Eikon Therapeutics, Inc. (EIKN) Earnings Call Transcript & Summary

Good morning, everyone. I am Imogen Mansfield. I'm a Biotech Analyst at Cantor, and I am delighted to be joined today by 2 legends, the CEO of Eikon, Roger Perlmutter; and Dr. Tim Yap, who is a legendary clinical trialist and physician at MD Anderson. So welcome. Thank you for joining to discuss PARP1 with us. We will be going through PARP1 biology, discussing the unmet needs left by the first generation of PARP inhibitors and then going through Eikon's programs and spending some time at the end talking about Werner helicase. So to kick us off, Dr. Yap, would you like to tell us a little bit about your background and the trials that you're involved with for the PARP1 field and I guess, synthetic lethality more broadly. And just to confirm, we've just discussed this top line, but Dr. Yap is involved in several programs with Eikon and will not be sharing any nonpublic information today.

Thanks so much, Imogen. Good morning, everyone, and really thank Imogen for the kind invitation. Great honor to be here with Roger. And my name is Tim Yap. I'm at MD Anderson. I've been here for 10 years. Before that, I was at the Institute of Cancer Research and the Royal Marsden Hospital for about 12 years, where I've had a big interest in synthetic lethality, being involved with the development of many first-generation PARP inhibitors and then, of course, now the new generation PARP1 selective agents and also many other DDR agents. And also, I guess, Werner helicase that we'll be covering as well. So wonderful to be here, and thanks so much for the invitation.

Great. Thank you, Yap. And Roger, I'm sure that many of our listeners have met you in the past, but it would be great for you to share your background as well and give us a quick overview, a 2-minute overview of Eikon.

Thank you, Imogen. And thanks very much for making this possible. It's a great privilege to be here with Tim Yap. He's modest, but he is a towering figure in clinical research, and it's a privilege to be here with him. So I'm a physician scientist. I worked for many years studying signal transduction in hematopoietic populations when I was a professor at the University of Washington in Seattle, moved to Merck to try to apply some of those lessons to drug discovery. I had a brief -- well, okay, 12 years at Amgen, taking a small little company called Amgen and turning it into a great big giant company called Amgen, which I then retired from, had no intention of doing that kind of job again, but was recruited back to Merck to lead research and development there again and did that for a number of years. My focus has been quite broad in the treatment of infectious disease and malignancy and also metabolic disease, but I have focused quite a lot on methods to improve cancer treatment and in particular, the introduction of checkpoint inhibitors. And we did that at Merck. When I say we, I mean everybody at Merck, I was just there to applaud. But we did that in a quite robust way, and I think really it transformed cancer care. But that led me to think about how to proceed still further in this area. And it was at that point that I began working with the company that became Eikon. The premise of Eikon is that we can use super-resolution microscopy to visualize individual proteins and living cells. And in doing so, we can develop novel methods for screening for active pharmaceutical ingredients that would alter the behavior of proteins. It turns out that all drugs change protein motion. In fact, that's largely how they work. That wasn't something that we knew about before we got started with this. It took quite a long time for us to build the instruments necessary to apply super-resolution microscopy fruitfully to drug discovery. But we have now after for some years, reached that point and have been able to use our platform to introduce, what we think are going to be, important new medicines into the therapeutic armamentarium. We'll talk about one of those, 1005, which is a Werner helicase inhibitor perhaps towards the end of the period today. But in the meantime, we also were able to use our tools fruitfully to look at some areas in DNA damage repair, particularly because that's an especially good area for us to apply our tools to. And we were able to identify some very, very selective PARP1 inhibitors. One of the things that my colleagues and I had done when we were at Merck is we would have worked together with the group at AstraZeneca to develop olaparib, which is the leading dual PARP inhibitor. And Tim knows that drug very well and has used that very effectively. We felt that it was possible to find drugs that could have similar therapeutic efficacy but a superior safety profile, particularly with respect to hematologic toxicity, which frankly is limiting for the dual PARP inhibitors. We were able to identify 2 very good series of molecules from a small company in China called Impact. We partnered with them and have developed 1003 and 1004, a brain penetrant one, 1004, which Tim has been working with, I think, at MD Anderson and then a non-brain penetrant one, 1003, which is somewhat further along, but both of them are making good progress in the clinic. We're optimistic that they will turn out to be meaningful improvements for patient care. And that's, I think, much of what we're going to talk about today.

It is. And for those who haven't seen, we'll also be getting updates for both of those programs at ESMO, and we're going to talk about that as well. So, I guess, to just set the scene, Tim, would you be able to remind us what synthetic lethality is and kind of the basics of what PARP enzymes did?

Yes. All right. Let's start off with a tough question. So it's never easy to explain synthetic lethality without some slides, but I'll have a go. But essentially, if you think about 2 genes, X and Y, essentially, if both genes are working and viable, you essentially get a viable functioning cell with no issues. If you have an issue with one of them, loss of function of one of them, the cell still lives and there are no issues. But if you actually have an impact or a nonfunctioning X and Y gene, that is when the cell will undergo apoptosis and cell death essentially. An easier way to think about things is to think about synthetic lethality as a table with 4 different legs, each leg representing a DNA repair pathway. And that could be base excision repair pathway, which is controlled by PARP. PARP stands for poly ADP-ribose polymerase. There are several different members of the PARP family. But really, it's PARP1 and PARP2 that are relevant to what we're all discussing from a pharmacological perspective. And so if we go back to that table, one leg represents base excision repair that's controlled by PARP. Another leg could be homologous recombination, which is the error-free way of repairing DNA double-strand breaks and that's something controlled by, for example, BRCA, the BRCA genes, BRCA1, BRCA2. And if you think about how this applies to the clinic? How does this table apply to patients? We know that there are patients with BRCA1, BRCA2 alterations. This could be inherited. For example, Angelina Jolie has a BRCA1 mutation. And these patients, we know, are at great risk of developing different cancers, and that includes breast, ovarian, prostate, pancreatic cancers and also other malignancies as well. And so if we're dealing with an individual who has a high-risk penetrant germline BRCA1 or BRCA2 mutation, they have a nonfunctioning homologous recombination pathway. In other words, their table is standing on 3 legs rather than the 4 legs. And so if you think about that 3-legged table and you come in with, say, a pharmacological inhibitor of, say, PARP and you can actually block that other leg that controls base excision repair pathway. And if you administer a PARP inhibitor to a patient who has a BRCA mutation plus a cancer, that's going to lead to the taking out, if you like, of that third leg. And that table is not going to stand on 2 legs, and that table is going to collapse. In other words, that cell, that tumor cell is going to undergo apoptosis and cell death because you're taking out that third leg. But if you think about the normal cells in these germline carriers, they have a functioning homologous recombination. The BRCA gene is functioning. And so that table is still standing in the normal cells with 3 legs without any issues versus the tumor cells, which will collapse and die and undergo apoptosis because you're taking out the third leg. And so it is that difference between the cancer cells and the impact that you can have with a PARP inhibitor in those individuals that will lead to that whole synthetic lethality and the real personalized medicine, if you like, to kill the cancer cells without necessarily impacting the normal cells. I hope that summarizes things.

That's great. So within PARP, what is the difference between the function of PARP1 and PARP2? And we'll get to talking about the first-generation agents, but they all inhibit both of those enzymes?

They do. So they impact the basic excision repair pathway. But importantly, from years of research done by many different groups, we know that PARP2 as an enzyme is critical for erythropoiesis. And so by inhibiting PARP2 that will lead to potential increase in anemia, neutropenia, thrombocytopenia, so myelosuppression because of the impact on erythropoiesis. And really, when we think about how we can optimize cell kill, really it's PARP1 inhibition that we want to achieve without necessarily hitting PARP2 as an enzyme. And so really, that provided the rationale for developing these new generation PARP1 selective agents over just the first-generation ones, which target both PARP1 and PARP2 and even some of them target PARP 3 as well. And so that more selective pharmacological inhibition of PARP1 versus PARP2 or PARP3 or the other PARP enzymes really, I guess, provides us with a novel way of developing a new class of agents, which is cleaner without off-target effects and which really focuses in on the PARP1 inhibition and cell kill. And the expectation here is that this will lead to greater PARP1 inhibition in patients because as you think about it, if you're taking off the PARP2 inhibition, you can actually drive much higher doses of a PARP1 inhibitor into patients, and therefore, achieve much greater pharmacodynamic inhibition in patients. And the hope here is that you can actually keep patients on a PARP1 selective inhibitor for a much longer period of time without dose interruptions, without dose reductions because of the PARP 2 liability.

Yes. Okay. Great. And we will dig into PARP1 selectivity more in a second. But I had one other question for you on the role of mutations. So beyond BRCA, there are other mutations that are on label for several of the approved PARP inhibitors. So how do those mutations impact the sensitivity of those cells to PARP inhibition?

Yes, great question. So if we think about it, actually, BRCA1, BRCA2, which is the often talked about alterations. These are really just surrogates for what we're really targeting. And what we're really targeting is homologous recombination deficiency. That is what we're targeting in cancer. And we need to ask ourselves, what else -- what are the other surrogates that also lead to homologous recombination deficiency. And it's not just BRCA1 and BRCA2, it's also PALB2 mutations that we often see in breast cancer. It's also RAD51C, RAD51D. There are also other alterations such as [ FANCA ], whole sleuth of different alterations from CHEK1, CHEK2, ATM, so on and so forth. And we've seen that in prostate cancer, for example, the approval of olaparib and other PARP inhibitors, it's not just in BRCA1 and BRCA2, but in about 14, 15 different alterations, all of which lead to homologous recombination deficiency. The ultimate goal, of course, and this is probably beyond the scope of this discussion, but it would be wonderful if we could actually identify and develop functional homologous recombination deficiency assays, which is what we're working on here at MD Anderson. And also many other companies are working on this as well to really develop a functional assay that will identify tumors in patients that have homologous recombination deficiency directly. And that could help us go beyond just the BRCA1, BRCA2 and all of the other alterations that I've already mentioned. So instead of identifying patients who will respond through these different surrogates, we can actually directly identify patients with HRD.

Yes. And it has been a bit of a bumpy ride for the first-gen PARPs in the respective HRD-positive patients versus negative with the label changes for olaparib. I guess, there when patients who didn't have any -- who are HRD negative, so homologous recombination deficiency mutation negative. What would be the rationale for including those for PARP inhibitor? I guess, is it because we just aren't able to tell if there is a defect in the homologous recombination pathway.

Yes. I really see the changes in the label, for example, in ovarian cancer and the resistant setting. That's really more fine-tuning of the patient selection. It's not that these drugs were failures in all of those other indications. We need to remember that the first indication was in ovarian cancer in the maintenance setting, not in the front line, but really in patients who've already had other therapies, including platinum-based chemotherapy agents. And so with the SOLO-1 trial from AstraZeneca leading to frontline approval of olaparib, obviously, if someone's already had a PARP inhibitor, that does change how we respond in terms of the resistance that has already set in. Giving patients another first-generation PARP inhibitor after someone's already been exposed and resistant to another first-generation PARP inhibitor or even the same one, that to me doesn't quite make sense. And so the indication changes really, to me, reflect that change with the indications and the labels with the SOLO-1 trial showing great benefit in patients with frontline BRCA1 and BRCA2 ovarian cancer. And so that to me was more of a fine-tuning of the different PARP inhibitors and the patients that withstand the greatest chance of responding.

Yes. And if we think about -- we'll get to this future landscape and the opportunities for PARP1 inhibitors in more detail. But in terms of the mechanism by which this would work, there's some literature about chemotherapy agents sensitizing patients to PARP inhibition. So how is that working?

Yes. There are similarities, of course, between platinum-based chemotherapy agents like carboplatin, cisplatin in terms of the impact on DNA damage and cross-linking of DNA strands and leading to cellular apoptosis. And so we need to address upfront that there are similarities between platinum-based drugs and PARP inhibitors. And of course, the big differences are that PARP inhibitors are orally based drugs that are given as pills. Number two, they are better tolerated versus chemotherapy agents. And because they are better tolerated, these are drugs, pills that we can give to patients for a very protracted period of time without the side effects that we see with platinum-based agents. And so as we think about that, it makes sense to actually try and combine chemotherapy agents plus PARP inhibitors. And even as we think about the current landscape, combining ADCs, antibody drug conjugates, which are obviously, I would call it -- and Roger is very humble about his achievements with pembro. We used -- I would say when he was at Merck, we were in the era of PD-1, PD-L1 inhibitors. And we're certainly now in the era of ADCs. There are so many different ADCs out there. And a big challenge now is how do we enhance and build on the first-generation ADCs that have already been approved, for example, Enhertu, Dato-DXd, Trodelvy, all of those drugs and a good combination to think about -- and combinations need to be front and center of what we do. And so combining PARP inhibitors and ADCs, particularly TOP1 payload ADCs is a very rational approach, and we can talk about that if you want, the mechanisms. But certainly combining a TOP1 payload ADC plus a PARP1 selective agent certainly makes a lot of sense from a scientific perspective and hopefully, from a clinical perspective as well.

Yes. I guess, quickly, we will get you to explain that to everyone. So what is the mechanism by which a TOPO1 payload would sensitize a cell to PARP inhibition?

Yes. So as we think about how TOP1 payload ADCs work, essentially, there is a formation of the TOP1 complex that binds to the TOP1 molecule, and that basically screws up the whole repair mechanism and stops transcription translation in cancer cells and leads to cell kill. However, there is a molecule that comes in to actually remove that TOP1 payload from the actual damaged DNA. And guess what that molecule is, that molecule is PARP1. So wouldn't it make sense to actually come in with a PARP 1 selective inhibitor to stop that molecule from coming in and removing that TOP1 complex and that will help actually maintain the damage that one is already achieving with a TOP1 payload ADC. And so to me, as we think about rational combinations because right now, everyone is combining everything with an ADC, I don't think that's the right thing to do. I think we need to go back to science and first principles and to really match up lab research with translational research and clinical research. And certainly, a great partner and a rational partner to combine with these TOP1 payload ADCs would be a PARP1 selective inhibitor for all of the reasons I mentioned.

Yes. But the heme tox being the primary reason?

Well, from a mechanistic perspective, efficacy, the molecule that removes the TOP1 complex from the DNA damage in these cells really is PARP1. And so it's really PARP1 that we need to address. And that's the reason -- and the rationale for combining a PARP1-selective inhibitor with an ADC.

Okay. Cool.

But if I could jump in, I'd say that we wouldn't mind having a PARP -- a dual PARP inhibitor, PARP2 inhibition as well, if it weren't for the fact that, that limits to a considerable extent, our ability to dose patients with the drug because of the underlying hematologic toxicity. And that's -- Tim, you can speak to that very clearly, but patients have a lot of difficulty even in the maintenance setting after platinum treatment as we did with olaparib initially, they have a lot of difficulty staying on drug. The anemia is significant. And for many of the dual PARPs, there's very substantial neutropenia and also platelet effects, thrombocytopenia. Olaparib is, I think, the best tolerated. But even so, it's hard to maintain people on this. If it is really true, we believe it is, but if it is really true that by selectively inhibiting PARP1 and not PARP2, we can improve tolerability, then we can approach all of these important areas that Tim, you've outlined.

Yes. And to build on what Roger just said, which I completely agree with, it's also about maintaining patients at meaningful doses at the RP2D, at the recommended doses that have already been shown to be effective. If there is a way of developing more selective agents without the heme tox, we can avoid dose reductions, dose interruptions because all of that will impact ultimately on the efficacy of the PARP inhibitor. And that's the whole rationale really for the development of these PARP1 selective agents. We're thinking long term here. We're thinking about survival. We're thinking about PFS and OS. And so if we can maintain patients at the starting dose of the PARP inhibitor, wouldn't that be great? And we've already seen from other PARP1 selective agents from other companies that you can achieve much greater pharmacokinetic drug exposures as well with a PARP1 selective agent versus the first-generation PARP inhibitors. And the truth is when we were developing the first-generation PARP inhibitors, we did see DLTs, a lot of myelosuppression at higher doses. Even at the recommended doses, we still do see myelosuppression, as Roger was alluding to. And therefore, if we could actually come up with a way of dialing out the PARP2 and really focusing on the PARP1 inhibition, that will help create an effective drug, but importantly, a better tolerated drug with higher drug exposures, better PK, better PD and to keep those patients on that particular dose and schedule without dose interruptions and dose reductions.

Yes. And also, we can use the -- we can go into first-line therapy in principle much more readily with novel chemotherapeutic agents because we won't be adding the myelosuppression to them, which is often a consequence of new therapies, including antibody drug conjugates. So the idea of combining these together is very appealing. This all has to be demonstrated. Of course, it's not -- we don't know if this is going to work.

So a few more questions on the mechanism. Would we expect any efficacy loss from not inhibiting PARP2? I guess, in the context of the first generation of PARP inhibitors, they all do hit both PARP1 and PARP2. Any thoughts there, Tim?

Great question. I think we could use early clinical data that have already been generated by AstraZeneca are data that have already been presented with saruparib. And we -- even with their PARP1 selective agent by dialing out the PARP2, they're still seeing impressive efficacy in those clinical trials. So I think that in itself answers and addresses that question.

I think the criticism is that they see myelosuppression that's not very different from what they saw with olaparib and you published some of that data. The exact reason why that's true is unclear, but it may be that the selectivity of saruparib as the first of the PARP1 nominally selective inhibitors is not quite selective enough. And that's still enigmatic, I think it's fair to say.

Yes. And I guess the other thing for PARP inhibition that we haven't touched on yet is the concept of trapping versus inhibition. And for the 4 approved PARP inhibitors, they also differ quite substantially on that scale. So help us understand the differences there, which one is more important? Or do we need both?

I think there are different uses for a trapping PARP inhibitor versus a non-trapping PARP inhibitor. But you quite rightly state that the 4 approved first-generation PARP inhibitors are all good trappers. The one PARP inhibitor, first-generation PARP inhibitor that does not trap PARP is veliparib, and that is a drug that's not approved as a single agent. And we don't tend to see monotherapy activity even in BRCA-mutated cancers or at least a lower rate of responses. And so certainly, for -- from a trapping perspective, you do need some PARP trapping as you think about the development of these drugs as monotherapy agents to really drive cells into apoptosis, you do need some trapping there. As you think about combinations, that's where probably trapping becomes less important. It's still important, but you probably don't need as high of a trapping capability or capacity versus, say, a monotherapy approach because you're basically building and enhancing the efficacy of a cytotoxic drug, whether it's platinum, whether it's an ADC. And so it's a different function that you're using the PARP inhibitor with.

And Roger, I guess, as you were evaluating 1003 and 1004, what was your kind of goal in terms of trapping and the profile that you saw there?

I think as Tim says, trapping seems to be the easy part in a way. Most of the agents that you find do trap the poly ADP-ribose polymerase enzyme on DNA. It's sort of a feature of many of the DNA damage repair enzymes that if you inhibit their activity, one of the things that you do is you drive them on to DNA in a nonproductive context and then they just sit there. And that's what we call trapping. I think that the enzymatic activity, which involves the transfer of the ADP to the proteins in the area and broadly speaking, I think the enzymatic activity is important. I think that, that's a critical factor ultimately in driving efficacy. So for us, what we wanted to see was selectivity at the enzymatic level. Trapping selectivity clearly has been achieved, but enzymatic selectivity was harder, and that was what was so appealing for the molecules 1003 and 1004, which are between 650 and 800-fold selective at the enzymatic level. It turns out, and this goes beyond -- clearly beyond our conversation today that PARylation, this business of transferring the ADP ribose, is a broad regulatory mechanism that's used in a whole variety of different settings. As Tim mentioned, there are 17 of these enzymes encoded in the genome. Not all of them are poly ADP-ribose polymerases. Some of them are mono-ADP-ribose polymerases with a similar structure, but all of them are involved in regulating various aspects of gene expression, DNA manipulation, DNA damage repair. So there's a lot of running room there scientifically to understand how we can modulate PARylation as a way of changing responses to other therapies, I think.

Yes. So before we go on to the indications that you are pursuing with 1003 and 1004, in terms of the 4 approved PARP inhibitors, could you give us a quick snapshot of the strategy there for how they've gone into different tumor types because it is quite complicated. There are in lots of different tumors in various combinations or monotherapy maintenance versus treatment settings.

Yes. I mean it's a lot.

How do you kind of map it out for yourself?

Yes. I think of it in terms of the 4 canonical cancers that where we do have PARP inhibitor label. So ovarian, breast, prostate and pancreatic cancer. And olaparib is approved in all 4 of those indications. And as we think about which setting in ovarian, it's in the frontline maintenance setting based on the SOLO-1 data. In breast cancer, it's in 2 different settings in the adjuvant, but also in the relapse setting. In prostate cancer, it's approved in many different indications now, and that's where it's getting very busy because of approvals, not just in the monotherapy relapse setting, but also in combination with the new hormonal agents that are out there like abiraterone and enzalutamide, and it's a very busy space with many different combinations that are ongoing. And then in pancreatic cancer, it's approved in a maintenance setting in the frontline germline BRCA-mutated tumors in patients who are responding to the initial platinum or chemotherapy agents. So olaparib is approved in all 4 of those indications. Obviously, you also have niraparib that is approved in ovarian cancer. You also have talazoparib that's approved in breast cancer. And what's the fourth one?