Thank you for standing by, and welcome to ORIC ASH 2023 Business Update Call. At this time, all participants are in 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 one on your telephone. To remove yourself from the question queue, you may press star one one again. I would now like to hand the call over to Dominic Piscitelli, Chief Financial Officer. Please go ahead. Good afternoon, and welcome to the ORIC Pharmaceuticals ASH 2023 conference call. My name is Dominic Piscitelli, and I'm the Chief Financial Officer. Earlier today, we issued a press release highlighting initial clinical data from the phase I-B trial of ORIC-533 in multiple myeloma. You may find the press release posted on the investor page of oricpharma.com. We have pre-recorded our prepared remarks, after which we will host a live Q&A session. Before we begin, starting on slide two, during this conference call, we will be making forward-looking statements, including forward-looking statements based on our current expectations and projections about future events and trends that may affect our business. ORIC'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 ORIC, please refer to our recent filings with the SEC. ORIC specifically disclaims any obligation to update any forward-looking statements except as required by law. This presentation contains interim results based on initial data from the ORIC-533 clinical trial as of the database cutoff date of November 28, 2023. During this presentation, we will not be speaking to any additional data subsequent to such date. Now turning to slide three. During today's call, we'll discuss the preclinical highlights for ORIC-533, initial phase I-B trial results, and next steps for the program. Joining me on the call today, we have Jacob Chacko, CEO, Lori Friedman, CSO, and Pratik Multani, CMO. Now let me turn over the call to Jacob. Thank you, Dominic. Turning to slide four. ORIC-533 is our small molecule, orally available inhibitor of CD73. CD73 has garnered a lot of attention as a potential therapeutic target in oncology due to the potential of reversing adenosine-related immunosuppression. Unfortunately, several competitor molecules have a lack of potency or an inability to maintain potency in the face of the high levels of adenosine that can be found in the tumor microenvironment. Also, because it's a chemistry challenge to develop an orally available CD73 inhibitor, nearly all competitor molecules are antibodies, which comes with obvious limitations on tumor penetration and ease of administration. With ORIC-533, we believe we've developed a best-in-class CD73 inhibitor that overcomes these limitations. And finally, through our relationship with the Anderson Lab at Dana-Farber, we gained proprietary insights that allowed ORIC-533 to be developed as a first-in-class treatment for multiple myeloma. Today, we're excited for the first public disclosure of clinical data for ORIC-533. In our phase 1b study, we've demonstrated that ORIC-533 can be dosed orally once daily, that it has an exceptionally clean safety profile, that it achieves dose-dependent immune activation, and that it is able to generate clinical activity as a single agent in patients with heavily pretreated multiple myeloma. All of these characteristics, along with its mechanism of reversing immune suppression, make it an ideal combination partner for various existing approved myeloma therapies. Now, let me hand it over to Lori to remind you of the preclinical differentiation and rationale for ORIC-533 in myeloma before Pratik covers the phase 1b trial results and next steps for the program. Thanks, Jacob. It's my pleasure to speak with you today about our ORIC-533 program. We'll start on slide six with an overview of the role of CD73 and adenosine in immunosuppression and resistance in cancer. The diagram provides an overview of the adenosine pathway and depicts adenosine production through catabolism of ATP in the tumor microenvironment. Adenosine impairs antitumor immunity, and high levels of adenosine and CD73 are both associated with poor prognosis in cancer. CD73 is a cell surface enzyme, which is the final step in generating adenosine. Thus, CD73 plays a pivotal role in the immunosuppression and therapeutic resistance driven by adenosine. We chose to inhibit CD73 as the key target and therapeutic approach to reducing adenosine levels and enhancing antitumor activity. In the next few slides, we'll share highlights of comprehensive preclinical profiling and characteristics that demonstrate the best-in-class potential of ORIC-533 for patients with multiple myeloma. Slide seven illustrates ORIC-533 very strong potency in T-cell proliferation assays, which importantly is maintained in conditions of high AMP. This context is important because when cancer tissues are hypoxic or include dying cells, ATP and AMP can flood into the microenvironment in extremely high quantities. As you can see, ORIC-533 has strong nanomolar potency, even in high AMP environments. These experiments compare ORIC-533 to AB680, a small molecule inhibitor of CD73. In both T-cell proliferation assays and activation assays, ORIC-533 is orders of magnitude better at maintaining potency in this context. The table highlights a deeper look at what's driving the strong potency, which is the slow off rate of ORIC-533 from the CD73 protein. This study indicated that once ORIC-533 binds the CD73 protein, the drug is slow to dissociate. Further experiments in cells showed the drug effect continued to be sustained after a drug washout, as expected with a slow dissociation rate. Blocking adenosine production can reverse immunosuppression and lead to the activation of T-cells, and on slide eight, we show results from a functional assay measuring the increase in interferon gamma production in T-cells. Comparisons were done for a variety of adenosine pathway inhibitors. Starting with the graph on the left, ORIC-533 has picomolar potency, while AB680 potency is 30 times lower, with EC50 in nanomolar range. In the center graph, the anti-CD73 antibody, oleclumab, demonstrated no single-agent activity at the concentrations tested, indicating the EC50 is above 30 nanomolar. In the graph on the right are data for an adenosine receptor antagonist, which requires a high drug concentration of 10 micromolar to produce an effect. These results demonstrate that ORIC-533 outperforms other clinical-stage adenosine pathway inhibitors in the ability to reverse immunosuppression and restore T-cell activation. On Slide nine is a reminder that there's already clinical proof of concept for blocking CD73 to reverse immune suppression. The anti-CD73 antibody, oleclumab, was assessed in a randomized study and showed evidence of improved outcomes in combination with an anti-PD-L1 immune checkpoint inhibitor in non-small cell lung cancer. Notably, until this ASH conference, with the presentation of ORIC-533 clinical activity signals, neither oleclumab nor any other CD73 therapeutic has disclosed single-agent activity, to our knowledge. We thought a path for phase I that could initially be explored as single agent and chose multiple myeloma for an initial clinical assessment of ORIC-533. On Slide 10, we'll shift from the intrinsic properties of the ORIC-533 compound to discuss the rationale for ORIC-533 in multiple myeloma. First, patient samples from multiple myeloma have demonstrated that the tumor microenvironment is adenosine-rich. Further studies have shown that high CD73 and high adenosine are associated with poor prognosis and therapeutic resistance in multiple myeloma. Second is the compelling mechanistic rationale, which is supported by research from Dr. Kenneth Anderson's lab at Dana-Farber Cancer Institute. The mechanism is notable because it was derived from studying bone marrow samples from relapsed refractory myeloma patients to investigate the root cause of resistance. Third, using ex vivo assays derived from bone marrow samples from myeloma patients, ORIC CD73 inhibitors reversed immunosuppression and demonstrated impressive single-agent activity. Now let's turn to Slide 11. We collaborated with the Anderson lab to perform a series of experiments on human tumors collected from multiple myeloma patients. Bone marrow samples were collected from patients, and the isolated immune cells and cancer cells were used in ex vivo assays. First, as diagrammed on the left, to assess immunosuppression, the plasmacytoid dendritic cells and T-cells were co-cultured in the presence or absence of ORIC CD73 inhibitor to test the hypothesis that CD73 inhibition would reverse immunosuppression and cause T-cell activation. Next, multiple myeloma cells from that same patient's bone marrow were isolated and added to the immune cells. After culturing together for 24 hours, the mixture was analyzed to determine what% of multiple myeloma cells were killed by autologous T-cells. On the right, in bone marrow samples from three myeloma patients, the PDC and T-cells were co-cultured with or without ORIC CD73 inhibitor, and T-cell activation was measured. In the bar graph, you'll see that T-cell activation was minimal in untreated samples, while the addition of a CD73 inhibitor strongly increased the activation of T-cells. This reversal of an immunosuppression led to the results on the bottom right, where the T-cells were able to attack and kill the multiple myeloma cells. In summary, on Slide 12, ORIC-533 entered phase 1 in multiple myeloma based on the compelling preclinical profile. ORIC-533 is the first oral inhibitor of CD73 entering the clinic for patients with multiple myeloma. Its potency is superior in T-cell activation assays when compared to other pathway inhibitors. ORIC-533 demonstrated reversal of immunosuppression in a series of ex vivo patient-derived multiple myeloma assays, driving T-cell-induced cytotoxicity of myeloma cells. Importantly, the clean non-clinical toxicity profile supports exploration of potential combinations across multiple treatment regimens. As summarized on the right, ORIC-533 has demonstrated immune cell modulation of several important cell types. In contemplating combination regimens, the finding that memory T-cells are increased is important, as there is substantial evidence that memory T-cells drive therapeutic activity for CD3 bispecific antibodies. I'll now turn it over to Pratik to talk about the initial clinical data for ORIC-533. Thank you, Lori. Turning to Slide 14, we are conducting a phase I dose escalation study in patients with relapsed or refractory multiple myeloma, who are no longer eligible for therapies known to provide clinical benefit. The key objectives are to determine single-agent safety, pharmacokinetics, and assessment of anti-myeloma activity. In addition, extensive pharmacodynamic measurements are included, consisting of measuring CD73 functional activity in serum and bone marrow and analysis of immune cell numbers and activation state. The study initiated at a daily dose of 400 mg. We have since dose escalated through 2,400 mg and intend to continue to a top dose of 3,200 mg once daily. On Slide 15, we have the baseline characteristics of the patients enrolled on the study. As of the updated data cutoff of November 28, 2023, 23 patients with multiple myeloma were enrolled across doses ranging from 400-2,400 mg once daily. Patients had a median of six prior lines of therapy before coming on study. Almost half of patients had high-risk cytogenetics, 100% were triple-class refractory, and 91% penta-refractory. In addition, 57% of patients had previous anti-BCMA bispecific and/or CAR -T therapy. Overall, this is a highly refractory patient population, having already received most, if not all, available therapies before coming on our trial. Looking at the PK profile of ORIC-533 on Slide 16, based upon the first four dose levels through 1,600 mg, we observed oral bioavailability with increased exposure with increasing dose. Importantly, the estimated plasma half-life of approximately 24 hours supports once daily dosing. Based upon preclinical ex vivo models of myeloma, we calculated a target exposure zone corresponding to cytolytic activity, depicted here on the PK plot by the gray shading. The superimposed PK suggests that daily doses of 1600 mg or higher may provide an exposure commensurate with the anti-myeloma cytolytic activity we saw in our model system. Now turning to Slide 17 and looking at safety, we see that ORIC-533 was exceptionally well tolerated. Across all dose levels, all treatment-related adverse events were only grade 1 or 2 in severity, without any specific recurrent toxicity. To date, there were no dose-limiting toxicities, dose reductions, or treatment-related serious adverse events. This clean safety profile was predicted by the non-clinical GLP toxicology studies for ORIC-533, which were similarly without significant toxicity despite high dosing. Overall, the safety profile for ORIC-533 makes it an ideal agent for combination with other myeloma therapies, which themselves can carry significant safety liability. Turning to Slide 18 and the first of our pharmacodynamic readouts, we assessed CD73 functional activity in serum and bone marrow to evaluate target engagement. Based upon the first four dose levels through 1,600 milligrams, measurements of soluble CD73 enzymatic activity in patient serum samples showed robust inhibition by cycle 1, day 15 in all patients across all dose levels, and complete and sustained inhibition by cycle 1, day 8 in all patients at the 1,600 mg dose level. Cell surface CD73 activity of bone marrow mononuclear cells showed 50%-95% inhibition after one treatment cycle, with the largest suppression observed at 1,600 mg, the highest dose level for which we have these data. Thus, we feel confident about strong target engagement, including in the bone marrow. Slide 19 shows the first of two measures of immune cell effects, both in terms of changes in immune cell numbers and also functional activity. Flow cytometry analysis of T- cells from peripheral blood demonstrates strong initial evidence of immune activation in the majority of patients at doses at or above 1,200 mg. There was an increased abundance of CD8 positive T- cells in blood and an increase in the fraction of activated cells. On Slide 20, we saw a similar effect on NK- cells. At doses at or above 1,200 mg, there was an increased abundance of NK- cells in blood, along with enhanced NK- cell activation. Overall, these findings suggest an ORIC-533 dose-responsive modulation of both CD8 positive T-cells and NK- cells, which are key immune effector cells, and this treatment effect was measurable even in these highly refractory patients. Finally, on Slide 21, we also measured soluble BCMA levels in serum. Soluble BCMA levels have been reported to correlate with clinical response to treatment and predict progression-free survival of various therapies. In patients on this trial, there were minimal reductions up to the 1,200 mg dose level, but at the highest dose level where we have data, there were notable reductions indicating that ORIC-533 was having a measurable anti-myeloma effect. Beyond these immune measures, we set a high bar for this program, which was to see single-agent clinical activity, something no other adenosine pathway inhibitor has reported. We are gratified that we were able to see multiple such examples across the study, particularly at the higher dose levels, two of which are depicted in the ASH poster. On Slide 22, you can see the first case, which is of a 74-year-old man with refractory myeloma with significant non-secretory extramedullary disease. He had four prior lines of therapy and was penta-refractory before being enrolled on this trial. He received ORIC-533 at a dose of 1200 mg daily with minimal adverse events. Given that the disease was non-secretory and extramedullary, PET CT imaging was used to follow the disease. Serial imaging showed stabilization of previously progressive disease with marked reduction in FDG PET activity of multiple target lesions, which he maintained over 6 months before eventually progressing. Thus, ORIC-533, with minimal attributed adverse events, was able to stabilize this highly refractory patient's disease, which had been progressing to the last treatment, and this effect was durable. A second clinical example is on Slide 23 and is of a 55-year-old woman with relapsed refractory multiple myeloma. She had penta-refractory disease and had also received prior anti-BCMA bispecific therapy as her most recent treatment, to which she was progressing before study entry. She received ORIC-533 at 1,600 mg daily, which she tolerated well. She experienced an immediate decline in her serum paraprotein to a maximum 41% reduction, making this a minor response, which was confirmed on a subsequent measurement four weeks later. This reduction in serum paraprotein was accompanied by an 80% decrease in serum BCMA levels, underscoring that this was likely a true anti-myeloma effect. The patient then progressed after approximately three months on treatment. Again, in this highly refractory patient, who progressed after anti-BCMA antibody therapy, ORIC-533 was able to generate a measurable clinical response with minimal attributed adverse events, underscoring the potential of immunomodulatory therapy in myeloma through adenosine inhibition by ORIC-533. Finally, we have a third case, not presented in the poster, of a 76-year-old woman with refractory myeloma who was enrolled early in the trial. She had eight prior lines of therapy before enrolling on the study and receiving ORIC-533 at a dose of 400 mg daily. Although at a lower dose than the other patient examples, her exposure was the highest in her cohort and closer to what was expected for an 800 mg dose. She demonstrated an immediate 67% reduction in her urine paraprotein levels after the first cycle. She remained, she maintained this reduction through cycle 3, when she withdrew consent due to grade 2 fatigue. Nevertheless, early on in the trial, this was our first evidence that we were potentially having a clinical effect with ORIC-533. Turning to slide 24, in summary, from this first-in-human phase 1 trial of ORIC-533, we can conclude that ORIC-533 is a highly potent adenosine pathway inhibitor that demonstrates oral bioavailability with a half-life that supports once-daily dosing. ORIC-533 has an exceptionally well-tolerated safety profile and is able to achieve complete inhibition of soluble CD73 activity in serum and and substantial reductions of cell surface CD73 activity in cells from bone marrow. At doses at or above 1200 mg, ORIC-533 leads to increases in number and activation of both CD8 positive T-cells and NK cells, and at doses of 1600 mg, ORIC-533 achieves meaningful reductions in serum BCMA levels, suggestive of anti-myeloma activity. Finally, preliminary evidence of clinical anti-myeloma activity has been demonstrated in multiple patients with relapsed or refractory multiple myeloma, including post anti-BCMA-directed antibody therapy, making ORIC-533 the first adenosine pathway inhibitor to demonstrate single-agent clinical activity. This overall profile of ORIC-533 makes it an ideal combination candidate with other immune-based myeloma therapies, including anti-CD38 antibodies, anti-BCMA bispecific antibodies, and CAR- T therapies. Beyond this theoretical rationale, however, Lori will now provide preclinical evidence we have developed further supporting such combinations. Back to you, Lori. Thank you, Pratik. On slide 25, as we step back to put the clinical data into context with the immune mechanism of action, we felt it was important to assess the bone marrow milieu at baseline upon entry into the trial. As shown in this plot, in these heavily pretreated patients, the immune cell composition varies greatly from one patient to the next and indicates dysfunction in the bone marrow of many patients, who may not be able to mount an immune response even after reversing immunosuppression. These results suggest that clinical activity could be enhanced through combination with a therapeutic that would increase T- cells in the tumor microenvironment, such as CAR- T therapy- or BCMA CD3 bispecific antibodies. On slide 26, I'll discuss numerous lines of evidence and rationale supporting how ORIC-533 may enhance T cell-directed therapies. First, the therapeutic premise of targeting CD73 is to reverse immunosuppression driven by adenosine in the tumor microenvironment. Second, specifically for CD3 bispecific antibodies, there's evidence in both clinical and preclinical literature that memory T- cell subsets are important in driving the therapeutic activity. When envisioning a combination, we believe that the addition of ORIC-533 would double down on this important efficacy mechanism to improve antitumor activity. And third, studies of resistance to CD3 bispecific antibodies indicate that resistance may be driven by deficiency in interferon gamma signaling. Notably, ORIC-533 increases interferon gamma in preclinical studies, as shown on the right. Thus, there's strong mechanistic rationale for combination of ORIC-533 with T-cell-directed therapies in multiple myeloma, and notably, these combinations are enabled with the clean safety profile of ORIC-533. On slide 27, we'll discuss the final aspect of the potential for ORIC-533 in combination. Here, we're focused on the rationale to combine with anti-CD38 antibodies. First, ORIC-533 in preclinical studies has been shown to restore NK-mediated cytolytic activity. This is important because anti-CD38 therapies reduce NK- cells, and ORIC-533 may boost activity to reverse that effect. Second, anti-CD38 is also an enzyme that acts in the NAD pathway to eventually produce AMP, which is processed by CD73. Thus, to the extent that CD73 enzymatic function contributes to antitumor activity, ORIC-533 would augment that function. On the right, we show our first experimental combination data in ex vivo bone marrow assays from three patients with multiple myeloma. Both agents showed single-agent activity and lysis of myeloma cells, and the combination showed an improved effect, providing preclinical proof of concept. Thus, we believe there's great potential for ORIC-533, with its clean safety profile and demonstrated impact on immune cells in the clinic, to enhance the therapeutic activity of standard of care agents in multiple myeloma. I'll now hand it over to Jacob for the program and pipeline status and next steps. Thank you, Lori. We believe the clinical results presented today demonstrate the potential of ORIC-533 as a best-in-class CD73 inhibitor and first-in-class for the treatment of multiple myeloma. As you heard from Pratik, in our phase I-B study, we've demonstrated that ORIC-533 can be dosed orally once daily, that it has an exceptionally clean safety profile, that it achieves dose-dependent immune activation, and that it is able to generate clinical activity as a single agent in patients with heavily pretreated multiple myeloma. All of these characteristics, along with its mechanism of reversing immune suppression, make it an ideal combination partner for various existing approved myeloma therapies. As you heard from Lori, the strong scientific rationale for combinations with two classes of myeloma therapies in particular. Now, turning to Slide 30, as we contextualize next steps for the program, we're proud of the results generated by ORIC-533, and we feel strongly that the most appropriate next step in clinical development will be to run combination studies with either BCMA or CD38-directed therapies. At the same time, we have the good fortune that multiple of our clinical programs have achieved proof of concept, either from our own data or via read-through from competitor data. We recently presented data for ORIC-114 that demonstrated a competitive safety profile and CNS activity, which positions it as a potential best-in-class therapy for multiple populations within non-small cell lung cancer. And with ORIC-944, competitor data has demonstrated the powerful potential of combining a PRC2 inhibitor with an AR modulator to achieve profound benefit for patients with prostate cancer. We believe both of these programs have the potential to enter registrational studies within the next two years. That will require a level of focus from our team at ORIC that necessitates prioritization of our clinical pipeline. As such, we intend to complete the single-agent dose escalation for ORIC-533 in the coming months, and then combination studies will only be pursued with the operational and financial backing of a future partner for that program. Turning to Slide 31, as a result of our decision to focus resources on ORIC-114 and ORIC-944, and to only pursue future combination studies for 533 with the help of a partner, our cash runway has been extended into 2026, even with the increased expenses associated with moving two programs towards registrational studies. We are excited about the pipeline we've assembled at ORIC, and we remain committed to making data-driven decisions that channel our resources to the highest ROI programs that can have maximum impact for patients. Before we open it up to Q&A, we'd like to thank our investigators, as well as the entire ORIC team, who've worked diligently to tackle our mission on behalf of patients. Most importantly, we'd like to thank our patients and their families. With that, let's open it up for Q&A. As a reminder, to ask a question, you will need to press star one one on your telephone. To remove yourself from the question queue, you may press star one one again. Please stand by while we compile the Q&A roster. Our first question comes from the line of Anupam Rama of JP Morgan. Hey, guys. Thanks so much for taking the question. Two quick ones from me. So in the presentation, you made several references to markers of single-agent activity, paraprotein decrease, increases in markers of immune activation, decreases in soluble BCMA. How would you characterize the sort of importance hierarchy of those various markers of activity, which kind of supports the single-agent activity you're seeing? And then second question, how do you think about ORIC-533 potentially demonstrating more single-agent activity if you were to go in earlier lines of patients where the immune system is more intact, you have higher T- cells? And do you think that the fact that you had this patient population that had prior BCMA-directed experiences kind of complicates your ability to see the efficacy signal as a single agent? Thanks so much. Hey, Anupam. Thanks for the questions. We'll have Pratik take both of those. Hey, how are you? Let me take them one by one. So your first question about sort of the meaningfulness and the hierarchy of the changes we saw in our study. So I think before I answer that, it's first sort of important to level set the context for our data. First, I'm not aware that any other CD73 inhibitor has reported any single-agent activity in any indication, so that's kind of the background for this. And then our patient population was heavily-- was highly refractory. Now, that word or phrase, highly refractory, gets thrown out-- thrown around a lot, but I think in our case, it's perfectly accurate. 100% of patients were triple-class refractory, 91% penta-refractory. Patients had a median of six lines of prior therapy, with more than half having either anti-BCMA bispecific, CAR- T, or both. So in that context, of these heavily pretreated patients, we're applying a drug with an immunological mechanism of action rather than a direct cytotoxic mechanism. And so we're relying on the ability of ORIC-533 and its ability to inhibit adenosine to activate the patient's immune system against their myeloma. So keeping all of this in mind, we think the single-agent activity we've seen is meaningful. We've been able to show target engagement, CD73 inhibition, which was a basic requirement. But on top of that, our pharmacodynamic readouts, we're able to see measurable effects on immune cells, both CD8 positive T-cells and NK- cells in this highly immunocompromised patient population. But I think the most notable findings, however, are the measurable clinical effects, specifically the drops in soluble BCMA levels, and then also our multiple examples of clinically measurable anti-myeloma activity, drops in serum and urine paraprotein. So coupled with a clean safety profile, I think, you know, these effects are meaningful, and it really positions 533 well as a combination agent with other active myeloma therapies. Now, your question about whether we might expect to see more activity, if we were to move it earlier line patients, who had a better or more intact immune system, and then how does the anti-BCMA complicate our interpretation? So again, you know, these are highly refractory patient populations, so, we are necessarily then relying on their own immune system to mount this anti-myeloma response. That's why, frankly, we want to look more closely at the baseline cellular composition of the bone marrow in the patients on our trial. As you heard Lori mention, during the presentation, we saw significant heterogeneity, particularly in terms of baseline numbers of T-cells and NK- cells, which are the effector cells that we're relying on. So if we were to move earlier in the therapy of these patients when they have a more intact immune system, I think we'd expect more clinical activity. As you know, this is the case with virtually all anticancer therapies. In myeloma, specifically, daratumumab, high responses like 90%+ in the first line setting, albeit in combination, but in the fourth or fifth line setting, it's 20%-30%. And then more broadly speaking, but probably more on point, the checkpoint inhibitors really, you know, do have better outcomes in the first line setting versus later lines. So, we would expect sort of a similar trend if we were to move this drug into earlier lines of therapy. With respect to the specific interaction with prior anti-BCMA, it's hard to know. You know, the example I presented of a patient who had the confirmed minor response, this patient was post anti-BCMA therapy. And so, you know, I think, you know, our question is, if we combine with that therapy, can we improve outcomes over BCMA alone? Thanks so much for taking our questions. Thanks, Anupam. Thank you. Our next question comes from the line of Colleen Kusy of Baird. Hi, good afternoon. Thanks for the updates, and thanks for taking our questions. So just following up, one more granular question and one kind of bigger question, bigger picture question. Yeah, on that confirmed minor response, can you talk a little bit more about what you think the impact was of that anti-BCMA therapy, and if that contributed at all to the confirmed minor response in that patient vignette, and what you make of the relatively short duration of response in that patient? And then bigger picture, you know, as you've talked about, you're the first adenosine-targeting drug in multiple myeloma, and you have this mechanism of action data from the Anderson lab. Can you talk about what aspects of that mechanism of action for adenosine in multiple myeloma were either validated or not in this early look at the data? Yeah, thanks, Colleen. Pratik will take the first question, and then Lori will take the second one. Okay, so, yeah, no, this is a good question. When I saw those data, I asked the principal investigator for that patient the exact same question. And so I'm telling you what he told me. So he was convinced that the effect that we were seeing was due to ORIC-533 for two reasons. One, the interval between the prior anti-BCMA therapy and then the patient coming on trial was three months, long enough to discount any holdover activity from the previous treatment. And then along with this extended interval, the patient was, and our patients were required to be progressing on study entry. So this patient was progressing after their prior BCMA, before they came on study. And so those two sort of facts together, convinced him and, you know, I think convinces us that this is, related to ORIC-533 or attributable to ORIC-533. In terms of the relatively short duration, I mean, you know, this is, I don't want to belabor it, but a heavily pretreated patient population. I think we were able to work with whatever immune cells were, present in that patient, but clearly the treatment effect was not strong enough to maintain that response. Hey, Colleen, this is Lori. So, to answer your question about the mechanism and what was seen in Kenneth Anderson's lab at Dana-Farber, and compare that to what we saw in the clinical study, we're very pleased. So that, all the key immune hypotheses that were observed in the ex vivo assays at the Dana-Farber, preclinically, have been observed in patients in phase one. So first, the hypothesis generally of CD73 inhibition to reverse immune suppression in myeloma, was supported by the ex vivo studies of bone marrow aspirates from myeloma patients. And there we saw that ORIC-533 increased the abundance of CD8 positive T-cells and also NK- cells, as well as increasing the percent of activated CD8 T-cells and NK- cells. Furthermore, the Anderson Lab showed these cytolytic immune populations were able to attack and kill the autologous myeloma tumor cells in a dose-dependent manner. Then correspondingly in the phase I, ORIC-533 also demonstrated dose-dependent immune activation. At the higher doses, ORIC-533 showed an increase in CD8 positive T-cells and NK- cells, as well as an increase in the activation of the CD8 positive T-cells and NK- cells. We haven't yet completed all the analysis of subsets of immune cells, so we have further assessments coming that will parse out the subtypes of T-cells, for instance, to also see whether the increase in memory T-cells is observed in the clinic. One thing I would add quickly, the majority of the ex vivo data in the Anderson lab was obtained using a steady state concentration of ORIC-533. And the comparable exposure in the clinic we've seen is starting to be reached at the 1600 mg dose level. So thus, I feel that continuing the dose escalation to 2400 mg and 3200 mg should exceed the target exposure. And we tried to illustrate that on the PK plot in the top gray line. Thank you. Great. That's helpful. Thank you. Thanks, Colleen. Thank you. Our next question comes from the line of Maury Raycroft of Jefferies. Hi, thanks for taking my questions. Just given the clean safety profile of 533 and some of the evidence of dose response you're seeing, why not continue exploration further in the dose escalation study? And as you look to partner, what do you envision as the ultimate clinical path for 533? And what combo options would make the most sense, or would you be most excited about pursuing for 533? Thanks for the question, Maury. Let's have Pratik take the first one, and then Lori can kinda summarize what makes us most excited on the combo front, at least scientifically. Sure. So I'll answer the question about the, the dose escalation. So, you know, we expected that ORIC-533 would have a clean safety profile in the clinic, just, as I've mentioned earlier on the. Based on the GLP toxicology data. And that's why we put in so many pharmacodynamic measurements to help guide our dose selection. So, you know, as we presented at the 1,600 milligram dose level, we are seeing measurable effects on a number of factors related to activity, target engagement, peripheral blood, in the peripheral blood and in the bone marrow, immune cell changes, changes in soluble BCMA levels, and then the patient examples that I presented. So. And that's at, you know, 1,600 and 1,200 mg, where we saw those effects. So we're intending to go to 3,200 mg, so double the current dose, for which we have data, to really answer the question of, does going higher matter? But we don't intend to go higher than 3,200, because, as Lori just said, the projected PK at that dose should put us well above the target range we projected from our preclinical work. The other factor is just something more practical, which is pill burden. At 3,200 mg, the pill burden is meaningful. It's certainly something we can overcome through more formulation work and looking at food effect to see if we can improve absorption. But as I said, our current projections make us feel quite comfortable that we don't need to go above 3,200. At that point, we'd rather pivot and start looking at combinations, as we mentioned. And Maury, to your second question, about what's the most exciting ultimate clinical path for ORIC-533. So I wanna start by just taking a step back. The reason we chose CD73 as a target was to reverse immunosuppression that's driven by adenosine in the tumor microenvironment. So now we've seen this mechanism play out in the clinic, and thus we think ORIC-533 is best developed as a combination agent to augment the clinical activity of immunologically driven therapies. In myeloma, those therapies would include anti-BCMA, CD3, bispecific antibodies and CAR-Ts, but also more conventional therapies that could have an immunological mechanism to their activity, including anti-CD38 antibodies and the IMiD class of drugs. In today's phase I results, we do directly show that the patients treated with ORIC-533 at higher doses had an increase in T-cell abundance and T-cell activation. Thus, I'm most excited about therapies that are directly T-cell driven, such as the BCMA, CD3 bispecific antibodies. And then, as Pratik mentioned, with ORIC-533 having an exquisitely clean safety profile, I think it should be explored across multiple standard of care regimens. Thank you. Got it. Thanks for taking my questions. Thanks, Maury. Thank you. Please stand by for our next question. Our next question comes from the line of David Nierengarten of Wedbush Securities. Hey, thanks for taking the question. Kind of on similar lines to Maury's question. When you're thinking about the decision to partner it or to talk about partnering it now versus, you know, maybe you know, with a basket study of different molecules, or maybe calling on a few big pharma companies to maybe get some free drugs to help out with cost, you know, and develop it a little bit more, before licensing it, maybe you could walk us through a little bit. Yeah, thanks for the question, David. I can take that. This is Jacob. Sure. You know, I think in terms of what we wanted to see, in the single agent experience with 533 in myeloma, we've seen, you know, in terms of the go, no-go decision to go forward in the combination studies. But I'll provide some additional context. So heading into the study, prospectively, we laid out that we'd want to see target engagement, so effectively shutting down CD73 activity. We wanted to see immune modulation, you know, given, as Lori said, what the hypothesis of the Anderson lab was and what they saw preclinically. We wanted to see activation on the immune side, including CD8 positive T-cells and NK- cells, and we saw that in a dose-dependent manner. A third piece that we wanted to see was safety. I mean, that wasn't something that was perhaps surprising, just given the GLP tox data for 533 projected that it would be safe. But as you saw today, it's got an exquisitely clean safety profile. And then the final piece was, even though no CD73 inhibitor in any oncology indication has shown single agent activity, we laid that out as a bar for ourselves, as a very high bar for ourselves, just given that it was important to see that before getting comfortable with going forward into combo studies. And we, you know, we've seen that in various ways as Pratik articulated, whether that's the falls in serum BCMA levels, or more importantly, the reductions in paraprotein. So overall, we met the criteria for moving it forward in the prospectively defined criteria for moving it forward in the combo studies. And I'd say, if we were in a vacuum or if we were making a decision in a vacuum, we probably would be taking that forward in the combo studies, ourselves. Or like you said, kind of with the help of free drug at a minimum from one of the big, companies out there that have these agents, and have a vested interest in myeloma. All of that said, we're not making the decision in a vacuum, and the reality is that, you know, we presented data on ORIC-114 just a few months ago, in EGFR and HER2 exon 20 in non-small cell lung cancer, and obviously met some very early proof of concept go, no-go thresholds for that program that put it sort of within striking distance of starting registrational studies, like we said on the call today, you know, less than two years from now. Similarly, for ORIC-944 in prostate, there's a really important data set that's already out there from a competitor that shows the importance of combining a PRC2 inhibitor with an AR modulator. Bottom line, David, is just given the everything else going on in the pipeline, in a good way, in terms of the activity and the fact that we wanna really hit the accelerator on those two programs, 114 and 944, we just have to figure out how to maximize the ROI of the total pipeline, and that means devoting focus and attention and resources to 114 and 944. Unfortunately, that means that 533 becomes an out-licensing candidate. I think in a more perfect world, if capital wasn't such an issue and if the cost of capital wasn't so high as it is for all small-cap biotech companies, we probably would be doing that study for 533 on our own, meaning that combo study. Thanks. Yep. Thank you. Our next question comes from the line of Matt Biegler of Oppenheimer and Company. Hey, guys. Thanks for the question. Speaking of partnerships, can you comment on the state of your relationship with Pfizer? You know, they made an investment last year, and you guys, and I, I thought ostensibly that was because of 533. Do they still have a member serving on your scientific board? And, you know, do you think they're maybe more interested in the EED program, or how should we kind of read into that? Do you think that they still might be the best partner for 533? What's your thoughts? Thanks. It's a great question, Matt. So the reason why we put that collaboration in place with Pfizer, almost exactly a year ago, was because it would reduce the operational and the financial burden of eventually running a combo study for 533 in myeloma. We already, back then, had a sense that one of the interesting combo studies to run would be in combo with a BCMA-directed therapy, and so there was a ton of strategic rationale for putting that collaboration in place with them. Even with the context of a reduced operational and financial burden to move 533 forward in the combo studies, we, you know, we still made the decision, like I said, to deprioritize ORIC moving that forward on our own, you know, without a partner. All of that said, the relationship with Pfizer continues to be quite strong. They continue to be, obviously, very interested in myeloma within oncology. They will retain that seat that you mentioned, that they have on the SAB. I want to be clear, it is specific to 533-related topics, so CD73-related topics, and it doesn't give them access to information beyond for ORIC's pipeline beyond ORIC-533, the CD73 inhibitor. And so that'll, that SAB seat will stay in place, you know, until we either terminate the program formally or partner exclusive rights for the program to another third party that's not Pfizer, where ORIC doesn't retain any rights or until the term of the agreement ends, which is, you know, middle of 2025. But the relationship with them continues to be, you know, quite positive, and obviously, they've got a program directed towards PRC2, just like we do. So I can't comment sort of beyond their interest in CD73 at this point. Understood. Thank you. Yep. Thanks, Matt. Thank you. Our next question comes from the line of Yigal Nochomovitz of Citigroup. Please go ahead, Yigal. Yeah. Hi, thank you for taking the questions. Jacob and team, with respect to the combo work, could you talk about the, the timing of dosing? Because you're, you're obviously you have a, you have a drug which can improve the, immune cell penetration into the tumor, which you, which you're showing. I'm just wondering, in terms of sequencing of dosing, what have you, what have you concluded there as far as how you would do the combo, to prime, prime the tumor for the, the more, cytotoxic, immune-mediated therapies that you're, that you're talking about? It may make sense to, to sequence perhaps, as opposed to be dosing them at the same time. Yeah, it's a great thought, Yigal. Let me ask for Pratik to comment on that. I mean, we've had the same sort of discussion that you're proposing as well amongst ourselves and with others and our investigators. I think the base case is simultaneous dosing. You're right, there may be some value in sort of priming patients with 533 before you start the BCMA. But since those are not, you know, it's not a single dose of anti-BCMA, but it's you know, recurrent dosing, I think there's probably no significant difference in priming versus just giving them simultaneously. At some point, you will have the priming in place, and you're continuing to give anti-BCMA. So, the base case is simultaneous. I think it's just more convenient that way as well. Okay. And then on the Pfizer, I know that was from their venture fund, if I recall. It was a $500 million venture fund, and they put in $25 million to you guys and others as well. Do you know if they can re-up and come back and do another investment just now that this data is out there, and they have a better idea of the profile? Or is it or is that not how it's gonna work? That's a great question, Yigal. I don't. That's probably a question better directed to them. I think in terms of the source of the funds, it came out of their PBGI fund, which is the Pfizer Breakthrough Growth Initiative Fund. I don't know exactly where that fits with respect to their venture fund, but I think it is actually slightly distinct from their venture fund. And typically, what I've seen from their PBGI fund is that they make these $25 million equity investments into usually public, sorry, public companies, sometimes private. But I, I've never seen them re-up. But hey, look, I mean, there's always a first time for everything. But I wouldn't, I wouldn't hold my breath on that, and that's probably a question that's better directed to them. Okay. All right. Thank you. Thanks, Yigal. Thank you. Our next question comes from the line of Michael Schmidt of Guggenheim Securities. Hey, good afternoon. This is [inaudible] on for Michael. Thanks for taking our questions. Two quick ones from us. First one, did you see dose response on some of the PD biomarkers you talked about? And based on those PD data, how much do you think efficacy could further improve at higher doses? Second question, do you think the unique single-agent activity observed here in multiple myeloma is more of a result of 533's high potency or a result of pursuing the right disease indication? In other words, do you expect the results can be repeated with CD73 antibodies? Thank you. So in terms of your first question, yeah, actually a number of observations we made in our pharmacodynamic readouts were dose responses. So, CD73 inhibition, NK -cell numbers and activation, CD8-positive T- cells, numbers and activation. The soluble BCMA drops really only happened at 1,600 milligrams, and we didn't see much change below that. And so I think, you know, that's why we are continuing to dose escalate. That's why we do intend to dose escalate to double the dose that we have presented in the data today. And so we think that we can capture the upside as a single agent with that degree of dose escalation. In terms of, you know, what we're seeing, is it unique to 533 or unique to myeloma? Well, I mean, we chose myeloma, because we thought we would have a good chance of seeing single-agent activity, with our agent. That said, I don't think the single-agent activity that we're seeing applies, just broadly speaking, to all adenosine pathway inhibitors because of the, what we feel are unique properties of ORIC-533 in terms of its high potency. So, I, you know, I, I think, we, we picked this for a reason. I think it. The data bear that out, but I think ORIC-533 is uniquely positioned to capitalize on, on myeloma. Okay, thank you very much. Thanks, Yigal. Thank you. As there are no further questions in queue, that does conclude the Q&A portion of the call and our conference call for today. Thank you for participating.