Oric Pharmaceuticals, Inc.

Good day, and thank you for standing by. Welcome to the ORIC Pharmaceuticals fourth quarter and full year 2021 financial results and operational update call. At this time, all participants are on a listen-only mode. After the speaker presentation, there will be a question and answer session. To ask a question during the session, you will need to press star 1 on your telephone. Please be advised that today's conference is being recorded, and if you require any further assistance, please press star 0. I want to hand the conference over to speaker today, Dominic Piccitelli, Chief Financial Officer. Please go ahead.

Good afternoon, and welcome to the Oreck Pharmaceuticals' fourth quarter and full year 2021 financial results and operational update call. Following the market close today, we filed our Form 10-K and issued a press release with our financial results for the fourth quarter and full year ended December 31st, 2021. You may find these documents posted on the investor page of orcfarmer.com. We have pre-recorded a portion of our prepared remarks, after which we will host a live Q&A session, so please bear with us if we have any technical difficulties. Before we begin, starting on slide two, during this conference call, we will be making forward-looking statements. OREC's actual results may differ materially from those expressed in or indicated by such forward-looking statements. For a description of risk factors associated with investing in OREC, please refer to our recent filing with the Securities Exchange Commission. OREC specifically disclaims any obligation to update any forward-looking statements except as required by law. Now turning to slide three, I'll briefly walk you through our agenda and introduce our speakers. During today's call, we'll primarily focus on an update on ORAC 101, after which we'll provide a pipeline update and summary, followed by Q&A. Joining me on the call today, we have Jacob Chaco, CEO, and Prateek Multani, CMO. Now, let me turn over the call to Jacob. Thank you, Dominic.

Turning to slide four. As you know, over the past two-plus years, we have conducted dose escalation and dose expansion studies, testing two separate therapeutic hypotheses, for GR inhibition as a means of overcoming resistance to chemotherapy in various cell tumors and to AR modulators in prostate cancer. We recently completed interim analyses from both combination studies, and we believe that further development of ORAC 101 should be discontinued due to a lack of sufficient efficacy signal to meet our benchmarks, which Prateek will tell you more about shortly. In both studies, we took on a difficult challenge, namely, in later line patients who had already progressed on a prior cancer therapeutic, we were attempting to add a GR antagonist in order to resensitize them to that prior therapeutic. While that was a high bar, it was an important clinical question to evaluate because of the limited treatment options available to those patients today. The challenges of assessing efficacy signal in a single-arm study of a combination regimen are obvious, So our team put in place two well-designed clinical trials that were complemented by a robust translational effort. We're confident that we've explored the GR hypothesis appropriately and also confident in making this decision. While we're obviously disappointed that ORIC 101 is not continuing, we're proud of the scientific rigor and thoughtful clinical design that allowed us to make an efficient but thorough decision. Despite the discontinuation of ORIC 101, we believe we have one of the most robust and differentiated pipelines in small-cap biotech. We've been intentional about assembling a broader pipeline of both novel and validated targets that are attempting to address areas of high unmet need with either first-in-class or potentially best-in-class approaches. Last year, we filed three INDs or equivalents for single-agent trials being initiated this year for ORIC 533 in multiple myeloma, OREC 114 in EGFR HER2 cancers, and OREC 944 in prostate cancer, with data from all three programs expected in the first half of 2023. Each of these programs has a unique angle or angles that we believe will help differentiate them in the clinic. Beyond these three clinical stage programs, our discovery research team last year advanced two programs in the lead optimization, one of which we recently introduced as our PLK4 program, which we believe is a first-in-class synthetic lethality approach for breast cancer. Finally, we've been thoughtful about bolstering our balance sheet and managing our resources efficiently, so we believe we're well-capitalized to weather a sustained market downturn. With the discontinuation of ORIC 101, our cash runway has now been extended from the first half of 2024 to the second half of 2024, and that guidance assumes advancement of all our pipeline programs. With that said, let me now turn the call over to Prateek to walk you through the summary highlights of the ORIC 101 studies.

Thank you, Jacob. Turning to slide six, we have been conducting two clinical trials of ORIC 101, each examining a distinct mechanism of action of GR inhibition as a means to reverse cancer resistance. The first study is a combination of ORIC-101 with enzalutamide in patients with metastatic prostate cancer. Given that ORIC-101 was not expected to have single-agent activity, we chose this patient population specifically so that we could identify a clinical signal in the single-arm setting as efficiently as possible, namely patients with metastatic prostate cancer who are progressing on enzalutamide. By adding ORC101 at the time of enzalutamide progression, our objective was to test the hypothesis of reversal of enzalutamide resistance through the simultaneous inhibition of GR as a potential bypass pathway, a novel paradigm for treatment post-enzalutamide or any androgen receptor modulator, since most second-line approaches involve switching to entirely different mechanisms of action. Here, we were trying to extend the efficacy of enzalutamide itself. This multicenter open-label study was performed in two parts. We previously reported on Part 1, which was the dose escalation portion of the trial, through which we identified the recommended Phase II dose, or RP2D, of ORIC101 to be 240 mg once daily in combination with standard dose enzalutamide. The determination of ORIC-101 dose relied heavily on extensive translational work that was an integral component of the trial. This effort included baseline and on-study tumor biopsies and serial blood sampling for pharmacokinetics, pharmacodynamics of GR signaling, and tumor genomic profiling at baseline and longitudinally on-study. Pharmacokinetic sampling demonstrated that at the RP2D, we were achieving exposures of ORC101 that were sufficient to inhibit the target. And through our pharmacodynamic studies, we were also able to confirm that we were achieving target shutdown through the measurement of downstream GR target genes. After establishing the RP2D, we enrolled patients into the dose expansion portion of the trial with a planned interim analysis after 28 patients. The primary endpoint of Part 2 was disease control rate at 12 weeks, with progression-free survival as an important secondary endpoint. Another important consideration was that through the profiling of patient tumors at baseline, we were able to identify a target patient population for ORC101, in which we would expect GR to be a potentially active mechanism of resistance. This population excludes patients whose tumors harbor one of the well-described alternate mechanisms of resistance, namely primary resistance variants of the androgen receptor, such as splice variants or point mutations that inhibit enzalutamide binding, and markers of lineage plasticity, implying that the cancer had become AR independent. In addition, we would also focus on the patients whose tumors were high expressors of the glucocorticoid receptor, which is the target of ORC101. After enrolling 10 patients to identify the RP2D in Part 1, per protocol, we enrolled 28 patients into the dose expansion and followed them for at least 12 weeks in order to perform the primary efficacy analysis of disease control rate. Whereas previously with small numbers, we had focused on time on treatment as an outcome measure, now with the additional patients and follow-up, we shifted to our secondary endpoint of progression-free survival, which has ample regulatory precedent. And although this was a single-arm study, we referenced as benchmarks of efficacy the progression-free survival for such agents as cabazitaxel and docetaxel, which are used in the post-enzylutamide setting, as well as the new agents and combinations that are in development, such as cabozantinib plus atuzolizumab. Turning to slide seven, let me summarize the results of this analysis. First, in terms of safety, the combination regimen was generally well tolerated at the recommended phase two dose. Next, with respect to drug exposure and target engagement, extensive PK PD work demonstrated that we were achieving ORAC 101 levels sufficient for GR target coverage, which we were able to confirm by measuring the down regulation of GR target genes. Finally, based upon tumor biopsies at baseline, we identified that the majority of patient tumors expressed moderate to high levels of GR. Nevertheless, despite achieving ORIC101 exposures consistent with biological activity, we were not able to demonstrate evidence of sufficient clinical benefit on any of the efficacy endpoints. In particular, the primary endpoint of disease control rate at 12 weeks in the target patient population of patients with moderate to high GR expression and no evidence of alternate resistance through AR alterations or lineage plasticity was 33.3%, and the median PFS in the same patient population was 3.7 months. Of note, these values were not meaningfully different from the DCR and PFS recorded in the unselected patient population. In the context of the efficacy of approved therapies for patients after progression on an AR modulator, as well as the efficacy data with new therapies and regimens currently in development, the outcomes seen in our study of ORAC101 with enzalutamide were insufficient to support continued development. Turning to slide nine, the second trial studied ORAC101 in combination with NAB paclitaxel in patients with advanced solid tumors. This multicenter open-label study was also performed in two parts. We previously reported on part one, which was the dose escalation portion of the trial, through which we identified the RP2D of ORC101 in combination with nabpaclitaxel to be 160 milligrams of ORC101 with 75 milligrams per meter squared of nabpaclitaxel weekly for three weeks on a four-week cycle. In this study, as with the enzalutamide study, we had an extensive translational component, including pharmacokinetic sampling, and pharmacodynamic testing of GR target genes, which demonstrated that at the RP2D, we were achieving exposures of ORC101 sufficient to inhibit the target and that we were achieving target shutdown. And the nabpaclitaxel dose, although lower than the labeled dose for frontline therapy, resulted in rates of neutropenia without growth factor support that indicated that we had a sufficient dose for these late-line patients. After establishing the RP2D, we enrolled patients in the multi-cohort dose expansion portion of the trial with three cohorts of interest. Pancreatic ductal adenocarcinoma, ovarian cancer, and triple negative breast cancer. And a fourth cohort opened to patients with other tumor types. The primary endpoint of part two was objective response rate with progression-free survival as an important secondary endpoint. the eligible patient population was defined to again put us in the best position to identify clinical signal in a single-arm setting as efficiently as possible. Specifically, we required patients in the dose expansion to have previously been treated with and progressed on a taxane-based therapy. While this is a higher bar, we felt that only in this way could we distinguish an ORIC-101 effect from pure taxane-driven clinical activity. While there is a taxane-retreatment effect in ovarian cancer and TNBC, this effect is generally modest, and so we set a benchmark for PFS in our study of six months for ovarian cancer. On the other hand, in relapsed PDAC, there is no measurable taxane-retreatment effect reported in the literature, and so we were looking to achieve a PFS of three months or longer with ORG101 and nab paclitaxel in this cohort. After enrolling 21 patients to identify the RP2D in part one, we enrolled a total of 61 patients across the four dose expansion cohorts and followed them for at least 12 weeks in order to perform the primary efficacy analysis. Turning to slide 10, the safety profile of this combination regimen was generally well tolerated at the recommended phase two dose. And as I stated, PK data showed good target coverage and PD data demonstrated evidence of target engagement. In addition, baseline biopsy of patient tumors showed high levels of GR expression across most tumor types, but particularly in two of the tumor types of interest, PDAC and ovarian cancer. Expression was so high across most patients tested in these two tumor types that preselection by GR status was not necessary to identify subset target patient populations. Although we demonstrated evidence of biological activity and high levels of the target glucocort receptor, we saw only one confirmed partial response in the ovarian cancer cohort and no objective responses in the PDAC cohort. Furthermore, the median progression-free survivals were 1.9 months in PDAC and 2.2 months in ovarian cancer. In these patients who were taxane pretreated, we did not see sufficient evidence that the addition of ORAC101 to nab paclitaxel reversed resistance and resensitize these patients' tumors to re-treatment with taxane chemotherapy. Therefore, we conclude from these data in these expansion cohorts that there was insufficient activity to support continued clinical development of this regimen. Now, turning to slide 11, I'd like to review what we've learned from these two clinical trials and consider how that might help us interpret the clinical data presented here today, and offer our opinion on why we may not have seen sufficient clinical benefit. First, we learned that a glucocorticoid receptor inhibitor could be safely combined with both cytotoxic chemotherapy as well as an androgen receptor modulator. Second, we learned that in these combinations, ORIC101 was capable of achieving clinical exposures in patients sufficient to cover and inhibit the target glucocorticoid receptor. We could measure this effect of GR target shutdown in patient samples longitudinally over the course of treatment. So, if we were hitting and shutting down the target, then why did we not see clinical effect? From the translational work we performed as part of both studies, the tumor genomic profiling suggested that an answer may lie in tumor heterogeneity and or redundancy of resistance mechanisms. By tumor heterogeneity, I mean differences within tumor lesions and between tumor lesions in the relevance of GR as a resistance pathway. In a single tumor, some cells may indeed be relying upon GR as a resistance pathway, but other cells in that same tumor may be relying upon alternate non-GR mechanisms. A similar difference could also be present between two separate tumors within a single patient. we would expect that ORIC101 would only affect the cells with GR as a resistance mechanism while not affecting the other cells, resulting in absence of measurable clinical benefit. In addition, resistance pathways may be redundant within a cell. In such a setting, one or more coexisting resistance pathways in addition to GR may be sufficient to drive tumor progression when GR is inhibited. Such tumor complexity may be a possible explanation for the lack of clinical benefit seen in these two clinical trials. And then finally, it's possible that the GR pathway itself is not a key tumor dependency in patients, and so observations made in the lab don't transfer to patients in a clinical setting. We're obviously disappointed that the results from these two clinical trials didn't meet our bar for clinical benefit and further development. Negative trials are not uncommon in oncology drug development, especially when studying novel target biology, which doesn't always translate into the clinic. For that reason, we designed these studies with clearly defined patient populations to enable us to get to an answer as quickly and as efficiently as possible. I think we achieved that. The studies were well run, and they delivered sufficient data to enable us to make the tough but right decision to discontinue the ORC101 programs. We expect to share more details on these clinical studies in future publications. In conclusion, I would like to thank the ORIC 101 team, the study investigators, and the study support staff at all our participating clinical sites, and most of all, the patients who participated in the trials and their families. With that, let me hand it back to Jacob.

Thank you, Prateek. Now turning to slide 13. At ORIC, our mission is overcoming resistance in cancer, an inherently challenging goal. It's for that reason that we have adhered to certain core principles to guide our journey. First, our patients are battling for their lives, so we're going to continue tackling areas of high unmet need where we can have a meaningful impact. Second, we will continue to design trials that allow us to make data-driven decisions and get to an answer as efficiently as possible so we can allocate resources into our most promising programs. And finally, we've been explicit about our intent to assemble a pipeline through both internal discovery and external BD that has a mixture of novel first-in-class targets that rely on differentiated biological insights as well as potentially best-in-class chemistry approaches to validate the targets in order to strike the right aggregate risk profile across the entire pipeline. Last year, we filed three INDs or equivalents for single-agent trials being initiated this year for OREC 533 in multiple myeloma, OREC 114 in EGFR HER2 cancers, and OREC 944 in prostate cancer, with data from all three programs expected in the first half of 2023. In just the first quarter of this year, we've enrolled our first patient on OREC 533 in We've cleared our CTA and initiated multiple clinical sites in Korea for OREC 114, and we're in the process of activating sites for OREC 944. Beyond these three clinical stage programs, our discovery research team last year advanced two programs in the lead optimization, one of which we recently introduced as our PLK4 program, focused on novel, highly selective inhibitors targeting a synthetic lethality approach as a potential treatment for breast cancer. In short, although 101 is not progressing to the next stage, our pipeline is one of the most robust in small-cap biotech, and we remain committed to our goal of developing life-changing therapies for patients with cancer. Now let me turn it over to Dominic to summarize our financials, revised cash runway, and upcoming milestones.

Thanks, Jacob. Turning to slide 14, operating expenses for the fourth quarter of 2021 are totaled $22.8 million, resulting in a net loss of $22.8 million. For the full year 2021, operating expenses totaled $78.9 million, resulting in a net loss of $78.7 million. Net cash used in operating activities for the 12 months ended December 31, 2021, totaled approximately $60 million. We ended the year with $280.4 million in cash and investments. As a result of the discontinuation of ORIC 101, we now expect our cash runway to extend into the second half of 2024, which is well beyond the expected initial data disclosures from our three clinical programs in the first half of 2023. Please see our press release and 10-K for additional details about our fourth quarter and full year 2021 financial results. We'll wrap up our prepared remarks on slide 15. We're very proud of the team and pipeline that we've assembled here at ORIC. While we are disappointed that ORIC 101 won't be advancing, we've always been committed to making rapid and data-driven decisions, and we are excited about the robust pipeline of potential best-in-class and first-in-class molecules that we have assembled. We expect to provide data updates from our three ongoing clinical programs in the first half of 2023. These include initial Phase I data from ORIC 533 in patients with multiple myeloma, initial Phase I data from ORIC 114 in EGFR HER2-driven cancers, and initial Phase I data from ORIC 944 in patients with prostate cancer. Before we open it up to Q&A, I'd like to thank all the investigators and the entire ORIC team who've worked throughout the COVID pandemic to continue tackling our mission on behalf of patients. And mostly, most importantly, I'd like to thank our patients and their families, whom we hope to help overcome resistance in cancer. With that, let's open it up to Q&A.

As a reminder, to ask a question, you will need to press star one on your telephone, and to withdraw your question, press the pound key. Please stand by while we compile the Q&A roster. Our first question, from JP Morgan. You may begin.

Hey, guys. Thanks so much for taking the question. I know on slide 11, you guys outlined the potential reasons for a lack of benefit with ORAC 101, but I guess more mechanistically, like, where do you think the thesis broke down here, given Coricept had STAT-Sig results in ovarian cancer? And, you know, you guys showed some interesting sort of stable disease duration benefits in PDAC previously. Thanks so much.

Hey, Anupam. Thanks for the question. I'll have Pratik take that. Hey, Anupam. It's a good question. I think it's a little bit hard for us to comment on the course of data, especially in the ovarian cancer study, because we don't have full insight into their study beyond some of the top-line results in their conference presentation from last year. I do think that two populations, theirs and ours, are likely different and were treated differently. Our study, as we've emphasized, required patients to have received and progressed on a taxane-containing regimen, and we don't know how that compares with the relic correlate studies. They required platinum resistance, but were silent on taxane progression. Also, if you look at their presentation from last year, their population had two and a half prior therapies, in the ovarian cancer study, whereas ours, it's for prior therapy. So certainly, we had a more refractory population, and by design, we wanted patients who were taxane refractory because we wanted to demonstrate an ORC101 effect and not a taxane retreatment effect, which can be seen in ovarian cancer. We don't have the taxane interaction with ORC101, the PK interaction, but the relic-correlant molecule does. And we don't know the PK across the three arms of their study. And then finally, we've also worked hard to develop a regimen that did not require growth factor support prophylactically, which is kind of the standard of care in this patient population. The Corset regimen does require that. However, in their control arm that only got the Abraxane, only half the patients got GCSF versus 100% on the experimental arm. You know, we don't, you know, we think that the two studies really can't be compared side by side because of the difference in patient populations and how they were treated.

Yeah, so if I'm just adding to what Prateek mentioned, you know, I think we very deliberately set ourselves up for a high bar to find signal in terms of taking on a late line patient population. But that was important for a combination regimen in a single arm study. we had to set that kind of a high bar so that we could clearly call the question of whether or not there was signal. And in terms of managing our resources prudently, that's why we did that, so that we could make this decision as quickly as possible. And that's why we've come to the conclusion that we did today. And a separate point, as Prateek mentioned about the use of GCSF, we felt that it was pretty important from both a patient care perspective as well as just what would be commercially viable to be able to thread that needle without GCSF. So again, that was an explicit decision that we made in charting out a longer-term potential path here.

Thanks so much for taking our question.

Thank you.

Our next question will come from the line of Kevin DeJeter from Oppenheimer. You may begin.

Hey, Greg. Thanks for taking our questions. Appreciate the really transparent release today. In the interest of transparency, can you just comment on the tumor agnostic basket, any findings in there that you think could be hypothesis-generating for others who may explore the field subsequently?

Sure. I'm happy to do so. So we treated 20 patients across seven tumor types in that other tumor basket, and we saw one partial response in a patient with esophageal cancer and nothing else.

Got it. Thanks for that. And then with regard to the PLK4 program, can you just talk a little bit about, you know, target product profile there in terms of, you know, selectivity of the compound for PLK4 and just how we sort of think about, you know, breast cancer as, you know, the optimal, you know, population to explore that hypothesis?

Yeah, Kevin, I can talk at a very high level about it just because I don't want to front run the preclinical poster we've got coming out at ACR here in a couple weeks, but essentially the TPP is aiming to be very potent and very selective. It is a key synthetic lethality pathway, and it's in a tumor type that's of high interest to us in breast cancer, so it fits with everything else that we do and like target-wise internally, but I'd ask you to maybe hold off for a few weeks or a month or so here until we present the poster at AACR, and then we can get into more detail on that.

Great. Thanks for taking our questions.

Thank you, Kevin.

Our next question comes from Colleen Cussey from Baird. You may begin.

Great. Good afternoon. Thanks for all the updates, and thanks for taking our questions. So first one on ORIC 101 and prostate. I think at the last update at the Tribal Conference, You had four patients that were still on treatment at that time. Do you have any update on what their time on treatment was?

Yeah, so we had six patients in that bucket at the time, and four were ongoing at the time of the triple conference presentation. They've all since progressed based on radiographic progression. Their time on treatment, two were at 3.7 months, one at 7.1 months, and one at 9.2 months. So they all have come off since that presentation.

Okay. That's helpful. Thank you. And you had made a comment in the presentation about how the PFS for the selected patients and the unselected patients were similar. How should we understand what the outcome was there?

Sure. That's a good question. Let me sort of expand on that. The patients with the AR resistance variants and the lineage plasticity markers did progress very rapidly. So these were the patients who had signs of their tumor already being AR resistant. So enzalutamide and returning sensitivity to enzalutamide wasn't going to provide any benefit to them. And so that was not part of our target patient population. And so when we did exclude them, that did push up the PFS of the remaining group. And so then we subsetted the remaining patients by baseline GR expression status. because we're interested in the patients who had high GR expression. But there were patients for whom we did not have information on GR expression. And the reason was that there were no tumor cells in their biopsy specimen. And this group had a relatively longer PFS, and it's likely because they had an overall lower tumor burden. So when we removed the GR unknown group, the PFS in the GR high group went back down. And so that's why we overall didn't see a difference between the two selected and unselected populations.

That's interesting. Thank you. And last one for me. I think prostate is also going to be a focus for OREC 944. So are there any learnings you think you can take from this development and kind of apply that to future trials of prostate cancer?

Sure. So this is an entirely different target, and rather than reversing resistance, 944 has the potential for single-agent activity, and we've demonstrated that in multiple enzalutamide-resistant prostate cancer models. This is something we didn't have with ORIC101, which going into the clinic didn't have the potential for single-agent activity. In addition, you know, EED inhibition represents a novel mechanism of action, and it's relevant as tumors evolve. While for ORC101 we were essentially trying to revive enzalutamide activity, a mechanism which the cell had already become resistant to. So, you know, we think that EED is taking sort of a fresh pass at the cancer cell. And despite the fact that there are potential resistance mechanisms in these late-line patients, EED would be novel for those cells and potentially clinically active. That said, we do have, as we had in our ORC101 studies, an extensive translational component to look at tumor heterogeneity and other resistance mechanisms so we can characterize the patients on study more fully and potentially come up with a target patient subset that would be more amenable to EED inhibition.

Great. Thanks for taking our questions.

Thanks, Colleen.

Our next question comes from Mari Raycroft from Jefferies. You may begin.

Hi, thank you for taking my questions too. I was going to ask one on ORIC 101 and then one on 533. I guess for 101, can you expand on what you saw with tumor heterogeneity and discuss an example of tumor heterogeneity observed in the study?

Sure. So we probably have the best data from the prostate study. We were able to do baseline and on-study biopsies as well as circulating tumor DNA profiling so we could watch the tumors evolve while the patients were on the study. And so in that trial, we saw multiple examples of patients who, despite being within our target patient population, so they did not have AR resistance variants or markers of lineage plasticity and were GR high at baseline, they gained one or more of these resistance mechanisms or other potential resistance factors while on study. such as gaining ARV7 or MYC or loss of PTEN or TP53. And some of these patients, these alternate clones were minor at baseline but grew while on study. And so that was the heterogeneity and redundant resistance mechanisms I was referring to earlier.

Got it. Okay, interesting. And for 533, the monotherapy data in triple-class refractory myeloma, that's not expected until first half of 23. But can you comment if you're in discussions with pharma partners to evaluate combo regimens in myeloma and other tumor types to run in parallel?

Jacob, I can't comment specifically, but I'll just tell you generically that we have lots of conversations along those lines with lots of pharma partners. on the various programs in our pipeline, but we don't really comment on specific discussions of individual programs.

Got it. And for combo strategy, is there anything additional you're saying at this point on that?

The one thing, and I think your question highlights it, is we're absolutely of the mindset that for 533, we're not planning to run out a single agent trial over a long period of time and then decide at that point whether we're going to green light a combo or not. It's pretty clear here that in that triple quad pentarefractory population, if we see even modest activity as a single agent, then we ought to quickly explore that in combinations. And you'll remember that Ken Anderson, in the call that we hosted in December at ASH, Dr. Anderson, you know, mentioned exactly that point, that as soon as you see modest single agent activity, you ought to test combinations. You probably ought to test multiple combinations in terms of combination partners, meaning that The preclinical models don't give you great evidence of one specific combo class to combine with, so we probably will combine with multiple of the combination classes that you might think of doing. And we would do that pretty much, I mean, almost in parallel with the single agent studies that are going on, provided that we've seen, you know, that modest activity that I mentioned.

Got it. Okay. Thank you for taking my question.

I think that's where you were driving with your question about the conversations we may or may not be having. Yep.

Right. Yeah. Thank you.

Yep. Thanks, Maury.

Our next question comes from Yvonne McCormick from Sydney. You may begin.

Hi, team. This is Ashik Mubarak on FreeVol. Thanks for taking my question. I'm sorry to hear about the discontinuation. I think you alluded to this in the previous question, but can you discuss a little more what secondary pathways of resistance you're hypothesizing may have contributed to the lack of resensitization?

So some of these were ones that we screened out at baseline but developed while on study. So ARV7 would be a resistance pathway that secondary, alternate, that restored GR inhibition wouldn't address that. P10 loss, TP53 loss are also associated with resistance. So those are the other mechanisms that we saw. And we saw others as well. Those were examples.

Okay, got it. And then maybe switching to the CD73, have you guided to when you expect to complete enrollment in the Phase 1B? And maybe what does that imply about what kind of follow-up you might present next year?

We haven't guided at this point. It's just too early, just given that the trial initiated literally this quarter. So we have not provided that guidance yet.

Okay, got it. Thank you very much.

Our next question will be, sorry. Our next question will be from Michael Schmidt from Guggenheim, New England.

Hey, good afternoon. This is for Michael. Thanks for taking our questions. Two questions on your pipeline program. The first one on your new POK4 program. Can you maybe help us understand the opportunity and the size of the TREEM 37 amplification? And secondly, on 114, you initiated the Phase 1 study. Help us understand how you plan to measure 114-CNS activity in the Phase 1 study, and will you plan to enroll active brain meds patients in the future? Thank you.

Thanks. I'll take the first, and I'll ask Prateek to take the second. So on the first, you know, as I mentioned earlier to Kevin, we probably, we've got a poster coming up at ACR on PLK4, So I'd probably defer the specific answers around market size and just differentiation until then. I think the main thing to point out on PLK4 is, you know, totally consistent with what our strategy has been from the beginning. We plan to put forward programs that are both from our internal discovery programs as well as through external opportunistic BD. In this case, it's one that came from our internal discovery efforts. single agent potential mechanism of action, like I said, a synthetic lethality pathway that's relevant to breast cancer plus a couple other tumor types. And importantly, and we've been explicit about this as well, is we've always wanted our pipeline to have a mix of first-in-class targets that rely on differentiated biological insights and then potentially best-in-class targets that rely on chemistry or biological insights. And in this case, this is, we believe, a potentially first-in-class opportunity. Our team got a jump on this target a while back ahead of a paper that was published in Nature that came out last year. And so we're pretty excited about it because it's a potentially first-in-class opportunity, like I said, with a single-agent hypothesis in a tumor type that we care a lot about. So stay tuned for the poster at AACR, and then we can get into more specifics at that point.

Hi, this is Prateek. To your question about 114 and CNS activity, so we are more liberal in our phase one eligibility criteria in terms of allowing patients into the study, not just with treated and stable brain meds, which is what most other studies allow, but also allowing patients with active brain meds as well that are asymptomatic. So we are allowing untreated brain meds into even our phase one.

Thank you very much.

Thank you.

Thank you. I'm not showing any further questions in the queue. That will conclude our conference call for today. Thank you so much for your participation and your interest in ORIC. You may now disconnect. Everyone have a great day.