Syndax Pharmaceuticals, Inc. (SNDX) Earnings Call Transcript & Summary

It goes for a second there.

So I was just saying if you're screening a population that relatively big, and you want a fraction of it, you have to build that into your clinical trial design. This is just a practical comment. You have to have enough sites open and you have to have an easy way to screen patients and build that into your clinical tunnel.

Yes. I think it was covered. I won't add anything else.

Okay. All right. Good. Well, let's move into some of the more company-specific questions. Maybe I can start with you, Jacob. So in terms of ORIC-101, you already mentioned the glucocorticoid receptor antagonist targeting solid tumors as well as prostate cancer. So it would be helpful if you could just give everyone, who is less familiar with ORIC, just a high-level overview of the rationale for glucocorticoid receptor antagonism as a mechanism to combat resistance to -- for example, in prostate cancer to combat AR-dependent drug resistance as well as chemotherapy in solid tumors.

Sure. Yes, happy to. I'll give the quick notes version of some pretty complicated biology. So with ORIC-101, the lead asset, it's an antagonist of the glucocorticoid receptor. And really why the company was founded in the early days was Charles Sawyers, who is one of our founders, had been instrumental to the discovery and development of both Xtandi and Erleada for prostate cancer. And he was asking a question of why were patients eventually becoming resistant to those drugs that otherwise do quite well for patients for a long time. So from the work in his lab, they essentially implicated the glucocorticoid receptor as a mechanism of resistance really acting as a bypass pathway for the androgen receptor because GR, it can activate. It has a very overlapping set of transcriptional targets as the androgen receptor has. And so the idea was that when you treat patients with Xtandi or Erleada, and it's blocking AR signaling, GR seems to then get upregulated and essentially take over for AR signaling. And so if you could come up with a selective and potent GR antagonist, dose it with an AR modulator, you could then block both the AR and the GR pathways and hopefully resensitize patients. So that's where the company originally started, and that was where the focus on prostate cancer came. In parallel with all of that and actually outside the company, there's a whole separate group of KOLs who had started looking at GR as a mechanism of resistance to chemotherapy in general. And there what they found was that GR seemed to be playing a role directly in -- related to transcriptional targets that are implicated in AMT and antiapoptosis, so actually a different mechanism of action. So we decided to run with that as well. And so internally, we did a lot of preclinical work, testing both the both mechanisms of action; GR as a bypass for AR and prostate, but then also separately GR's role in promoting antiapoptosis and EMT in solid tumors. And so for that reason, we've now got 2 different Phase IB dose-escalation studies underway with ORIC-101. So one is ORIC-101 plus Xtandi in prostate cancer, and then the other is ORIC-101 plus ABRAXANE in patients with various solid tumors.

I'm going to hand the baton over to my colleague, Mohit, who has got some questions for IDEAYA and Calithera.

Great. I mean yes -- so maybe I'll start with Susan. You -- by the way, you guys are doing great actually. So you could have conducted the whole panel, amazing. So no, I mean, just specific questions on your KEAPSAKE program, which actually you have an interim data readout in 2021. And we know that with NRF2 and KEAP1 alterations, patients have a really poor survival, 8 months or so with standard of care. When we see the data in 2021, Susan, can you please help us frame what sort of signal improved -- signal or improvement we need to see or you need to see to advance the drug into a more controlled setting or expand the program here?

Sure. So you know it's an interesting trial we're running. It's first line patients, and we're giving them a standard of care, which means they can get IO drug, anti-PD1 as well as their standard chemo, which will include a platinum therapy. And so what we're trying to do is add to the standard of care. And the reason we picked this KEAP/NRF mutation tumor type or patient population is because they do so poorly clinically. So it's just a very poor prognostic factor. So normally, you think of the first line trial as being something you'd have to conduct over a long period of time. Unfortunately, for these patients and what got us very interested in the pathway from a clinical perspective was that they're winding up with progression-free survivals in the 3- to 5-month range, and these patients are failing 1 standard of care multiple agent therapies in a really surprising way. And that's half to less than half of what you would expect for a median progression-free survival in regular patients that don't have a KEAP or NRF mutation. And the overall survival is even more startling. So in retrospective studies, this is about an 8 months of median survival population compared, again, to wild type that don't have KEAP/NRF mutations, which are in the double digits. So we're looking for, in the interim data, a progression-free survival trend taking you away from the KEAP mutant median PFS of 3 to 5 months and increasing it more towards the wild type, which, again, we would expect to be in the 9-, 10-month range. And so just a couple of months change in PFS would be moving you quite straightforwardly in the right direction, and that's what we're looking for along with any increases in response rate or whatever. But when it's a population interesting, it's such a high unmet need that you can get relatively quickly a feel for whether you're moving this population closer to wild type. And we're enrolling the study in the United States in many different sites. So we hope to be able to accelerate this process of screening for patients and getting them on the trial, getting a look at the interim relatively quickly and then using that data to design the next study, which would be a bigger study. So a clear registration path, I think, if you have reasonable data in a population that usually would have -- be having more benefit in the first line.

Got it. This is very helpful. And maybe Yujiro, a question for you. I mean you are -- so you have been developing your synthetic lethality platform for quite a while. And now with this whole platform, synthetic lethality as an approach to treat cancers is coming to the lime light. I mean there are multiple companies are trying to do something similar to you as well here. Could you briefly touch upon what are the unique features of your platform that help IDEAYA stand apart from the peers? And as a field, where do you think the field is going? I mean do you -- how do you think this field will evolve over time?

Sure. We think the synthetic lethality space over the last several months has actually been a really remarkable time. We've seen a lot of different pharma partnerships done over the last couple of months, pretty big, large partnerships across a lot of different targets, a lot of different programs. And we have seen over the last year or so just continued really remarkable data coming out of the PARP-BRCA space and others. So I think on a lot of levels, it's been a really exciting period. We started our efforts over 5 years ago. We were the first synthetic lethal research-based company to go public, spring of last year. And really, for us, we think really the key value that we provide in all of this, especially from a research perspective, is the integration of various different technologies. So on the target discovery and biomarker discovery side as all the panelists have been talking about, we utilize various molecular biology tools, including CRISPR knockout, sRNA knockdown, dual CRISPR as well as other approaches related to bioinformatic. And we've now integrated that fairly extensively through key capabilities on drug discovery that are specifically tailored towards the type of targets we're finding. So we've invested heavily on structure-based drug design. We've actually solved the crystal structure for all 4 of our synthetic lethal programs; 2 of them, we think, are actually potential first enrolled structures that have been resolved. And I do think those are key assets as part of our GSK partnership that was announced a few weeks ago. Where is the field going? Obviously, I think that's a long answer. I'll be brief. But I think for the whole field, that's really exciting because I think we are seeing really the next wave of synthetic lethal programs hopefully enter the clinic. So I think for the whole field, that's really great news, whether that's from us or one of our peer companies. Yes, I think it's going to be a really exciting next couple of years. So the biology is really blooming. And from that first wave of PARP, WEE1, CHK1, ATR, DNA-PK so on and so forth, I would say there was a several year lull, and I think we're kind of getting past that now. Then it should be really exciting to see how this develops over the next few years.

Great. I'll pass the baton over to Joel.

Thanks, Mohit. So Briggs first, Syndax is striking to see how much the company has changed over the last year, in that there was an unfortunate Phase III failure, but you wouldn't necessarily notice that from the stock price because there's been 2 early-stage clinical assets that have both advanced and generated clinical data and caught a lot of attention. I think maybe the one that has caught the most attention is the menin inhibitor. So I'd like to ask you about that one. Could you summarize the clinical data over -- that's come out over the last year or so? And maybe give us an update on the status of that program?

Yes, sure, Joel. So thanks very much. Look, we're very fortunate that in the precision oncology space, we benefit from years of work that other people have done with either specific genetic mutations like EGFR mutations, or in the fusion world that Jacob has worked, and in others, where we know who the patients are they're diagnosed. In our case, we're fortunate, those patients are diagnosed at the time of their presentation with acute leukemia. And we know about these MLL-r rearrangements. They're sort of, in a way, a standard fusion protein that we've seen, as I said earlier, for BCR-ABL or for EML4-ALK or for the TRK fusions or RET fusions. They're unique, they're different in that it's not a kinase that is causing the fusion protein, it's actually a transcription factor fusing to another protein that targets that to a specific location on chromatin. And so it's essentially a protein-protein interaction that we're blocking. We're, again, quite fortunate in that protein-protein interaction is a linear amino acid sequence, it's not too big faces bumping into each other. And so as we went into the clinic, we had very nice, I think, target validation, very nice preclinical data that suggested this was a valid target and had done some work to figure out sort of what kinds of exposures we might need in order to get the drug to work. So we presented some data at AACR earlier in the year where we went through that whole story, how we made the molecule, knowing the crystal structure of the target and designing a molecule that would fit there, going through the preclinical data to show that this seemed to be a valid target, both from genetics and from using our molecule, and then the work we did to try to predict what exposures we would need to get efficacy. We were, I have to say, very, very fortunate that early in the trial, our drug is metabolized by CYP3A4. And so when you combine the CYP3A4 inhibitor, you actually get higher exposures. The second patient to enroll on the trial who had a specific translocation that we're looking at, got quite high exposures because they were on a CYP3A4 inhibitor and got exposures that we thought would predict response and the patient had a complete response. So I think that was exciting to people who are working on the target to know that, in fact, at least there's 1 patient that's been described now in the public domain, where when you hit this target with the right PK, you can get a complete response. At AACR, we had presented the first 6 patients. It was primarily a preclinical presentation, but we presented a little bit of the clinical data. And so we've continued to advance that program, and we anticipate that by the end of this year, we should have a recommended Phase II dose or doses that we want to take into future trials, and we look forward to presenting that whole completed Phase I trial in the first half of 2021.

Thanks, Briggs. And back to you, Yigal.

Okay, great. Thanks, Joel. Thanks, Mohit. Jacob, back to you, if you don't mind, just a more practical question in terms of your ongoing trials. You have the prostate trial as well as the ABRAXANE trial in solid tumors. One of those is reading out in the first half of the year, next year, and the other one in the second half of the year. So think a lot of investors would just like to get to the extent that you can comment and update on where these trials are in dose escalation? And what are the factors involved in determining which of those trials, the solid tumor or the prostate trial, is going to end up reading out first?

Sure thing, Yigal. Yes. So the ABRAXANE trial got a 2-quarter head start on the prostate trial. The ABRAXANE trial started roughly middle of last year, the prostate trial started in Q1 of this year. And the only reason why we've left it open-ended as to which will read out when is that the ABRAXANE trial is, obviously, enrolling multiple different tumor types. It's a bit more complicated on the recommended Phase II dose selection that takes place there. The enzalutamide trial is all in prostate. And so we're just leaving the window open that potentially the prostate trial could catch up timing-wise. What I'll say is I'm not yet ready to commit to which one reads out in which half next year, but they're both enrolling well. And I think probably as many of the panelists here would say, despite the challenges that COVID has presented to all of us, in particular, with oncology trials, I think we've been fairly well insulated from that. And so they continue to enroll well. And we continue to reaffirm our guidance that by the end of this year we'll pick the recommended Phase II dose for both of those studies and then start the expansion cohorts for both of those studies.

And on the solid tumor front, is there any reason to believe that ORIC-101 would work better in a particular solid tumor, in combo with Abraxane versus another? Or is that's more of an open question?

You know I'd say it's more of an open question. At least preclinically, we see very compelling activity with the GR antagonist in many different tumor types, so whether that's ovarian, triple-negative breast, so multiple different tumor models and also, I should say, multiple different chemo classes. So while we're starting with ABRAXANE because of its ubiquitous use, we've seen compelling activity, at least, preclinically with taxanes, platinums and antimetabolites. We've chosen -- obviously, we've got to start somewhere, so we're starting with the taxanes with ABRAXANE because of its wide use and the fact that it's not dosed with any upfront steroids, and so it makes it much easier in terms of a starting point. But I think if you look at competitor company, Corcept, which is also developing GR antagonists, they've already publicly reported on responses in pancreatic cancer, ovarian cancer and a few other tumor types as well. So I think it's open.

Got it. And maybe if you could just spend a 1.5 minutes, 2 minutes just on some of your earlier stage assets, which are interesting, CD73 inhibitor, which I believe you have an IND going in, in the next -- first half of next year. And then, of course, the new asset that you've been licensed from Mirati, the PRC2 inhibitor, if you could just offer your thoughts on the strategic rationale for bringing those in and what the market opportunity for those assets looks like?

Yes, yes. I'll give the 60-second version for that. So as we -- I mentioned upfront, precision oncology is a huge area of focus for us as we think about developing the pipeline. Beyond that, we also have 2 other areas that are of high interest to us. The key tumor dependencies, which Susan referenced earlier, and then also hormone-dependent cancers. And so everything in our pipeline checks at least 1 of those boxes, if not multiple of them. Susan, I know, knows the adenosine pathway well. And so we've spent time there focused on the adenosine pathway and specifically on CD73, developing a small molecule, orally available inhibitor of CD73 that we believe differentiates quite nicely. The plan for that is to file an IND in the first half of next year. But beyond it, I think just stepping back a little bit from the pipeline itself, we're really fortunate to assemble the first rate clinical team that was actually with me at Ignyta, and then a research leadership team that is largely out of Genentech. And so with that team's capacity, we say we're also going to go on the hunt for other interesting assets. So we had long-dated discussions with Mirati, found an asset, an EED inhibitor, which targets the PRC2 complex. It's an approach that Novartis and others have taken to look at prostate cancer specifically as well as some other liquid tumors. And so initially -- so we in-licensed that asset from Mirati. We plan to file an IND in the second half of next year. It's really part of that second-generation of PRC2 inhibitors, and we'll initially focus on prostate cancer for its development. But we're actually right now preclinically exploring other biology as well to see if there's other indications of interest we'd want to take it into.

Perfect. Well, maybe in the last 3 minutes, we could just do a quick lightning round. And just everyone can go through what they see as the next big catalysts for each of your companies over the next 6 to 12 months. And also just briefly mentioned the extent to which COVID has impacted your clinical development and what you've done to minimize the COVID headwinds?

Sure, I can start. So Calithera has a potential registration trial, randomized blinded trial, reading out end of fourth quarter or early first quarter in RCC. So we're really excited about that. It's a combination of using our glutaminase inhibitor, telaglenastat, with cabozantinib which is a tyrosine kinase inhibitor. And then we're looking forward after that to interim data from the trial we've been discussing, the KEAPSAKE trial, which is KEAP/NRF mutants in first line lung in standard of care versus standard of care alone. And then we also have an arginase inhibitor, CB-280, which is in cystic fibrosis patients that just started enrolling very recently, and we hope to see data in 2021 as well. COVID actually caused delays on both our CF and our oncology trial start for CF and lung, and delayed it by about 1 quarter and that was unfortunate. But other than that, we've been super lucky. We finished the enrollment of our RCC trial before COVID hit. And COVID has caused delays in how to bring the data in and clean it, but has not caused delays in patients getting their scans and being on trial, et cetera. So we feel like we dodged a bullet on this.

Got it. Jacob?

Yes. Sure. So key catalysts for us coming up with ORIC-101, as I mentioned, in 2021, we'll have 2 interim data readouts, one for each of the dose-escalation studies that are going on. So one of those will happen in the first half of next year with, the other one in the second half of next year. Those data readouts will encompass, for each of those 2 arms, all the initial dose-escalation data, but then also the early expansion cohort data for both of them. And so that will be for 101. And then as I mentioned, for CD73, ORIC-533, that will enter -- well, that will -- we'll file an IND on that in the first half of next year. And then for ORIC-944, the EED inhibitor, we'll file an IND in the second half of next year. And then in terms of COVID challenges, I think, as Susan referenced, there's -- in terms of data collection, data gathering, data cleaning, some of that, obviously, some challenges. I'd say, in general, the team has been able to navigate around it. And we've been fortunate but have really just put in some creative solutions, like doing blood draws out of the patient. The clinical team -- Susan and I were talking about this in a separate conversation, the clinical team has been remarkably efficient at doing trial site initiations remotely and virtually, and that's probably the way of the future in a lot of ways. So we've been able to, generally speaking, navigate around COVID, and it hasn't affected our time lines.

Got it. Briggs?

Sure. So the 2 major readouts we have at the end of this year, we'll be presenting sort of Phase IB data on our CSF1R inhibitor in chronic graft-versus-host disease. And then early in 2021, we'll be presenting the Phase I data on our menin inhibitor in AML, both MLL-r and NPM1 patients with AML. So -- and I would say from a COVID point of view, like the others, our programs have generally not been affected, and our clinical teams have done a super job of keeping things on track.

Perfect. And finally, Yujiro?

Sure. Yes. So for us, obviously, the last month or so ago, we announced a significant partnership with GlaxoSmithKline across 3 of our synthetic lethal programs. So I'd say, in terms of key catalysts, we're very focused on getting MAT2A IND filed by the end of the year. We continue to be on track for that. We do believe we have a potential best-in-class molecule in the space. And we do anticipate we'll put out some data on that. And obviously, I think there is a lot of interest and attention towards the MTAP deletion space in general. So we think that's going to be a potentially significant catalyst. Beyond that, we have 2 additional programs in PARG as well as pol-theta, where we have publicly guided that we are on track to pick a development candidate for those 2 programs as well over the next couple of quarters. So I would say, yes, we're really excited about the next couple of quarters here as we see synthetic lethality mature. In terms of our clinical program, IDE196, in collaboration with Pfizer, we did announce the initiation of a MEK combination. We have guided towards interim data for that towards end of next year, early the following. So I think that's also going to be a key potential readout as well as our GNAQ/11 basket trial where we did recently announce the skin melanoma expansion. And so we are guiding towards, first half of next year, interim data on that as well. In terms of COVID, I think similar to the other panelists, we have seen certain areas of enrollment on the basket trial side. We have seen some impact in terms of scan timing, so some patients being very cautious about coming into hospitals to get their scans. So I think these have been sort of more one-off cases that we're monitoring very closely. But yes, overall, I would say they have been manageable, and we have been generally able to stay on track for several of our key target catalysts.

Perfect. Well, thank you all so much for your participation. I hope you enjoyed it. Good luck with the one-on-ones during the conference, and, more importantly, good luck with your clinical development strategy across the board. Thank you.

Thank you very much.

Thank you so much.

Thank you.