's a small dataset, but, you know, in our view, that's pretty encouraging. And so what they have done is, since then, they have moved into a randomized portion, where they are studying, in a similar patient population, the PRC2 inhibitor plus enzalutamide versus enzalutamide.
We haven't seen that data yet. They have spoken, that it sounds promising, and they have since kicked off some phase III studies. They started dosing patients last month. So, based on what they're doing is encouraging. I think based on what they've shown to date is encouraging, so we are kind of excited by the data they put out. We think it's validating for the target and the field in prostate cancer.
Absolutely. Yeah, and just to add a couple points to that. So as you said, Matt said, you know, you look at the radiographic PFS that they've shown here, it's significantly higher than you would expect with Xtandi alone. You know, what they have said, as Matt said, they have this ongoing randomized study. I should point out that that is an open label study, so they do... You know, we believe they have that data. At their oncology day, they were asked a question, they responded that the decision to move forward into two phase III registrational study was based on both phase I data as well as this randomized data. And that randomized data is 40 patients. These are post-abiraterone patients, about...
So it's been randomized to either enzalutamide alone or enzalutamide plus mevo, which is their PRC2 inhibitor. And they said, again, they're moving into two phase III studies. One is in this post-abiraterone setting, and the second is in first-line metastatic CRPC. They seem to be really excited about it. They just posted the new. You know, they said they were gonna start enrolling the study in August of this year. They posted one of the two studies on ClinicalTrials.gov, and the direction they're giving is they're gonna start that second study in 2024 as well. So this does seem to be a high priority for them. And this, you know, honestly, this is a direct read-through to us.
Everything we've profiled, our drug versus their drug, we seem to be as good and maybe slightly better in certain instances, but preclinically across the board. But again, this is a huge, huge market. This is prostate cancer. If you look at the current AR inhibitors, if you look at enzalutamide, apalutamide, darolutamide, they're doing over $10 billion in sales. So we do think this is a huge opportunity, even if we're second to market. You know, again, if we're on schedule and we start our phase III study in the second half of next year, you know, we're about four-to-six months behind them, so we're not too far behind, and this is a huge market.
So even if we're as good as them, I think it's a great upside opportunity for us, and we think it's any data they put out is a direct read-through to us as well. You know, one of the main questions we get is, "When is Pfizer gonna put out their randomized data?" That's a question we'd like to know the answer to as well. Unfortunately, we don't. You know, I think some people are assuming that they're gonna put it out either late this year or early next year. ASCO GU could be an opportunity for that. But again, we don't know if and when they're gonna put out that dataset.
Gotcha. Okay. And then, is there any differentiation then between your molecules, then, that allows you to maybe have more flexibility with combinations with AR inhibitors? And what's your, you know, strategy and thinking around which AR inhibitors to move forward with, with a phase III combo?
Yeah, I think it's too early for us to say we're... You know, to claim we're better than them, so I don't think we want to do that. We'll have to see that in the clinic. I think with regards to which AR inhibitor we decide to combine with, we think all three are great drugs, right? So again, the... Combined, they're doing around $10 billion in sales. Obviously, enzalutamide is co-owned by Astellas and Pfizer, so it makes sense for Pfizer to do that. J&J owns apalutamide, and then Bayer has darolutamide. We have started those combination studies this year. We have said a couple things. We said that we started the studies with both apalutamide and darolutamide in the first half of this year. This is dose escalation.
The objective here is really to select the recommended phase II dose for the combination. And then we've also given ourselves the flexibility in the protocol to allow to combine with enzalutamide if we do. We're pretty much agnostic on which one we take forward in the phase III study, to be honest with you. They're all great drugs, both clinically and commercially. They've all got their slight differences. I'd say daro, the one difference there is some expected DDIs with combining with both apalutamide and enzalutamide that Pfizer showed as well, that we would, in theory, have the same issue that you would not expect to see with darolutamide.
From a commercial perspective, you know, enzalutamide is the first to go off patent. They're expected to go off patent in 2027 . And then thirdly, I'd say when you look at apalutamide and darolutamide, those two drugs don't currently have a label in the metastatic CRPC setting. So this could be a nice strategic way for those drugs to get approval in that setting, in combination with a drug like ORIC-944.
Gotcha. And then just, on the DDIs, like, so then what lessons have you learned from that combo that you look to like improve on so you can avoid the DDI issues?
Yeah, I don't think it's necessarily an improvement thing. I think it's basically, you know, these enzalutamide and apalutamide are inducers of certain CYPs and these PRC2 inhibitors are metabolized by these CYPs. So in order to maintain certain exposure, you'll have to increase the dose in order to get to the right dose level. This is exactly what Pfizer did, and again, that data seems really, really great. So we don't view this as an issue. It's just a little something you have to work through. When you think about dose escalation, you'd have, in theory, more dosing cohorts than you would with combining with darolutamide.
Gotcha. Okay, so a lot of opportunity here in prostate cancer for ORIC-944. Beyond prostate cancer, do you see ORIC-944 moving into any other tumor types and, you know, what data supports that potential?
Wanna take it, Matt?
Yeah, I think it, it's a good question, and I think I would start, maybe just with prostate cancer. And so we in-licensed this program a few years ago. Our focus for the program was always prostate cancer. We thought that, you know, one, that's an area of our expertise, you know, based on our founders and our scientific personnel, as well as our clinical development team. So that's really what we've been focused on. And as Dominic mentioned earlier, you know, the opportunity, the unmet need in prostate cancer is significant. There are multiple different lines of therapies we can go after, so I think in some ways, it is a full-time job to go after prostate cancer.
That being said, there is extremely encouraging, both historical as well as emerging data, pre-clinically coming out, that there are many different tumor types where this could be, a similar type of mechanism, and it is exciting. Things from lung cancer and colorectal cancer, and things like that. So we are evaluating that. I think we like the fact that just based on our phase I data we've shown, it seems like we have a very good molecule. We think we have solved a lot of the drug property issues that have kind of plagued the early generation, programs. We talked about Pfizer and kind of, you know, even the drug-drug interaction thing. At least from what we've seen, you know, a half-life of close to twenty hours plus is very promising. Clearly a once-daily therapy.
Pfizer's molecule, on the other hand, seems to be twice daily. They are dosing pretty high. It seems to be maybe a three- to four-hour type half-life. So we think there's some differentiation, you know, there, that we feel very good about our molecule, so I think we're very busy exploring that as aggressively as we can in prostate cancer. But we are evaluating, you know, other things as well. So I think, you know, potentially stay tuned there. But, you know, prostate cancer is the focus now. I would mention, maybe just to round out that last question, you know, we did sign some clinical trial collaboration agreements with Bayer and Janssen. And so Janssen is providing us a little bit of expertise and some drug supply with apalutamide.
So we are in a combination study with apalutamide in collaboration with Janssen. We also have a clinical trial collaboration, similar type of arrangement with Bayer as well for darolutamide. So we are exploring, you know, both of those in parallel. It's a little bit different than enzalutamide and we'll kind of see where the data takes us, but, you know, that's kind of been the focus, you know, this year for ORIC.
Great. So then maybe just expanding on those, collaborations, and looping back in ORIC-114, what is your thinking then on your clinical development pipeline on registrational studies and commercializations? Is this like an independent pursuit, or are you looking to bring in partners, you know, at appropriate times?
Yeah, those are discussions we have all the time. I think, from a business perspective, from a strategy perspective, I think you have to be prepared to do this yourself. Right, you can't assume you're gonna get the right deal at the right time. So our base case assumption is that we're gonna proceed forward into the registrational studies with both programs ourselves. We believe, again, given the operational expertise and the teams that we've assembled, we can handle that. With ORIC-114, as we talked about, there is an accelerated approval path forward there, so those are not big lifts. Those are relatively smaller studies and quicker studies with potential accelerated approval. And then when you talk to ORIC-944, obviously, those are much larger studies. They are bigger lifts.
This is prostate cancer, much longer studies and more expensive studies, but we believe we could handle up to two of those phase III studies. As Matt said, if you start thinking about earlier line studies in the hormone-sensitive patient population, then it becomes overwhelming, and it probably does make sense to look for a strategic partner. But our base case assumption is that we're doing this ourselves, and we're starting those registrational activities for those studies as early as the second half of next year for both those studies. And obviously, if the right deal comes across the table, we're objective people who are gonna do what's in the best interest of our shareholders and look at those in lieu of everything else.
Great. Okay. Maybe we can spend a couple minutes then on just your discovery platform right now, your discovery stage assets. So ORIC-613, your PLK inhibitor, I believe it's in IND-enabling studies. Can you provide an update on this program and-
Sure. Go ahead.
Go ahead. Oh, you. Yeah, so this is a PLK4 inhibitor. This is part of our internal research and discovery efforts. We're excited about this program. We are pretty much wrapping up the IND-enabling work on this program at this point in time. And again, here, this is a synthetic lethality approach. So what we've said with this is we're kind of assessing next steps with this. You know, one thing we do take very seriously is prioritization of our pipeline. As you know, in December of last year, we did have a program, ORIC-533, which is a small molecule CD73 inhibitor that we're exploring in multiple myeloma. We presented the early data at ASH. And basically, based on that, even though the data was interesting, we had a really clean side effect profile.
We saw early signs of activity in heavily pretreated patients, but we have decided to look at strategic options for that program, based on what we have. Basically, we're prioritizing ORIC-114 and ORIC-944. Stay tuned for next steps on PLK4, I guess, is what I'm saying. We do still have internal research discovery engine. We have a number of early-stage preclinical programs that we're excited about, but we take a hard look, given the cost of capital, given the markets these days, on where we spend our dollars.
Gotcha. Okay, that makes sense. So maybe on those dollars, can you update us on the current run rate and what milestones that gets you through and what investors should be watching for?
Yeah. So we ended the second quarter with $309 million in cash and investments. And based on our current operating plan, that gives us cash running into late 2026. And our current operating plan assumes we're starting registrational studies for both ORIC-114 and ORIC-944 in the second half of 2025. So that's a fully burdened success scenario, I guess. Obviously, if there was any partnerships, if there was any attrition, that would extend our runway even further.
So that gets us through the first half of next year, obviously, which obviously will have the readouts on ORIC-114, and again, the start of those potential registrational studies in the second half of next year as well. So we feel we're in a solid position. We've got good runway. We're excited about the three programs we have, the two programs we have at hand that we're advancing forward, and we look to continue to provide updates throughout the year.
Gotcha. Okay, and maybe just in the last minute, we can touch on business development a little bit more. Are you guys always actively seeking, like, new products to license in?
We actually are. Yeah, that was kinda. Well, that's probably my primary role at the company since I started. It's been almost five years now. And ORIC-114 and ORIC-944 were both, you know, from our business development efforts. We've continued to look for programs, and I would say we always see very interesting opportunities, especially in this environment. We do think we have the capabilities and we have executed on business development before. So we are. We continue to evaluate programs. It has always been, you know, since we brought in the last two programs a few years ago, the bar is extremely high, which I think is a good thing, you know, that I like for us.
You know, we are, you know, very, very stringent on our scientific criteria, very stringent on our capabilities. I think if we were to in-license something, it would be in an area that we know very well. You know, we're obviously investing in lung cancer, prostate cancer. And so I think anything that we would do would be very consistent with what we have done in the past. At the same time, I think we feel we don't really need anything at the time. And so I think for us to transact, it would have to be very compelling, you know, the right program at the right time, obviously at the right financial structure and things like that. But we continue to evaluate things. And so we'll keep you posted on that as well. But that, I do spend a lot of time on that.
Got it. Okay. Gentlemen, thank you for coming in today for the Fireside Chat. It's been a pleasure, and I think we can wrap it up there.
It's great. Thanks for having us.
Thank you. Thanks.