ORIC Pharmaceuticals, Inc. (ORIC) Earnings Call Transcript & Summary

Great. Welcome, everyone. Thanks for sticking with us through the afternoon hours of our first day of the Virtual Oncology Leadership Summit. As you know, I'm Yigal Nochomovitz, one of the biotech analysts here at Citigroup. If you have questions for ORIC management during the session, just e-mail me, and I will scan them and be able to relay them to the company. So with that, It's my great pleasure to have with me senior leadership from ORIC, Jacob Chacko, the CEO; Dominic Piscitelli, the CFO; and Pratik Multani, the CMO. So thank you all so much for taking the time. I think it's a story that a lot of the people listening are familiar with. But nonetheless, Jacob, I think, helpful to set the stage for us, give us just a quick sense of the pipeline? What are the key priorities for the company over the course of 2024?

Sure. Thank you for having us, Yigal. I think most folks are well familiar with the pipeline. So I'll keep my introductory comments quite quick. We are a company that, from a big picture perspective, focus is on cancer resistance or extends for overcoming resistance in cancer. That in a nutshell sort of tells you a lot about the pipeline that we put together. But specific to the pipeline though are that we've kind of focus on small molecules, primarily and in solid tumors, primarily, and so with rare exception, you'll see that, that's what the pipeline entails. We have 3 different programs that are in Phase Ib studies currently, that folks are familiar with. There's ORIC-944, which is a PRC2 inhibitor, that's being developed in prostate cancer. There's ORIC-114, which is an EGFR and HER2 exon 20 inhibitor, being developed in non-small cell lung cancer. And then there's ORIC-533, which is a small molecule, oral inhibitor CD73, which we're developing in multiple myeloma. As most people are probably familiar within just the last 4 to 5 months, we've had readouts on all 3 programs. The company has also publicly stated that for 2 of those programs, ORIC-114, the EGFR and HER2 exon 20 inhibitor, as well as ORIC-944, the PRC2 inhibitor, we've seen enough data from both ourselves, as well as in some cases, competitors to give us preliminary proof of concept, such that we want to take those programs forward to the next stage of development. We anticipate that by second half of 2025, we could potentially have both of those programs in pivotal studies. So quite a bit of activity going on at the company.

All right. Good. That was a very good and efficient overview. There's obviously been a lot of eyeballs on ORIC-944, your PRC2 inhibitor. So let's start there. First of all, if you could just walk us through the biology of targeting PRC2 and specifically the EED domain and why that's important for prostate cancer? And then we can move into some of the early data and the competitive landscape.

Sure. We could probably spend the entirety of the session, Yigal talking about the underlying biology of PRC2 inhibitor and epigenetic dysregulation. But, so I'll leave my comments at a very high level, which is that essentially what happens in prostate cancer, folks are very familiar with enzalutamide, apalutamide and darolutamide, which are second gen AR modulators that have done a phenomenal job for patients with prostate cancer. Eventually, those prostate tumors, though end up evolving to get escape around those drugs. And essentially what ends up happening is that the prostate tumors become less and less AR dependent over time, eventually end up getting more AR independent. And so the thought is that a PRC2 inhibitor through its impact on epigenetic regulation and dysregulation can actually push the prostate tumors to stay in an AR-dependent state. So in other words, in a state in which those other secondary gen AR modulators have their best activity. And so the thought is, and we've shown this through preclinical data, another competitor, Pfizer, has shown us through their own preclinical data, that there is synergy in combining an AR modulator with a PRC2 inhibitor. Now there's nuances that we can get into, as to what we mean by PRC2 inhibitor. In our case, it's an EED, it's -- they're targeting the EED subunit of the PRC2 complex. In the case of Pfizer and other competitors, it's they're targeting the EZH2 subunit of the PRC2 complex. In either case, you expect to have strong inhibition of the PRC2 complex. And like I said, we can get into some of the other nuances later in the discussion.

Well, that is a pretty sophisticated crowd, I think. So is there some -- is there a comment you want to make in terms of why EED versus EZH2? Or is it just another way to attack the target?

Yes. It's -- at the highest level, Yigal, it's another way to attack the target. What I'd say is though, there has been -- the PRC2 inhibitors have been around for a long, long time. The whole first-gen approach was really focused on the EZH2 subunit that we mentioned. I think for folks that have followed this space for a long time, people will be well aware that the #1 property -- the #1 issue or problem in the space has been drug properties. And what I mean by that is if you look at the various PRC2 inhibitors that have come through over the course of time, whether that's EZH2 or even in the case of an EED inhibitor that came before us in MAK6, what you've seen is one of -- one or both of 2 problems. One is a short half-life. So oftentimes, the drugs in this space have a half-life on the order of anywhere from 1 to 4 hours, which is obviously quite short. The second issue has been CYP auto induction. And so that's a property whereby, the only approved PRC2 inhibitor is tazemetostat, which happens to the be ECH2 inhibitor. Tazemetostat actually has both of these issues of a short half-life, as well as CYP auto induction and it's well documented that you get dose-dependent decreases in exposure for those drugs that have CYP auto-induction issues. And so in the case of ORIC-944, it happens to target the EED inhibitor. In the EED subunit of PRC2, but really, we were agnostic as to which of the subunits you would target. The whole point being, we just wanted a drug that had good drug properties. This is a program that we acquired from Mirati, back in 2020. And what we like about the approach that the Mirati scientists took when they were developing this drug is Mirati was also agnostic as to EED versus EZH2 inhibition. They saw the same issues we did, which is that the drug properties for these PRC2 inhibitors, whether they were EED-focused or EZH2 focused, have been quite poor. So Mirati laid out a high bar target candidate profile. They then synthesized several EED inhibitors, as well as EZH2 inhibitors, and they just let the preclinical experiments dictate which program won. So they put them all through the paces in terms of what met the high bar target candidate profile, in terms of drug properties. They looked at the in- vivo activity of the various compounds, the one that empirically won was the drug that is now ORIC-944, which is an EED inhabitor. So that's what I love about it is, it was literally just an empirical preclinical experiment that brought this drug to the forefront in terms of what Mirati was developing. Now separate from that empirical experiment, there is absolutely theoretical rationale why it is better to target the EED subunit than it is to target the EZH2 subunit. The main factor being long-term resistance. So, on a like-for-like basis, an EED inhibitor and an EZH2 inhibitor, that both have exactly the same drug property, is exactly the same potency, you would expect to see equal ability to inhibit PRC2 activity upfront. Where you would still see a difference though potentially is in the long run around resistance. And that's because EZH2 inhibitors would be susceptible to acquire resistant mutations in EZH2. They'd also be susceptible to bypass resistance from -- or bypass activation from EZH1, that neither of those pathways or resistance would be applicable to an EED inhibitor. So that's why on a like-for-like basis, with equal drug properties, equal potency, the [ tie ], if you will, would go to -- would be broken by the EED inhibitor's ability to prevent long-term resistance. But there is a big supposition of what I just said, which is that there's like-for-like drug properties. And again, we don't think there's like-for-like drug properties. We actually think 944 has fantastic drug properties, compared to the competitive landscape out there.

Okay. That was very comprehensive, very helpful. So let's shift then to the clinical. So you showed us the Phase Ib data, some -- I say, a sneak peek of the Phase I data January, summarize that for us. And then, of course, the next big update is in the middle of the year, what should be -- should we expect in terms of the obvious questions, the number of patients, the key metrics we need to be looking for? What would you see as the threshold for success to move the program forward?

Yes. Let me ask Pratik, our Chief Medical Officer, to cover what we just presented, and then I'll talk about expectations beyond that for future data updates.

Sure. Thanks, Jacob. So the data that we presented came from our ongoing Phase Ib study of ORIC-944, single agent in advanced prostate cancer. And, as with any Phase I dose-finding study, we had the standard objectives for the trial, such as single agent safety, pharmacokinetics and demonstrating target engagement. But on top of that with the issues that Jacob just really went into, that have compromised the first- and second-generation PRC2 inhibitors, one of the overarching objectives of this -- initial readout was focused on demonstrating that ORIC-944 did have best-in-class potential based upon its superior drug properties. So we showed in this update a number of points. First, preclinically, we disclosed data demonstrating true biological synergy with AR inhibitors in prostate cancer models. And so this really sort of further supports our development path of combining ORIC-944 with AR inhibitors. Second, I'm getting to Jacob's point, we demonstrated strong drug properties with ORIC-944,and that was, as I said, a key objective of this data disclosure. No CYP auto induction, a long half-life greater than 10 hours compared to historically less than 4 hours with the other PRC2 inhibitors, robust target engagement. And this was measured by H3K27 methylation in peripheral blood cells, and we saw maximal decrease across multiple dose levels starting as low as 200 milligrams once daily. And then finally, a well-tolerated safety profile with only grade 1 or 2 treatment-related adverse events, less than 900-milligram dosing. So safety, target engagement, and importantly, the drug properties that Jacob referenced.

Okay. And then, Jacob, you want to touch on the -- how we should think about the next set of updates in the middle of the year?

Yes. So what we announced at the start of the year, Yigal was that -- sorry, it looks like my computers having some lag issues. Are you able to hear me?

I can hear you. It's a tad choppy. I don't know if the opening exchange can clean that up, but I can hear you.

Yes. It might be that our CFO, Dominic is pretty cheap and hasn't given me a computer upgrade in a while Yigal. So it might be there on our side. But I'll try my -- I'll try my best on the audio. So we gave an update at the beginning of this year that the data update that Pratik provided. But beyond that, we said operationally, we had seen enough from a competitor program, namely Pfizer's, to green light the ongoing advancement of the program. And I'm sure we can get into what it is we saw at the Pfizer data that we found interesting. And so what we said was that from an operational perspective, our plans in the first half of this year were to start the combination work of ORIC-944 with one or more AR inhibitors. There's obviously 3 different options out there for second-gen AR inhibitors. There's apalutamide from Janssen. There's darolutamide from Bayer, and then there's, of course, enzalutamide from Pfizer -- Pfizer-Astellas. And so, we said that we would combine 944 with one or more other AR inhibitors as part of dose finding work, all of that in anticipation of, like I said, in the second half of 2025, starting potential registrational studies, with one of those AR inhibitors. The other thing that we said in the beginning of this year was that we anticipated providing another program update in the middle of this year. We were intentionally generic in the language we used, the same program update, the reason being, that could be anything from an incremental, clinical data update out of the single agent dose experience. It could be simply just a program update talking about the fact that we had, in fact, gotten the combo studies up and running. It could be the provision of free drug agreements, in place with one or more parties. It could be additional preclinical data because actually, this is one of the few areas where additional preclinical data could be quite derisking. Certainly, if it was preclinical data, they compared us head-to-head with Pfizer or compare ORIC-944, with an AR modulator, head-to-head with Pfizer's compound with an AR modulator. So it could be any of the above, Yigal, we just wanted to sort of give ourselves maximum flexibility in terms of what that update would look like in the middle of the year.

Okay. So that would be obviously get narrowed down at some point when we start to see conference abstracts and the like disclosed. Is that fair?

That's fair. Correct.

Okay. And then you cited the 3 ways you could combine with the AR modulators. Sounds like you're testing all of them. Is there one that's preferred or -- or it's just a question of seeing how they play together in a human being?

Yes. Why don't I ask Pratik to talk about whether there's one that's preferred and maybe even before he does that Yigal, I'll just kind of talk about what it is we saw from the Pfizer data that got us excited about greenlighting -- the moving forward of this program in combination with one or more of those AR modulators. I think, again, at this point, many folks are well aware of the Pfizer data that was presented last year. This is a program that they've been developing over the course of a number of years. They had their first major update on this program at ESMO of 2022, that showed a headline PFS number that was very interesting. But it didn't really give you the breakdown of the different patient populations. And I think what was new to people last year was that on a Pfizer earnings call, in May of last year, they provided a more detailed breakdown of 2 different populations of patients in the CRPC setting, who they had given their drug in combination with enzalutamide. In the case of one of those populations of patients, those were patients who had already had enzalutamide in progress. So they were enza experienced. They were then getting enza for a second time, but this time in combo with Pfizer's EZH2 inhibitor. There was a second population of patients who had never had enza, had only had abiraterone and progressed. We're getting enzalutamide for the first time. But again, in combination with Pfizer's EZH2 inhibitor. What they were able to show in both of those populations was a profound improvement in what you would have expected in terms of radiographic PFS. So in the case of the enza experience population where you would have expected 2 to 3 months radiographic PFS, they were able to see something on the order of 3x that, in terms of radiographic PFS. And in the case of the enza naive population, where you would have expected 4 to 5 months of radiographic PFS, again, they saw 3x that in terms of the radiographic PFS that they saw in combo with their EZH2 inhibitor. Those data, I think, are what got us excited about pursuing this, in combo with one or more of the AR inhibitors that you referenced. And then I'll ask Pratik to comment specifically on whether we view those AR inhibitors to be different.

Well, the short answer to that question is actually, we don't have a preferred AR inhibitor at this point. They're all biologically acceptable in terms of the synergy and the clinical effect we're trying to achieve. So they're all right now under consideration, enzalutamide, apalutamide, darolutamide, they're all clinically and commercially successful. So there's no winner from that perspective necessarily. So we are, as Jacob said, planning to look at identifying the recommended Phase II dose of ORIC-944, with one or more of these AR inhibitors just to give us flexibility for further development downstream. That said, each of the AR inhibitors are not identical in terms of some of the drug properties. Enzalutamide and apalutamide, both induce CYP3A, which increases the metabolism of ORIC-944, to compensate for this drug-drug interaction, we would expect to need a higher dose of ORIC-944 in combination. And this is true for other PRC2 inhibitors as well, including the Pfizer [ 1497 ] molecule. So they themselves had to up-dose the [ 1497 ], in order to compensate for the DDI with enzalutamide. And so we would expect the same. The only molecule that doesn't have that property is darolutamide, with no CYP induction. And so we wouldn't necessarily expect to adjust the 944 dose in that combination.

Okay. But you're saying that it doesn't necessarily make daro a better choice. It just means...

Yes. Just they have [ the price factor ].

Achieve the same exposure.

Exactly.

Yigal, If you think -- if you talk to KOLs in this space, whether that's oncologists or urologists, who all have lots and lots of experience with the 3 different AR inhibitors. I think they would tell you that, they are all fantastic AR modulators. They've all done fantastic for patients. The efficacy is right on top of one another. The safety profiles are right on top of one another. So it actually gives us maximum strategic flexibility, as we think about what's the right partner to take forward into a global Phase III study. The other really interesting aspect here is that enzalutamide goes generic in 2027. And so it's really not only Janssen with apalutamide, and Bayer with darolutamide that [ ought to care ] about a new novel mechanism of action in the form of a PRC2 inhibitor, it's really any large pharma with the prostate franchise ought to care about a new PRC2 mechanism here, that could be provided with a soon-to-be generic enzalutamide, as early as 2027.

Okay. Now my understanding, and I don't know how accurate this is, but I believe that there is going to be an update from Pfizer. Mainly referenced the update last year in May. What more can we say about the next update from their program? And how might that impact your view of the development for ORIC-944?

Yes, it's a great question, Yigal. I think probably Dominic can tell you that the most common question we get these days is about the data from another company, not in our selves. It's really people asking about when is Pfizer planning to provide an update here. And -- so I think folks will just probably have to ask Pfizer to figure that out in terms of when they're providing an update and what exactly -- what form that update will take, I think people are aware that they're having an oncology R&D Day at the end of this month. And then I think there's been some talk of an update from them in mid-2024, which I think some people are assuming will be ASCO. But I don't know beyond that, any of the details of what they're providing -- what they're planning to share or not. From our perspective, I think what we saw from their update last May was more than enough in terms of providing derisking to the path taking this forward. There's obviously 2 different populations in the CRPC setting, where, like I said, they achieved 3x the radiographic PFS that you would expect to see. So, while it would be helpful and informative to see a little bit more info from them or a little bit more of a data update from them. I think we've seen what we need to see, in terms of greenlighting the next stages of development for our own program.

Okay. Just remind me, the work you're doing in the combo with the 3 AR drugs that -- those are in patients that are naive to those mechanisms? Or they've seen them before? Just -- it wasn't clear. Can you just clarify just to compare to what Pfizer did?

Sure. Pratik can talk you through that as well as the overall big picture study design.

Yes.

Yes. So the dose finding that we're doing for combination would be in patients analogous to the Pfizer population, in terms of patients who have come off of abiraterone, but haven't had any of the AR signaling inhibitors.

Because -- as Jacob was saying, there was a Pfizer cohort that had prior Xtandi that then was rechallenged with the combo and showed not some nice activity. But in your combo work, you're not going to be rechallenging with enza right, plus -- they did not have enza prior, when you do enza plus 944. Is that correct?

Right.

Okay. And then as far as the pivotal, I know it's a bit of a ways off. I think you referenced 2025, Jacob, and you have a lot to figure out in terms of combinability. But is there a base case, as far as work you would do there? I mean would you follow the retreat with XTANDI plus 944? I mean not necessarily XTANDI, but AR mechanism plus 944. Is that the base case? Or you just need to do more work to sort this out?

Yes. Well, Pratik and his team tell me that second half 2025 is not that far off Yigal. So let me ask him to comment on that.

I think there's a lot of options on the table still. I think the biggest signal that Pfizer has disclosed to date is in the [ abi ] experienced patient population and then giving them an AR pathway inhibitor, in combination with PRC2, in our case ORIC-944. I think that would be sort of an obvious population to go after. But there are other populations as well, as you said, sort of the post AR pathway inhibitor retreatment with a combination. So right now, it's all on the table, frankly.

Okay. But it would be a population that's seen one of the primary like seen [ abi ], you wouldn't go true frontline, is that true?

It's all...

It's all...

Yes, it's all up for discussion and debate, Yigal. I think the population that we know for sure, ought to be part of it just based on -- well, actually, there's 2 populations that Pfizer is at this point, de-risked, in terms of the data that they showed. But I think the one that is probably most exciting just in terms of ability to have the most and longest impact on patients, that we've seen thus far is that post abiraterone pre-enzalutamide or pre-second gen AR modulator population. That said, the biology and the biological rationale would suggest that you probably ought to test it even earlier. So pre-abiraterone in a CRPC setting, for example, or maybe you want to go into an even earlier setting. So a CSPC setting or hormone sensitive setting. I mean all of the above could be studies that ought to be run at some point. I think if you look at the history of prostate cancer drug development, not just within PRC2 inhibitors, but more broadly for drugs that have been approved in the space, you've seen multiple lines of therapy, where drugs have gotten their approvals. For example, enzalutamide is approved in 3 different lines within prostate cancer, in 3 different settings. And so that is probably the long-term plan for the program is to eventually be developed in multiple different Phase III studies, that are really covering the prostate landscape. So I think as we alluded to in our initial comments, we, as a small biotech, are absolutely capable, both financially and operationally of running 1 or 2 of these pivotal studies for -- in prostate cancer. But if you're going to really develop this correctly, you ought to get the help of a big large pharma partner to do this in multiple different settings. And that's sort of the advantage we have here of having many parties that ought to have an interest in this just strategically. So that at some point, we would foresee ourselves striking at global partnership to be able to develop this the right way, which is in multiple different settings, including the earlier ones that we alluded to.

Okay. I think we've covered 944 in substantial amount of detail, which is good, unless there's anything else you wanted to touch on. Okay. Let's move to 144. Obviously, this is the exon 20 EGFR HER2 inhibitor. Also, you presented some recent data at ESMO last year, dose escalation. Maybe we could start with a quick recap of that.

Sure. Pratik, do you want to go for that?

Sure. So happy to recap the data we presented at ESMO. But before I get into the specifics, I think it's important to provide some context of how we ran our study and the patients that we enrolled versus previous Phase I studies with other EGFR exon 20 inhibitors. So almost every other drug that has come before us in this space, excluded patients who have previously been treated with an EGFR exon 20 inhibitor and excluded patients with untreated brain mets. Now these are 2 very important exclusion criteria and really apart from us, the only other company that included these patients in their Phase I, was Blueprint. Now we all know that Blueprint recently discontinued the development of their program. So at this point, it's really just us. And so we have allowed patients who had previously been treated with EGFR exon 20 inhibitors and patients with untreated brain mets, which then if you compare across studies, our broader inclusion criteria led to 81% of the patients that we enrolled previously were treated with an EGFR exon 20 inhibitor and 86% had baseline brain mets, including active and untreated brain mets. And so that is really the context in which to put our data. So in these heavily pretreated and, I would say, advanced patients, ORIC-114 was well tolerated. We had minimal EGFR wild-type related toxicity and little to no evidence of off-target toxicity. Most of our adverse events were Grade 1 or 2, a low rate of Grade 3 diarrhea at only 6% and no events of Grade 3 or higher rash. And then only a 4% dose discontinuation rate due to safety. So the safety profile, we think, is a winner for the molecule. And then on the efficacy side, our sort of premise going into development with this molecule was demonstration of CNS activity, and we were able to demonstrate that across multiple dose levels and in both patient populations, that we enrolled in the trial, EGFR exon 20 and HER2 exon 20. In particular, just to highlight, we presented a case of a patient, who had previously been treated with chemotherapy and then got amivantamab. And she actually did very well on amivantamab for almost a year, but then progressed. And the side of our progression is not surprising given that amivantamab doesn't have CNS activity, which is, she progressed in the brain as well as systemically. So after that she came on to our trial, and these are active brain mets. They had not been previously treated with surgery or radiation, and this patient nicely went on to a confirmed complete response, not just in the lungs, but also in the brain. And this patient as of the data cutoff was still ongoing at 9 cycles on treatment. So a very good outcome for this patient, despite having now come off of chemo and amivantamab. And really, just to highlight, this is the only demonstration of an EGFR exon 20 inhibitor giving you a complete response in the brain in a patient who had active brain mets. So in addition to this one, we were -- we also presented another case of a patient treated at a low dose, 45 milligrams who had 2 of their 3 CNS lesions resolve on study. And in the patients with HER2 exon 20 mutated lung cancer, we saw also multiple responses across a range of doses, including one partial confirmed response that had actually a 100% decrease in all the target lesions, but had some persistent nontarget lesions, that prevented it from being called a complete response. So based upon all of these data, that we disclosed at ESMO, as Jacob said, we've made the decision to go into multiple dose expansion cohorts in the first half of this year, with a look towards registrational activities next year.

Okay. And then how are you thinking about those registrational activities? Because obviously, as you pointed out, there are some competitors in the space. Ami plus chemo in the front line and there's some other oral TKIs, also in pivotal studies in the frontline, as well as second line. What are your thoughts and how you might differentiate from those? I mean, of course, you mentioned ami not having the brain penetration, but some of the oral TKIs are also claiming brain penetration.

They're claiming it but not demonstrating it. I think that's an important distinction to make. And so we have really persisted with our view that we have an accelerated approval opportunity with ORIC-114, based upon our demonstration, and we have to continue to demonstrate it CNS activity. And so despite some of this changing landscape, we feel that this opportunity exists. CNS activity really has been kind of a driver for best-in-class profiles, not just in EGFR, but across a lot of targeted therapies in lung cancer. And that's for obvious reasons, third or more patients present at baseline with CNS mets and those who don't, many of them, if not all of them, given enough time, will go on to develop CNS disease. And if treated with non-CNS active agents, they will more likely relapse in the brain, which is what you saw in what was sensibly a successful PAPILLON study, the frontline [ ami-chemo ] study that you referenced, they had a positive study. But if you dig into the data and look at how the patients who have brain mets, fared versus those who didn't, the hazard ratio for the patients where the history of brain mets was considerably inferior to those who didn't. And so again, you're still missing out that CNS activity and compromising the outcomes of the patients who have CNS mets at baseline. And so time and time again, ALK, ROS, RET and then sort of conventional EGFR mutations. The drugs that come in with demonstrable CNS activity have come to the top. And so that's where we think the opportunity for 114 persists. So our base case that is an accelerated approval opportunity with ORIC-114 based upon this CNS property.

And have you -- are you still in the dose -- you highlighted the dose or you determined the dose at this point? Or is there still more work to do there? And can you flesh out in a little more detail, what let some of these dose expansion cohorts would look like?

Sure. So we are going to be starting dose expansion, this first half of this year. And those will be in 3 patient populations, first EGFR exon 20, now not the patients that we enrolled in Phase I. These will be patients who are naive to prior EGFR exon 20 inhibitor, than patients with HER2 exon 20 mutations and then something we haven't gotten into yet are patients with atypical EGFR mutations.

Yes, that's an interesting comment. Are you referring to the class of what are called the PACC mutations or something else?

Exactly.

Yes, tell us about that.

Yes. Yigal, it depends on who you ask, some call them PACC mutations, some call them uncommon mutations, others call them atypicals. We tend to call them atypicals, but they're all referring to the same thing. But yes, Pratik can talk about why we're excited about that opportunity as well.

Okay, sure.

So actually, maybe we didn't get as much press at ESMO. We actually had a separate poster that outlined the work that we've done preclinically in these atypical EGFR mutations. So first of all, the patient population is actually larger than EGFR exon 20. And with all the competition that we referenced in each of our exon 20, there's very little in the atypicals. In fact, the only approved agent afatinib for 3 specific mutations is highly toxic and really not well accepted by physicians or patients. And so there's, I think, a wide open opportunity for development for this specific set of mutations. And as I said, potentially a larger patient population overall. So at ESMO, we showed that we have high potency against a range of these PACC mutants. And in fact, our potency against many of them is higher than our potency against EGFR exon 20. Which is why we started enrolling them not just our plans for dose expansion, but even in our Phase I so far.

I'm curious -- I mean, this is a fairly new class. Is it atypical or PACC pack. I mean when you design 114, was this sort of rationally designed to potentially address these? Or was this sort of more of a serendipitous finding that it happened to have activity against its broader set of mutations?

Yes, it's more of the latter, Yigal. So we actually -- we in-licensed this program from [indiscernible]. So we didn't design this ourselves. What we like about the program when we in-licensed it, was that it was exquisitely [ potent ], exquisitely selective for EGFR exon 20 and HER2 exon 20, it was brain penetrant. And so it really had the key characteristics that we thought were differentiated in those 2 populations, which is the CNS activity and then also on the safety side, we didn't expect to see a lot of wild type toxicity related to EGFR and more than we did not expect to see a lot of off-target toxicity. Which a lot of these other programs have a lot of issues without target toxicities because of their kinome trees that are not very clean. What was completely serendipitous was that there -- it does appear to be some homology between EGFR exon 20 and these atypical mutations. Such that a handful of compounds are quite active against both. As Pratik mentioned, this drug actually happens to be even more potent against the atypical EGFR mutation, slightly more potent against the atypical EGFR mutation, than it is against EGFR exon 20 mutations. And so that gives us an even wider therapeutic index for the atypical mutations relative to EGFR wild type than we have in the case of EGFR exon 20. So the fact that in the ESMO update, we already showed clinically very strong activity with 114 in EFGR exon 20 mutations as well as HER2 exon 20 mutations and the fact that the drug is even more potent against atypical EGFR mutations should bode very well for what we will eventually show clinically in atypical EGFR mutations. Again, one thing I want to be very clear on is at the time of ESMO, we had not enrolled any patients. We hadn't tried to enroll any patients with atypical EGFR mutations, because we're really just focused on those first 2 populations: EGFR exon 20 and HER2 exon 20. So when we provide an update in the first half of next year, there will be an update on the first 2 populations, EGFR exon 20 and HER2 exon 20, but importantly, it will also include atypical EGFR mutations, the first patients that we enrolled with those mutations. And the reason I think that's so important, Yigal, is -- for a second, if we just -- let's just focus on the EGFR-related mutations. Let's put HER2 exon 20 to the side, just for argument sake. If we are only developing this drug for EGFR exon 20, it is -- that's a larger patient population than either ROS lung or RET lung. And on top of it, if you add in atypical EGFR mutations, it's now a larger patient population than ALK lung. And so I know that one of the main critiques of the targeted therapies, especially in recent years, as they've fallen out of favor with investors, has been somewhat disappointing commercial launches. But really, we think here that the opportunity for 114 in a couple of these different populations. So let's say, EGFR exon 20 and atypical EGFR mutations is actually quite substantial and something that investors, I think, are missing these days.

Okay. And that's very helpful. And an area I think people maybe explored less is the HER2 exon 20. What is the scale in that population, the market size there? And what about some of -- do these HER2 selective TKIs not worked in the exon 20 setting, or even like in HER2 would that work? Tell us a little more about that.

Yes. I'll talk just at a high level about the size of the population, then ask Pratik to comment on your other question. HER2 exon 20, as a population in non-small cell lung cancer is just slightly smaller than EGFR exon 20. So it's on its own quite attractively sized population from a commercial opportunity and patient impact perspective. . And it happens to be 1 of the 3 populations that we're looking at the time of the ESMO data update. We, in fact, had one more confirmed PR in the HER2 exon 20 population, than we did even in the EGFR exon 20 population. So it is very much on our radar. But let me ask Pratik to comment on your question around the competitive landscape and in particular, the role of HER2 in that space.

Yes, happy to. So for HER2 exon 20, actually, the only approved agent, the only benchmark right now is in HER2 overall response rate of just under 50%, with a duration of response of -- they had multiple dose levels -- 16.8 months at the lower dose level. But even at this lower dose level, they had 40% of patients developing Grade 3 or higher treatment-related adverse events. And a 13% rate of interstitial lung disease. So with that efficacy, it comes quite a bit of toxicity. And although in HER2 has demonstrated CNS activity in that study, they excluded patients with brain mets that required steroids. So that excludes patients who have sort of larger brain lesions. And as I said, we don't do that in our studies. There are 2 molecules in development, a Bayer molecule and a BI molecule. They're still very early stage. They have response rates of about 40%. We don't know what degree of CNS activity they have. So those are the benchmarks. We feel good about our potential though.

So this is impact Yigal, on less crowded space than EGFR exon 20 in terms of the competition that we face here in the clinic and the exact same aspects of differentiation apply here, which is the safety profile of 114, and then also the CNS activity of 114, ought to bode well for our ability to differentiate in this HER2 exon 20 space.

By the way, just one -- I mean it's not really trivial, but it's just interesting detail is that this -- or the 114 that you in-licensed has activity against both EGFR and HER2 in the same exon. I mean, is that -- I don't think that's a coincidence. Is there something -- was there some sort of like gene duplication? Or is there very significant homology between EGFR and HER2 that results in activity against the same exon with this molecule? Just curious.

Yes. I don't think it's coincidence either Yigal. I think there is some homology, which is why it's potent against both.

Okay. Yes, makes sense. Now -- moving...

And then just one -- just one other point, sorry, I just wanted to follow up on one point that Pratik was making just around the role in HER2 in this space because I know in HER2 has earned some well-deserved praise, for its activity in breast cancer. But I think that you can see in the HER2 exon 20 lung space, it is not very widely used, not certainly not the kind of use that it gets on the HER2 amplified breast side of the indications. And the best indicator of that, if you look at -- we were very explicit and transparent about the prior therapies that our patients have received at the time of the ESMO update. And you can see in the case of EGFR exon 20, the vast majority of patients that received amivantamab prior to enrolling onto the study. In the case of HER2 exon 20, it was only a small number that it actually previously received in HER2, there was really a smattering of lots of different other drugs, including investigational drugs that those patients have received. But in HER2 really doesn't get widespread use in that HER2 exon 20 space, namely because of the toxicities that Pratik mentioned to you, and HER2 literally has a higher incidence of Grade 3 interstitial lung disease, then we have total Grade 3 incidents for ORIC-114. So there's a real toxicity issue for in HER2 and the HER2 exon 20 side.

You mean if you add up all the Grade 3 AEs across everything, it's less than the 1/3, whatever is like a 1/3...

It's less than the 13% interstitial lung disease or Grade 3 or higher from HER2.

And that's at the lower dose level, I'd say.

Right. Okay. All right. So then -- okay, so let's move on to ORIC-533, quickly? I know that's one you sort of deemphasized and you gave an update last year around ASH. So what is the plan there? I mean it's kind of -- is it fair to say it's like on the shelf? Or how do we characterize the status?

Yes. Let me ask Pratik to just summarize what we presented at ASH a couple of months ago, and then I'll talk about how to put that into the context of what we're prioritizing and deprioritizing.

Sure. So we conducted a Phase I study in patients with refractory myeloma with single-agent ORIC-533., We were able to show a number of things, PK wise, a clinical half-life of 24 hours. So once a day dosing, currently well tolerated with no Grade 3 treatment-related adverse events, Grade 3 or higher. And we were able to demonstrate multiple points of immune modulation, [ ceded ] positive T cells, NK cells. So, we were modulating the immune system, as we had intended with a very clean safety profile. And then something finally that is unique to this pathway, we were able to demonstrate clinical activity on clinical evidence of anti-myeloma activity including reductions in paraprotein levels in multiple patients.

Yes. And so when you put it into context, Yigal, we're actually really excited about what we presented with ORIC-533 at ASH, in the sense that it is, as Pratik mentioned, the only time a CD73 inhibitor has been able to show single-agent clinical activity. In this case, it's an eighth line, ninth line myeloma patients. And people have to keep in mind, it's through a pretty indirect mechanism of action in the sense it's not directly cytotoxic, as a CD73 inhibitor, essentially, what you're expecting is that the CD73 inhibition that's provided by 533, is turning down the adenosine levels in these patients and thereby turning up T cell activity and T cell engagement, and that's what's leading to ultimately the multiple myeloma cell lysis and the multiple examples of patients that had paraprotein decreases, as Pratik mentioned, including in one patient with a minor response by the working group criteria. All of that would suggest that we want to take it forward in the combination, most likely with the BCMA directed therapy because that's where there is the strongest scientific rationale for combining this mechanism of action with an approved class of myeloma therapies. That and -- that's probably what we would be doing in a vacuum. But we're not in the vacuum. We're in a situation right now, which is quite a good situation of having both ORIC-114 and ORIC-944 having a substantial amount of derisking in terms of taking those forward into the next stage of clinical development. And like I said, we want both of those programs to be in pivotal studies by the second half of next year, second half of 2025. And that is really right around the corner. And so the company operationally needs to focus all our resources on getting those 2 programs ready for pivotal studies, 6 quarters from now and that being the case, we just don't have the bandwidth to also ourselves move 533 forward into a combo with a BCMA-directed therapy. And so that's what we announced at the time of ASH, that we do intend to finish out that single-agent dose escalation here, over the coming months with the ORIC-533. But after that, we intend to pursue hopefully, a partnership where someone with an existing myeloma franchise and ideally, a BCMA-directed therapy could take that forward for the combo studies. And we can then focus our attentions on 114 and 944.

Okay. And then there's one more program to discuss, which is still working its way towards the clinic, which is the PLK4. Tell us a little bit about that target? Where would you want to develop that asset?

Yes. So with PLK4, this is a program that is relevant to a synthetically valid pathway in patients that have TRIM37 amplifications. You tend to see those in about half of neuroblastoma and about 20% of breast cancers. This is a first in -- potential first-in-class opportunity for us with a differentiated and selective program. And so we've had mentioned last year that we had a development candidate that we were putting through the paces on IND-enabling work. Nearly all of that has been completed at this point. But we have not yet said what the explicit plans for this program are namely because, again, we're very, very focused on ORIC-114 and ORIC-944 at this point. And so with the entire clinical team's bandwidth focused almost exclusively on pushing those 2 programs forward, we've said that it's TBD on what we plan to do with ORIC-613, the PLK4 inhibitor at this point. So stay tuned for more updates later in the year.

Sorry. So you mean that you're -- are you pausing the pre-IND work or you're doing that, but just at a very low capital commitment?

The latter continues, to do the pre-IND work at a low capital commitment and really just not wanting to take the eye off the ball on either 114 or 944. And so at some point later this year, we'll have an update on exactly where we stand with 613 and what we plan to do with it.

Okay. And we got to bring Dominic into the conversations. He's waiting patiently. So can you report on the financial health of the company, the cash runway, how you might -- how you're allocating capital across the various programs, et cetera?

Yes, sure. So Yigal, we ended 2023 with $235 million in cash and investments. As you know, we did complete a tight financing in January. We raised $125 million in gross proceeds from 6 specialist funds. There were 3 existing funds and 3 new investors in that pipe, as well. With those proceeds, including the financing, we did extend our cash runway into late 2026. And that's a fully burdened number that assumes success on both 114 and 944, as well as our earlier stage programs. And as Pratik and Jacob outline today, that does assume initiating registrational studies in the second half of 2025. So that's, again, a pretty hefty number that doesn't assume any partnerships or anything on any of the programs as well. So from a cash perspective, we feel pretty good about where we stand today. With regards to business development, as you know, our strategy is to kind of use a two-pronged approach to building out the pipeline, using both, obviously, our internal discovery engine as well as business development. If you look at our pipeline today, as you can see, we've got both internally developed programs as well as in-license programs. So that's still part of our strategy. Obviously, given the focus on 114 and 944, we have a very high bar for what we bring in. And last thing I'll say is given the team's area of expertise, we really focus on prostate, lung and lastly on breast cancer as well. So...

Yigal, it's not for lack of trying. I mean, we have -- just to be clear, we've been looking for the last 3.5 years since we last in the licensor program. We've been looking at literally dozens and dozens of different programs because as you can imagine, in the current market environment, there's a lot of opportunities with companies that either don't have sufficient management team bandwidth or cash or both. And so we're looking at an abundance of those opportunities, and we hope to pull the trigger on something, but it's got to clear all our high bars in terms of the scientific differentiation, the potential for clinical differentiation and of course, economics that make sense for us. So nothing yet, but we're going to continue looking.

By the way, that just makes me wonder with the PLK4, is it that you couldn't find something externally, so you felt just make your own? Or how did that ...

That's a great question. And actually, it comes into something that's a bit more philosophical in terms of how we think about which of the programs lend themselves towards internal discovery, as Dominic mentioned, versus which ones lend themselves to being in-licensed. And so in general, Yigal, if it's a novel unvalidated target novel mechanism of action, and unvalidated target, those are the kinds of things we like to work on from our own internal discovery capabilities because we can then build the in-house expertise around what is oftentimes very complex biology and PLK4, I would absolutely put into that bucket of types of targets. So that's why we worked on it internally. Our team got a jump-start on that target a couple of years actually before there were 2 seminal publications in nature on PLK4. So that's the kind of thing that really lends itself nicely to working on it internally before others even know about a target or have that, the wherewithal to focus on it. And then EGFR exon 20 is a perfect example of the kind of target where it's a validated target, very clear mechanism of action, well understood by folks. It's really more about the differentiation of a specific molecule versus what's otherwise already out there, and that lends itself to in-licensing in many cases, where it's not really about novel biological understanding for those validated targets, it's more about just some angle on the chemistry. And if someone else has a better approach or a more advanced approach than what we have, we're perfectly happy to in-license it. So, in the case of the PRC2 inhibitor for prostate and the EGFR exon 20 inhibitor for lung, that both were in-licensed, but I'd argue those were both more along the validated end of the spectrum on targets.

Makes sense. And then just final question. I mean most of the focus for this year will obviously be on 944. Wanted to run through the catalysts for the year. I know 114 will be greater next year.

Yes. Dominic, do you want to talk about that?

Yes. I think we've covered most of it during the call today, but just to quickly run through it for 114, what we said is we're going to initiate the expansion cohorts in the first half of the year and then we provide an update in the first half of next year. So stay tuned for that. And then 944, again, kind of the milestones are starting the combination studies in the first half of this year, then a program update mid-year from ourselves. And Jacob kind of outlined what the options are around that. And then lastly, kind of the registrational studies in the first half of next year. I mean it's not our catalyst, but obviously, any read-through from competitors or something that's kind of on people's radar as well.

And, so I just want to clarify one thing. The start of registrational studies in the second half of next year.

Yes. Thank you, Jacob for that.

I want to put too much pressure on Pratik.

Put more pressure on Pratik. If you say it's like it's a real now, so he has to do that.

All right. Well, this is a lot of fun. Thank you again. Lot to look forward to. Very exciting to see quarters coming up for you guys. So I'm sure we'll have fun to chat on soon. Thank you.

Yes. Thanks for having us Yigal. We appreciate it.

All right. Take care, Yigal.

Thank you.