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

Welcome, everyone, to the 39th Annual JPMorgan Healthcare Conference. My name is Anupam Rama. I'm one of the senior biotech analysts here at JPMorgan. I'm joined by Matt Bannon and Tessa Romero from the team. The next presenting company is ORIC. And presenting on behalf of the company, we have CEO, Jacob Chacko. [Operator Instructions] With that, I'll turn it over to Jacob.

Thanks, Anupam, and thanks for having us to present at the conference. Good afternoon, everybody. So I'll begin by quickly going through about 20 minutes of prepared remarks and slides, which you've got available to you. And starting on Slide 2, just mention that I will be making some forward-looking statements today. After that, we'll open it up for 20 minutes of Q&A. So starting on Slide 3. At ORIC, our name encapsulates our mission. So ORIC stands for overcoming resistance in cancer. And that really describes the entire pipeline of novel therapies that we've developed, both internally sourced as well as externally sourced, at ORIC devoted to a number of different mechanisms of resistance, innate, bypass and acquired resistance mechanisms that have plagued various oncology pathways. We're quite proud of the team that we've assembled at ORIC. So we have an experienced leadership team that I personally have known for over 30 years and has worked together in multiple prior contracts at successful oncology companies like Ignyta, Medivation, Aragon and Genentech. Under that team's leadership, we've been able to advance a broad pipeline of programs, first and foremost, ORIC-101, our lead program, which is a selective and potent glucocorticoid receptor antagonist, which is currently in two different Phase Ib studies, essentially evaluating two different mechanisms -- two distinct mechanisms of action that we believe lead to oncology resistance. I'll talk more about those two studies a little later in this presentation. But beyond that, we have also, as I mentioned, through both internal discovery efforts and also external strategic in-licensing, broadened our pipeline with 3 additional programs that we expect INDs in the course of this calendar year. And so that really has enabled us to set ourselves up for multiple upcoming catalysts in calendar year 2021, namely two different data readouts from our lead program, ORIC-101, one of those in the first half of the year, the other in the second half of the year, and then like I mentioned, 3 INDs or equivalents in 2021 for other programs that are targeting novel mechanisms of resistance. Beyond that, as many of you know, we IPO-ed in April of last year and also completed our first follow-on offering last year. So that's put us in a strong cash position with the cash runway into the second half of 2023. So moving over to Slide 4. We're quite proud, as I mentioned, of a broader leadership team at ORIC that we've brought together, that has expertise in all aspects of building a leading pre-commercial oncology company. Really that starts with distinguished founders that worked together previously at Memorial Sloan Kettering as physicians and scientists as well as Aragon, which is devoted to hormone-dependent cancers. But beyond that, we've built a broader ecosystem as well. So we've got full preclinical discovery research capabilities under the leadership of a team that we largely recruited out of Genentech, which had worked together previously there. We also have full development, clinical and regulatory capabilities, and that team is largely a team that we recruited out of Ignyta and Aragon, who had worked together previously in those settings. And then finally, we also have extensive BD and strategic in-licensing capabilities from a team that had worked together previously in Medivation and Ignyta. So as you can see, we took these prebuilt teams, stitched them together into a broader ecosystem at ORIC, and that's really given us the full slate of capabilities to be able to execute upon our mission. So on Slide 5, stepping back for just a second. As you look at successful oncology business models over the last several years, they have tended to focus either on building their pipeline through internal discovery efforts or through external BD and in-licensing efforts. And you can see some examples of those 2 business models here on Slide 5. On Slide 6, what you'll see is that at ORIC, we have really -- because of the full slate of capabilities that we've brought together under one umbrella at ORIC, we've really been taking approach to building the pipeline that is source agnostic. So essentially best molecule wins, whether that molecule is discovered internally at ORIC or whether we source it externally through in-licensing. Either way, best molecule wins, but that's really enabled by the special team that we've brought together with all the different capabilities at ORIC. And so as you then look at the oncology landscape and sort of what's fair game, one thing that we are very clear to ourselves is what's in and what's out. And what I mean by that is on Slide 7. So owing to the team that we've brought together here with founders who are experts in hormone-dependent cancers, a clinical team that are experts in precision oncology and a preclinical research team who are experts in key tumor dependencies, every program in our pipeline, whether it's internally sourced through the discovery efforts of the company or externally sourced through business development, must check at least one, if not multiple, of these areas of expertise for us to be interested in that program. And so that's what you see reflected on Slide 8, as you look at the overall pipeline, which is a pipeline that adheres exactly to those key areas of expertise. And as I mentioned, it's both internally sourced and externally sourced. So ORIC-101 is our lead program, as I mentioned, a glucocorticoid receptor antagonist, which has now over the course of the last year, picked the recommended Phase II dose for 2 different studies -- studying 2 different mechanisms of action. And that is now in the part 2 of the Phase Ib studies, the expansion cohorts for those 2 mechanisms of action. So I'll talk a little bit more about that program. Beyond that, through the internal efforts of our discovery team, we also have a small molecule, orally available inhibitor ORIC-533, which we plan to file an IND in the first half of this year. And then as I mentioned, through our external BD in-licensing activity, we've also, in the last 6 months, brought into the pipeline, ORIC-944, which is an allosteric PRC2 inhibitor targeted at prostate cancer; and ORIC-114, which is a selective and potent brain-penetrant exon 20 insertion mutation inhibitor. And that we plan to file an IND for both 944 and 114 in the second half of this year. So in other words, 3 INDs over the coming 12 months. Beyond that, we also have an internally sourced discovery research set of programs. The lead program of those, we advanced a lead optimization in the last few months. So as you can see on Slide 9, there is a tremendous amount of activity across that full pipeline in 2020, as we advance ORIC-101 to selecting the two different recommended Phase II doses that I'll talk about a little bit more today. And then also both through internal efforts and external sourcing, advance ORIC-533, 944 and 114. And we hope that, as you see there on the expected milestones for this year, not only to have the 2 readouts for ORIC-101 for the 2 different programs, but also 3 INDs or IND equivalent filings later this year. What that ultimately sets us up for is that this same time next year, in early 2022, we hope to have 4 clinical programs targeting these multiple novel mechanisms of resistance. So we're quite proud of the progress in 2020 and look forward to an eventful 2021. Now let me switch for the rest of my time and really focus mostly on ORIC-101, our lead program. And so if you go over to Slide 11, I'll start talking about this mechanism of resistance, which is targeting the glucocorticoid receptor as a mechanism of resistance to 2 different types of cancer therapies. So the left side of Slide 11 shows you really what we view as the problem statement, which is looking at this analysis by IHC of various tumor types. You can see the GR, the glucocorticoid receptor is overexpressed at varying degrees across multiple different tumor types. The reason that this matters is on the right-hand side of Slide 11, which is this is a retrospective analysis done on patients with ER negative breast cancer, but you can see the same pattern retrospectively looking at endometrial cancer and then Charles Sawyers, one of our founders saw the same pattern in prostate post enzalutamide, which is that retrospectively, when you look at these patients, bifurcated into those who are GR high versus GR low expressers, you see a meaningful difference -- a meaningful separation in the survival curves between those two populations. So that's what got us excited originally to target the glucocorticoid receptor for our lead program, ORIC-101. Now on Slide 12, you can see, as I mentioned earlier, that there are two different distinct mechanisms of action that KOLs have advanced, both of which implicate the glucocorticoid receptor. So on the left-hand side of Slide 12, you see just a snippet of some of the papers in academic literature, which was generated around glucocorticoid receptor acting as a bypass mechanism to anti-androgen therapy in prostate cancer. And essentially there, what has been hypothesized is that when the AR modulators shut down androgen receptor signaling, essentially the glucocorticoid receptor is upregulated and takes over for that AR signaling, acting upon a very similar set of downstream targets as the androgen receptor would have done. In the case of -- on the right-hand side of Slide 12, you see a different set of KOLs advanced some hypotheses around the glucocorticoid receptor binding to transcriptional targets that impact cellular processes like EMT and anti-apoptosis. Both of these groups of KOLs essentially hypothesized that a glucocorticoid receptor antagonist might be able to reverse those mechanisms of action as they relate to oncology resistance in these two different indications. And as you can see at the bottom of Slide 12, both of these indications individually are quite large. So this was obviously a great interest to us. And is what really was the catalyst for us at ORIC, developing GR antagonist and now putting that into studies to evaluate both of these mechanisms of resistance. I'll very briefly refresh just on some of the preclinical rationale here. So Slide 13 shows you, in the case of prostate cancer, what Charles Sawyers and his colleagues observed, which was looking at clinical samples of patients treated on enzalutamide and then evaluating those patients, both at baseline as well as after 8 weeks of enzalutamide therapy, what they observed was that the glucocorticoid receptor was overexpressed in patients who had a poor response to enzalutamide even at baseline, but even more pronounced than that and more notable was after 8 weeks of enzalutamide therapy. So after the pressure that enzalutamide was putting on the androgen receptor, you see even more pronounced overexpression of the glucocorticoid receptor as a bypass mechanism after those 8 weeks of therapy. On Slide 14, very briefly on the chemotherapy side. As I mentioned, glucocorticoid seemed to, at least based upon preclinical evidence, essentially apply a pro survival phenotype onto tumors. And that takes place for a variety of different cellular mechanisms like EMT, apoptosis, adhesion and stemness. So the theory of the case, as you can see on the right-hand side of Slide 14, in the bottom row is that with a glucocorticoid receptor antagonist like ORIC-101 on board, you are essentially able to reverse those mechanisms of resistance and thereby make the tumor more amenable to standard cytotoxic chemotherapy. So with the theory of why it made sense to come up with the GR antagonist, the company then got started from internal resources developing from scratch a glucocorticoid receptor antagonist. And that is now ORIC-101, our lead program, which you can see on Slide in 15. In here, it's profiled on a variety of different characteristics that matter for overall oncology therapies, and then compared to a competitor that has 2 -- 3 different molecules actually in different GR studies today. And what you can see is, namely, we were able to come up with a molecule ORIC-101 that is incredibly potent against the GR -- against the glucocorticoid receptor, as you can see by the IC50s, but lacks some of the CIP liabilities that have played competitor molecules. Now ultimately, as you then look at some of the preclinical evidence on both Slides 16 and 17, which I won't go through for the sake of time today, but you can see on Slide 16, some of the highlights of ORIC-101 in studies in in-vitro models of prostate cancer and essentially the ability to resensitize those models to enzalutamide therapy after they have become resistant. And then on Slide 17, you see a similar type of model looking at preclinical, in this case, in-vivo model of triple-negative breast cancer xenograft, where you see good tumor control with paclitaxel in that xenograft up to a point, but then eventual escape. But with ORIC-101 onboard, you see almost flat lining of that model. And so that really gave us the confidence then a few years ago to launch what you see on Slide 18, which is a pretty comprehensive clinical development plan exploring both of these mechanisms of action. The left side of Slide 18 has now been completed, which is a series of different healthy volunteer studies, establishing a single agent profile of ORIC-101, which showed good PK properties, good target engagement and overall, a very well-tolerated profile. Really what we spent the bulk of calendar year 2020 doing was then pushing that forward into a Phase Ib two different dose escalation studies. And the output of that was that we recently selected the recommended Phase II dose for the Abraxane combination study and we announced just yesterday that we've selected a provisional recommended Phase II dose for the prostate study as well. So I'll talk about those in a second. But the plan now is then if you go to Slide 19, is to start expansion cohorts in both of those studies. So Slide 19 shows you that the overall design of the prostate program, the Phase Ib part 1, as I mentioned, is the left side of Slide 19 and that has been completed, which was a very rapid dose escalation. So really over the course of calendar year 2020, we dosed our first patient in the prostate study and then escalated that through 3 different cohorts and ultimately selected 240 milligrams daily of ORIC-101 in combination with the standard dose of enzalutamide 160 milligrams daily as our recommended Phase II dose -- provisional recommended Phase II dose. And that really will be confirmed by the Safety Review Committee Meeting, which takes place next week. After that, we'll start the expansion cohort enrollment here in an unselected patient population, looking at a variety of different GR statuses. And the intent of that is to do an initial readout of this study, but the early expansion cohort data as well as the escalation data in the second half of 2021. If you move over then to Slide 20, this is the trial schema for the Abraxane study. And you can see a very similar design here. The left-hand side of Slide 20 the part 1 of the Phase Ib has already been completed, which took place over the prior 6 quarters, during which we escalated through 5 different cohorts, ultimately picked a recommended Phase II dose of 160 milligrams of ORIC-101 dosed continuously, and then in combination with the weekly -- standard weekly regimen of Abraxane -- 75 mg per meter square of Abraxane on a weekly regimen. We have now picked the recommended Phase II dose there, as I mentioned, and now started the expansion cohorts, which are in three specific -- three tumor-specific baskets, pancreatic ductal adeno carcinoma, PDAC, ovarian cancer and triple negative breast, and then a fourth basket, which is really more of a catch-all miscellaneous for other tumor types. And so that expansion cohort study is ongoing at this point. It was started about a month ago. We plan, as we put out in our release yesterday, to have some initial data from both that dose escalation study as well as the early expansion cohort data at a medical conference in the first half of this year. So quite a bit of activity on ORIC-101 evaluating both of these mechanisms of action. And as we said, an eventful 2021 that we have planned in terms of the first data that will read out from both of these studies. With my remaining time, I'm just going to touch very briefly on the remainder of the pipeline. So if you go over to the Slide 22, starting with ORIC-533, which is our small molecule oral inhibitor CD73 really, the left-hand side of Slide 22 shows something, which I think has now been widely demonstrated, which is really the advantage of small molecule inhibitors of CD73 over the antibody approaches to shutting down adenosine production in these models. And so that's where ORIC and this newer generation of company's largest small biotechs has really started to focus our efforts, which is on small molecule oral inhibitors. In 2020, we really made a lot of progress on this program in a number of different fronts. But primarily, if you look at Slide 23, in the first half of 2020, we were able to demonstrate the differentiation of ORIC-533 versus other small molecule inhibitors of CD73 namely in terms of potency, but -- and also having slow off rate. But also, as you can see on the right-hand side of Slide 23, in a high A&P environment, being able to maintain that potency, which is a very important and experimental condition in these tumor microenvironments. In the second half of 2020, we then really focused a lot of our attention on an outside KOL collaboration, looking at the activity of ORIC-533 in patient-derived models as a single agent, really with the intent of coming up with not only differentiated preclinical profile I talked about, but also differentiated clinical development path potentially. And we're happy to announce that after seeing some compelling data out of those -- out of that KOL collaboration, we've now committed that after filing the IND for this program in the first half of this year, we intend to pursue a single agent development path for ORIC-533 in that undisclosed tumor type, of course, undisclosed for competitive reasons. Switching gears now to our third program. Going over to Slide 26. I'll just mention very briefly, ORIC-944, which is our allosteric PRC2 inhibitor. This was the program that was the culmination of about a year's worth of dialogue with Mirati Therapeutics. Mirati had done a nice job -- the preclinical team at Mirati had done a nice job of coming up with a very differentiated PRC2 inhibitor that was targeting the EED subunit of PRC2. Really with two big advantages, as you see on Slide 26. One was a biological advantage over the first-generation approach, which is the EZH2 inhibitors in the sense that there are some biological advantages related to essentially preventing bypass mechanisms of resistance that made a lot of sense to target EED. The second advantage of the molecule that Mirati came up with -- that the scientists at Mirati came up with was its drug properties. And as many of you know, the EZH2 inhibitors have had poor drug properties, but this program from Mirati on the EED side was able to come up with a differentiated profile. As I mentioned upfront, we know our areas of expertise and 1 of those areas of expertise is hormone dependent cancers. And so 1 of the things that we did was establish an MTA with Mirati, and you can see some of the results of that on the right-hand side of Slide 27, where we put this molecule into enzalutamide-resistant prostate models, which, of course, is 1 of our areas of expertise. And you can see very compelling preclinical evidence as a single agent on the right-hand side on Slide 27, where we're seeing 85% TGI in this very difficult enzal-resistant prostate model. And so this is what got us excited to develop ORIC-944 initially in prostate cancer. So we're going through a standard IND-enabling work this year and the intent is to file an IND for this program in the second half of this year, after which we intend to study it initially as a single agent in prostate cancer. And then finally, I'll just touch very briefly on ORIC-114, which is our brain-penetrant EGFR HER2 Exon 20 inhibitor program. This was again the result of in-licensing activity that took place over the last 6 months. We announced in October of last year, the culmination of a year's worth of dialogue that resulted in this program. For many of you who know the targeted therapy space, you know that outside of KRAS, Exon 20 insertion mutations are probably the largest population of patients in a targeted therapy indication that does not have an approved therapy today. One of the things that we looked at are really two things that we looked at in prioritizing as we looked across that landscape was, one, finding a molecule that was selective for Exon 20 insertion mutations over wild type, which has been a challenge of the other players in the field. The second, which has really been a challenge for every single player in that field, has been finding a molecule that had CNS activity, which is quite important given the prevalence of CNS metastases in this patient population. And so we feel like we were able to find a really special asset in ORIC-114, which was developed by the South Korean company, Voronoi, really had optimized across both of those fronts that I mentioned. You can see on Slide 29, the kinome selectivity screens will show an exquisitely clean molecule. And then on Slide 30, ultimately, across the two dimensions that I mentioned, the left-hand side of Slide 30 shows you in vivo model with activity that's comparable to the leading player in the space at 1/10 of the dose. But importantly, on the right-hand side of Slide 30, not just systemic activity, also very compelling intracranial activity, again, here at 1/10 of the dose of the leading competitor in the space. So we're quite excited about this molecule as well. The plan is to file an IND equivalent, really CTA in South Korea in the second half of this year, after which this will enter the clinic as well. So just wrapping up on my prepared remarks, if you go over to Slide 32, you can see a really robust pipeline of novel therapies that we have advanced in ORIC through this novel strategy of both internal sourcing through our discovery research efforts, but also external sourcing through really strategic in-licensing transactions on the business development front. And it set us up for a very eventful calendar year 2021. So as you look at Slide 33, quite a few milestones this year that we expect, the two different readouts for ORIC-101, the Abraxane combination in the first half of the year, the prostate combo in the second half of the year; and then, of course, 3 INDs or IND equivalents throughout the remainder of the year as well with 533 in the first half of the year and then 944 and 114 expected INDs or IND equivalents in the second half of this year. So lots of activity, really, really busy 2020 that we just concluded, but probably an even busier 2021 that we're looking forward to. So with that, I'll pause and turn it over to Anupam for questions.

Great. Thanks so much. And I wanted to just remind the folks on the webcast, if you want to ask the question, just send it through the portal, and I'm happy to ask on your behalf. Jacob, you want to introduce the broader team on the line here, and we can get started.

I will. Yes, I'm joined for the Q&A by our CFO, Dominic Piscitelli.

Great. So Jacob, maybe a quick strategic question, right? In your slide presentation, you talked about your external business development capabilities as well as kind of your internal. But the last 6 months, a year or so, we've heard a lot more about sort of the external business development. How do we think about continued external business development? And is 2021 kind of the year where we might hear a little bit more about what you've got going on in the internal pipeline?

Yes. Yes, it's a great question, Anupam. So we're really proud, as I mentioned in my prepared remarks, really proud of the ecosystem that we brought together to work under umbrella. And I think you'd be hard-pressed to find another company that -- of our size and stage that's been able to do the same thing, namely stitch together these distinguished founders with preclinical capabilities, with clinical capabilities and also with really differentiated external strategic in-licensing capabilities. And so it was really with the team we brought together that we decided to take a source agnostic approach to building the pipeline. And that's what resulted in the two different in-licensings that we did last year. Now all of that said, if you look at the activity that's really placed us in a position where 2021 has probably got to be a year of operational execution on the pipeline that we've got because there's obviously a heavy lift to do the two initial readouts for ORIC-101 well as the three INDs or IND equivalent filings that we're doing for the other three product candidates. And so I would be surprised if you see us announce here any other BD transactions in this calendar year. It's probably -- that's probably more of a, call it, 9 to 12 months or later type timing that we'd look to for any other further in-licensing. The 1 caveat I'll say, though, is if you're doing BD correctly, these things take a long time to develop. So in the case of ORIC-114 from Voronoi, in the case of ORIC-944 from Mirati, from the initial dialogue to actually consummating those transactions took 12 months, almost exactly to the day for both of those. So if we start conversations right now, and we're actively looking right now for other new differentiated programs, that will take 9 to 12 months to be able to execute one of those.

And maybe talk a little bit about ORIC-101 -- sorry, is there an echo?

No, I can hear you just fine.

So on ORIC-101, so are you thinking about sort of an AACR or ASCO type of update? You talked about having the solid tumor update in the first half at a medical conference. And I guess since this is the initial readout, what level of sort of efficacy would kind of get you excited, right, given it's a heterogeneous population and probably heterogeneous in terms of GR status as well. So how do we think about that?

Yes. Yes. So for the Abraxane readout in the first half of the year, Anupam, and this applies frankly to the enzalutamide as well, philosophically as a company, we like to use high-profile medical conferences for purposes of these kind of readouts. So that's why we've said that with the Abraxane initial readout in the first half of the year, people should expect either AACR or ASCO is the venue that we would like to present that data in and keeping in mind that ASCO tends to be the one that's a little bit more clinically oriented, that's probably higher on the list in terms of where we present that data. That helps set expectations for that data. And I always cringe a little bit when people start to look for efficacy and ORR percentages in dose escalation type data from a Phase Ib. But essentially, we think of this as hierarchies of things that we need to see and to prove from that data. So overall, to set expectations, this will be a combination of dose escalation data as well as the early expansion cohort data. We're expecting approximately 25 patients' worth of data across those two and think about it as roughly half and half, half from the dose escalation portion, half from the expansion cohort portion. And so I think, first and foremost, we've been talking about for now the better part of the year, the benefits of developing a GR antagonist from scratch, that doesn't have the same CIP liabilities as a competitor compound that was essentially repurposed from endocrine. So I think, first and foremost, people will need to look at the sum total of our dose escalation data and our expansion cohort data see that we're able to prove that. Do we have a better, safer, better tolerated profile? Are we able to get better exposures from a PK perspective, a better target engagement from a PD perspective than our competitor compound? And I think one thing that you can probably even start to read into it is we've selected a recommended Phase II dose of 160 milligrams daily of ORIC-101 without prophylactic GCSF. The competitor is using prophylactic GCSF in order to manage those drug-drug interactions. And so that should be an early indicator of what we're hoping to be able to demonstrate at least in terms of that first set of boxes, as I mentioned. Now beyond that, as you talk about kind of -- I know your terminology of a win scenario.

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Yes, yes. What we'd really like to do from a win scenario perspective, ideally is be able -- as people start to focus in on the expansion cohort patients, namely the patients treated at the recommended Phase II dose, which keeping in mind, we're not selecting for GR status. Although we'll retrospectively be looking at GR status, amongst those, call it, dozen or so patients, they're ought to just proportionately be some who are GR positive. And we'd love to be able to see in some of those patients anecdotally who are GR positive, who you would not otherwise expect to see a response, see some signals of anti-tumor activity. And what I mean by that phrase that you wouldn't expect to see a response otherwise is clearly, this is not a randomized study with a control arm, but one thing that we have done for the Abraxane study to make it as meaningful as possible is that in the expansion cohorts, we're seeing that the patients must have had a prior taxane-based regimen and progressed. And so that will help make that data as interpretable as possible in that if you have some -- if you have patients who have progressed on a prior taxane-based regimen, who then some subset of them are GR positive, we can look at those patients and see if we're seeing antitumor activity that really ought to be due to ORIC-101, not just some kind of retreatment effect with Abraxane.

We have a question in the e-mail portal here, which is, can you give us an update on the competitive landscape for GR antagonists, and what they've seen in solid tumors? And what drives the differences between your molecule and the competitive landscape molecules?

Sure. So let me start with just what drives the differences and then talk about what the competitor has been able to show so far. So we have talked a lot about us developing a molecule from scratch. That was every bit is potent against GR as the competitor molecules, really all the competitor molecules, when we talk about those come from a company called Corcept Therapeutics. Corcept has done a great job of advancing various GR antagonists for endocrine purposes. They're now also studying those in oncology indications. And so they have strong GR antagonism properties in those molecules, just like ORIC-101 does. But with ORIC-101, we don't have same liability across CIP 2C8, which is critical to the metabolism of taxanes and enzalutamide. And our competitor compounds, we believe, do have that liability. And so that's where we predicted that we ought to be able to dose RGR antagonist to get a higher exposure without those same kind of drug-drug interactions. The course of despite the potential liabilities of their CIP 2C8 liability and what that has meant in terms of what we believe is a suboptimal recommended Phase II dose that they've had to move forward with in their Phase I, they showed some good signals of activity. So they showed responses in PDAC, pancreatic ductal adenocarcinoma, as well as ovarian cancer as well as some other tumors, where they saw responses in pretreated patients, meaning patients who had had a prior taxane-based regimen where you wouldn't have expected to see those responses. Now they also showed a safety profile that was really challenging, where, for example, neutropenia was at the very top of the list, and that's a very clear Abraxane-related side effect and could be due to the fact that they're seeing so much neutropenia could be due to the fact that they're having drug-drug interactions, and that's why they've had to use prophylactic GCSF. So in summary, what they've shown so far was decent activity on the activity side and efficacy side, but really with some major safety and tox liabilities. Now what that activity, I think, then enabled them to do was go straight from a Phase I study in PDAC into a registrational study in PDAC, which they started in the middle of last year. And then also a randomized ovarian study, a Phase II study in ovarian, and they plan to have data from both of those studies in the first half of this year, which obviously, we're going to be watching quite closely and eagerly to see if that upholds what they were able to see in the Phase I.

Got it. Another question in the portal here is, on the Exon 20 program, what's the therapeutic index versus wild-type eGFR and as compared to the competition, specifically Takeda?

Yes. So it's impossible if I'm to quote a point estimate for -- in answer to that question. I mean I think this is something that all the companies in that field go through great lengths to try to quote the therapeutic index of Exon against Exon 20 insertion mutations versus wild type, really to see if you've got a window to be able to get activity against those Exon 20 insertion mutations without the rash and diarrhea that you're seeing from companies like Takeda and Spectrum with the leading molecules in the space. The newer generation of companies like Black Diamond and Cullinan and ourselves, our touting molecules that we believe are selective. As we -- as part of our diligence when we diligence this molecule and looking at some of the work that Voronoi did, both oral and we focused on the most common Exon 20 insertion mutations, and there's really 4 of them that drive about 50% to 60% of the total patient population. And across the most common Exon 20 insertion mutations, we had a window versus wild-type of at least multiple -- at least multiple fold to much higher than that. And so we feel that there is a therapeutic window there. The other thing that I think is important, though, is not just the therapeutic window based on those assays, but really, as you start to get on the hierarchy of evidence, as we looked at the -- I showed you in today's presentation some of the animal models, so mouse efficacy model, looking at ORIC-114. In those mouse efficacy models, Voronoi did not see evidence of skin flakiness or diarrhea or body weight loss in their mice, whereas they did see that same evidence in TAK-788 in those models. And so that, as you start to think about hierarchy of evidence is much more important and hopefully more translatable than even some of the biochemical assays that people like to quote.

I am going to hand over to Matt for question.

Yes. I had 2 questions. First one for Jacob. With these 3 disclosed preclinical programs, they all target the innate mechanism of resistance, and we'll learn some more about them in 2021. But I guess at this point, which one of them gets you the most excited? And then for Dominic, just wondering what's built into the 2H '23 cash run rate guidance?

Sure. Yes, I'll start there, Matt, and it will probably segue nicely over to Dominic, which is -- the short answer is, last year -- August of last year, we had a virtual offsite for our senior team and really debated the merits and demerits, frankly, of ORIC-101 and ORIC-533, our internal programs as well as planning for success. We were hoping to be successful on the in-license of the compound from Mirati, ORIC-944. And then also, we were already deep in negotiations with Voronoi at that point in the Exon 20 program. So we debated the merits and demerits of all 4 of those programs and said, okay, if we're successful in these 2 in-licenses, how do we prioritize these, what do we pick and choose to prioritize based on our balance sheet after the IPO. And long story short, we had a heated debate and essentially, everyone wanted to progress all 4 of them because they are also differentiated from a scientific and clinical -- and hopefully, clinical perspective. So that's really what led us to then say, well, what if we had an extra $100 million. And so why don't we try to top-up the balance sheet here so that we can actually advance all 4 of these programs and don't have to pick and choose because we really do see differentiated potential in all 4 of the programs. So maybe that's a segue for Dom to talk about the balance sheet and the runway.

Yes. So a great follow-up to Jacob. We ended the year with $293.6 million in cash and investments. And obviously, that includes the proceeds from the follow-on finance that we completed in November. And with that, that does give us cash runway into the second half of 2023. What that does assume, as Jacob highlighted, that really assumes that we move forward with all of our programs and that we retain 100% rights to all of our programs. So that does not assume any partnering out or anything like that. And that does assume a full success scenario for us as well. So we've got about 2.5 years of cash runway from today based on our current operating plan.

The e-mail question here on the PRC2, just thinking about prostate cancer, there's been some setbacks in the EZH2 space from some competitors. So and you discussed this in your presentation a little bit about why it's biologically different, but what specifically maybe gives you some confidence in prostate cancer, where EZH2 has had more difficulty?

Yes, yes, definitely, Anupam. So there's really been -- as we looked at that target, 1 thing we loved about it was that PRC2 is a validated target. And Epizyme did a lot of work to validate that target with tazemetostat, specifically as an EZH2 inhibitor. And we love that, that target plays well to prostate cancer. So as we started talking to Mirati about the PRC2 inhibitor that they had developed, 1 thing we like was that Mirati really took a target agnostic approach in the sense that they said they want to develop something for PRC2. They could either drug EED or EZH2. So EZH2 being the first-generation approach, EED being sort of the second-generation approach with Novartis is taken with MAK683. And so we like that they decided they're going to make both kinds of inhibitors and really try to solve 2 problems. So one was, there was a biological rationale why EED may be better, essentially because it doesn't have the same bypass resistance pathways that might impinge on the EZH2 inhibitors. But secondly, as you alluded to, the drug properties for the EZH2 inhibitors have been quite tough. I think Constellation 1205 through their own admission, is kind of the poster child of it, but tazemetostat doesn't have great drug properties either. And so what Mirati did is essentially optimized for biological activity preclinically and then drug properties and compare them across the whole spectrum of a very tough target candidate profile, and the winner was an EED inhibitor. And so that's what's become ORIC-944 for us. So we think it ought to differentiate on both fronts relative to what folks have seen so far, certainly out of the EZH2 inhibitors.

Okay. With that, I will thank Jacob and Dom for a really productive session. Thank you, guys, so much for taking the time. Super informative.

Terrific. Thank you. We appreciate the time today.

We will chat soon. Thanks, everyone.