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

Ladies and gentlemen, thank you for standing by, and welcome to ORIC Pharmaceutical Business Update ASH Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded. [Operator Instructions] I would now like to turn the conference over to your speaker for today, Dominic Piscitelli. You may begin.

Good afternoon, and welcome to the ORIC Pharmaceuticals Business Update ASH Conference Call. My name is Dominic Piscitelli, and I'm the Chief Financial Officer at ORIC. This afternoon, we issued a press release highlighting preclinical data from our CD73 inhibitor program as well as new preclinical data on ORIC-114, our EGFR HER2 program. You may find the press release posted on the Investor page of oricpharma.com. We have prerecorded a portion of our prepared remarks, after which we will host a live Q&A session. So please bear with us if we have any technical difficulties. Before we begin, starting on Slide 2, during this conference call, we will be making forward-looking statements. 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 Securities and Exchange Commission. ORIC specifically disclaims any obligation to update any forward-looking statements, except as required by law. Now turning to Slide 3, I'll briefly walk you through the agenda and introduce our speakers. During today's call, we'll focus primarily on ORIC-533 for multiple myeloma, after which we'll provide a pipeline update and summary followed by Q&A. Joining me on the call today, we have Jacob Chacko, CEO; Lori Friedman, CSO; Pratik Multani, CMO; and our guest KOL, Dr. Kenneth Anderson. Now let me turn over the call to Jacob.

Thank you, Dominic. On Slide 4, you can see the broad pipeline we've put together at ORIC through a combination of stellar internal drug discovery and opportunistic business development. That activity has helped us build one of the most robust pipelines in small-cap biotech. Earlier this year, we provided 2 initial Phase Ib data readouts from our ongoing studies of ORIC-101 in combination with Abraxane in solid tumors and with Xtandi in prostate cancer. But beyond our lead program, we publicly committed to filing 3 INDs or IND equivalents this year for our other clinical candidates, and I'm proud to say that we've delivered on that commitment. The focus of today's call is on ORIC-533, our small molecule orally bioavailable CD73 inhibitor, which we intend to develop initially as a single-agent in multiple myeloma. We have the honor of being joined today by Dr. Kenneth Anderson with whom we've collaborated on the critical preclinical work, establishing the potential role for ORIC-533 in multiple myeloma. After prepared remarks by our CSO, Lori Friedman; and CMO, Pratik Multani, we'll move into moderated Q&A with Dr. Anderson, followed by some brief updates on our other clinical candidates and general Q&A. Slide 5 summarizes why we are so excited about the potential for ORIC-533 in multiple myeloma. As is widely known, the adenosine pathway is associated with therapeutic resistance in cancer due to its immune suppressive effects in the tumor microenvironment. Within the adenosine pathway, there are 3 potential nodes of attack, of which CD73 has demonstrated significant therapeutic potential. This is best exemplified by the recent COAST data set, which were generated from a randomized controlled trial of a CD73 antibody in combination with the PD-L1 inhibitor in lung cancer. While the CD73 landscape is crowded, we believe we've developed a best-in-class inhibitor that differentiates from the competition in multiple ways: first, as one of the only orally bioavailable small molecule inhibitors, which provides deeper tumor penetration and other advantages over antibodies; and second, as an inhibitor that is markedly more potent than other adenosine pathway inhibitors, including, importantly, in a high AMP environment that mimics the extremely high level seen in the tumor microenvironment. Beyond the inherent differentiation of ORIC-533 itself, we've also identified a differentiated clinical development plan that we believe will set 533 apart from the competition. In collaboration with Dr. Anderson's lab at Dana-Farber, we've established that ORIC CD73 inhibitors have compelling single-agent activity in multiple myeloma patient-derived assays. The single-agent activity against patient-derived multiple myeloma systems compares favorably with standard of care therapies. With these compelling preclinical rationale in hand, ORIC-533 becomes the first CD73 inhibitor to enter development for multiple myeloma. Importantly, its favorable preclinical safety margin supports potential combinations with a wide breadth of therapeutic agents, whether that's future combinations in multiple myeloma or future I/O combinations, like those being pursued by competitors today. I'll now turn the call over to Lori and Pratik to walk you through the preclinical rationale and clinical development plan in multiple myeloma before we jump into Q&A with Dr. Anderson. Lori?

Thanks, Jacob. It's my pleasure to speak with you today about our ORIC-533 program. We'll start on Slide 7 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 has been shown to impair antitumor immunity and high levels of adenosine and CD73 are both associated with poor prognosis in cancer. High adenosine levels in the tumor microenvironment are generated in several ways, including through the release of extracellular ATP upon cell death or in hypoxic tissues. CD73 is a cell surface enzyme, which is the final step in generating adenosine. That 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 immunity. 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. Starting on Slide 8 with potency and selectivity. The first table depicts ORIC-533's ability to block adenosine in biochemical and T cell assays. And in both assay systems, ORIC-533 demonstrated very strong potency with IC50s that are picomolar. The second 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 with CD73 protein, the drug is slow to dissociate. We followed up on this finding with further experiments in cells that showed after the drug was washed out of cell culture media, the drug effect continued to be sustained as expected with the slow dissociation rate. And finally, the third table shows the selectivity against a panel of CD73 related enzymes with ORIC-533 having no off-target activity. Together, these features indicate potential best-in-class properties for ORIC-533. In the adenosine assay featured on Slide 9, we compared ORIC-533 in a head-to-head study with another small molecule inhibitor of CD73, AB680, and with an antibody inhibitor of CD73, oleclumab. ORIC-533 more potently blocks adenosine production than both of the clinical comparators in 2 aspects: first, from the perspective of EC50 potency, which is how far the curve is to the left; and second, from the perspective of fully blocking adenosine production, as demonstrated by the ORIC-533 curve going to the bottom, while the antibody oleclumab did not. These results show that ORIC-533 differentiates quite nicely in this adenosine assay. On Slide 10, our results from T cell proliferation assays, introducing an important experimental condition of high levels of AMP into the assay to reflect the tumor microenvironment. 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 environment, reflective of the tumor microenvironment. Slide 11 shows the comparison of ORIC-533 to AB680, a small molecule inhibitor of CD73 in T cell assays with high AMP of 1 millimolar. In both T cell proliferation and activation assays, ORIC-533 is orders of magnitude better at maintaining potency in this context. Blocking adenosine production is predicted to reverse immunosuppression and lead to the activation of T cells, and Slide 12 shows results from a functional assay measuring immune activity. This assay quantifies the increase in interferon gamma production in T cells and comparisons were done for ORIC-533 against a variety of adenosine pathway inhibitors. Starting with the graph on the left, results are shown for small molecule inhibitors of CD73. ORIC-533 has picomolar potency in this moderately high AMP condition, while AB680 potency is 30x higher with EC50 in the nanomolar range. In the next graph, the anti-CD73 antibody, oleclumab, demonstrated no single-agent activity at the concentrations tested, indicating the EC50 is about 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 13, we'll shift from the intrinsic properties of the ORIC-533 compound to discuss the rationale for ORIC-533 in multiple myeloma and present highlights of new results shown at this ASH conference. First, patient samples for multiple myeloma have demonstrated that the tumor microenvironment is adenosine rich. Further studies have shown that high CD73 and high adenosine are associated with core prognosis and therapeutic resistance in multiple myeloma. Second is the compelling mechanistic rationale, which is supported by research from Dr. Anderson's lab at Dana-Farber. This mechanism is notable because it was derived from patient-based ex vivo assays, studying bone marrow samples from relapsed/refractory myeloma 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. This activity is favorable to standard of care therapies in literature comparisons. In upcoming slides, I'll go through the results supporting each of these points. Slide 14 highlights the adenosine levels in bone marrow, which are significantly higher in multiple myeloma patients compared to control. As the disease progresses from MGUS, monoclonal gammopathy of undetermined significance, to become myeloma, the tumor microenvironment plays a larger role and becomes more important. This progression coincides with increasing levels of adenosine in the bone marrow microenvironment, which is immunosuppressive and allows multiple myeloma cells to survive and grow. On Slide 15 is the mechanism that connects the dots from the multiple myeloma cell growth back to a unique cellular relationship that upregulates CD73. This mechanism was discovered by the Anderson Lab at Dana-Farber, our collaborators on ORIC-533. The key discovery is that plasmacytoid dendritic cells or PDCs mediate immunosuppression via CD73 upregulation, which leads to myeloma cell survival and growth. To break it down, we have 3 figures highlighting the mechanistic steps that allow myeloma growth. First, in the figure on the left, CD73 levels were assessed under conditions where PDCs were cultured in the presence or absence of autologous multiple myeloma cells from the same patient bone marrow sample. CD73 levels were found to be upregulated when PDC and myeloma cells were cultured together. In the second figure in the center, co-culture of PDC and multiple myeloma cells led to a significant increase in adenosine, which produces an immunosuppressive environment. And finally, on the right, in 5 different patient donors, multiple myeloma cell growth and survival was enhanced in the presence of PDCs due to the immunosuppressive environment. Taken together, these results led to the hypothesis that inhibiting CD73 in the microenvironment would reverse the immunosuppression triggered by PDCs in the bone marrow of multiple myeloma patients. Now let's turn to Slide 16. To confirm this hypothesis, we collaborated with the Anderson Lab to perform a series of experiments on human tumors collected from relapsed/refractory 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, to assess immunosuppression, the PDC 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 the 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 percent of multiple myeloma cells were killed by autologous T cells. On Slide 17 are results from the first experiment assessing reversal of immune suppression. On the top right, in bone marrow samples from 3 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 the untreated samples, while the addition of ORIC CD73 inhibitor strongly increase the activation of T cells. Not captured here were additional data of positive immune effects that were shown on the ASH poster, including CD73 inhibition triggering plasmacytoid dendritic cell activation and CD73 inhibition stimulating the proliferation of CD3 positive T cells. Together, these indicate that immunosuppressive microenvironment was reversed with the addition of a CD73 inhibitor treatment. Continuing to the next step in this series of experiments, on Slide 18, immune cells isolated from bone marrow samples of 5 myeloma patients were co-cultured either with or without the CD73 inhibitor. These autologous immune cells were then cultured with multiple myeloma cells from each respective patient. The ability of the autologous T cells to induce killing of multiple myeloma cells was quantified through FACS analysis and is shown in the plot on the bottom right. The red triangles are results from each individual patient sample treated ex vivo with the CD73 inhibitor, while the untreated sample from the same donor is shown as the black circle. The Y axis indicates the amount of myeloma cell death or lysis, induced by reversing immunosuppression and unleashing the cytolytic activity of endogenous T cells. An average of around 40% lysis of multiple myeloma cells was achieved after 24 hours of treatment. Together, these results demonstrated that single-agent ORIC CD73 inhibitor reversed PDC-mediated adenosine-driven immunosuppression and restored T cell activity, leading to an impressive amount of killing of multiple myeloma cells. Now I'll turn to Slide 19. Having confirmed the mechanistic hypothesis, we then wanted to assess cytotoxicity towards myeloma cells in an assay utilizing the entire bone marrow milieu. This is an important context because in the prior series of experiments, the immune cells were isolated and PDC and T cells were used to specifically assess the mechanistic hypothesis. However, in this assay, the entire mixture of mononuclear cells from the bone marrow were used which might contain other resistance mechanisms. The assay schema is shown on the left. Mononuclear cells from the bone marrow of 3 multiple myeloma patient donors were cultured. This includes the heterologous mix of immune cell population as well as myeloma cells. The cells were cultured for 2 days in the presence or absence of ORIC CD73 inhibitor after which FACS analysis was used to quantify the amount of myeloma cell death. On the right side, you'll see the addition of CD73 inhibitor induced an average of around 40% lysis of multiple myeloma cells in this ex vivo patient assay. Thus, we were pleased that the CD73 inhibitor activity was maintained in the context of the entire bone marrow milieu. Additional data on the ASH poster included CD73 inhibitor causing decreased adenosine in this assay, which once again links the mechanism to the antitumor activity. On Slide 20, we wanted to be able to put these results in context with standard-of-care therapies commonly used in multiple myeloma. There are multiple examples of the bone marrow mononuclear assay in the literature, one of which is shown on the left. These ex vivo results show that lenalidomide and bortezomib have minimal activity in relapsed patient samples, while daratumumab can induce significant lysis of myeloma cells, averaging around 30% to 40%. For comparison, on the right side are the ORIC CD73 results from patients with relapsed/refractory myeloma, which compare favorably to the previously reported data with other therapeutics. In summary, on Slide 21, ORIC-533 exhibits potential best-in-class properties, and we're now progressing to Phase I in multiple myeloma based on the compelling preclinical profile. ORIC-533 is the only oral inhibitor of CD73 entering the clinic for patients with cancer. Its potency is superior in both adenosine assays and T cell activation assays when compared to other adenosine pathway inhibitors. As we've shown today and at the ASH conference, ORIC CD73 inhibitors demonstrated single-agent activity in a series of ex vivo patient-derived multiple myeloma assays and we're excited to be entering clinical development for multiple myeloma. Additionally, the clean nonclinical toxicity profile supports exploration of potential combinations across multiple treatment regimens. I'll now turn it over to Pratik to talk about the clinical development plans for ORIC-533.

Thank you, Lori. Shifting gears, let's turn to Slide 22 and talk more generally about multiple myeloma, the current therapeutic landscape and where we see the potential for ORIC-533 in this indication. Multiple myeloma is the second most common hematologic malignancy in the U.S. with a prevalence of over 130,000 patients. And each year, there are approximately 30,000 new cases as well as 13,000 deaths. After a long period when chemotherapy was the mainstay of treatment, we are now in an era of rapid growth in the number of available treatments, with a wide variety of mechanisms of action, including the introduction of multiple immunomodulatory agents, proteasome inhibitors and more recently anti-CD38 antibodies. In addition, recent advances in biologics, including antibody drug conjugates, bispecific T cell engaging antibodies and CAR-T therapies provide patients with a host of new treatment options. Nevertheless, despite these many recent and innovative advances, patients still become refractory, and therefore, will continue to need additional treatment options, particularly therapies that may be active and well tolerated in what is termed the triple-class refractory setting. This is the patient population in which we will begin studying ORIC-533 in our upcoming Phase Ib clinical trial. Turning to Slide 23, our first-in-human Phase Ib study of ORIC-533 in multiple myeloma will be conducted in patients for refractory II or ineligible for treatment regimens known to provide clinical benefit. This essentially means that patients will be at least triple-class refractory, although in addition some patients may also receive the newer antibody or cellular biologics as well. Patients who are enrolled will receive ORIC-533 as a single agent dosed once daily in cohorts of a successively rising dose levels using a modified i3+3 design. We will dose escalate based upon safety but have incorporated into the trial extensive translational studies looking at exploratory biomarkers of target engagement through analysis of CD73 enzymatic function as well as profiling of immune cells and cytokines. Along with pharmacokinetics of ORIC-533, we will use this collective body of pharmacodynamic data to determine the recommended Phase II dose, which may not be defined by maximum tolerability but rather by maximum biological effect. Once we identify the RP2D, we then intend to proceed to cohort expansion to further define safety as well as assess initial efficacy using standard IMWG criteria for response and progression-free survival. Furthermore, our plan is that without waiting for completion of the expansion cohort, we would currently initiate exploration of ORIC-533 combinations with other standard agents that are used for the treatment of multiple myeloma. Turning to Slide 24, our principal objective with this initial Phase I single-agent clinical trial is to identify the recommended Phase II dose that we can take into further development. Based upon the compelling preclinical work that Lori discussed earlier on this call, however, we believe there may be meaningful single-agent clinical activity. And through the expansion cohort, we expect to demonstrate this potential. Nevertheless, there is [ present ] within multiple myeloma of therapies with insufficient stand-alone single-agent activity that still have great activities combinations with other available treatments, which is why we are planning to embark upon combination development soon after we identify the RP2D. We are still defining our priorities for combination development, but the immunomodulatory modalities currently in use would be top on our list, including anti-CD38 antibodies as well as the immunomodulatory imide drugs. In addition, the CAR T cellular therapies and bispecific antibodies similarly have compelling combination rationale. And finally, the safety, pharmacokinetic and pharmacodynamic data for ORIC-533 that we gather from this trial will inform us of the potential for future development in solid tumors in combination with checkpoint inhibitors and other immuno-oncology therapies. With that overview of our near-term clinical plan, let me now turn to Slide 25 and introduce our guest expert today, Dr. Kenneth Anderson, Kraft Family Professor of Medicine at Harvard Medical School and Program Director of the Jerome Lipper Multiple Myeloma Center and LeBow Institute of (sic) [ for ] Myeloma Therapeutics at the Dana-Farber Cancer Institute. The preclinical work with ORIC CD73 inhibitor in multiple myeloma detailed in the ASH poster was done in his lab using a model system they developed to evaluate the potential for new agents in multiple myeloma. Welcome, Dr. Anderson. By way of background, perhaps you could tell us a bit about your academic work, your research interests and clinical practice?

Surely. Thank you for this opportunity to be with all of you tonight or whatever time zone you're in. I have been working on multiple myeloma, both in preclinical studies and new drug development, clinical research for, honestly, over 4 decades now. And over the last 2 decades, in particular, as everyone on the call knows, we've been blessed with multiple advances with the IMiDs and the proteasome inhibitors and the monoclonal antibodies. And that was very, very exciting. But as is evident in the last few years in particular and at ASH now, we're really in the revolution of immune therapies in multiple myeloma. And so it is very exciting to think about immune therapies and especially first-in-class immune therapies like ORIC-533. As was said earlier by a couple of the speakers, Lori and others, we've had preclinical models in which we've tested the IMiDs, the proteasome inhibitors, the monoclonal antibodies. And in particular, we'll talk more about this in a bit, but the models that we have utilized together with ORIC for these studies presented at ASH have been used to evaluate these drug classes, including immune therapy, such as the IMiDs and monoclonal antibodies, even the immunotoxin. So we have a track record of being able to assess preclinically what looks to have great promise in the clinic.

Thank you, Dr. Anderson. And let me just say, we're very privileged to have you join us for this call. So you talked about your interest in immunotherapies. I'd like to specifically focus on the adenosine pathway. That's been a pathway of interest to you even before you started working with us on the ORIC CD73 inhibitor. Can you tell us a bit about the mechanistic rationale and what you've seen that convinces you that this pathway may be important as a new target in myeloma?

Surely. It -- again, this was covered beautifully by Lori in her comments earlier, but the -- reminding everyone that patients with myeloma have immunosuppression as a hallmark of the disease. And in the clinic, it's a susceptibility to infections. And I will just add in our COVID pandemic that has been further manifest with worse outcomes for patients with myeloma that become infected and a lack of ability for them to respond to vaccinations as the rest of us do. So this is a real world problem, and we really need to overcome this immunosuppression. So that's where the adenosine story comes in. We, for a long time, studied the microenvironment before it was even popular, and we have looked for soluble factors that are immunosuppressive as well as accessories cells in the bone marrow microenvironment. And one example that was alluded to earlier are the plasmacytoid dendritic cells that promote tumor cell growth survival and drug resistance and confer immunosuppression. We have shown as was illustrated for all of you earlier that adenosine levels are sky high in myeloma. It's a hypoxic bone marrow microenvironment. These high adenosine levels are suppressing T cell function and activation. They're suppressing NK cell degranulation and killing. They're suppressing the M1 type macrophage generation, and they're suppressing activation of dendritic cells. So this is contributing in a major way this process to the immunosuppression. So as you have mentioned, we have tried in the past adenosine receptor antagonist preclinically in multiple myeloma. And the preclinical models did show some qualitative effects, but honestly the doses required were really too high to translate towards the clinic. CD38 antibodies also could be implicated because decreasing the CD38 kinase enzyme activity can actually reduce in part at least the adenosine generation in the bone marrow microenvironment as well. So that's one of many effects of the CD38. But truthfully, when CD73 has now come along, we've studied CD3 monoclonal antibody, and now we're excited and have studied together with their oral inhibitor ORIC-533 that you've heard about. And that can, as we will talk about in a minute further -- even can overcome -- at least in part, in a qualitative assay, it can overcome this immunosuppressive effect of adenosine and effector cell function can be stimulated, including both T cells and NK cells. So honestly, this is the first one inhibitor of this pathway that is going to go to the clinic. And for that reason, we're excited about a new mechanism that may help our patients.

Thank you, Dr. Anderson. So yes, let's -- before we go actually to the ORIC CD73 inhibitor, maybe you could spend a minute to talk about the assay system itself because it's something that your lab has been first developed, but then also has been using serially to test compounds. And so maybe if you could comment on its translatability from preclinical into the clinical world.

Sure. So there's -- we have, over the years, developed assays of the tumor, used cell lines and ultimately going to patient cells. But the tumor in the microenvironment, we think to be very important. The microenvironment can, as I said earlier, promote tumor cell growth, but it confers resistance to drugs and immunologic agents as well. So if you can overcome the immunosuppression in the microenvironment that is going a long way towards enhancing response, and hopefully, prolonging response in myeloma. Now as was mentioned, that we've got a number of assays, but the 2 you heard about tonight are looking at the effector cells first by themselves. So there was the experiments where we used ORIC-533 together with the effector cells and subsequently looked at their lytic activity of those T cells in the presence of the target myeloma cells that gives us an idea of what's going on in this adenosine mechanism that is with effector cells initial incubation and as a subsequent incubation with the target cells. The second assay that was mentioned is we used the entire bone marrow milieu microenvironment, all the mononuclear cells are present. This, we think, is important because the tumor is there, but so are accessory cells like plasmacytoid dendritic cells, myeloid-derived suppressor cells, T regulatory cells and others that are a major part of the problem in terms of conferring immunosuppression. And when we've looked at assays of other agents in this model system, that it has been very -- in either of these model systems, but in the latter in particular, it's been very useful for us because agents that are active in the presence of the bone marrow milieu that can be stromal cells and cytokines and these accessory cells that I was just mentioning a minute ago, the agents that are active in that context are those in our view that over the last 20 years have been able to be active when conventional therapies, chemotherapy, et cetera, were not active. So we're excited about the ability to get lytic activity against myeloma even in this context. And as was illustrated, we do see activity of an entirely -- in an entirely autologous system. So this means autologous myeloma, autologous accessory cells that are attempting and mediating immunosuppression and high adenosine levels. In that context, the presence of ORIC-533, the CD3 inhibitor, can generate a response in terms of a T cell and NK cell-mediated killing. So I think we've used this system repeatedly for proteasome inhibitors, IMiDs. We've used it for a number of the immune agents, including new ones that are coming, BiTEs, et cetera. But this is the first time we've been able to inhibit CD73 and where -- with ORIC-533, and we're excited to test this and bring this to the bedside.

Thank you, Dr. Anderson. Are you able to put the CD73, the ORIC data into context with some of these other agents, either past or future that you've looked at?

Yes. I think I don't want to overstate this because we can't -- I think the assays, especially in the immune area, are qualitatively predictive. And I think that the level of killing, which you saw, both assays, the adding in the effectors to the myeloma and also the entire system at once is in the range of 30% to 40% killing, which is in the range that we've seen with other targeted and immune treatments. I do think, though, and I -- that's why we do clinical trials. We really do need to see what happens in patients. I do think that we can do the best we can, mirroring the patient. But -- and in that sense, we are excited about the level of activity we've seen. I think the other point that I wanted to make is that -- and it may be a question that some people wonder about is, how could this possibly be active in the far advanced setting? Well, the issue of patient setting, I think, as was shown, the adenosine levels go up in patients as you go from smoldering to myeloma and within myeloma too you get to relapse and multiple relapsed myeloma. So this is the mechanism, honestly, that we think would be probably the most active in the far advanced patients. So that, as you heard, the triple-class refractory patients are where we're going to start.

Yes. So if we then -- maybe then transition now to a discussion about the clinical landscape before we talk about the Phase I clinical trial. There's been a lot of -- ASH isn't over yet, but a lot of new data coming out about bispecific monoclonals, T cell engagers. Where would you place the medical need currently in myeloma? And what role do you think an oral CD73 inhibitor, which we expect at least from the nonclinical toxicology perspective, may have a very easy safety profile?

Yes. No, I think -- so it clearly fits into the immunomodulatory or immune treatment category. And I mentioned earlier, I think the immune therapies are the most exciting in our field right now. As everyone on the call knows, myeloma is very constitutively, genomically heterogeneous, and we have ongoing clonal evolution, we have ongoing DNA damage and these processes underlie relapse of disease. This is a real problem for us, and immune therapies, in my opinion, are -- have the best ability to deal with these resistance mechanisms that are intrinsic to the myeloma cell. So we're excited about immune therapies. And at ASH, the bispecific T cell engagers are very exciting, off-the-shelf, achieving remarkable response rates as high as 60% to 80% in relapsed/refractory disease. And the therapeutic index is improving as they learn how to deal with cytokine release syndrome. CAR-T cells are similarly exciting, a lot more logistically challenging to deliver, honestly, but again, their therapeutic index is improving as we learn how to deal with CRS and ICANS. And the durability is getting a bit longer. The cilta-cel trial reported today is showing that the durability of response is extending out as long as 2 years. But my point here is that CD73 is an oral agent. It's, in my view, very likely to have a very favorable therapeutic index and the ability to buy itself in our assays stimulate immune response is very exciting. And so that was the rationale for the Phase I trial, dose escalation trial, that you heard about. It's built in. So it's starting at a dose of 400 and you can de-escalate if we need to, but you can escalate up as high as 1,600 milligrams, at which point -- one of those levels we'll have a dose expansion based on the biologic activity, as you heard. But we're hoping for single-agent activity as we saw in our preclinical models but there's also a strong rationale for adding to some of the agents we already have. And we can talk about that in a minute, but also for adding to some of these novel agents with time. There -- in myeloma at least to date, we have not had a single agent and then been able to stop therapy without maintenance. In other words, we have always had relapse of disease. ORIC, with time after development in relapsed/refractory myeloma, could have a role in maintenance treatments or combination with a lot of the therapies we use currently in myeloma by stimulating an immune response, oral, well tolerated. It has the ideal characteristics, for example, of a maintenance medication in the future. Time will tell. But there's a lot of options that we need to think about for an oral immunomodulator.

And as we move into the clinic with ORIC-533, we're excited about having you and now your clinical team partner with us on taking it into Phase I. Maybe you could spend a minute or 2 talking about what your expectations would be from this first-in-human single-agent Phase I study?

Yes. So I think what we -- firstly, the clinical trial would be done, as you had mentioned, in triple refractory myeloma for everybody on the phone that's known, I think, but it's proteasome inhibitor immunomodulatory and CD38 antibody refractory. There's also a subcategory called penta-refractory, which means your refractory to both proteasome inhibitors, both IMiDs and CD38. And this particular Phase I clinical trial does not exclude novel therapy. So there could very well be in today's world patients who have had BCMA-targeted treatments as well, some of the therapies that you and I just mentioned, the BiTEs or even cellular CAR-T cells. So it's going to be a dose escalation. And I think what do I expect? I think that we're going to be doing all kinds of elegant, correlative science to look at effects on adenosine, to look for biomarkers of response, and to look for immune response parameters in the patients treated. My hope and expectation is we're going to see activity, meaning responses, M protein responses, that will be occurring associated with immune activity likely before we have an MTD. These immune therapies are much more associated with a biologically active dose rather than a maximally tolerated dose. And I think that is my expectation. When we actually get to that level, we're going to expand out -- recommended Phase II dose will be chosen and expand out with larger numbers of patients. I think it's 18 up to 43 patients at the recommended Phase II dose. We were hoping for 20% to 30% or more responses of durability of months, at least to start with. But honestly, with immune therapies that are well tolerated and oral, what we -- I would expect to say, and this is just my opinion, you would have responses, and these likely will deepen over time as we've seen with other oral immunomodulator like lenalidomide, for example, in the maintenance phase. One sees responses, and these deepen over time. So -- but we're going to do a dose escalation trial, oral therapy. We expect to see immune parameter responses. We expect to define a parameter or a profile that would hopefully correlate and someday predict response. And once having found the dose at which we have a favorable therapeutic index, we're going to do the Phase II expansion and -- or Part 2 expansion to get more robust data in terms of the response rate and side effect profile.

Well, Dr. Anderson, I really appreciate your enthusiasm for this sub molecule. You more than anyone has seen so many agents come through in development. So I appreciate your excitement about this, and we're looking forward to getting the program in the clinic, started. Maybe we could close out now with something you already touched on, which was looking down the road beyond single agent towards combination. What would be the combination just right now based on what we know about the biology that you would want to prioritize?

Well, I think, firstly, everyone on the call knows, we use combination therapies routinely in myeloma. So this is -- we want to prove single-agent activity and a favorable therapeutic profile. But once we've done that, that's what you need to be to be a good team member. So once we've defined that, what are the other candidates, immunomodulatory drugs would be an obvious good combination for their biologic effects would be additive or synergistic here. CD38 monoclonal antibody, as I mentioned earlier, can actually decrease in part adenosine levels and has multiple other mechanisms of action, including downregulating regulatory C cells and stimulating T cell proliferation. So I would expect, again, at least additive and maybe even synergistic activity with a CD38 antibody. One of the most recent things that's actually going to be presented in a few minutes by one of my fellows at ASH is the proteasome inhibitors inducing something called immunogenic cell death. So they actually stimulate an immune response that's selective against dying myeloma cells. And I would expect that, that response -- that biologic activity, if you will, would be markedly enhanced by a CD73 inhibitor. And then I already mentioned, we have the BiTEs and the CAR-T cells. So the beauty of those is what the extent of response that is achieved. But the problem that we're still facing there is the durability of response. And so because of the effects you've heard about of CD73, it would be hoped that they could be utilized as an oral adjunct along with these therapies and enhance the immune response and thereby prolong its duration as well. So I think it's a -- it has all the characteristics of a potentially very important combination -- in a number of different combinations.

Great. Thank you. Thank you, Dr. Anderson, for participating in this Q&A. Your insights have been invaluable. And as I said, your excitement is contagious. So we're looking forward to pushing this program forward. So let me end this section by saying thank you. And if you can stick around at the end of the call for additional Q&A, we'd appreciate it. But let me pass it over now to Jacob.

Thanks, Pratik and Dr. Anderson. As you can see, we're excited about this promising data set in relapsed/refractory multiple myeloma, and we're excited to pursue ORIC-533 in this patient population. While our immediate next steps are focused on enrollment and the Phase I dose escalation, we're already thinking through potential next steps that we would pursue in response to efficacy signals we may see in the coming year, as Dr. Anderson described. Stepping back, beyond ORIC-533, as you can see on Slide 27, we've assembled a robust pipeline of differentiated product candidates sourced from our internal drug discovery efforts and opportunistic business development. We're thrilled to have filed 3 INDs or IND equivalents this year. And by early next year, we'll have 4 programs in clinical studies evaluating indications with high unmet need. While the focus of today's call was the ORIC-533 rationale and ex vivo data in myeloma, throughout this year, we've generated substantial preclinical data on our next 2 clinical candidates that make the case for the potential best-in-class profile of ORIC-114 and ORIC-944. We just -- for just a few minutes, we'd like to remind you of those highlights, including new EGFR HER2 focused data for ORIC-114. Slide 28 shows a snapshot of 114, a brain penetrant, orally available inhibitor targeting EGFR and HER2 exon 20 mutations that we in-licensed last year. The outcomes for patients in these indications have been subpar thus far as molecules in the field have been limited first by a lack of selectivity for the target versus wild-type EGFR and various off targets; and second, by a lack of CNS activity, which is critical when over 1/3 of patients developed CNS metastases. Our comprehensive preclinical profile of 114 demonstrates an exquisitely clean kinome tree, good therapeutic window, significant tumor regression in multiple in vivo models without meaningful toxicity and compelling brain exposure and intracranial antitumor activity. We filed a CTA in Korea for 114 in Q4, and soon, we intend to initiate clinical studies. Since in-licensed the program, we've also conducted additional preclinical characterization to understand its differentiation versus other compounds in this indication. Lori will now cover some of these highlights.

Thank you, Jacob. On Slide 29, we further characterize ORIC-114 in a head-to-head in vivo study in an EGFR exon 20 insertion lung cancer model, in which ORIC-114 demonstrated greater antitumor activity than the competitor compounds. A 90% complete response rate was observed for ORIC-114 at a well-tolerated dose of 3 mg per kg once daily. In contrast, no complete responses were observed for BDTX-189 and only 2 complete responses were observed for CLN-081. Additionally, the CLN-081 cohort had 25% of animals that came off study due to significant weight loss. Together, these in vivo data indicate the potential for a broader therapeutic index of ORIC-114. In terms of characterizing ORIC-114's brain penetrants, Slide 30 shows highlights of extensive preclinical PK analysis of brain exposure. A key feature of ORIC-114 differentiation is that it was designed to optimize brain exposure across multiple parameters. Together, these compound characteristics translate in vivo into a high brain-to-plasma ratio in mice of nearly 1, as shown in the graph on the right, which is plotted with the Y axis on a log scale to easily distinguish which compounds have high brain-to-plasma ratio. Importantly, ORIC-114 high brain-to-plasma ratio was maintained at both 1 and 4 hours and the graph depicts the free unbound fraction. In comparison with other clinical compounds, ORIC-114 brain exposures are on par with osimertinib, which is deemed as CNS clinically active compound. In contrast, the free brain-to-plasma ratio of ORIC-114 is superior to other exon 20 directed agents and is also superior to the HER2 agent, tucatinib, and its active metabolite. In summary, the limitations of current therapies to address brain metastases in both the exon 20 mutant population and the HER2-positive patient population present an opportunity for ORIC-114. Switching gears to HER2 on Slide 31, one of the aspects of ORIC-114 that excites us is its potency against cancer cells with HER2 amplifications. HER2-positive breast cancer is around 25% of all breast cancer and up to half of HER2-positive breast cancer patients develop brain metastasis over the course of their disease. We hypothesized that tucatinib activity may be limited by modest brain exposure of the parent drug in its active metabolite in the brain. Thus, we initiated preclinical studies to investigate the opportunity for ORIC-114 in this disease setting. The in vivo result, shown on the left side of Slide 32, indicates that ORIC-114 has strong antitumor activity systemically in a subcutaneous HER2-positive breast cancer model. ORIC-114 and tucatinib both cause regressions in the subcutaneous model. However, on the right plot is a different story. This same HER2-positive breast cancer model was used in an efficacy study with the tumors grown intracranially. It's notable that oral dosing of ORIC-114 showed significant tumor growth inhibition in this intracranial model with superior antitumor activity in the brain versus tucatinib. These promising results indicate a potential expansion of the patient population that may be treated with ORIC-114 in the clinic, as Pratik will tell you about.

Thank you, Lori. Turning to Slide 33, as we discussed when we first in-licensed this molecule, our development focus continues to be exploring the potential for ORIC-114 in patients with tumors harboring either EGFR or HER2 exon 20 insertions. These molecular alterations are enriched in patients with non-small cell lung cancer. And since this malignancy is associated with a high incidence of CNS metastases, the CNS penetration of ORIC-114 may offer a distinct therapeutic advantage not seen with other exon 20 agents currently in development. With these new data that Lori has reviewed, we are now able to extend our development scope into HER2 amplification, which occurs most commonly in metastatic breast cancer, but can also be found in other malignancies such as certain gastrointestinal tumors. As with non-small cell lung cancer, metastatic breast cancer also carries a high prevalence of CNS metastasis, which again plays to the strengths of ORIC-114. Collectively, this development opportunity with the addition of HER2 amplification as a target of interest consists of almost 35,000 patients annually in the United States. Turning to Slide 34, we filed the CTA for our first in-human Phase Ib clinical trial in South Korea at the beginning of November, and it is currently under regulatory review. The study will enroll patients with advanced solid tumors who have either EGFR or HER2 exon 20 alterations or HER2 amplification or overexpression. Unlike many Phase I studies, ours will allow patients with CNS metastases that are treated or that are untreated but asymptomatic so that we can dose escalate in the patient population of interest from the very beginning. Patients who are enrolled will receive ORIC-114 as a single agent once daily using a modified i3+3 dose escalation design. Once we identify the recommended Phase II dose, we will then embark upon expansion cohorts that are defined by tumor types and alterations of interest. We expect to initiate this study early next year. Finally, turning to Slide 35, ORIC-944 is an allosteric PRC2 inhibitor that we in-licensed last year. This molecule targets the EED subunit of PRC2 and has been optimized to overcome some of the biological and drug property limitations of the EZH2 inhibitors, the first generation approach to tackling PRC2-related epigenetic dysregulation. This molecule has demonstrated in vivo preclinical activity superior to that of an approved EZH2 inhibitor in a DLBCL model. And it has further demonstrated compelling in vivo activity in 2 different enzalutamide-resistant prostate cancer models. We filed the IND for 944 in Q4 of this year, and I'm pleased to say that the IND is cleared, so we can now proceed to initiate single-agent studies in prostate cancer patients. Turning to Slide 36, we plan to take ORIC-944 into patients with metastatic prostate cancer, specifically patients who have progressed after at least 1 androgen receptor modulator but who have had no more than 2 prior chemotherapy regimens. Enrolled patients will receive single-agent ORIC-944 once daily on a modified i3+3 dose escalation design. After we identify the recommended Phase II dose, along with preliminary safety and PK, we will proceed to an expansion cohort to look at efficacy endpoints such as response rate, duration of response, clinical benefit rate and progression-free survival. We also have a number of exploratory biomarkers included in the protocol, particularly assessment of H3K27 trimethylation status as an important pharmacodynamic readout. We expect to initiate this study in the U.S. early next year. So we'll wrap up our prepared remarks on Slide 38. We're very proud of the team and pipeline we've built at ORIC. Beyond our lead program, ORIC-101, we've put together one of the most robust pipelines of potentially best-in-class molecules in small-cap biotech going after an array of validated targets. Today's call on the preclinical rationale and clinical development plans for 533 in multiple myeloma have hopefully highlighted our team's ability to discover and develop programs with differentiated, best-in-class potential and furthermore, our ability to find white space clinically, even within an area that has generated as much interest as the adenosine pathway. We intend to bring these same competitive differentiators to every program in our pipeline as we hopefully also are starting to see with ORIC-114 in EGFR and HER2 related indications. Before we open it up to Q&A, I'd like to offer our thanks to Dr. Anderson for joining us today to provide his perspective, to Dr. Anderson's Lab for collaborating with us to generate this interesting clinical path for 533, and to the entire ORIC team for the tireless work tackling our mission on behalf of patients. With that, let's open it up for Q&A.

[Operator Instructions] Our first question comes from the line of Maury Raycroft with Jefferies.

Hi, everyone. Thanks for hosting this event. Really interesting and helpful. I had a question on 533. I'm wondering if you can talk more about the rationale for pursuing a single-agent approach versus a combo approach in the triple refractory population? And is there a development and regulatory appeal behind the strategy?

Sure, Maury. It's Jacob. I can take that one. I mean basically, Maury, the way agents get developed in myeloma today is you often start out as a single agent, see whether you can see some modest activity as a single agent and then pretty quickly move into combination development strategies thereafter. So that's exactly the approach that we would take here. As Pratik described in his remarks and as Dr. Anderson alluded to, we would start as a single agent, but we're prepped and ready and already thinking about what the combo plans would be because we'd want to launch those pretty shortly thereafter.

Got it. Okay. And then maybe a question for Dr. Anderson. You mentioned the 20% to 30% response rate. Just clarifying if that's for a single agent in the triple-refractory population? And then you all talked about the combo classes you could combine with. Just wondering if you can talk about what the benchmarks are for efficacy success in the combo setting.

Yes, I can -- this is Ken. I think I was saying that thinking about single-agent activity for drugs that have gone before as sort of low bars, if you will, selinexor, as you remember, is in the range of 20% or a little bit more. I think we are -- as was mentioned by Pratik, we're going to go forward with a single-agent experience first. You really need to do that in order to see biologic activity, the correlative science and also side effect profile. But as he mentioned, it is highly likely like all other myeloma drugs that it would be combined with other agents. And again, it really depends on the setting in which you do the combination trial, frankly. But the combination approaches have often achieved response rates between 40% and 60%, and their durability is in the range of 8 or 9 months to a higher up to 11 or 12 months. So it really, though -- that's a general question because we really -- it would depend on the combination and most importantly it would depend on the patient population that you treated. So it will be -- it has -- the paradigm for drug development in myeloma has been well established. We have very, very good relationships with our regulators, and we can have a plan that honestly has been utilized many times before. Ultimately, after single-agent activity, these various combinations will be pursued vigorously because that's when the response rates will go way up high.

Our next question comes from the line of Anupam Rama with JPMorgan.

Yes. Can you expand on your comments on the criteria for selection of the RP2D? And maybe both for the company and Dr. Anderson. What biomarkers do you think will be most helpful in considering the biologic activity for an RP2D selection?

Thanks, Anupam. Let's have Pratik start on that one, and then Dr. Anderson can chime in.

Anupam, yes, so as Dr. Anderson already mentioned, we expect that this Phase I will be guided more by the translational work and the pharmacodynamic readouts than necessarily safety, although that's obviously part of every Phase I study. And so we will be looking at a number of readouts, but in particular, we're measuring functional CD73 activity, both in the peripheral blood and in the bone marrow from the patients on study, baseline and on treatment to -- with the intent to demonstrate that we're able to in vivo shut down CD73 and therefore, adenosine production. We'll also be profiling cytokines and immune cells as well, and we'll use this collective information to help us guide dose along with PK in terms of just making sure we're getting exposures that preclinically are compatible with, again, shutting down CD73. So it will be more than just a safety guided dose finding exercise, but as Dr. Anderson already said, a lot of translational work will go into it as well.

And I'll just pick up on that very quickly. It's not -- I'll just make a quick reminder for everybody. When we worked on the proteasome inhibitor over 20 years ago, we basically came up with the first schedule, which was twice a week for 2 weeks with a week off based on the inhibition of the proteasome and then the recovery of proteasome activity. So that first dose schedule that was approved was actually approved based on the biologic activity and recovery of the proteasome in that example. So here, as Pratik just said, I think that it's ultimately -- and they are prepared to do this. They have assays to assess CD73 blockade in patients with readouts ranging from adenosine to the immune parameters as he mentioned. So I think it's -- that's why we can be kind of confident that we're not going to need to go to an MTD. It's much more likely we'll see a biologically active dose.

Our next question comes from the line of Michael Schmidt with Guggenheim Securities.

This is Yige on for Michael. Two quick ones for 533. I guess, the first one, what were the prior treatment for the patients who you got the bone marrow sample from in your preclinical data? And do you think this CD73-mediated resistant mechanism depends on any prior treatment? And secondly, on the safety profile, how would the safety profile potentially differentiates from CAR-T and bispecifics, given the preclinical mechanism involves PDC activation, which usually results in a release of broad proinflammatory molecules?

Yige, let me ask Lori to take both of those. Thanks.

All right. You have to remind me -- I'll take the second one first. So we do not see evidence preclinically of cytokine release syndrome. And I believe that's because this mechanism is a very localized mechanism. So the adenosine is high in the bone marrow of these patients where the tumor is growing. And it's not a systemic high adenosine. So when we give the treatment we really had very wide therapeutic margins in our nonclinical safety studies. And we would predict that, that will translate nicely into the clinic. So that's why we've put so much time into developing our PD biomarkers because we don't think we'll have DLTs. And sorry, what was the other question?

I can take that one, Lori. This is Ken. I think the other question was the patients that we studied and they were myeloma cells and patient bone marrow mononuclear cells from patients who had triple-refractory disease. So refractory to the IMiDs, proteasome inhibitors and monoclonal antibody to CD38 as are the patients that are proposed for the clinical trial.

Our next question comes from the line of Yigal Nochomovitz with Citigroup.

Two questions. First for ORIC, just curious what you need to see as a single agent for 533 or in combo with another myeloma drug to move the 533 program forward? So in other words, what are your thoughts on the go/no-go efficacy bar? And then for Dr. Anderson. I'm curious to get your thoughts on blocking the adenosine pathway by hitting the adenosine receptor directly with the drug targeting A2A and A2B as opposed to blocking CD73. So is inhibiting CD73 preferable? And if so, I'd be curious why.

Thanks, Yigal. Let's have Pratik take the first one and then Dr. Anderson for your second.

In terms of the efficacy threshold for single agent, we -- some of this was already discussed with Dr. Anderson. I would just caveat some of those numbers with the fact that, in Phase I, not all patients will be getting -- will ultimately be determined as the recommended Phase II dose. So I think as a single agent, we can see response rates that are in the 15% to 20% range. That would allow us to feel confident that once we move into a more uniform patient population with a single recommended Phase II dose that we would see single-agent activity that would be compatible with other single agents that have been approved for myeloma. In combination, I think, as Dr. Anderson well said, it's hard to come up with any single number. It will depend on the benchmark of the combination itself, the base combo that we then add ORIC-533 to as well as the patient population we take it into. So I think that's -- that won't be a single number, but relative to combo and patient population.

Yes. This is Ken. And I'll answer the second one that you asked just quickly. I think -- the question was should we inhibit the adenosine receptors or adenosine, which is best. And I don't think we know the answer to that. I did mention that we had tried many years ago with adenosine receptor antagonist to test that idea. And we did not -- we honestly could not get sufficient blockade at where we thought we could get a therapeutic index. I do think I like the idea of blocking adenosine because of the multiple phenotypes that are conferred by high doses of adenosine in T cells, in monocytes, in dendritic cells, in NK cells. There's so many different biologic activities that it may be more difficult to block receptor than to inhibit the mediator of the immunosuppression. And I also think that getting to the adenosine, I kind of like because the myeloma bone marrow is very hypoxic. And as Lori mentioned a minute ago, that's going to hopefully help us in terms of the therapeutic index, too, because the inhibition of CD73 is going to be most important right in the bone marrow microenvironment where the tumors reside.

Yes, Yigal, I'll just add to what Dr. Anderson said that based on the profiling we've done, we have not found an A2A receptor antagonist that's been able to shut down this adenosine pathway nearly to the same degree as what we've been able to do with ORIC-533. So just the inherent properties of 533 itself, I think, give an advantage over the A2A receptor antagonist. Well, I think let me just interject. We'll continue to take questions here, but Dr. Anderson has got a couple of trainees that are giving talks at ASH, so he's probably got to adjourn to be able to join some of those meetings, but we can continue here with the ORIC team. So operator, back to you for questions.

Thanks very much. Thanks a lot.

Thanks, Dr. Anderson.

Thank you.

Our next question comes from the line of Colleen Kusy with Baird.

Could you talk a little bit about the level of CD3 overexpression that you see in multiple myeloma and whether you expect multiple myeloma to be a high adenosine environment?

Sure. Lori, do you want to address that one?

Yes. So there's several publications in the literature discussing high levels of adenosine in myeloma as well as high CD73 in myeloma. And Dr. Anderson's Lab has also looked at high levels of CD73. CD73 itself can be found on a number of different cell types within the bone marrow, everything from various immune cells to myeloma cells themselves. Importantly, when the plasmacytoid dendritic cells are put next to the myeloma cells in culture, you can see that the CD73 levels rise dramatically. And so that was some of the basis of Dr. Anderson's work trying to dig into the mechanism to understand what was really driving resistance with the presence of those PDCs. And the CD73 levels are driven transcriptionally but you can also see that the protein levels are high. And then, of course, when you have higher CD73 it is the final key step in producing adenosine. So the adenosine levels are also high. But there are several publications in the literature also describing high adenosine and high CD73 levels in myeloma.

Great. That's helpful. And following up on that, I think there was a comment earlier on the call that adenosine levels might increase in later lines of treatment. I guess could you -- could there be a patient selection strategy based on CD73 expression or adenosine levels? Do you think there's a threshold that you need to surpass to be active?

From what we can tell from the literature, it's more in the precursors of myeloma, where the levels are low. So like the MGUS, it's low. But then as soon as a patient has multiple myeloma diagnosis, the levels are high. So it is not clear whether we'll need a predictive diagnostic, but certainly, we are going to look at CD73 level in our Phase I study to see how -- what they look like, how high they are, what the heterogeneity is.

Makes sense. And then one last question. We see dexamethasone used commonly in the treatment of multiple myeloma. Would you consider that as part of your kind of single-agent approach with 533? Or would it be solely 533?

Yes. The Phase I study is with 533 alone. There's no dexamethasone cotreatment.

Thank you. I'm showing no further questions in the queue. Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect. Everyone, have a wonderful day.