Q4 2021 Oric Pharmaceuticals Inc Earnings Call

Operator: 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 in a listen-only mode.

Good day, and thank you for standing by and welcome to the old like Pharmaceuticals fourth quarter and full year 2021 financial results and operational update call.

All participants 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 one on your telephone. Please be advised that today's conference is being recorded and if you require any further assistance. Please press star zero.

Operator: After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you will need to press star one on your telephone. Please be advised that today's conference is being recorded, and if you require any further assistance, please press star zero. I would like to hand the conference over to our chief speaker today, Dominic Piscitelli, chief financial officer. Please go ahead.

And the conference Oh, Gee speaking today, Dominic should Kelly Chief Financial Officer. Please go ahead.

Dominic Piscitelli: Good afternoon, and welcome to the Oric 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 31, 2021. You may find these documents posted on the investor page of oricpharma.com. We have pre-recorded a portion of our prepared remarks, after which we will host a live Q&A session.

Good afternoon, and welcome to the ORC 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 31 2021, you.

You may find these documents posted on the Investor page of work form of Dot com.

We have prerecorded a portion of our prepared remarks, after which we'll host a live Q&A session. So please bear with us if we have any technical difficulties.

Dominic Piscitelli: 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 four linking statements. Oric's actual results may differ materially from those expressed in or indicated by such for-looking statements. For a description of risk factors associated with investing in Oric, please refer to our recent filing with the Securities Exchange Commission. Oric specifically disclaims any obligation to update any foregoing statements except as required by law. Now turn to slide 3. I'll briefly walk you through the agenda and introduce our speakers.

Before we begin starting on slide two during this conference call, we will be making forward looking statements.

<unk> 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 org. Please refer to our recent filings with the Securities Exchange Commission.

<unk>, specifically disclaims any obligation to update any forward looking statements, except as required by law.

Now turning to slide three.

We walk you through the our agenda and introduce our speakers.

Dominic Piscitelli: During today's call, we'll primarily focus on an update on ORIC-101, after which we'll provide a pipeline update and summary, followed by Q&A. Joining me on the call today are Jacob Chacko, CEO, and Pratik Multani, CMO. Now, let me turn over the call to Jacob.

Today's call will primarily focus on an update on Oracle one O. One after which will provide a pipeline update and summary, followed by Q&A.

Joining me on the call today, we have Jacob Chacko C E O in particular tiny CMO.

Now, let me turn over the call to Jacob.

Jacob Chacko: 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 Oric-101 should be discontinued due to a lack of sufficient efficacy signals to meet our benchmarks, which Pratik will tell you more about shortly.

Thank you Dominic turning to slide four.

As you know over the past two plus years, we've conducted dose escalation and dose expansion studies testing two separate therapeutic hypotheses for G. R inhibition as a means of overcoming resistance to chemotherapy in various solid tumors and to <unk> modulators in prostate cancer.

We recently completed interim analyses from both combination studies and we believe that further development of work one O. One should be discontinued due to a lack of sufficient efficacy signal to meet our benchmarks, which petite we'll tell you more about shortly.

Jacob Chacko: 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 signals 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.

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 G. R antagonist in order to re sensitize them to that prior therapeutic.

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 G. Our hypothesis appropriately and also confident in making this decision.

Jacob Chacko: While we're obviously disappointed that ORIC101 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.

While we're obviously disappointed that work one O. One 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 work one O. One we believe we have one of the most robust and differentiated pipeline and 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.

Jacob Chacko: Last year, we filed three INDs or equivalents for single-agent trials being initiated this year for Oric 533 in multiple myeloma, Oric 114 in EGFR HER2 cancers, and Oric 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 lead optimization, one of which we recently introduced as our PLK-4 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 positioned to weather a sustained market downturn.

Last year, we filed three ind's or equivalents for single agent trials being initiated this year for Orrick, 533, and multiple myeloma or 114 in Egfr her two cancers and Orrick 94, four in prostate cancer with data from all three programs expected in the first half of 2020 three.

Three.

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 into lead optimization, one of which we recently introduced as our P. L. K four 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.

Jacob Chacko: With the discontinuation of OREC 101, our cash runway has now been extended from the first half of 2024 to the second half of 2024, and that guidance assumes the advancement of all our pipeline programs. With that said, let me now turn the call over to Pratik to walk you through the summary highlights of the ORIC-101 study. Thank you, Jacob.

With the discontinuation of work one O. One our cash runway has now been extended from the first half of 2024 to the second half of 'twenty 'twenty, four and that guidance assumes advancement of all of our pipeline programs.

With that said, let me now turn the call over to Petite to walk you through the summary highlights of the Orca one O one studies.

Thank you Jacob.

Pratik Multani: Turning to slide six, Ashiq Mubarack said, We have been conducting two clinical trials of ORC101, each examining a distinct mechanism of action of GR inhibition as a means to reverse cancer. The first study is a combination of Oric 101 with Enselutamide 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 a single arm setting as efficiently as possible, namely patients with metastatic prostate cancer who are progressing on enzalutamide.

Turning to slide six we have been conducting two clinical trials of <unk> 101.

Examining a distinct mechanism of action of G. R inhibition as a means to reverse cancer resistance.

First study is a combination of work 101 with <unk> in patients with metastatic prostate cancer.

Given that work one O. One was not expected to have single agent activity. We chose this patient population specifically so that we could identify a clinical signal in a single arm setting as efficiently as possible.

Many patients with metastatic prostate cancer, who are progressing on absolute amount.

Pratik Multani: By adding Oric-101 at the time of enzalutamide progression, our objective was to test the hypothesis, a reversal of an insolute myrosis. The simultaneous inhibition of GR is a potential bypass pathway, a novel paradigm for treatment post enzalutamide or any androgen receptor modulator. Most Second Line Approaches involve switching to entirely different mechanisms of action.

By adding work one to one at the time of insulated by progression. Our objective was to test the hypothesis of reversal of ancillary might resistance to the simultaneous inhibition of G. R. As a potential bypass pathway.

Mobile paradigm for treatment post and solidified or any androgen receptor modulator. Since most second line approaches involve switching to entirely different mechanisms of action.

Pratik Multani: Here we were trying to extend the efficacy of enzalutamide itself. This multi-center open-label study was performed in two parts, previously reported on Part 1, which was the dose escalation portion of the trial, through which we identified the recommended Phase 2 dose, or RP2D, of ORC101, 240 milligrams once daily in combination with the standard dose and Zolidoprotein.

Here, we were trying to extend the efficacy of <unk> itself.

This multicenter open label study was performed in two parts.

Previously reported on part one which was the dose escalation portion of the trial through which we identified the recommended phase two dose or RPT of work on a one to be 240 milligrams once daily in combination with standard dose and Zulu Tonight.

Pratik Multani: Determination of work 101 relied heavily on extensive translational work that was an integral component of the trial. This effort included bass line and on-study tumor biop, serial blood sampling for pharmacokinetic, and pharmacodynamics of GR signal, tumor genomic profiling at baseline and longitudinally during the study. Pharmacokinetic sampling demonstrated that at the RP2D, we were achieving exposures of ORC101 that were sufficient to inhibit the target. We were also able to confirm that we were achieving target shutdown through the measurement of downstream GR target G. After establishing the RP2D, we enrolled patients into the dose expansion portion of the trial with a planned interim analysis after 28 patients.

The determination of work one O one dose relied heavily on extensive translational work that wasn't an integral component of the trial.

This effort included baseline and on study tumor biopsies and serial blood sampling for pharmacokinetics farmer.

Farmer co dynamics of GR signaling and tumor genomic profiling at baseline and longitudinally on study.

Pharmacokinetics sampling demonstrated that at the RP two D. We were achieving exposures of org one of one that were sufficient to inhibit the target and through our Pharmacodynamic studies. We were also able to confirm that we were achieving targets shut down through the measurement of downstream GR target genes.

After establishing the RP two D. We enrolled patients into the dose expansion portion of the trial with a planned interim analysis after 28 patients.

Pratik Multani: The primary endpoint of Part 2 was disease control rate at 12 weeks, with progression pre-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 Oric 101 in which we would expect GR to be a potentially active mechanism. David's population excludes patients whose tumors harbor one of the well-described alternate, Family, Primary Resistance, Variance of the Androgen Recept. Ashiq Mubarack, splice variants or point mutations that inhibit enzalutamide binding, and Marker's Lineage Pesticis, indicating that the cancer had become AR.

The primary endpoint of part two with 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 or what to what.

In which we would expect G ought 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 variance at the androgen receptor such a spice variance or point mutations that inhibit and dilutive by binding and markers of lineage plasticity, implying that the cancer had become a R.

Independent.

Pratik Multani: In addition, we would also focus on 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. Ashiq Mubarack, David Nierengarten, Pratik Multani, 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 agencies, Kab Turning to Slide 7, let me summarize the results of this analysis.

In addition, we would also focus on the patients whose tumors were high expresses of the glucocorticoid receptor, which is the target in the fourth quarter one.

After enrolling 10 patients to identify the RP two D and part one 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 was 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 Cabana Taxol and Docetaxel, which are used in the post <unk> setting as well as the new agents and combinations that are in development, such as Cabozantinib plus twos Elysium at.

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.

Pratik Multani: First, in terms of safety, the combination regimen was generally well-tolerated at the recommended phase 2 dose. Next, with respect to drug exposure and target engagement, extensive PK-PD work demonstrated that we were achieving ORIC101 levels sufficient for GR target coverage, which we were able to confirm by measuring the downregulation of GR. Finally, based upon tumor biopsies at baseline, we identified that the majority of patient tumors expressed moderate to high levels of GR.

Next with respect to drug exposure and target engagement extensive PK PD work demonstrated that we were achieving worked one on one levels sufficient for GR target coverage, which we were able to confirm by measuring the downregulation 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 G. R.

Pratik Multani: Nevertheless, despite achieving ORIC-101 exposures consistent with biological activity, we were not able to demonstrate evidence of sufficient clinical benefit on any of the efficacy tests. 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 Plus disease. 33.3% The median PFS in the same patient population was 3.7 months.

Nevertheless, despite achieving or we're gonna want 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 rates at 12 weeks in the target patient population of patients with moderate to high GR expression and no evidence of alternate resistance through a R alterations or lineage plasticity was 33, 3% and the median PFS in the same patient population was three seven months.

<unk>.

Pratik Multani: 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, the outcome seen in our study of Oric Wanawan with Enseludamide was insufficient to support continued, Turning to slide 9. The second trial studied Oric-101 in combination with NAB-paclitaxel in patients with advanced solid cancer.

Of note. These values were not meaningfully different from the D. C R and PFS recorded in the unselected patient population.

In the context of the efficacy if approved therapies for patients after progression on an air modulator.

The efficacy data with new therapies and regimens currently in development.

<unk> seen in our study of work where no one with Insulet, who might were insufficient to support continued development.

Turning to slide nine the second trial studied or 101 in combination with Nab paclitaxel in patients with advanced solid tumors.

Pratik Multani: This multicenter, open-label study was also performed in two parts, previously reported on Part 1, which was the dose escalation portion of the trial, through which we identified the RP2D of ORC101 in combination with NAVpaclitaxel to be 160 mg of ORC101 with 75 mg per m2 of NAVpaclitaxel 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. These demonstrated that at the RP-2..., we were achieving exposures of ORIC-101 sufficient to inhibit the target and that we were achieving target shutdown, and the NAB-paclitaxel dose, although lower than the labeled dose for frontline therapy. He resulted in rates of neutropenia without growth factor support that indicated that we had a sufficient dose for these late-line patients.

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 RP two D of work 101 in combination with Nab Paclitaxel to be 160 milligrams of <unk>. One O. One with 75 milligrams per meter squared of Nab Paclitaxel weekly for three weeks on a four.

A week cycle.

In this study as with the <unk> study, we had an extensive translational component, including pharmacokinetic sampling and Pharmacodynamic testing of GR target genes, which demonstrated that at the RP. Two D. We were achieving exposures of work Warner one sufficient to inhibit the target and that we were.

Cheating target shutdown.

And the Nab paclitaxel dose, although lower than the label dose for frontline therapy resulted in rates of neutropenia without those factors support that indicated that we had a sufficient dose for these late line patients.

Pratik Multani: After establishing the RP2, we enrolled patients in the multi-cohort dose expansion portion of the trial, with three cohorts of pancreatic ductal adenocarcinoma, ovarian cancer, and triple negative breast, and a fourth cohort open to patients with other tumors. The primary endpoint of Part 2 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 signals in a single arm setting as efficiently as possible.

After establishing the RP two D. We enrolled patients in the multi cohort dose expansion portion of the trial with three cohorts of interest.

Pratik Multani: Specifically, we require 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 taxidermy treatment effect in ovarian cancer and TNV... This effect is generally modest.

Pancreatic ductal adenocarcinoma.

Ovarian cancer and triple negative breast cancer.

And the fourth cohort open 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 and work where no one effect from pure taxane driven clinical activity.

While there is a taxane re treatment effect in ovarian cancer and T N B C.

The fact is generally modest and so we set a benchmark for PFS in our study of six months for ovarian cancer.

Pratik Multani: And so we set a benchmark for PFS in our study of six months for a variant. On the other hand, in relapsed PDAQ, there is no measurable tax and retreatment effect reported in the literature. And so we were looking to achieve a PFS of three months or longer with Oric-101 and nabpaclitaxel in this code. After enrolling 21 patients to identify the RP2D in Part 1, 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.

On the other hand in relapsed P deck, there's no measurable taxane retreat bit affect reported in the literature and so we were looking to achieve a PFS of three months or longer with Orca, one and Nab paclitaxel in this cohort.

After enrolling 21 patients to identify the RP to D. 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.

Pratik Multani: Turning to slide 10, the safety profile of this combination regimen was generally well tolerated at the recommended phase 2 dose. And, as I stated, PK data showed good target coverage, data demonstrated evidence of target, 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, PEDEC, and O'Barron.

Turning to slide 10, let's say.

The profile of this combination regimen was generally well tolerated at the recommended phase II dose and as I stated PK data showed good target coverage and P. D data demonstrated evidence of target engagement.

In addition, baseline biopsy a patient tumors showed high levels of GR expression across most tumor types.

But particularly in two of the tumor types of interest P deck and ovarian cancer.

Pratik Multani: The expression was so high across most patients tested in these two tumor types that preselection by GR status was not necessary to identify a subset target patient population. However, although we demonstrated evidence of biological activity and high levels of the target glucocord, we saw only one confirmed partial response in the ovarian cancer cohort and no objective responses in the PDAC code. Furthermore, the median progression-free survivals were 1.9 months in PDAC and 1.2 months in ovary. In these patients who are taxaim pretreated, did not see sufficient evidence that the addition of Oric-101 to NAB-paclitaxel reversed resistance and re-sensitized these patients to..., Retreatment with Taxane Chemotherapy.

Expression was so high across most patients tested in these two tumor types that pre selection by GR status was not necessary to identify a subset target patient population.

Although we demonstrated evidence of biological activity and high levels of the target acquired receptor. We saw only one confirmed partial response in the ovarian cancer cohort.

And no objective responses in the P Dex cohort.

Furthermore, the median progression free survivals were 1.9 months at P deck and two two months in ovarian cancer.

In these patients who are taxane pretreated, we do.

Nazi sufficient evidence that the addition of Oracle into one to Nab Paclitaxel reverse resistance and resets of ties these patients' tumors to retreat, but with Taxane chemotherapy.

Pratik Multani: Therefore, we conclude from these data and these expansion cohorts that there was insufficient activity to support continued clinical development of this red- Now turning to slide 11, I'd like to review what we've learned from these two clinical trials. Please 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 module.

Therefore, we conclude from these data.

And these expansion cohorts that there was insufficient activity to support continued clinical development of this regimen.

Pratik Multani: Second, we learned that in these combinations, Oric-101 was capable of achieving clinical exposures in patients, and efficient to cover and inhibit the target glucocorticoid receptor. We measured this effect of GR target shutdown in patient samples longitudinally over the course of a year. But, if we were hitting and shutting down the target, then why did we not see clinical effects? For the translational work we performed as part of both studies, tumor genomic profiling suggested that an answer may lie in tumor heterogeneity and or redundancy of resistance mechanisms.

Now turning to slide 11, I'd like to review what we've learned from these two clinical trials.

Or 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 out of 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 work one O. One 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 and 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 door of redundancy of resistance mechanisms.

Pratik Multani: 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.

By tumor heterogeneity, I mean differences within tumor lesions and between tumor lesions and the relevance of G. R. As a resistance pathway.

In a single tumor some cells may indeed be relying upon G. R. As a resistance pathway, but other cells and that same tumor maybe relying upon alternate non G. R mechanisms.

Pratik Multani: Similar differences could also be present between two separate tumors within a single patient. We would expect that Oric-101 would only affect the cells with GR as a resistance mechanism while not affecting the other cells, resulting in the absence of measurable clinical benefit. In addition, resistance pathways may be redundant within a cell.

A similar difference could also be present between two separate tumors within a single patient.

We would expect it worked 101 would only affect the cells with G. R. 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 and.

Pratik Multani: 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.

In such a setting one or more coexisting resistance pathways. In addition to G are may be sufficient to drive tumor progression when G ours inhibited.

Such tumor complexity, maybe a possible explanation for the lack of clinical benefit seen in these two clinical trials.

And then finally, it's possible that the <unk> pathway itself is not a key tumor dependency in patients.

Observations made into lab don't transfer to patients in a clinical setting.

Pratik Multani: 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. They don't always translate. 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.

We're obviously disappointed that the results from these two clinical trials Didnt meet our bar for clinical benefit in 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.

Pratik Multani: The studies were well run, and they delivered sufficient data to enable us to make the tough but right decision to discontinue ORC101. We expect to share more details on these clinical studies in future publications. In conclusion, I would like to thank Oric 101, 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.

The studies are well run and they delivered sufficient data to enable us to make the tough but right decision to discontinue the ORC 101 program.

We expect to share more details on these clinical studies and future publications.

In conclusion, I would like to thank the ORC Warner one team. The study investigators in 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 Marty.

Jacob Chacko: Thank you, Pratik. 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. [inaudible] 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 to our most promising programs.

Now turning to slide 13.

At <unk>, our mission is overcoming resistance in cancer and inherently challenging goal.

It's for that reason that we adhere 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.

Jacob Chacko: 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.

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 validated targets in order to strike the right al.

Brigade risk profile across the entire pipeline.

Jacob Chacko: Last year, we filed three INDs or equivalents for single-agent trials being initiated this year for Oric 533 in multiple myeloma, Oric 114 in EGFR HER2 cancers, and Oric 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 Oric 533, we've cleared our CTA and initiated multiple clinical sites in Korea for Oric 114, and we're in the process of activating sites for Oric 944.

Last year, we filed three <unk> or equivalents for single agent trials being initiated this year for <unk>, three and multiple myeloma Orrick 114 in Egfr her two cancers and Orrick 94, four 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 work by three three we've cleared our Cta and initiated multiple clinical sites in Korea for or 114, and we are in the process of activating sites for ore at 94 four.

Jacob Chacko: Beyond these three clinical stage programs, our Discovery Research Team last year advanced two programs in lead optimization, one of which we recently introduced as our PLK-4 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.

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 is our P. L. K four program focused on novel highly selective inhibitors targeting a synthetic lethality approach as a potential treatment for breast cancer.

In short, although one O. One is not progressing to the next stage. Our pipeline is one of the most robust and small cap biotech and we remain committed to our goal of developing life changing therapies for patients with cancer.

Jacob Chacko: Now, let me turn it over to Dominic to summarize our financials, revised cash runway, and upcoming miles. Thanks, Jacob. Turning to slide 14, operating expenses for the fourth quarter of 2021 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.

Now, let me turn it over to Dominic to summarize our financials revised cash runway and upcoming milestones.

Jacob turning to slide 14 operating expenses for the fourth quarter of 2021 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 $284 million in cash and investments.

Dominic Piscitelli: 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 ORC.

As a result of the continuation of work one O. One 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 will wrap up our prepared remarks on slide 15, we're very proud of the team and pipeline that we've assembled here at work. While we are disappointed that work one O. One wont be advancing we've always been committed to making rapid and data driven decisions and we're excited about the robust pipeline of potential best in class and first in class molecule.

Dominic Piscitelli: 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 1 data from ORC533 in patients with multiple myeloma, initial phase 1 data from Oric 114 in EGFR-HER2 driven cancers, and initial phase 1 data from Oric 944 in patients with prostate cancer.

Also 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 one data from <unk> 533 in patients with multiple myeloma.

Initial phase one data from <unk> 114, and Egfr her two driven cancers and initial phase one data from <unk> 94, four in patients with prostate cancer.

Dominic Piscitelli: 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, 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 panel key.

Before we open it up to Q&A I'd like to thank all the investigators and the entire or team who've worked throughout the Covid pandemic to continue tackling our mission on behalf of patients.

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.

Yeah.

Yes.

As a reminder to ask a question you will need to press star one on your telephone.

To address your question Chris.

Lisa Bartlett compile the Q&A roster.

Operator: Please stand by while we compile the Q&A roster. Our first question will come from Ana Anupam Rama from J.P. Morgan. You may begin. Thank you, 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 Coruscept has STAT-seq results in ovarian cancer, and, you know, you guys showed some interesting sort of stable disease duration benefits in PDAC previously. Thanks so much.

Our first question will come from the line of upon Rama from Jpmorgan maybe.

Hey, guys. Thanks.

Thanks, so much for taking the question I know on slide 11.

You guys outlined the potential reasons for a lack of benefit with Oracle one on one but I guess.

Mechanistically like where do you think the thesis broke down here given course, Ted Stat Sig results in ovarian cancer and you know you guys showed some interesting sort of stable disease duration benefits in PDR previously thanks, so much.

Pratik Multani: 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 CORSEP 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, but I do think that two populations, theirs and ours, are likely different and were treated differently.

Hey, Thanks for the question I'll, let <unk> take that.

Oh no pump.

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 topline results in their conference presentation from last year, but I do think the two populations theirs and ours are likely different and were treated differently.

Pratik Multani: 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 Rella-Correlate studies, which 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 had four prior therapies. So certainly, we had a more refractory population, and by design, we wanted patients who were taxing refractory because we wanted to demonstrate an ORF 101 effect, not a taxing retreatment effect which can be seen in ovarian cancer. We don't have the taxane interaction with Oric-101, the PK interaction, but the relacorrelate molecule does.

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 Rolla correlate studies they required platinum resistant but were silent on taxane progression.

Also if you look at our presentation from last year their population has two and a half prior therapies.

The ovarian cancer study, whereas ours its port prior therapies. So certainly we had a more refractory population and by design. We wanted patients who are taxane refractory because we wanted to demonstrate in Oregon and one effect.

Taxane re treatment effect, which can be seen in ovarian cancer.

We don't have the taxane interaction.

With that work one of one that PK interactions, but rarely correlate molecule does and we don't know that PK across the three arms of the study and then finally, we've also.

Pratik Multani: And we don't know the PK across the three arms of their study. And then finally, we've also... Mark 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 course of 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. So, 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.

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.

Relation.

Of course that regimen does require that however.

In their control arm that only got the abraxa in only half the patients got G CSF versus a 100% on the experimental arm. So we don't we think that the two studies really can't be compared it side by side because of the difference in patient populations and how they were treated.

Jacob Chacko: Yeah, so Anupam, just adding to what Pratik 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.

Yes, so if I'm just adding to what <unk> mentioned I think we very deliberately set ourselves up for a high a high bar.

<unk> signal in terms of taking on a late line patient population.

But that was important for our 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 can make this decision as quickly as possible.

And that's why we've come to the conclusion that we did today in a separate point its petite mentioned about the use of G. CSF. We felt that it was pretty important from a patient care perspective, as well as just what would be commercially viable to to be able to thread that needle without G. CSF. So again that was an explicit decision that we made in charting out a longer term potential path here.

Jacob Chacko: And a separate point, as Pratik 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. 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, great. Thanks for taking our questions. I appreciate the really transparent release today.

Thanks, so much for taking our question.

Thank you.

Our next question will come from the line of.

Kevin <unk> from Oppenheimer, you may begin.

Okay, great. Thanks for taking my questions I appreciate the really transparent released today.

Pratik Multani: Pratik, in the interest of transparency, can you just comment on the tumor agnostic basket, you know, any findings in there that you think could be, you know, hypothesis-generating for others who may explore the field subsequently? Sure, I'm happy to introduce it. So we did, we treated 20 patients across seven tumor types in that other tumor basket, and we saw one partial response in a patient with ovarian, I mean, with a suffigial cancer.

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 them its field subsequently.

Sure happy to do so so we did have we treated 20 patients across seven tumor types in that other tumor basket and we saw one partial response in a patient with ovarian.

You saw that yield cancer and nothing else.

Pratik Multani: Gavin, thanks for that. And then, with regard to the PLK4 program, can you talk a little bit about the 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 the.., you know, the optimal population to explore that hypox. 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 AACR here in a couple weeks, but essentially, the TPP is aiming to be very potent and very selective.

Got it thanks for that and then with regard to the P. O K four program can you just talk a little bit about.

The target product profile there in terms of selectivity.

Or okay. Okay.

For an interest how we sort of think about breast cancer as.

The optimal.

Population to explore that hypothesis.

Yeah, Kevin I can talk at a very high level about it just because they don't want to front run the preclinical posters that we've got coming out of the ACR here in a couple of weeks, but.

Essentially the TPP is is aiming to be very potent and very selective.

Pratik Multani: 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. Great, thanks for taking our questions. Thank you, Kevin.

It is a key synthetic lethality pathway and its 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 hold off for a few weeks or a month or so here until we presented a poster at ACR and then we can get into more detail on that.

Great. Thanks for taking our questions.

Thank you Kevin.

Operator: Our next question comes from Colleen Kusy from Baird. You may begin. Good afternoon.

Our next question comes from the line of calling from.

From Baird you may begin.

Yeah.

Colleen Kusy: 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 triple conference, you had four patients that were still on treatment at that time. Do you have any update on how long their 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.

Great. Good afternoon, thanks for all the updates and thanks for taking our questions.

First one on.

101 in prostate I think at the last update at the Triple Conference you had four patients that were still on treatment at that time excuse me update on on what their time on treatment wise.

Yeah. So we had six patients in that bucket at the time and four were ongoing at the time of the Triple Conference.

Colleen Kusy: Presentation. They have all since progressed based on radiographic progression, their time on treatment, two or three point seven months, one at seven point one months and one at nine points. So they all have come off since then.

Presentation.

<unk> all since progressed based on radiographic progression the time on treatment two or three seven months one in seven one months and one at nine two months.

So they all have come off since that presentation.

Pratik Multani: Ashiq Mubarack, 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.

Okay. That's helpful. Thank you.

You had made a comment in the presentation about how the PFS for the selected patients in unselected patients were similar.

Should we understand.

What's the outcome on that.

Pratik Multani: Let me 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 weren'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.

Sure.

A good question let me.

Expand on that the patients with the <unk> resistance variance in the lineage plasticity markers did progressed very rapidly. So these are the patients.

Who had signs of their tumor already being a resistance and solidified and returning sensitivity that <unk> wasn't going to do.

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.

Pratik Multani: And so then we subsetted the remaining patients by baseline GR expression status because we were 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.

So then we subset of the remaining patients by baseline GR expression status, because we're interested in the patients who had high <unk> expression, but where 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.

Pratik Multani: 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 and the GR high group went back down. Rama, that's why we, overall, didn't see it.

And it's likely because they had an overall lower tumor burden. So when we remove the G are unknown group the PFS in that in the <unk> High group went back down.

That's why we overall from didn't see a difference between the two selected and unselected populations.

Operator: [inaudible] So I did it now. That's interesting. Thank you. And last one for me, I think prostate cancer is also going to be a focus for Oric 944. So are there any learnings you think you can take from this development and kind of apply that to future trials at Pratik? So are there any learnings you can take from this development and kind of apply that to future trials at Pratik? Sure.

That's interesting. Thank you and then last one for me.

Think protein is also going to be a focus for or at nine point force are there any.

Do you think you can take from this development and you can kind of.

Apply that to future trials in prostate cancer.

Pratik Multani: So, you know, this is an entirely different target, and rather than reversing resistance, 9 for 4 has the potential for single agent activity, and we've demonstrated that in multiple insolute of my resistant prostate cancer models. This is something we didn't have with Oric 101, 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.

Sure.

This is entirely.

Entirely different target and rather than reversing resistance of <unk>.

<unk> four has the potential for single agent activity and we've demonstrated that in multiple ancillary might resistant prostate cancer models. This is something we didn't have with work went to one which going into the clinic didn't have the potential for single agent activity.

In addition E D inhibition represents a novel mechanism of action.

It's relevant while tumor as tumors evolve wild.

Pratik Multani: While for work 101, we were essentially trying to revive the activity of my bad activity, a mechanism which the cell had already become... 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 in the 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.

While for work on the one we were essentially trying to revive and dilutive might activity mechanism, which the cell had already become resistant to so we think that he 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 E. D would be novel for those cells and potentially clinically active that said, we do have as we had in our orkin in one studies and extensive translational component to look at tumor heterogeneity and other resistance mechanisms. So we can carry.

<unk> the patients on study more fully and potentially come up with a target patient subset that would be more amenable to <unk> inhibition.

Great. Thanks for taking my questions.

Thanks Kelly.

Operator: Our next question is a couple of lines from Mari Raycroft from Jeffries. You may begin. Hi, thank you for taking my questions. I was going to ask one on Ork 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.

Our next question will come from the line of Maury Raycroft from Jefferies. You may begin.

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

Sure. So we probably have the best data for the prostate study we were able to do.

Operator: 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 P10 or TP53. And in some of these patients, these alternate clones were minor at baseline but grew while on study. So that was the heterogeneity and redundant resistance mechanism.

This line and on study biopsies as well as circulating tumor DNA profiling. So we could watch the tumors evolve while the patients on the study.

So in that trial, we saw multiple examples of patients who despite being within our target patient population. So they did not have a resistance variance or markers of lineage plasticity and towards our high at baseline.

And one or more of these.

Since mechanisms or other potential resistance factors, while on study such as gaining <unk> seven or mix or loss of <unk> 10, or <unk> 53, and some of these patients. These these are alternate clones were minor at baseline, but grew while on study and so that was the heterogeneity and redone.

Resistance mechanisms I was referring to earlier.

Pratik Multani: Got it. Okay, interesting. And for 533, the monotherapy data in a triple class refractory myeloma, that's not expected until the first half of 23.

Got it okay interesting.

And for <unk> III, three monotherapy data in a triple class refractory myeloma, that's not expected until first half of 'twenty three but can you comment. If you are in discussions with pharma partners to evaluate combo regimens in myeloma and other tumor types run in parallel.

Jacob Chacko: But can you comment if you're in discussions with pharma partners to evaluate combo regimens and myeloma and other tumor types running in parallel? 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 about the various programs in our pipeline, but we don't really comment on specific discussions of individuals. [inaudible] Got it. And for the combo strategy, is there anything additional you're saying at this point about that?

No more of this is 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 one of the various programs in our pipeline, but we don't really comment on specific discussions of individual programs.

Jacob Chacko: The one thing, and I think your question highlights it, is that we're absolutely of the mindset that for 5-3-3, 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.

Got it and for combo strategy is there anything additional you are saying at this point on that the ones. The one thing and I think your question highlights. It is we're absolutely of the mindset that for phase III three we're not planning to run out a single agent trial over a long period of time, and then decided at that point, whether we're going to green light.

<unk> or not it's pretty clear here that in that Triple Quad Penta refractory population, if we see even modest activity as a single agent that we added quickly explore that in combinations and you'll remember that kayne Anderson in the call that we hosted.

Jacob Chacko: It's pretty clear here that in that triple quad penta refractory population, if we see even modest activity as a single agent, then we ought to quickly explore that in combinations. And you remember that Ken Anderson, on the call that we hosted in December at Ash, Dr. Anderson 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.

In December at Ash, Dr. Anderson 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.

That combination partners, meaning that the preclinical models don't give you great evidence of.

One specific combo class to combined with that we probably will combined with <unk>.

Multiple of the combination classes.

You might think of doing and we would do that.

Jacob Chacko: 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 questions. I think that's where you were driving.

Pretty much I mean, almost in parallel with the single agent studies that are going on provided that we've seen that modest activity that I mentioned.

Jacob Chacko: It's your question about the conversations we may or may not have. Right, yeah, thank you. Thanks, Maurice.

Got it okay. Thank you for taking my question.

You were driving me to your question about it.

Relations, we may or may not be having yep right yeah. Thank you.

Thanks Mark.

Operator: Our next question comes from Ina Yigal Nochomovitz from Sydney. You may begin. I think this is Ashiq Mubarack, contrary to all, thanks for taking my question and 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 persistence or hypothesizing may have contributed to the lack of re-centitization?

Our next question.

Hum.

You may begin.

Hi, Tim This is Oscar Mubarak al. Thanks for taking my question I'm, sorry to hear about the discontinuation.

I think you've alluded to this in the previous question, but can you discuss a little more what secondary pathways of persistence or Hypothesizing may have contributed to the lack of a rainy sensitization.

Pratik Multani: [inaudible] So some of these were ones that we screened out at baseline but developed while on study. So ARV-7 would be a resistance pathway that secondary alternates that, G.R. Inhibition wouldn't address that.

So some of these were ones that we screened out at baseline, but developed while on study. So <unk> seven would be a resistance pathways that.

Secondary alternative.

<unk> inhibition wouldn't address that.

P 10 loss T. P 53 loss are also associated with resistance.

So those are the other mechanisms that we saw and we saw others as well as those are examples.

Operator: Okay, got it. And then maybe switching to CD73, have you given any guidance on when you expect to complete enrollment in Phase 1B and maybe what that imply about what kind of follow-up you might present next year? We haven't given any guidance at this point, it's just too early, just given that the trial initiated literally this quarter, so we have not provided that guidance. Okay, God, thank you very much.

Okay got it and then.

Maybe switching to 60 73.

Have you guided to when you expect to complete enrollment in the phase one b and.

Maybe what does that imply about what kind of follow up and my 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.

So we have not provided that guidance yet.

Okay. Thank you very much.

Yeah.

Operator: Rx-Question will be 50 minutes, okay? Our next question will be from the line of Michael Schmidt from Guggenheim. You may begin. Hey, good afternoon. This is Yigal for Michael.

Our next question will be.

Sorry.

Our next question will be from line of Michael Schmidt from Guggenheim.

Hey, good afternoon. This is <unk> on for Michael Thanks for taking our questions.

Operator: Thanks for taking our questions. Two questions on your pipeline program. The first one is on your new POK4 program. Can you maybe help us understand the opportunity and the size of the TRMM37 amplification?

Two questions on your pipeline programs. The first one U P O K four program.

Can you maybe help us understand the opportunity and the size of the cream seventy-seventh amplification.

Jacob Chacko: And secondly, on 114, you initiated the Phase I study. Help us understand how you plan to measure 114 CNS activity in the Phase I study. And will you plan to enroll active brain meds patients in the future? Thanks. Thanks. I'll take the first one, and I'll ask Pratik to take the second one. So on the first point, as I mentioned earlier to Kevin, we've got a poster coming up at AACR on PLK4, so I'd probably defer the specific answers around market size and just differentiation until then. But I think the main thing to point out about PLK4 is, you know, totally consistent with what our strategy's been from the beginning.

And secondly on Walmart for.

He stated the phase one study.

Help us understand how you plan to measure well off for CNS activity in the phase one study and will.

Will you plan to enroll <unk> patients in the future. Thank you.

I'll take the first and I'll ask <unk> to take the second.

On the first.

As I mentioned earlier to Kevin we probably we've got a poster coming up at ACR on <unk> four.

So I'd, probably defer the specific answers around market size and just differentiation until then I think the main thing to point out that would be okay for us.

It's 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 we came from our internal discovery efforts.

Jacob Chacko: 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.

<unk> potential mechanism of action like I said, a synthetic lethality pathway, that's relevant to breast cancer plus a couple of other tumor types and importantly, and we've been explicit about this as well as we've always wanted our pipeline to house them.

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.

Jacob Chacko: 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.

On this target a while back ahead of paper that was published in nature. They came out last year.

So we're pretty excited about it because it's a busy 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 ACR, then we can get into more specifics at that point.

Jacob Chacko: So stay tuned for the poster at AACR, and then we can get into more specific... Hi, this is Pratik. It's your question about 114 and CNS activities. 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.

Hi. This is particular 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 in stable brain Mets, which is what most other studies.

Allow but also allowing patients with active brain Mets as well that are asymptomatic. So we are allowing untreated brain Mets.

Our phase one.

Pratik Multani: Alright, thank you very much. 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. [music]

Alright, Thank you very much.

I see.

Yeah.

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 <unk>.

You may now disconnect everyone have a great day.

[music].