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

Thanks, everyone. So welcome to the final session of the Tuesday morning of the 41st 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 and Priyanka Grover from the team. Our next presenting company is ORIC. And presenting on behalf of the company, we have CEO, Jacob Chacko.

Thank you, Anupam. It's exciting to be in person. It's exciting to get to see folks in real life and get a chance to talk to you about ORIC Pharmaceuticals, which is our company that's developing a pipeline of drugs targeted at cancer resistance. We're quite excited about the way we've built the company, the pipeline that we've built, and I'll get a little bit of time to share that with you today. Of course, I will be making forward-looking statements during the presentation today. So before I get into the specifics of the pipeline itself and each of the drugs, I'd like to just take a few minutes to tell you about why what we have built at ORIC is so special and why we think that the way we put the pipeline together is a unique way within the oncology space. So first of all, we've got a broad pipeline of both clinical and preclinical programs. There are 3 clinical stage programs that are in Phase Ib studies right now, all with expected single-agent mechanisms of action in various solid and heme tumors. And I'll talk about that a little later today. One of the interesting things about the way that we develop our drugs is that we have deep precision oncology expertise and translational expertise. What that enables us to do is, in most cases, develop these drugs with biomarker-driven patients selected clinical trials that ought to lead to accelerated time lines in the long run. Another unique aspect of the way we put the pipeline together is that when you look at how successful oncology companies have been built, oftentimes the pipelines come from internal discovery or from external business development activities. It's rare that you find a company that's able to do both of those things well, and we think that we do both of those things well. And that opens up a whole range of targets that our company is able to go after in terms of drug development. We have a senior management team that is well experienced, has worked together for many years at ORIC and even many years prior to ORIC at successful oncology companies together. And the value of that is hard to understate. And then finally, and crucially, especially in the current environment, we are well capitalized. We ended last year with $228 million of cash that provides us with runway into the first half of 2025. That is assuming success across every single program in the pipeline. So in other words, that's a very conservative cash runway guidance that we provide. And importantly, we've got 3 clinical updates for our 3 programs in the -- coming in the second half of this year. So let me break down a few of those aspects that I just highlighted for you before we get into the pipeline itself. We're really proud of the team that we've brought together at ORIC, and it really starts with our founders who started the company with the vision of going after resistance mechanisms in cancer. So ORIC stands for overcoming resistance in cancer. And that, in a nutshell, is the mission of the company. Beyond that, though, we've brought together a team with unique sets of capabilities and a team that's worked together in prior settings. And that starts with a discovery research team with leadership that worked together previously at Genentech, a clinical and development and regulatory team that worked together at places like Ignyta and Aragon. And then finally, a strategic and a business development and financing team that worked together previously at places like Ignyta and Medivation. What that high-functioning team in bringing those different capabilities together has enabled us to do is a unique way of building a pipeline within the oncology space. As I mentioned, we can look back over the years at successful oncology companies. And generally speaking, you will find that they either have internal discovery is the way that they have built their pipeline or through targeted business development. You can see examples of some of the successful companies that have done this in the past. At ORIC, we take a mantra of best molecule wins. And what that means is we start first with the target, the target that's of interest to us. If we can work on that target that's got a high unmet need patient population, and we can do it internally through a differentiated approach, we'll do it because we've got great chemistry and biological capabilities internally. But if someone else has a differentiated approach to that target or a more advanced approach to that target, we are more than happy to go look under a CDA and do business development conversations and potentially in-license something that meets our threshold there. I think what's really hard is when you have great internal discovery, and this is probably why more companies can't do this, it is very easy to say that yours are the best programs and it's easy to find the flaws in others. And I think we've built a culture that just has this mantra of best molecule wins. What it's led to is the pipeline that you see here today. So like I said, 3 different clinical programs, ORIC-533, ORIC-114 and ORIC-944. In the case of ORIC-533, it's a CD73 inhibitor that we are developing in multiple myeloma initially as a single agent. ORIC-114 is going after EGFR and HER2 mutated cancers, primarily in lung but also some other tumor types. And ORIC-944 is starting as a single agent as it's a PRC2 inhibitor, specifically focused on the EED subunit of PRC2 initially being developed in prostate cancer, again, as a single agent. I want to pause for a second on the far right column of this pipeline side because that's something that we take really seriously at ORIC, which is the differentiation. In what is otherwise a very crowded oncology landscape, we hold ourselves to a very high standard to figure out what is the angle that makes our drug better than what's out there today, because there are a lot of me-too type drugs that are being developed today. So we really take that differentiation seriously. We really take the phrase "best-in-class potential" seriously because if we don't see that best-in-class angle, we won't pursue it. In the case of CD73, as I'll talk to you today, we've developed a compound that is clearly differentiated preclinically from the other competitor compounds, but that wasn't enough for us. On top of it, we established a collaboration with an outside KOL and found a unique angle to develop this as the only CD73 inhibitor that's being developed in multiple myeloma, initially as again, as I said, as a single agent. In the case of EGFR Exon 20, it's a space that people know well because there's a lot of companies going after that target. But nearly every one of those companies and drugs has a fatal flaw, which is that they are not CNS penetrant. And for that target for as with every targeted therapy target, CNS penetrants is key because 1/3 of the patients present with CNS metastases, the first site of progression is often in the brain. And so that's why it's important to have a CNS-penetrating compound and what we prioritize. This is a good example of a program that we found a company that was working on this and was further advanced than anything we could have done on the internal side. And so we put it through the paces of diligence on the preclinical side and then in-licensed the program. And then with PRC2, that's a target that many of you will know more colloquially as EZH2. The PRC2 complex has 3 different subunits. Most companies have approached it from the EZH2 angle. We're approaching it from the ED angle, which gives us, again, a narrower competitive space and some benefits over what's come before. And then I won't have time to talk about it today, but we do have a preclinical pipeline as well, an active entry effort that continues. The first program there that we've unveiled publicly was a PLK4 program. It's a small molecule selective potent inhibitor of PLK4 relevant to synthetic lethality pathways, specifically in breast cancer and neuroblastoma. Again, a differentiated angle here that's primarily based on our team's biology understanding and expertise to get a jump start on others that has given us a first-in-class potential with that program. So as we've taken this unique approach to building the pipeline, what it's enabled us to do is a pipeline that was very intentionally put together to have different risk reward profiles in the programs. And what I mean by that is you look at the programs and as they are rated across these various spectrums, you can generally see that in some cases, we go after on the far left, validated targets. So Exon 20 is a great example of this. That is clearly a validated target, 2 approved agents, multiple other agents in development. The biology is super easy to understand. The bar that we're trying to meet is easy to understand in terms of what counts as a good agent and/or a great agent in that space. What comes with that though, obviously, is a more competitive landscape. And it's one that again with our brain penetrants, we think we've carved out a competitive angle. Those are generally the kinds of targets that suit ourselves well to being found through business development. On the far-right end of the spectrum, though, you'll see more novel targets. These are opportunities that are potentially first-in-class. The biology is a risk in these targets. The reward for that risk is broader populations and a first-in-class opportunity. And those are the kind of opportunities that suit themselves well towards internal discovery where our team has a specific biological angle or differentiation. And so what it's given us, like I said, is this pipeline with a mix of risk reward profiles. 2022 was a busy year for us. There's a lot of words on this slide, but I'll summarize it for you in saying that 3 clinical stage programs were initiated in first patient dosing in the first half of last year. That's a huge undertaking for a small biotech company. We continue to dose escalate all 3 programs last year through multiple cohorts, expanded sites globally, demonstrated good oral bioavailability of all 3 of those compounds, demonstrated dose proportional increases of exposure of all those compounds across multiple cohorts and have not yet reached MTD for any of those 3 programs. On top of that, we also advanced our discovery pipeline. And again, with PLK4 we selected a lead candidate, a development candidate that is now in IND-enabling work. And then finally, on the corporate side, in what was otherwise obviously a very tough macro environment, we were able to strike a deal with Pfizer where Pfizer put a $25 million investment into ORIC. And then on top of it, also established a clinical collaboration around our CD73 program in multiple myeloma, which I will talk about shortly. The net of that activity on the financing and strategic side was extending our cash runway into the first half of 2025. So the Pfizer collaboration is summarized at a high level here. This was a deal that we announced just about 3 weeks ago. And what it was is a $25 million equity investment that Pfizer has made into ORIC at a premium. And then importantly, what it's done is also opened up a clinical development pathway for us. If we choose at ORIC's discretion to pursue a BCMA, a combination study of 533 with Pfizer's BCMA, CD3 bispecific, at ORIC's discretion, we can then pursue that study with Pfizer running the study. That's obviously a huge strategic benefit to us, operational benefit to us if in the future we choose to do that. And then Pfizer Oncology CSO will also join our SAB, which is obviously a huge benefit as well. Now let me dive into each of the programs in turn. And just given the short time we have here, I'm going to go relatively quickly through the 3 clinical programs. The adenosine pathway is -- where 533 is focused. It's obviously a pathway that is well known to folks in the oncology space. There are 3 main nodes in that pathway that can be targeted, and we believe CD73 is the most promising of those. Now there's a number of CD73 inhibitors out there that you'll all be familiar with, as you can see, some listed on Slide 12. The main issue in this space has been essentially all the early compounds that have come before, focused on antibodies as the way to drug CD73. The reason being it's a challenge to come up with a small molecule oral inhibitor of CD73. And that's why you don't hear about small molecule oral inhibitor of CD73. Our team, we believe, was able to crack that challenge in coming up with ORIC-533. And as you can see in the profiling here versus various categories of molecules that have gone after CD73, we are much more potent, and we retain that potency in a high AMP environment, which is a very important experimental condition to replicate the kind of high levels of adenosine that you see in these patients. Now as I mentioned in my upfront comments, it was not enough for us to have a differentiated preclinical profile. We also want to find white space on the clinical development side. And so that's why we pursued an outside collaboration with Dr. Ken Anderson at Dana Farber, who had independently found through his team's work that there might be a role for CD73 inhibition in treating patients with multiple myeloma. Dr. Anderson's observations were that you get high levels of adenosine in these patients with multiple myeloma. And the thesis was that if you can give them a CD73 inhibitor, you can perhaps turn down the levels of adenosine, thereby taking off the brakes on T cells, in other words, increased T cell activity and lead to better lysis. So you can see on the left-hand side here of Slide 13, in Dr. Anderson and in his labs a proprietary ex vivo patient assays, where they take bone marrow aspirate from patients treated at Dana Farber, which are relapsed refractory patients, exactly the kind that we're going to see in the study that we are seeing in the study. And you can see that with ORIC-CD73 inhibitor on board, he gets about 40% lysis in this assay. To try to give some historical context for that, you can see because his lab has tested out all the active agents in the same masses, you can see on the right side of the page, what they saw with other active agents. And obviously, you can see that ORIC-CD73 inhibitor is as good, if not better, than any of the other active agents that Dr. Anderson has tested. So that leads me then to the Phase Ib study, dose escalation study that was started in the first half of last year. As I mentioned, we dosed our first patient in Q1 of last year. Standard 3+3 dose escalation design. We will obviously be undertaking a dose optimization portion of the study shortly here as is required under project Optimus. Ultimately, when we have a recommended Phase II dose and depending on how the results of this study play out, we will then decide on whether the path forward is as a single agent for an accelerated approval pathway along with various combination studies or the more base case of various combination studies. We'll have data -- initial Phase I data publicly released for this program in the second half of 2023, very likely at a major medical conference. For ORIC-114, our EGFR Exon 20 inhibitor, this again is a target that I think is well known to people because it's attracted a lot of attention. There are 2 approved agents and multiple agents in development, but the flaw with -- almost every one of those programs is lack of CNS activity. Because -- and this is relevant to this target as well as other targeted therapy targets, so many patients present with CNS metastases. And because that is the first site of progression for patients, it is almost dogma now with lung KOLs that you need brain-penetrant compounds to handle the whole population, not just the folks with CNS mets at presentation, but even the ones who don't present with CNS mets because you'd like to prevent eventual progression and CNS metastases. You can see here in the kinome profiling of this, ORIC-114 is exquisitely clean on the kinome tree compared to other molecules that are either approved or in development for this indication. On Slide 17, you can see some of the in vivo data that we've generated and the highlights of that. On the far right, we'll show you versus, again, other competitor compounds, the strong in vivo results with deep progressions that we've been able to see with ORIC-114. Slide 18 shows you on the left side, systemic and on the right side, intracranial activity versus various comparators. And again, you can see that ORIC-114 is as good or better than other agents in terms of the systemic activity. But most importantly, it is much better in terms of the intracranial activity in these preclinical models. Now one of the other targets that's relevant to ORIC-114 is HER2 Exon 20. This is a space that is, of course, less competitive than the EGFR Exon 20 space. It is also a space with high unmet need patient need. You can see how our drug compares to tucatinib, an approved agent. And on the left-hand side, again, you can see the systemic activity versus tucatinib. And on the right-hand side of the Slide 19, you can see the intracranial activity, which again is quite impressive preclinically. So this study also initiated in Q1 of last year also is going through 3+3 dose escalation. We also expect to do dose optimization work here and then select an eventual recommended Phase II dose before deciding what the registrational path looks like. But first things first, in the second half of this year, we anticipate presenting the first publicly available data from this program, again, at a major medical conference, most likely. And then finally, ORIC-944, our PRC2 inhibitor. So PRC2 is a complex that most people have probably heard of, even if they didn't realize they heard of it. And what I mean by that is there's 3 different subunits of the PRC2 complex. Obviously, there's a lot of EZH2 inhibitors that have been in development. There's one that's approved in 2 different indications. That's where most of the focus has initially been as the EZH2 portion of this complex. Us and Novartis, really, at this point in the clinic have taken a different approach, which is to focus on EED. And EED has some benefits, both biologically and from a drug property point of view over EZH2 that I won't have time to get into today, but leads to a differentiated angle versus the EZH2 inhibitors. This is one, again, that landed on our radar from business development. Mirati was developing this compound initially as a better version of tazemetostat. They had tested it in multiple heme models. As you can see here on the right side of Slide 23, looks better than tazemetostat in those heme models, but our interest primarily in this was prostate cancer. That's where a lot of the PRC2 complex inhibitors have been developed. So we brought this under MTA into ORIC and this is the benefit, like I said, of having all the capabilities that we do is we brought it under MTA, had our preclinical team run it through the paces, looking at various enza-resistant prostate models, and we saw 80% to 85% TGI in really difficult prostate models where other -- where EZH2 inhibitors top out at about 40% to 45% TGI. This is what gave us confidence in in-licensing the compound and like I said, developing it initially in prostate cancer as a single agent. So you can see here on Slide 25, the schematic here, which you're used to seeing at this point from the other 2 programs is traditional 3+3 dose escalation. This study initiated in -- first patient was dosed in Q2 of last year. We've escalated through multiple cohorts. We expect to do some dose optimization work here this year and then eventually to decide on what the path forward is in terms of single agent versus combination paths forward. Obviously, in this post AR modulator space, which is the population that we're enrolling, there's quite a bit of work that's being done in combination with other AR modulators and that might be a path that we would take with this as well. But again, first things first, initial clinical data from this is expected in the second half of this year, again likely at a major medical conference. So in closing here, you can obviously hear my enthusiasm and the team's enthusiasm for the pipeline that we've built. We think that it is a unique pipeline with distinct risk reward profiles across these 3 different clinical stage programs with other internal discovery programs coming along after it like PLK4 and some others that are unnamed. We obviously have put together, I think, a unique team here, a unique pipeline. We think that this is a pipeline and a company that will do great things on behalf of patients. And you can see on the bottom of this slide, the 3 milestones that I mentioned, again, initial Phase Ib data expected from each of our 3 clinical stage programs in the second half of this year. So with that, I think I'm right at time, and we'll open it up for questions.

[Operator Instructions] Jacob, the time lines for the 3 readouts, 533, 144 and 944 have shifted from the first half of this year to the second half of this year. Is there something specific overall that guides that decision for all 3 programs? Or are there individual considerations for each program that delayed?

Yes. The explanation is really simple there on the palm and it's literally the extra money from Pfizer. So when we did that deal a few weeks ago, the extra $25 million gave us cash runway into the first half of 2025. Importantly, what that did is give us the flexibility to do things the way we want to do, a bit free from external pressures of sharing data, which is we want to dose optimize sooner rather than later as part of project Optimus. So we try to be very clear in the corporate update that we gave early this week and to take it all off the table that there's no enrollment issues in the studies. There's no issues with oral bioavailability. No issues with being able to escalate through multiple cohorts or get good dose proportional increases in exposure. So any of the operational type issues that could lead to pushing out data are not what's in play, literally what it is as extra cash, extra runway, extra breathing room that lets us do things the way we want, which is to first optimize dose and then give a more mature data set in the second half of this year and one where we can hopefully be more explicit about what the recommended Phase II dose is or at least what we've narrowed it down to.

Got it. Questions from the audience? Jack, there's -- you made some interesting comments about the Pfizer collaboration in terms of 533 and having the discretion to move forward with the BCMA combo, should you choose. But with the collaboration in place, could you do single agent and that in parallel? Or would you pick one or the other?

We could do -- short answer is we could do both in parallel. We don't have to pick one or the other or we could pick one or the other. So in other words, the full discretion is for us. So the beauty of the collaboration that we struck with Pfizer is it's -- I think of it as a one-way call option in a lot of ways in the sense that once we've got a more comprehensive Phase I data set, we will look at that -- we at ORIC will look at that data set and decide do the data justify moving this forward in both a single agent accelerated pathway as well as various combinations or do we just want to do the combinations? If we want to do the -- or do we want to do nothing because we just don't have sufficient signal to do any of those things. If we want to move the combinations forward, there's obviously 3 major classes that people think of in the myeloma space, which are the anti-CD38, CMAs and the proteasome inhibitors and now BCMAs are on the radar as a fourth class. So we might want to do combinations with any or all of the above. The benefit of the way this collaboration has been struck with Pfizer is that we have full discretion at ORIC to decide which path forward. And ultimately, that will come down to the single agent signal or not that we see.

Okay. Any questions from the audience?

I think it's all you, Anupam.

I think so. The other question I have is maybe on the earlier stage pipeline on the PLK4. You've talked about now moving into the IND studies. What does the initial development phase look like? And when you look at the whiteboard of kind of indications and unmet needs, where could that go, program go?

For PLK4, specifically?