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

Welcome, everybody, to the 40th Annual JPMorgan Healthcare Conference. My name is Anupam Rama. I'm one of the senior biotech analyst here at JPMorgan. I'm joined by [ Malcolm Kuno ], Priyanka Grover and Caleb Smith from the team. Our next presenting company is ORIC, and presenting on behalf of the company, we have CEO, Jacob Chacko. [Operator Instructions] With that, Jacob, take it away.

Thanks, Anupam. Thanks for having us. It's our pleasure to talk to you today about ORIC Pharmaceuticals. We've only got, I think, about 20 minutes to go through quite a bit of information in the slide, so I'm going to go at a decent clip and then, Anupam, make sure to save enough time for Q&A at the end. So Slide 2, just walk through some of the standard forward-looking statements, but let's jump right into the presentation on Slide 3. And this in one slide I think encapsulates why we were so excited about what we're building at ORIC. ORIC stands for Overcoming Resistance in Cancer. And in a nutshell, that encapsulates the mission of the company. So everything in the pipeline is targeted at various resistance mechanisms that are relevant to oncology today, either innate resistance or bypass resistance or acquired resistance, but essentially going after some of the hardest to treat cancers in oncology today. As you'll see here, we think that we've put together one of the most exciting pipelines in SMID-cap biotech. As you look at the programs, we'll spend some time today talking about ORIC-101, our lead program, which is going after a novel target, the glucocorticoid receptor. And that's relevant to multiple large patient populations of high unmet need. Apart from that though, we have also put together, both through internal drug discovery efforts as well as external business development in licensing efforts, one of the -- a broader pipeline that goes after validated targets as well with best-in-class approaches, and I'll talk at a high level about 3 of those programs today. Beyond that, we've taken a precision oncology approach to the way that we've built the pipeline. That's important for a number of reasons. One is it helps us select the right patient populations and get the right drug to the right patient. From an ROI perspective though, as a company, what it enables us to do is accelerated clinical time lines. And so therefore, to get to value inflection points as quickly and as efficiently as possible. Beyond that, I think one of the things that I touched on earlier is just the unique way that we've built the pipeline at ORIC which is really through 2 dual engines. We've got great internal drug discovery, and I'll touch on some of the aspects of that shortly in my presentation, but we pair that up with targeted opportunistic business development. And so you'll see that in our first 4 pipeline programs, 2 are from internal discovery efforts, 2 are from external BD efforts, and we continue to envision building the pipeline in such a manner going forward. Finally, we've got an experienced management team that's worked together in multiple prior settings, building successful oncology companies, and the company is very well funded through multiple value inflection points. Because of the pipeline we've built, we see ourselves giving 5 data updates over the next 6 quarters on the first 4 programs and beyond that, with the cash runway that extends into the first half of 2024. So quite a bit of runway in which to really execute upon the pipeline. Moving over to Slide 4 and diving into the story. I'll just touch at a high level about the company itself, the strategy and kind of what's interesting about what we put together and then we'll double-click on each of the programs. So starting on Slide 4, as I alluded to in my opening comments, we're quite proud of the fact that we've brought together a set of distinguished founders and a research team, largely hailing from Genentech, a clinical team, largely hailing from Ignyta and Aragon and some other companies, paired up with a business finance and Investor Relations team from both Medivation and Ignyta. And what it's enabled us to do is really turbocharge our efforts at building out the pipeline that I mentioned earlier. Slide 5 walks you through our approach to building that pipeline. I think one of the most interesting things about the way that we've built ORIC is that we've done it in a way that is agnostic to the source of the molecules of the programs. And what I mean by that is if you take a step back and look at the way that successful oncology companies have been built over the last 10 years, for the most part, you'll find 1 of 2 -- or 2 different models and companies sort of aggregate into 1 of the 2, which is either great internal drug discovery, and you see some examples of companies that have done that in the past, or really targeted great opportunistic business development. And you'll see examples of companies that have done that in the past. I think you can count on one hand the number of companies that they've been able to do both of those things successfully. At ORIC, that is what we're attempting to do. And essentially, we take the view that best molecule wins. We first identify a target that we find that is of interest and with high unmet medical need. If we can address that target with the program we develop through our internal drug discovery, we'll do that, because we've got great biology and great chemistry and a whole host of preclinical functions represented internally at ORIC. But if another company has a better approach or one that is more accelerated further along, we're quite happy to engage in business development discussions and try to in-license that compound instead in order to kick start the time lines. What it's led to is what you see on Slide 6, which again, as I mentioned earlier, we think is one of the most exciting pipelines in small cap biotech today. You can see the first 2 programs, ORIC-101 and ORIC-533. One is a GR antagonist. The other is a small molecule oral CD73 inhibitor. Both are homegrown from our internal drug discovery efforts. On the far right of the chart, you can see what we view as the key differentiation of those programs. Similarly, ORIC-114, our EGFR/HER2 exon 20 inhibitor, and then ORIC-944, our PRC2 inhibitor, also have key angles of differentiation. But in those cases, we brought them in through internal -- through external efforts on business development and in-licensing. Beyond that, we have a pretty robust discovery pipeline as well with undisclosed targets that we will be disclosing at some point over the coming 1 to 2 years. But again, going after both first-in-class and best-in-class targets. I want to pause for a second on Slide 7, and this really, to me, encompasses all the accomplishments that took place over calendar year 2021. And then importantly, it sets us up for a very exciting 2022 and beyond. And this is on a number of fronts as you look at the pipeline. So first, starting with ORIC-101. As many of you know, last year, in 2021, we continue to enroll both trials of ORIC-101 successfully, so the Abraxane combination trial on various solid tumors where we presented initial data at ASCO last year and then the Xtandi combination trial in prostate cancer where we presented initial data at the Triple Conference last year. That ongoing steady enrollment has really set us up nicely such that we anticipate in the first half of 2022, we will have enrolled sufficient patients and followed them for a long enough period of time that we'll be able to look at those data sets to see whether there is a sufficiently interesting efficacy signal that would warrant moving one or both of those studies into later-stage studies, namely registrational studies that could start as early as the end of this year or early next year. If on the other hand, we don't see sufficient signal in one or both of those studies, we would look to, at that point, cut bait on the study. And so we're really looking at these updates for ORIC-101 in the first half of this year. And I know we'll get into this in the Q&A with Anupam as really go/no-go decisions for the ORIC-101 multiple studies that are in process. Apart from that, we were busy in 2021 on the other 3 programs. So we filed 3 INDs or equivalent in 2021, and that was for ORIC-533, our CD73 inhibitor; ORIC-114, our EGFR exon 20 inhibitor; and then ORIC-944, our PRC2 inhibitor. I think you would be hard-pressed to find companies of our size that had filed even 2 INDs last year, and this team was able to successfully file 3 IND equivalents. What it set us up for is the initiation and early dose escalation of those 3 programs this year in 2022 and really sets us up nicely to have the initial publicly available data sets for each of those programs in the first half of 2023. So what that means is collectively for ORIC-101 and those next 3 programs, we are looking to put out 5 clinical updates over the coming 6 quarters across those 4 programs. So quite a bit of activity in terms of data that you'll be seeing from our pipeline over the coming 18 months. Beyond that, and this is for those -- a bit of a longer-term horizon. We do, as I mentioned, have the internal drug discovery efforts and have made really nice progress there as well. So beyond 101 and 533 that were homegrown, we also have a whole set of other targets -- programs going after, like I said, both first-in-class and best-in-class opportunities. Two of those were advanced in the lead optimization last year in 2021. We do anticipate that what that allow us to do is that at some point this year, we will talk about one or will unveil one new program or indication later this year. So stay tuned for that. So with that opening, let's dive straight into the programs itself, and I'll ask you to jump over to Slide 8 -- sorry, Slide 9, as we start to talk about ORIC-101. So as many of you are familiar, there's 2 different mechanisms that we are testing with ORIC-101. There's really 2 main big groups of KOLs that have independently stumbled upon the glucocorticoid receptor as a potential mechanism of resistance in cancer. So one of those groups, mainly led by Charles Sawyers, our founder -- one of our founders at ORIC, has implicated the glucocorticoid receptor as a potential mechanism of bypass resistance to androgen receptor modulators in prostate cancer. And so the hypothesis that they put forward is that a selective and potent GR antagonist ought to be able to help resensitize patients who have otherwise progressed on a next-generation AR modulator like XTANDI, for example, but applies to any of the AR modulators as well. The hypothesis, therefore, was to design a GR antagonist and then test that in the clinic. A separate group of KOLs separately have implicated through preclinical work and a lot of retrospective clinical work, the glucocorticoid receptor is essentially a mechanism of resistance to various chemotherapies. In that case, not as a bypass mechanism but really through the impact of the glucocorticoid receptor on various cellular processes like EMT and anti-apoptosis. And so it's really that group of KOLs that have studied the combination of GR antagonist or suggested the study of GR antagonism in combination with various chemotherapeutics. As you can see, these are each indication onto themselves, are very large indications in areas of high unmet medical need. As you go over to Slide 10, you can see that we, of course, completed quite a bit of work in terms of healthy volunteer studies for 101, but now are -- right in the thick of 2 different Phase Ib studies, testing out both of these mechanisms of interest. So one, the combination of ORIC-101 with Abraxane in various solid tumors and then the other one, in combination of ORIC-101 with XTANDI in prostate cancer. Now jumping over to Slide 11, you'll just see overall a trial schematic that outlines for you the key details about the ORIC-101 combination study with Abraxane in solid tumors. As I mentioned, we did present some initial data from this study at ASCO last year. And as I mentioned, in the first half of this year, we'll provide an update on this study as well. We are enrolling patients in 3 tumor-specific cohorts in this study, and those are outlined on the right-hand side of the page, which is PDAC, triple negative breast and ovarian cancer and then a fourth catch-all really for other miscellaneous tumor types. Apart from that -- and I know we'll get into more details on that study during the Q&A with Anupam shortly. So apart from that, on Slide 12, you can see the overall trial schematic for ORIC-101 in combination with XTANDI in prostate cancer. You'll hear as well some very -- you'll notice that we've completed, just like we did with the Abraxane study, a very standard 3+3 design to arrive at the recommended Phase 2 dose. We're now on the thick of enrolling the expansion cohorts in this study and look forward to providing an update in the first half on this study as well. So with that, and I know that we're pressed for time here, so I'm going to leave some of the content around the 101 data that's been presented thus far and kind of what to expect in terms of the upcoming updates. I'll leave those aspects for the Q&A. And so I just want to very quickly touch on the rest of the pipeline before we move over to Q&A. Moving over to Slide 14, you'll just see a few slides to talk you through at a high level why we're so excited about starting here our CD73 program. So CD73 is a target that I think is well known to many. It's obviously a key node within the adenosine pathway. I think after the AstraZeneca COAST data presented at ESMO last year, it has become, I think, widely thought of as a validated target and one that's obviously drawn quite a bit of attention. We think that with ORIC-533, we've come up with a very differentiated approach. One, a molecule with best-in-class properties that is preclinically differentiated from multiple classes of adenosine pathway inhibitors, whether that's small molecule or antibody approaches for CD73 or A2A receptor antagonist. And for that matter, the CD39 inhibitors as well. Now on top of the preclinical differentiation, we also articulated last year somewhere where we're going to be differentiated as well, which is on a clinical development plan. And that's namely to study this drug as a single agent in multiple myeloma, and we'll talk about that very shortly. But first, on Slide 15, this shows you at a very high level snapshot how we think about the space of competitors within the adenosine pathway and how we differentiate quite nicely. This is just one example, but in a number of different preclinical profile and experiments that we've done, this program differentiates nicely on potency. Of course, [ oral bioavailability ] because most of the field is not being able to come up with small molecule [ oral ] CD73. And including as it's been able to differentiate in a high adenosine or high AMP environment as well, which is another key aspect just given the high levels of adenosine that you get in these tumor macro environment. And Slide 16 touches on the rationale. We, at ASH in December of last year, presented along with Dr. Ken Anderson, who's been our collaborator from Dana-Farber on a variety of preclinical experiments, looking at ORIC CD73 inhibitors in multiple myeloma. We were able to, at the ASH conference, lay out a very robust preclinical rationale as to why we and Dr. Anderson and others are so excited to test 533 as a single agent initially multiple myeloma and then eventually in combination therapies would be the plan. And you can see on Slide 16, one snapshot, just one data slide of many that we presented. But in particular, I think the key to draw your attention to here is Dr. Anderson and his lab have come up with a proprietary model that's essentially able to look at ex vivo autologous patient data, so essentially multiple myeloma cells drawn from patients in this proprietary model with a variety of agents that are designed for multiple myeloma treatment to assess the activity of those agents at least in those models. And what you can see on the left-hand side of Slide 16 is that ORIC's CD73 inhibitors were able to achieve something like 40% lysis-ing these models. And on the right-hand side of Slide 16, you can see how that benchmarks, of course, with all the caveats about not comparing across preclinical -- different preclinical data sets, but you can see in the very same model that Dr. Anderson's lab has run, how various approved agents and classes have done in the same models. And obviously, our CD73 inhibitor benchmarks quite favorably. So this is what gets us excited about now studying this in the clinic. And so you can see that on Slide 17, at a high level, the schematic for this 533 study in multiple myeloma. As others have done, we will start this as a single agent initially. But as soon as we see modest activity as a single agent, we would then be quite excited about greenlighting various combination studies for ORIC-533 in multiple myeloma as well. One of the things -- and I just want to pause here for a second, that makes us excited about this is that while CD73 and the adenosine pathways were at larger or crowded path, we think that with 533, of course, we've been able to come up with a molecule that seems quite differentiated, at least preclinically from others. But in particular, with this clinical development plan, we will be the only CD73 inhibitor that we're aware of that is testing a single-agent hypothesis and specifically a single-agent hypothesis in multiple myeloma. We anticipate that the first publicly available data set from this study will be available in the first half of 2023. This study has initiated, and we will now be enrolling through the course of this year and look forward to providing an update in the first half next year. Very quickly on the last 2 programs. I'm jumping over to Slide 19 and talking about ORIC-114, our EGFR/HER2 exon 20 program. And this is a program in a field that I think is, again, a field where a lot of agents have come before us, but I think with suboptimal profiles from our perspective. And really, there's 2 things that matter the most in this field. One is selectivity and that's selectivity for exon 20 mutations versus wildtype. The second thing is brain penetrants. And on the first point, we think that we've got a molecule which we were able to in-license here from Voronoi, which is more selective than the molecules that are either approved or currently in clinical testing. You could see on Slide 19 the kinome tree that shows an explicitly clean kinome tree compared to other [ of the ] molecules. And then moving over to Slide 20, you can see that what that leads to, along with the potency of the molecule, is in head-to-head competition with other clinical stage molecules. The structures are known and against which we profiled, it compares quite favorably in in vivo experiments in terms of tumor regressions and really from the efficiency point of view. This is in the context of not seeing significant body-weight loss and other signs of potential toxicity. Now we've done much other profiling versus other competitors on the selectivity front and on the efficacy front. But I think important to highlight is the CNS activity of this compound. The leading agents in the exon 20 space, whether approved or in clinical development, do not address CNS metastasis. And that's important because 35% of these patients develop CNS metastasis. The majority of these patients progress at their first site of progression in the brain and that's why a brain penetrant compound is so important. On the right-hand side of Slide 21, you see the benchmarking that we've done in vivo versus Takeda's molecule and then in particular, against osimertinib, which is not for EGFR exon 20, but it is considered to be a CNS -- a clinically active CNS compound, and we've been able to effectively show superiority, both of those in in vivo experiments. Most recently, on Slide 22, you'll see some of the benchmarking we've done versus HER2 inhibitor tucatinib. HER2 is another indication of interest for us with this molecule. And what it leads us to is the clinical development plan you see on Slide 23, which is really we filed a CTA for this program at the end of last year in Korea. We're awaiting clearance by Korean FDA and shortly thereafter, we'll initiate the study and start the dose escalation. You can see on the far-right side of Slide 23, the various patient populations that we'll be focused on. Finally, with just a couple of minutes remaining, let me give you the quick headlines on ORIC-944, our PRC2 inhibitor. This is one that we in-licensed from Mirati in October of 2020. There's various reasons why PRC2 inhibition via EED ought to be superior to EZH2, and you can see it on the right-hand side of Slide 25, but I think easier is to show you the data. The right-hand side of Slide 26 shows you a head-to-head with tazemetostat. This is an DLBCL model, and you can see how this molecule outperforms that model. But in particular interest to us, of course, just given our focus on both precision oncology and hormone-dependent cancers is what you see on Slide 27, which is running this model in experiments in enzalutamide-resistant prostate cancer models. And you can see quite good tumor growth inhibition demonstrated in both of these models. And these are models where competitors cap out at about 40% to 45% tumor growth inhibition. So we will be starting this agent shortly in the clinic. The IND was cleared by the FDA at the end of last year. We're now in the process of starting up site initiations and then enrolling -- and then shortly thereafter enrolling patients as a single agent in prostate cancer and you see that study design in Slide 28. So you can see a lot of activity in a very short amount of time. And like I said, we've built up one of the most exciting pipelines we think in small-cap biotech as outlined on Slide 30 and as I just talked to you about. And what it leads us to is on Slide 31, really just setting the company up for a quite a bit of, obviously, operational activity in 2022 and beyond across this pipeline. But one that we said, like I said, is going after both novel targets as well as validated targets with either first-in-class or best-in-class approaches, utilizing the precision oncology angle to do it, hopefully, with the accelerated clinical time lines. And at the bottom of Slide 31, you can see articulated the various milestones that we see coming out over the next 18 months or so. So again, at a high level, 5 data updates over the next 6 quarters for these 4 programs. So let me wrap up there in terms of the slides and prepared remarks and then open it up to Q&A from Anupam and others.

Jacob, you want to introduce the broader team on the line?

Sure thing. I'm joined today by Dominic Piscitelli, our CFO.

[Operator Instructions] We do have one question in the question portal which is for the ORIC-101 updates. Are those both going to be at the same time or staggered? And will they be at a medical meeting?

Great question, Anupam. So we have not given guidance on that. We want to sort of preserve maximum flexibility for ourselves. So right now, the guidance is that we'll provide those updates in the first half of this year, could be at a medical meeting, could be outside of a medical meeting and maybe at the same time or separated. It kind of just --really what it comes down to is when we've accrued enough patients and followed them for a long enough period of time that we can make those go/no-go decisions, we'll, at that point, give those updates. And if it lines up at the same time and at a medical meeting, that's great. But if not, we don't want to be bound by that.

Okay. How are you thinking about refining sort of the biomarker GR cutoff strategy here based on the data you kind of know to date?

Yes, that answer, I think I would bifurcate, Anupam. It depends on the study. So let's start with the Abraxane study. On the Abraxane study, I would say that the exercise is a little bit simpler than it is on the prostate study in terms of the translational effort. And the reason I say that is because essentially on the Abraxane side, it's really just a question of what's the right GR cutoff level to use. And so that, I think, is just -- that will be determined once we again have a big enough data set. We can look back respectively of that data set, try to correlate that to where we're seeing activity and then decide using an [ IHCA ] score, which, as you probably know, there is a continuous score anywhere from 0 to 300. That's the right cut off. That kind of could be the same for various solid tumors or maybe it's different. We'll have to kind of see what the data set suggests. I think one thing that we have learned already is that pancreatic cancer PDAC tends to be incredibly GR positive. So there may not be a need to select patients for GR status with pancreatic cancer because of how positive PDAC tends to be. For ovarian and triple-negative breast, my guess is we will need to do a selection exercise. And so that will be part of the exercise we do by looking retrospectively. On the prostate side, the reason it's a bit more complicated is there is a question of what's the right GR cutoff level. But on top of it, as part of the translational effort, we also identified a couple of areas that -- a couple of subset the patients we would want to select out. And by that, I mean patients that show markers of lineage plasticity. In other words, they're kind of on their way to neuroendocrine differentiation, or patients with various AR resistant variants. The best example of that is the AR-V7 splice variant where you wouldn't expect enzalutamide to work in those patients anyway. And so that translation exercise, we've actually done the bulk of the heavy lifting last year to identify those selection -- or the exclusion areas that we would probably be selecting patients out for. We're still kind of TBD on what's the right GR cutoff level. But again, looking retrospectively at the full data set, we ought to be able to determine that.

And on the solid [ tumor ] side, last year and even just now, we talked a lot about pancreatic cancer as a potential really interesting indication. So what are the gating factors to better understanding a more fulsome strategy in pancreatic specifically?

Yes. Pancreatic, the reason we highlighted that one in the ASCO update last year was it was the fastest enrolling of the cohorts on the solid tumor side. It enrolled faster than TNBC and ovarian, and that's continued to be the case. So I think when we give the update in the first half this year, almost certainly, that will be focused on pancreatic. Pancreatic, the benchmarks are really clear. I mean basically, the agents that are approved are on the NCCN guidelines for second-line pancreatic cancer. It gets you 3 months of PFS. In the third line, nothing is approved, but what gets used from the NCCN guidelines gets you about 2.5 months of PFS, and it only gets worse from there. So in this patient population, where we're enrolling for the most part, third line and worse, meaning later line patients, if we were able to see something along the lines of 3-month PFS, or in other word, a benchmark you've used for an approved agent in the second line, that's probably something that would get us excited from a PFS perspective. So from a signal-seeking perspective, Anupam, really the point here is to accrue enough patients, and we think we ought to have 20 or so patients by the time we do this update and have them followed long enough that we can say either yay or nay, we're seeing the signals and achieving the thresholds that we're aiming at or not. And that's something that it was just too early to make that decision last year because we have just started the expansion cohorts. Some patients were still ongoing. And it's a -- and the end was too small to form any definitive decisions, but we ought to be in a position to make that go/no-go this year, like I said.

I mean an interesting discussion that I think has evolved here is whether you're talking about pancreatic cancer or prostate cancer, for example, what is the sort of importance of prolonged stable disease, say, versus traditional responses in -- on the key end points, as we think about next steps, right, ORR versus PFS or OS or something like that. How do you think about the stable disease context versus traditional responses?

Yes. Yes. What I'd say there, Anupam, is I think investors and even companies have been sort of conditioned in some ways by the targeted therapy paradigm where in a Phase 1 study, you can just simply look at ORRs and sort of use that for purposes of accelerated approvals and whatnot. I'd say that ORIC -- and that is certainly relevant to EGFR exon 20 and some of the other things that we're doing in the pipeline that are more targeted therapy oriented. But for ORIC-101, it's very traditional drug development. And if you think about the FDA approval paradigm for something like or an agent like ORIC-101, almost certainly if we're in registrational studies, the endpoint is going to be a durability base like PFS or eventually overall survival. But PFS is what we'd be focused on in these late-line patient population as opposed to ORR. And that just has to do with the population itself, the fact that they're late line, the fact that we're treating them with agents they've already progressed on. So every one of these patients in the Abraxane study has already progressed on a taxane-based therapy. Every one of the patients in the XTANDI study has progressed on XTANDI and you're throwing ORIC-101 on top of that. So these endpoints are almost certainly if we are in registrational studies at some point are going to be PFS-based endpoints as opposed to ORR.

Got it. Maybe switching gears a little bit to ORIC-533. You told us that we should be expecting data in the first half of next year. So I guess what are the reference benchmarks to consider here for the initial data that would get you excited in the context of the population that you're enrolling to be like, look, we're going single agent expansion, we're going to go move forward with combos.

Yes. So I think the way I think about it, Anupam, is the multiple myeloma development landscape, I think, has been well trodden, and there's a pretty clear path to follow, and I don't think we'll be dramatically different than others that have come before in terms of how we think about A, B and C in terms of that development strategy. So we'll start now as a single agent with 533. This will be a triple-, quad-, penta-refractory population, if they'll have exhausted the typical standard of care regimens before they get to us. I would be looking for a modest single agent response rate, call it, 15% to get excited about moving into various combinations. And I'll talk in a second about what those combinations might be. But there is -- every agent that's been approving myeloma has typically also gotten a single agent approval as well. That tends to come with a higher -- a slightly higher response rate threshold, call it, 20%, 25% plus response rate. So we very much are thinking of this as a dual-prong strategy. Start as a single agent, but as soon as you see some modest single agent activity, we would want to start exploring the combination approaches. We've been asked by folks what's the most likely combination candidates. We've had lots of discussions with Dr. Anderson at Dana-Farber about it. He's, as I mentioned, he's been our collaborator on this. I think the general consensus is you probably have to combine with each of the 3 traditional classes, so the anti-CD38, the proteasome inhibitor and an IMiDs. Could even potentially think about BCMA or CAR-T combinations just given that you don't predict that this molecules can have very much in the way of toxicity and so ought to be quite combinable and that those are things that ought to just be elucidated in the clinic. So I think that the path here is walk before we run, start and see if we see some modest single agent activity, but as soon as we see that, start getting ready for some combo work.

We've got a question in the portal, which is, "You brought in 114, 944 through business development. So is the focus right now basically on the internal -- the pipeline as it stands now? Or are you going to further supplement the existing pipeline via BD."

Well, I'll tell you that the goal is, is to continue supplementing through external BD as well as the internal discovery efforts. What's in our control is the internal discovery efforts, of course, because as I mentioned to you, we progressed 2 programs from the internal discovery pipeline into lead optimization last year. We're hoping that the first of those programs can have an IND as early as next year, if not that, then first half 2024. One of those is for a target that is a validated target. I guarantee you people will know the target because there's at least one public company that gets a decent amount of valuation for that, but we think we have a better approach. And then the other one is for a first-in-class target that's probably novel to a lot of folks. So we -- we're hoping to keep building pipeline with a combination of both novel and validated targets. The reason I said that's in our control was clearly internal discovery, we can kind of be masters of our own fate there. On the BD side, we've been looking -- so I want folks to keep one thing in mind, which is we were looking for programs on the BD side since mid-2019 when we were a private company right after our Series D because I thought this is a high-capacity team that can handle it. And we looked for 5 quarters, did diligence on over 100 compounds before we identify them and brought under MTA the 2 that we transacted on, 1 in August of 2020 from [ Radi ] and then the other in October of 2020 from Voronoi. So we do deep diligence on the BD side, and we've continued to have BD discussions ever since October 2020 to today. So over the last 5, 6 quarters, we've had, again, dozens and dozens of conversations but not pull the trigger on anything on the BD side because nothing has cleared the bar of those clinical differentiation -- preclinical, I should say, differentiation, clear path on the clinical side we were excited about and met our economic terms. So we've got a very, very high bar in BD, but we're continuing to look.

Maybe just quickly, cash position and runway.

Yes, I'll take that one, Anupam. So we ended the year with $281 million in cash and investments. And based on our current operating plan, that funds through into the first half of 2024. And just to provide a little more specificity around that guidance, that is a fully burdened nonrisk-adjusted number. So that does assume that all 4 of our clinical programs as well as our early-stage discovery programs are moving forward. So as Jacob highlight it before, that does give us the runway to kind of turn over a number of clinical updates on our -- across our portfolio.

To put a final point on that one, Anupam, is what Dominic means by a full-success scenario is that if one or more of the programs we just talked about has attrition and comes out of the pipeline, that runway extends. So we feel really good about the pipeline we've got, the value inflection points that we think are coming over the next 6 quarters. Our ability to just be aggressive on both the internal discovery front and the external BD front, all with a very well-funded balance sheet.

Okay. Jacob, Dom, I want to thank you guys so much for a super productive session. And I hope you guys have a good rest of the conference.

Likewise. Thanks for having us and thanks for the great questions.

Thanks, Anupam.