Okay, welcome back to the 44th annual TD Cowen Healthcare Conference. I'm Marc Frahm from the biotech team here. I'm joined by my colleagues, Tyler Van Buren and Troy Langford. We're really pleased to have with us on for this next panel on development programs in breast and lung cancer, from Black Diamond Therapeutics. Mark Velleca, the CEO from G1 Therapeutics. Jack Bailey, CEO from Monte Rosa Therapeutics. Filip Janku, their CMO. From Olema Oncology, Shane Kovacs, their COO. And then Alan H. Auerbach from Puma Biotechnology, their CEO as well. Maybe to show the way we'll run this is, the first portion of the panel will go through some more general topics, that kind of cut across breast and lung cancer, and kind of and across all of these companies and their development programs and how they think about things. And then we will transition eventually into more company-specific programs, and go down the line with those. So to start off with, maybe we do hear about IRA impacts on trial design, longer-term trial design planning, and how you think about ordering settings. And I think, in particular, in some of these tumor types like breast cancer, that's really come up. So maybe to start there, and maybe I'll start with Shane. If you wanna just kind of discuss how your thinking about the space has or has not evolved kind of over the last year or two as this has become law and started and is beginning to be implemented. An IRA impact and how you think about. Oh, yeah. Yeah. So, I mean, for us, we're obviously in the metastatic setting in breast cancer. And the initial, clinical entry for us is in the second, third line metastatic setting. And we're in a pivotal trial right now. And we have plans to pursue in the front line in combo with Kisqali. And obviously, the sort of median the duration of running a second, third line study, you get to PFS quicker than you do in a front line study. And so that goes to this question, the strategic question about launch sequencing. And if you're limited because obviously, in the front line setting, the duration, the the expected duration is 3 or 4x what it would be in the second, third line setting. And so the commercial opportunity is significantly larger in first line than it is in second, third line. And therein lies the question: would you delay or postpone a second-, third-line launch because of IRA so that you could maximize that sort of area under the curve? I think that is the strategic question. And I think for us, you know, as we do our modeling, one is we wanna bring this our drug to patients as quickly as possible. So we've initiated our second-, third-line study that's gonna read out for us in 2026. We're actively planning for our front-line study now. We have, you know, hoped to initiate that by the end of the year, early 2025. And that study obviously takes longer to read out. As we've modeled out and as a former banker, we do a lot of financial modeling. And you kind of model out through 2040, going out 15 years. You know, for us at least, the early analysis we've done is that IRA impact is really around government pay patients, Medicare, Medicaid. So on commercial pay, you wouldn't necessarily the pricing wouldn't be impacted by any discounts that might be accrued to IRA. And so overall, the impact, and it's, at least the way we've modeled it, IRA impact. It's not gonna be like generic pricing coming in all of a sudden and taking you down by 90%. So I think as we look at overall, you know, is there some impact to NPVs as a result of IRA? Probably. Is it drastically undercutting the value of our company that we would change the way we're gonna bring the drug to patients? No. So, we're just going forward, I think, is our plan, pursue the second, third line sequence, get this drug through clinical development as quickly as we can, and get the patients that it might benefit. Jack, you have a marketed product already. Just how is this kind of impacting your kind of strategic planning of, you know, how to manage the company going forward, you know, given what may or may not come down the pike later in its life? Yeah. I first of all, I think it's a great question. I think the immediate impact for us is less. But I think what is very interesting, I think, to your audience is the fact that if IRA was in existence prior to our initial indication in small cell, I'm not sure it would have come about. We're a small molecule, even though we're reimbursed under Part B. And for those of you familiar, the extensive stage small cell lung space is one of the smaller tumor types. And at day's end, there hasn't been that much interest in it because at this point, it's not about curing the patients. It's more about quality of life. But I think it would have been hard, potentially, for our investors to get behind this being the initial indication if the IRA was in place. Because frankly, there's other bigger tumor types we are looking at and have looked at, that are much larger that they would have said, "Let's skip small cell and just go to the bigger ones under this IRA regime." That's exactly what we don't want, right? You want more innovation, especially in some of these tough-to-treat tumors. You want patients to be front and center on this. You don't want to have to take what is already pretty hard in terms of taking an idea and the science into an approved molecule, and now have to layer on top of this the fact that, especially in oncology, I'm gonna skip a small tumor type to Shane's point to simply go for a bigger one. Maybe that's, you know, larger in prevalence incidence or maybe a treat to disease rather than we're limited cycle dosing. So for us, I don't think small cell would have come to light, frankly, if IRA was in place. So and that, to me, is a good textbook example. Is that what we want? And Alan, maybe for you, one, you have a marketed product in the space. But also, you're planning, you know, development for your pipeline asset, Alisertib, just, you know, maybe compare and contrast dosing and how you're approaching it. Yeah, absolutely. So when we licensed neratinib, I don't think, you know, IRA was not in place. So we didn't really think about that. Now we've licensed the drug alisertib, which is the Aurora Kinase A inhibitor. Obviously, it has much broader, you know, applicability, if you will, into a lot of tumor types. And yeah, you know, unfortunately, IRA, whereas, you know, look, every biotech company gets in with the goal of helping patients. Unfortunately, IRA has made it so that you have to take what I refer to as like a Icarus-like drug development plan. Icarus being the Greek mythology character. You fly too high to the sun. You're gonna burn and crash. That's what you have to do. You have to think forward about, "What can I develop and not pop on that radar screen because it's gonna be detrimental to the shareholders?" That, unfortunately, is probably detrimental to patients. It's really unfortunate. With alisertib, we don't quite have the concern yet because with the drug's mechanism being Aurora Kinase A, we're very lucky to have licensed the drug from Takeda who put it into, you know, well over 1,000 patients. And it's clear that where we see the best activity is in mechanisms where the Aurora Kinase A pathway is activated. So the three that are kind of on our radar screen is, you know, small cell lung, which, you know, as Jack mentioned, is a smaller indication, so not a concern. In HR-positive breast, which is a larger indication, but it's just in the subgroup that have, you know, biomarkers or mutations that are applicable to the Aurora Kinase A pathway. So again, gonna lower the numbers, if you will. And then more recently, we described that, we have an ongoing study that we'll be presenting this year at ASCO, where we add Alisertib onto Tagrisso at the time that a patient fails Tagrisso. So it's EGFR-mutated, non-small cell lung cancer. And in a biomarker subgroup that's about half the patients, you know, we're getting a wonderful signal of activity. And that data will be presented. So luckily, with Alisertib, because we're only going into subgroups of larger tumor types, it isn't quite hitting the radar screen yet. But, you know, is it something we think about? Every company in this conference is thinking about it. Yeah. Over the past couple of years, we've seen interest in ADC-based approaches increase, especially in breast and lung cancer. And so I guess, how do you all see the standard of care in these two different indications evolving around these new treatment approaches? And where do you think the unmet need still remains? And maybe I'll just leave it open to the entire panel for whoever feels like they have relevant commentary. Maybe I'll kick it off. I mean, we know it, I mean, depending on whose data you look at, something like an excess of 100 different ADC companies. So this is a wave like we've never seen, frankly. Clearly, to your point, it's really about breast and lung. Early on, obviously, Trodelvy and some of the Trop-2s focused in on sort of second, third line, as an indication already. But clearly, some of the data, the studies reading out to move into first line and then ultimately to move into more of the early stage setting, where obviously, it's a bigger category and more treatments to benefit more patients. And then, yeah, on lung, obviously, the other big one that they're focused in on, I think, you know, as somebody that's in the triple-negative breast cancer space, it has the potential to really shift it. We've done our own look at how trilaciclib may be able to help those ADCs. So we're all for anything that's gonna give more options to physicians. But, yeah, I think this is a wave like we haven't seen in bigger than the checkpoints were, so. Maybe, Mark, do you wanna add on here, you know, because you're kind of facing this, right? Like the post-Tagrisso, that portion of your development program, right? There are some data sets from these ADCs, but they're not really, you know, addressing the direct mutation, which is what you're trying to go after. Just how do you kind of see that evolving? Yeah. I mean, there's no doubt they can deliver, you know, robust response rates. You know, durability, I think, is still a question. And there's also no doubt that it is still chemotherapy. And there are, you know, lots of associated toxicities. It's an IV infusion. So if there's an option for a patient that's an oral therapy, that's well tolerated, I think that's, you know, listening to your lung panel, earlier this morning, that was more on the bispecifics. But I think for patients, a well-tolerated oral therapy is always gonna be preferred to something that's more toxic and is IV. Shane, are ADCs gonna take over breast cancer? So we're in the same I mean, we're on the same view with, like, an HER2 and obviously, in DESTINY04 data showing activity in HER2-low, etc. So we see in HER2 is obviously a great asset. It's a great drug. And it's doing well for patients. And it will continue to probably move up the therapy chain and replace chemotherapy. But there's no question that first line standard of care in ER-positive HER2-negative metastatic breast cancer is a CDK4/6 today plus an endocrine therapy today that, on average, keeps the, you know, median PFS of 24-25 months. It's a significant improvement from where it was, you know, 10 years ago when it was monotherapy AI, which was 14 months. So we've gone from 14 months to 24-25 months. And that's a once-a-day oral therapy for patients. When they progress and if a patient has an aggressive tumor and they would otherwise go to chemo in the future, we're gonna see, and that one might go to Enhertu instead of chemo. But you stick with a once-a-day oral therapy that's well tolerated. If that helps a patient for two or three or four years, that's what you do. And Philip, you know, as a former clinician, maybe put that hat on, you know, how these decisions are made, you know, maybe a broadly active ADC but then a targeted therapy for that specific patient subpopulation. Just maybe walk through that and how you're approaching it. Well, I think the ADC, such as I had a few of you explained, it's been like a great improvement of a great improvement in the field of metastatic breast cancer, both HER2-positive as well as HER2-low. But things not to be discounted is it's an IV therapy. It has a low frequency of interstitial lung disease, but it does exist. And it can be including actually potential fatal consequences. So it kind of just built on what Shane said. I mean, it's already compared to hormone therapy, which is actually quite well tolerated. It's a it's one daily pill. I think, I wouldn't necessarily worry about the fate of the oral therapies. I mean, it's a that's and that's not been true only for oncology. I mean, if you look at for many other fields, in oncology or outside of oncology, the oral therapies are often preferred over the injectable alternatives. No question, though. It's great innovation for patients for cancer patients. And it's improving, you know, treatment paradigm for patients with lung or breast. So it's just great. There's just nice to have all those different things in the bag for the oncologist to use. Maybe as a final general question and a lead-in to kind of company-specific, round-robin that we'll do, what are the biggest unmet needs in your respective spaces at the moment, whether it be technologies employed, regulatory or commercial considerations, or more specific indications? Whoever would like to kick it off. I'll start. Well, for EGFR-mutant non-small cell lung cancer - and I know we're gonna talk about next-generation sequencing - it's the realization that there are many more mutants out there than we first appreciated. And, for the most part, there aren't drugs that target those, what we call non-classical mutations. So we see a very large unmet need in the EGFR mutational landscape, not just in second, third line in patients that progress off of Tagrisso, but in first-line patients who are now presenting, again, with increased adoption of NGS with these non-classical mutations where there aren't drugs available for patients. So I think that's a big unmet need. And again, a really good opportunity for a well-tolerated oral therapy. Anyone else? I mean, for us, it's all about extending so overall survival. Obviously, PFS comes earlier. So in metastatic breast cancer, the longer we can push out PFS and OFS and OS, sorry, the better. That's the goal with all of these therapies. If you're adding in an ADC, if you're bringing in now a new CERAN that's gonna best indeceive the AIs, I mean, it's just continuous innovation to continue in the metastatic setting to push out survival and to push out PFS. And we even see that with that early launch of our Orserdu, right, the Menarini drug that was originally Radius, which was originally being developed for its estrogenic effects, you know? And they stumble on and use it now and see has activity in metastatic breast cancer, which is great. And the early commercial launch in ESR1 mutant is astoundingly strong, which begs to the unmet need in breast cancer, you know? And we anticipate we're gonna, you know, do significantly better. Little things, which I would highlight. There's an unmet need, which kind of applies to both lung cancer, small-cell and non-small-cell, as well as breast cancer. It's actually like a targeting of the MYC pathway, which is actually driver behind a substantial number of cases for all of these indications. And while, especially in lung cancer, to less extent in other indications, we made some noticeable advances by targeting certain activated pathways, whether it's EGFR, whether it's actually MET/ALK or, MIG/TRK or many other advances we can talk about. The MYC actually remain or even KRAS, but for that matter, but the MYC actually remains largely untouched. And that's actually what we are trying to change. Okay. Maybe we'll start going into some of the company-specific questions. So it's not to be accused of picking favorites. We'll go alphabetically by the company names. So we'll start with you, Mark, at Black Diamond. So maybe you started to touch on this a minute ago, the idea of these non-classical mutations. You know, at times, the company's also referred to them as acquired or intrinsic based on the setting. Just can you maybe explain a little bit of how these differ from the quote-unquote "traditional" EGFR mutations where we think about Tagrisso and the predecessors before Tagrisso? Yeah, sure. We've learned a lot about, you know, the EGFR mutational landscape over the last 20 years. We'll continue to learn. In fact, we'll have an oral presentation at AACR describing this rapidly evolving mutational landscape. The first drugs, the first and second generation, were against these class two mutations, Exon 19 deletions and L858R. Great drugs, but resistance developed. The primary mechanism resistance for those first-generation first and second-generation drugs was T790M, which is a drug resistance mutation, drug can't bind. Along comes Tagrisso, very well tolerated, potent activity on those class two mutations, and addresses this primary drug resistance mutation. It got initial approval in second line. Now it's in the first line and adjuvant setting. But, you know, cancer smart, it finds a way to continue to grow. And it's done that in two ways in the case of Tagrisso. It's a new drug resistance mutation called C797S. That's kind of the new T790M. We don't really see T790M anymore in this country. But what we've also found, and this gets to the point of so many more patients getting next-generation sequencing, are this whole host of non-classical mutations. So these are all over the receptor, not just in the kinase domain but in the extracellular domain, throughout multiple exons. They all have oncogenic activity. John Heymach published on this at MD Anderson, Jänne, at Dana-Farber. And for the most part, Osimertinib does not inhibit those non-classical mutations. They're there in probably 30% of non-small cell lung cancer patients. And what's really interesting is they're often co-expressed with L858R. We all know that Tagrisso doesn't work so well in that L858R population. So, you know, for us, you know, recognizing that there's this whole host of mutations, classical, non-classical, and this new drug resistance mutation, you need a fourth-generation EGFR patients need a fourth-generation EGFR inhibitor that can adequately cover that very broad spectrum of mutations. And that's what we believe we have in BDTX-1535. Maybe can you speak to the frequency of these kind of in aggregate in those different settings, the upfront versus the? Yeah. You know, upfront, again, we'll have more to say about this at AACR. It's upwards of 30%. Now, some of that is in combination with L858R. But some of it is just non-classical mutations on their own, 10%-15%, and then another probably 10%-15% in combination with L858R. Now, in the second- and third-line, and this has been published again, Julia Rotow and Jänne published a paper last fall about for those patients that stay on pathway with EGFR mechanisms of resistance to OC, about half are C797S. About a third are non-classical. And the other are a combination of non-classical plus C797S. So we see patients coming off of Tagrisso who have a classical, a non-classical, and C797S. So again, you need one drug that can adequately address all of those. Okay. Great. So maybe let's move to Jack and G1 Therapeutics. So obviously, you all have Cosela approved for SCLC right now. So maybe can you just talk about the progress that you all have made in the launch of Cosela in SCLC to date? And maybe what do you see as the key drivers of continued uptake of the product in SCLC over 2024? Yeah. So, we're our first indication is, you said, is in, small cell lung cancer, smaller tumor type. It's on a supportive care front. You know, from our standpoint, for a product that was breakthrough designated by the FDA, got dual NCCN committee endorsement 6 weeks post-launch. I've been in oncology for 30 years. I've never had that that quickly is on the ASCO guidelines. It speaks to the innovation, that this product represents, which is great leadership of folks like Mark here, who was my predecessor. And, and also the need there's a need in the market. We, you know, oncologists who use this product have over 90% highly satisfied with it. If you look at the reorder rate, it's at 85%. Nurse practitioners and nurses love this. I think our challenge is really, a couple-fold. And the payers love it. It saves $19,000 per patient. I think for us, it's more of the systemic challenges that your typical oncologist has, of being able to bake this into the EMR, preferably in an opt-out status because, again, with a smaller category, you're seeing a couple of these patients a quarter. We're really battling habit, right? For 30+ years now, somebody gets put on chemotherapy. It's really a reactive process of monitoring their, you know, white blood cell counts, red blood cell counts, platelet counts. And if something occurs, then we have another intervention. You get hospitalized for febrile neutropenia. You get a transfusion. For us, we think Cosela represents exactly what the healthcare system needs, which is this is preventative, right? It's multilineage. So it's not single lineage. You're not dealing with red blood cells, white blood cells, and platelets individually. It's all of them. It's great value. As I said, it reduces hospitalizations to the point where you're saving $19,000 per patient. Highly innovative is shown by the endorsement, as I said, by NCC and ASCO, etc. But it's really bringing that to life in the mind of the physicians so that we can break this habit of being reactive and not remembering it. Now, institutions that have adopted it well, whether it be an MD Anderson, an MSK, that's great. But we have a lot of other academic institutions that, again, you work through the normal healthcare process that, you know, oncologists now are subjected to. And it's a long road. So, you know, for us, the product works. It worked great. Those who use it love it. Whether it be the patient, the physician, the nurse, it is really about trying to systematize this process so that we're not relying on breaking a 30-year-old habit and then remembering that patient comes in, that you're using this preventatively, not reactively. So for us, you know, we've done that through the establishment of a strategic accounts team. We've expanded that quite a bit. We're seeing really nice progress there. We do find the role of contracts can help on some of these organizations. And then the ASCO guideline endorsement that came Q4 last year, we're really leveraging that. So those are some of the things that we think will continue to drive the performance of the product, the revenue growth, and the patient benefit. The last thing I'd have to say, just because we dealt with it last year, is the chemotherapy shortage, right? We all know since 2010, this country has wrestled with, in particular, generic sterile injectable shortages. Last year, this country had a major outage of platinum-based chemotherapy for a whole bunch of reasons we can go into later if you want. But for a country of our means to be dealing with that and our product is used on top of chemotherapy, it was a little disappointing. But the good news is, it resolved itself at the end of Q3, and we're back to 20+% growth. So we look forward to continuing with that. Great. And then maybe moving to breast cancer a little. The company's obviously indicated that it now expects the final OS analysis from the phase 3 PRESERVE-2 study in Q3 2024. Yeah. I guess, how confident do you feel that the study can complete within this timeframe? And then should it succeed in this study, how quickly do you think you can file an SNDA for Cosela and the indication? Yeah. So this is our phase three study, as Troy said. And it's slated for Q3. It's an event-based study. But, you know, we model and project out. So we feel very confident it'll be in the Q3 timeframe. At day's end, assuming a positive study, we would move quickly to engage with the FDA and look to be filing an SNDA, which it's already been given fast-track status by the FDA because, again, tough tumor type here and triple negative, not a lot of options. Our study is an all-comers. As we know, the only thing really available today is Keytruda/Pembro in the PD-L1 positive. So our study, if it replicates what we saw in the phase two, which was a 60%-70% reduction for all-comers, if we replicate that, this will be the single biggest improvement to triple negative to date. Again, the FDA has already signaled they want to make sure they work with us to get this to patients as quickly as possible. Great. We'll move on to Monte Rosa with Filip. Filip, you started touching on it a minute ago on just the idea of targeting MIG. Of course, your drug is trying to address MYC-driven tumors via GSPT1. Can you explain the rationale of why it makes sense to go through GSPT1 and particularly using a degrader? So a couple of things, actually. GSPT1 controls the terminal phase of translation. So it's a translation termination factor. So as its name implies, it actually is responsible for effective termination of the translation process. And the MYC-driven tumors are heavily addicted to the translation. So the translation is really ramped up and needs to function at a high level to kind of execute that oncogenic potential of the MYC-driven tumors with the activation of the MYC pathway. GSPT1 is not really druggable by any other means. It's an undruggable target by the means of being targeted by inhibitors. So that's why the degraders through molecular glue actually makes perfect sense. It's, and thanks to our platform, we were actually able to come up with the molecule with the properties such as MRT-2359 has, which is oral, which is actually highly selective and which actually shows the differential potential on selective effect on the in the MYC high setting versus non-MYC-driven or normal cells, which actually then results in selective effect on the cells which you want to affect and sparing the cells which you don't want to affect. Good. Then you've kind of shown some phase 1 data last fall. Maybe describe the kind of highlights of that data in particular, kind of where you're getting from a degradation profile of, you know, how deep and how prolonged the degradation is relative to kind of what the target was based on your pre-clinical modeling. So a couple of things. We had an interim disclosure of our existing phase 1 clinical trial, which we actually disclosed on October 17th of last year. It was actually data from 21 patients treated across three dose levels. And essentially, the goal of the disclosure was actually several to show the pharmacodynamic effects, to show pharmacokinetic, to show safety, and also the early efficacy data, although since it was early in the dose escalation, it was a relatively limited data set. But we felt that the data were actually quite exciting. There is one important thing about the GSPT1 degraders that when it comes to the effect on the MYC cells, not all GSPT1 degraders are created equal. So it just doesn't work that you select any GSPT1 degrader, and you can expect the differential effect on MYC high versus MYC low. The reason is, the reason is actually following. If you have a degrader, which is like, which is like super fast, and it creates like a fast and deep degradation, you might actually lose the differential effect. So when we did all the preclinical work because the knowledge about the GSPT1 and effect on MYC-driven tumors was not really out there, so we had to do a lot of work to elucidate that, we actually found out that the optimal level of degradation to see the differential is actually about 60%-70%. And it actually makes perfect sense because, I mean, if you kind of keep ramping up GSPT1 degradation, you will ultimately start hitting other cells as well. So what we showed in the disclosure, we actually showed that consistently with that, with that expectation that that optimal degradation is somewhere around that 60% ballpark, which we have seen repeatedly, including the PDX studies that we've seen that in the clinic as well. We've seen that in all dose levels. In other words, all dose levels were actually as expected. That's something which we communicated before, that all doses were actually fully pharmacodynamically active. While the PKs were actually showing the dose proportional increase, the pharmacodynamics was further saturated from the dose level 1. In addition to that, we actually found out that despite you see the full pharmacodynamic effect, the first 2 dose levels were actually safe. They had really no grade 3 treatment-related events. There were mostly grade 1, a little bit of grade 2, mostly GI, fairly manageable toxicities. The third dose level, which was the highest dose level, actually turned out to show some DLTs, which would be hematological toxicity, thrombocytopenia. Again, that was expected. That was expected based on what we have learned preclinically. In addition to that, obviously, our study is not designed to select, at least in the phase one, for, based on the biomarker status. So we enroll certain tumor types such as non-small cell, small cell, lung cancer, or MYC-amplified tumors. But we don't preselect based on MYC expression. We do that exposed in the tumor biopsies. And so we don't necessarily control the proportion of the biomarker-positive patients. But our anticipation was that about one-third of patients would be biomarker-positive. And that turned out to be the case. So out of these 21 patients across three dose levels, we had 15 who were at that, at that time available for response, and about six came as biomarker-positive. And in this patient population, we've seen actually one confirmed response, one unconfirmed response, and one actually prolonged stable disease in, while stable disease sometimes doesn't create the same excitement if it was a small cell lung cancer patient. So if you have actually multiple ones, in small cell lung cancer not growing, that's a meaningful outcome as well. Okay. Let's move to Olema Oncology. Shane, so you guys had a great update at ESMO in Madrid, monotherapy update. Maybe you could start with palazestrant. Maybe you could start by giving the highlights of that data set and how it compares to the monotherapy data sets presented by the other degraders. Yeah, sure. So, I'd say that the last 12 months, we presented a lot of data, clinical updates, monotherapy in combo. Most of it was all in Q4. And I think for us, it's significant. The data we presented last year significantly de-risked the company and makes our path forward very clear. We had an oral presentation at ESMO in Madrid in October. It was presented by one of our lead PIs, Nancy Lin at Dana-Farber, who's been one of our biggest enrollers. And I think hands down, we now we think we have absolutely the best-in-class single agent activity, for what we think is going to be a new evolution in standard of care for the treatment of positive breast cancer. We think that finally, this new class of SERDs or what we think are CERAN SERDs really is going to beat standard of care AIs in Fulvestrant and take over the treatment lines. Then aside from breast cancer, we think that our data clearly shows we got best-in-class activity, safe, well-tolerated, and really nice PFS. And that's the approval endpoint is PFS. You don't see a lot of responses in late line with an endocrine therapy, I mean, because it's just not the mechanism of action. We're cytostatic, not cytotoxic. And the approval endpoint, it's actually a higher bar to extend PFS than OS because OS shows up at your first scan or sorry, not OS, PR show up at scans, right? But extending PFS is what's important. So that was the data we showed. In our subset of second- and third-line only patients that were akin to the EMERALD inclusion/exclusion criteria, we showed about a 7-month median PFS, and about 5.5 actually in wild type. So we think we have a real opportunity to differentiate not only by hitting the ESR1 mutant, but the higher bar is to hit wild type in late-line patients. We actually bind probably more potently wild type receptors and shut off activity of wild type receptors, versus ESR1 mutant. But it's harder to show in a later stage patient that's still wild type single agent activity. Okay. Thanks for that. So, you guys have started the enrollment of your pivotal trial. So can you talk about the status of enrollment there, when we might be able to expect top-line data, and ultimately what you need to show for approval, potentially both, obviously, an ESR1 but also wild-type? Are there if you just replicate the data you've showed, do you think that's enough? Yeah. So we kicked off, opened up sites back, and I'd say November. We're enrolling now. It's a 510-patient global study. We are, actively opening sites right now. Sites are open all across Asia-Pacific, North America. We're pushing into opening up very soon Europe and Latin America. So it's truly global. It's about 220 or so clinical sites, like 15+ countries. So operationally, it's quite a big undertaking. As you know, in clin-ops, enrollment is always a hockey stick, right? Because you open up the sites, and then the enroll and then the screening starts to trickle, and it gains momentum like a snowball. So but that's all on track. We anticipate top-line data in 2026, so a couple of years out, which is a good thing. Actually, the longer it takes to get to a, you know, number of events, it means you're, you're doing well. For us, though, it's all an enrollment game. All of the data that came out could be from Emerald or acelERA or AMEERA-3 or SERENA-2. It all says that in a post-CDK4/6 experienced patient population, the control arm, and for us, it's physician's choice, but it will be mostly Faslodex, some AI. The control arm's going to have a median PFS in 2 months. I mean, all the data points to that. So that would be our expectation on what our control arm would do at a median. You know, if we think about your question on what is it, what do you need for an approval? I think Emerald is the approved drug recently by FDA and EMA. And what they showed is about a 2-month benefit, at the median point, right? You probably need at least two months because that's, that's the interval for which you're evaluating for radiographic progression, right? We do scans every eight weeks. And so that PFS curve, it has to be about radiographic progression, not clinical progression. It gets censored if it's a clinical progression. So it's all about radiographic progression. The interval by which you're doing that is two months, right? So you probably need about a two-month benefit at the median to make that clinically meaningful. And then you need a hazard ratio versus your control arm that's stat-sig and probably a hazard ratio of, I don't know, is it 0.7 or 0.75? Obviously, in the ESR1 mutant, Emerald had a 0.55, right? So when you look at those curves of their, their PFS curves of the Emerald study, clearly, it's not a proportional hazard as you would normally expect. A bunch of patients are not responding to monotherapy, endocrine therapy. They come off right at that first scan, and you see that precipitous drop in both the control arm and in that elacestrant arm. All the studies show that same thing: SERENA-2, AstraZeneca, you name it, right? Then the medians don't really tell you the story about the benefit of these drugs because once you get through those patients that come off at the first scan, then you get nice separation versus standard of care. That drove a 0.55 hazard ratio in ESR1 mutant for EMERALD. If we repeat our 7 months versus 2, that's going to be very clinically meaningful, 5 months versus 2 at the median. That's going to drive a hazard ratio that's much, much lower than 0.55. That would be in the mutant population. And then in the wild type, the bar's probably, again, a two-month or so, right? Because that's your interval for when you're doing scans, and you need probably a hazard ratio that's clinically meaning that's STAT-safe and, you know, 0.7 or 0.75 or better. So I think that's the bar for hitting mutant and wild type. And strategically, the advantage to getting an all-comer label versus an ESR1 restricted, mutant-restricted label is massive because you don't have to come and take the blood test, send it away, wait a week or two weeks, and then turn away half the patients. As soon as you come in for that visit, you just get the script for palazestrant. And so that means you get massive market share. Great. Thank you. Alan, we'll turn to you. You started to also touch on this before, you know, the history of alisertib with Takeda. You obviously, some of that data had been published. Some you had subsequently published. Maybe, summarize kind of the key takeaways from those data sets and, and importantly, how that's informed the trial you just started in small cell. So when we licensed alisertib from Takeda, they had done a tremendous amount of work with the drug across solid tumors and liquid tumors. And we were really focused on solid ones, specifically in small cell lung. They had originally done a study, which was a phase 2 trial in, you know, multiple different types, lung, small cell, breast, etc. But the drug showed good activity. It was like a, you know, 20% response rate, you know, 3- or 4-month PFS, which for small cell lung, it's kind of in the range. What was really interesting was they did a randomized study, which was paclitaxel with alisertib against paclitaxel plus placebo. And in the patients that had mechanisms of action that were known to be involved in the Aurora kinase pathway, so RB1 mutations, c-Myc amplifications, there was a statistically significant PFS benefit and an OS benefit. That was extremely intriguing to us because, you know, it wasn't something that was just cherry-picked like, "Okay, let's test 50 mutations. Which one did it work in?" etc. There were ones where up front in the protocol, they had said, "Look, this is where we think this drug is going to work best." And so in small cell lung, what's been interesting to me is, you know, in non-small cell, you've seen a tremendous amount of innovation in targeted therapies based on EGFR mutations and other aspects as well. You haven't yet seen that in small cell lung. Most of the drugs that have been approved have been more of an all-comers. This was a wonderful opportunity for us with, you know, a great data set to be able to try to, you know, replicate that on a prospective basis but also move forward on a development plan that was targeted just at the patients where we felt the drug had the highest probability of success. Okay. And as that trial's just started, you know, how are you thinking about kind of timeline to data, and then at least as importantly, you know, what does success look like in this draft? Yeah. So the trial, initiated in February, where at, I think, we've got a handful of sites open. There's a we'll have like 12-15 open by the end of this month. So by the end of the year, we'll probably be looking at, you know, a good amount of data that we'll have. And, you know, we'll obviously be in some way, shape, or form making that public for investors and then probably looking to present it at various medical conferences, you know, sometime next year, etc. In terms of what does success look like? So, you know, looking at the randomized data, you know, the randomized data that generated the statistically significant PFS and OS, you know, they had prospectively defined the biomarkers, but it was a retrospective analysis. So our feeling was, well, let's take this from a prospective perspective where we're looking more at the phase 2. You know, initially, let's look to enroll all-comers and then make it an adaptive trial design where when you start to see the activity in those biomarkers, you can start to enrich just for it. So now you're looking at more of a prospective identification. So what does success look like? You know, something that replicates what we saw in the randomized phase 2. So as a single agent, are we starting to see in the biomarkers where we know the Aurora kinase A pathway is active, you know, a better ORR, a better PFS, something that is, again, replicating that you're again seeing that these tumors that have pathways where the Aurora kinase A plays a role, we're seeing better activity in alisertib. If we can see that, I think that puts us in a fantastic position, you know, to be able to move forward, you know, from more of a registrational perspective. Yeah. I think that's helpful. So I think we'll go back to Black Diamond's Mark. This issue of testing has come up a few times in conversations in different comments. You know, of course, here, as we talked about a minute ago with you, there's the second line opportunity where, you know, the mutations have changed. How common is retesting at that so that you can figure out that, yes, Black Diamond's the best option for a patient? Quite common. And again, thanks to, to Tagrisso, right, when patients would get T790M and needed to document that. So it's become standard clinical practices on NCCN guidelines that if a patient progresses after osimertinib, you resequence. So we're confident that, that, you know, that's here to stay, in a post-Tagrisso world. You want to also just kind of describe the data you've been able to generate so far with 1535 in lung cancer, and kind of how that trial is evolving now that you're, you know, getting to the higher doses? Yeah, sure. So last fall at the Triple Meeting, Helena Yu from Memorial presented the phase 1 results of BDTX-1535. So this was the first clinical data. And really looks like a drug from a number of perspectives. First, extremely well-behaved PK, dose proportional, well-behaved at 100 milligrams. We've got good exposure. It covers all of the mutants that we would like to. And so activity at 100. We think 200's actually the dose and 300 is the MTD. So we have a range of therapeutic doses ahead of us. It is well-tolerated. The AE profile looks like osimertinib. Mostly grade 1-2 AEs are rash and diarrhea that you typically see with EGFR inhibitors, no other off-target tox. But most importantly is the efficacy. Now, these are very heavily pretreated patients, some of them up to 9 lines of prior therapy. Many of them had ADCs, bispecifics. Many had obviously seen a TKI. So out of 13 efficacy evaluable patients, we saw five confirmed PRs and one unconfirmed PR. Several of those PRs and several patients had prolonged stabilization of disease outwards of six to 12 months. So really encouraging signal of activity. And those patients, you know, we resequenced all of them. You could see they had all of the mutations that you'd expect to see in these later lines. So they had a classical driver, a non-classical driver, C797S, or various combinations thereof. We did ctDNA analysis on all of them, and you saw complete disappearance of the variant allele fractions that were found in those patients. So really good signal. It then rapidly moved to a phase two study with three cohorts. The first two cohorts, and there's 40 patients in each of those, and those they're all enrolling. The first two cohorts are in a second- or third-line setting. Cohort one is for patients who have C797S. Cohort two is for patients who have a non-classical mutation, again, in a second- or third-line setting. Cohort three was one that we went to the agency at our end-of-phase-1 meeting and said, "Look, there are a whole bunch of patients newly diagnosed who have one of these non-classical mutations, and there is nothing for them. There is an unmet need." And we got the green light to say, "Go ahead, start enrolling." And so we have done that. Really excited to have the opportunity to give patients a benefit of potentially a 1535 in that first-line setting. Data from that phase 2 trial, we've said second-, third-line in the third quarter of this year and in that first-line cohort, in 2025. And kind of similar to the question to Alan before, of just kind of what does success look like in those cohorts of? Yeah, you know, in second- and third-line, currently, the standard of care is, you know, the chemo doublet of platinum and pemetrexed. It delivers response rates in the 20s and, you know, DOR of about, you know, 4 or 5 months. So success would be something an ORR of 30+ and a DOR of 6 months. In the first-line setting, again, there really isn't anything for non-classicals. Osimertinib is used off-label, with much worse efficacy than it's seen with L858R and Exon 19 deletion. Afatinib has a label for three of these 50+ non-classical mutations, but it's poorly tolerated. So if we, again, benchmark versus chemo in a first-line setting, you'd expect an ORR of 50%+ and a DOR of around 12 months. So those would be the bars that we're looking to hit. Okay. Great. Yeah. Let's go to Jack for the next couple of questions. So the company's indicated that we should see updated OS data from the phase 2 study of Cosela combined with Trodelvy and later line mTNBC patients in mid-year. So can you just provide a little bit of extra color around what you expect to see from that data and what do you see as the next steps in development for that regimen? Yeah. So we've got a phase 2 study with Trodelvy. We released the initial safety data second half of last year, showed over a 50% reduction in a lot of the side effect issues that you have with a lot of these ADCs, especially Trop-2 ADCs, including significant reduction in neutropenia, some of the gastric distress, also. We had at a different health investor conference in January, we released the mature safety data and also the initial efficacy data. And what it showed, if you look at the ASCENT trial, which is sort of obviously the main Trodelvy study, they had 12 months of survival. If you look at our initial efficacy data, we provide 18 months, 17.9 months, overall survival. So a significant improvement in survival. And if you look at the 12-month survival rate, it's 59% versus 50%. So again, we'll see if those hold as, you said, trade mid-year this year. We've got the mature data reading out. But, you know, most folks said, "Hey, anything, you know, to Shane's point, almost 2-3 months better than what we see in ASCENT would be a real win in this population given the aggressiveness of triple negative." So for us, if that holds, somewhere in that vicinity, both on the median OS and the 12-month, we'd be very, very pleased. We would obviously look to probably do some partner. I mean, again, there's so many different ADCs out there. Folks are excited to both reduce some of their AE baggage, but also potentially differentiate further on efficacy. Yeah. And then really quickly on that, do you see potential for Cosela combined with other ADCs outside of later line mTNBC patients? Yeah. I think what we'd like to, depending on how our phase 3 in triple-negative goes along with this phase 2, both again, which read out here mid-year, you know, looking at mTNBC category leadership for us is really what we have our eyes on. If you think about that phase 3 study, you know, if we, it's a replicate study of the phase 2 study, which I said showed 60%-70% reduction in all-cause death. This is essentially the same study, although this is just first line. The phase 2 was first, second, and third line. And I think the thing that gives us a lot of confidence is if you look at the split between PD-L1 positives and negatives, it was about 15 months until the PD-L1 negative started split to split in the phase 2. If you look at where we're at with this phase 3, the enrollment went from June 21 to October 22. So this initial, this interim readout that hit just last month was right about that 15-month point. So we think that's, that, you know, time is on our side here, the more time we get on this. And then we also released, new data, at San Antonio Breast Cancer, which showed when you use trilaciclib, you get this benefit in a longer term because of the positive immune effect in the T memory cells that we, believe are helping to provide benefit once a patient gets it initially. And we had some pretty good separation there in this case, in particular with the ADCs. So we think time is on our side for this phase 3 and that that's positive along with, an encouraging, confirmation on this ADC combination. You've got sort of the waterfront covered there and be able to both create some good development opportunities, but also be, hopefully, well-situated in the mTNBC space. Great. Phil, when we were with you last, you kind of laid out the data that you did show last fall. Of course, now you're continuing to dose at those kind of higher dose ranges, a little bit on dosing schedule being worked on as well. But kind of how are you defining success as you get a larger data set at these more relevant dose levels? Mm-hmm. So, we are still in the phase one, although in very advanced phase of the phase one. So I think, going back to what I mentioned about the disclosure, one of the things which actually was really good to see that our expectation about safety was actually to large extent confirmed. One of the things which I didn't say that we, the schedule which we moved to the clinic was a schedule which was intermittent schedule of 5 days dosing followed by the 9 days off. So 5 on 9 off, 5 on 9 off, every 28 days. And that actually was based on multiple things. But maybe if I go a little bit to the history, the first GSPT1 degrader, which was the IV compound, brought to the clinic by Celgene and AML, actually used the 5 days dosing every 28 days. One of the reasons why they didn't get beyond the five days was that one of the on-target effects was actually low levels of calcium, which manifested typically around day five. So even though we expected that this would be much less an issue with our selective oral degrader, as a kind of cautionary measure, we actually moved with this 5/9 schedule, which again, the efficacy data pre-clinically were also super promising. But in line with our expectations, we were actually able to avoid any clinically significant hypocalcemia. And which actually really brought up the possibility that we can try to entertain the more dense schedules. That the 5/9 schedule is perfectly fine. But again, there's a conventional wisdom that if you have a target modulation for the prolonged period of time, that there shouldn't be really any downside of that and maybe there might be even an advantage. So we are actually at the moment testing 21/7 schedule, which is undergoing. And the next really milestone for the program will be the identification of the recommended phase two dose, which according to our guidance, we plan for the Q2, Q2 of this year. Of course, you know, the primary goal of any phase 1 is, right, finding that dose showing safety. But for better or worse, Wall Street does look at some efficacy data. Just kind of from that side, what would be pretty encouraging as you see it, recognizing it's not going to be a, you know, a few weeks' story? We would like to see, yeah. We would like to see kind of building up on the efficacy data, which we had in this like a very early data package, which we disclosed in October of last year. So Myc is not an easy target. So actually the showing significant and rapid tumor shrinkage in biomarker-positive patients treated with 2359 was definitely very encouraging. So we would like to continue seeing the data building up in that direction. And I was mentioning the biomarker-positive patient, but also, since we are not selecting, I mean, we would also have a substantial representation of the biomarker-negative patients. So the expectation would be, and that's actually we haven't really seen activity in the biomarker-negative. So we would like to see actually continuing differentiation with the more robust sample size, showing the differential effect between the biomarker-positives and biomarker-negative. Shane, turning to the palazestrant combinations, can you provide brief highlights of the presentations that Olema gave, for palazestrant in combination with Palbo and Ribo at San Antonio Breast at the end of last year? Yeah. So obviously first line entry means you need to be able to combine with the CDK4/6. That's the standard of care today. It's AI and CDK4/6 because that's the all-oral regimen. We believe that we can do better. Similar to EGFR and T790M, the most common resistance mechanism to first and second line EGFR is development T790M. And 40% of the time or so, that's what led to progression. Same deal here, very similar, actually higher. 50% of patients develop a single resistance mechanism, which is an activating mutation in ESR1, which means an AI is ineffective at suppressing that and those patients progress. So that's what we're coming at. It's a very similar playbook, right? We suppress wild-type and mutant. AI will not. That first line study will be 1:1 randomized. And as soon as that ESR1 activating mutation develops, that AI arm is going to progress and we'll suppress it and we'll get longer PFS. It should result in a, in a nice hazard ratio. So we think that the PTS is super high. The big, the big thing that I think Wall Street and investors think that combinability is trivial. We've seen everybody stub their toe along the way, from Sanofi to Roche to AZ to Lilly to Pfizer, all had DDIs or increase in either incidence, severity, and adverse events. So we've got two big, the two probably the biggest phase 2 combo studies, 60 patients with Ibrance, 60 patients with Kisqali. We're going to be we updated at San Antonio on both of those, back in December. And we've got another, I think, very important update coming in the future on our Kisqali combo. We, like everybody else, advanced with Ibrance first. Everybody else started their pivotal with Ibrance. There are three peers in that are in first-line. We're not going to go with Ibrance because today we know standard of care has, like you very rarely see in this industry, it's got, it's taken a 180. With that OS data that's come out, 3 for 3 with Kisqali, 0 for 2 for palbociclib, it means the prescribing habits are changing dramatically as we speak. The way to go today is a Kisqali combo. So you take the best SERD with the best CDK4/6, and that's the future standard of care. The data that we showed first and foremost is can you combine without any DDI, without any exacerbation of adverse events? And we, we've shown that now. Our Ibrance was around 30 or so patients, and now we're at 60. I think it was a little bit earlier on our Kisqali combo. It was like a dozen patients or so. I think we presented the IR deck around 2019. We'll have a very substantial update coming in the not too distant future. The efficacy still matures because the efficacy and you want that to mature. So patients, if you can show 8 or 10 or 12+ months of median PFS, because these aren't first line patients, right? The first line patients are going to go 24-30+ months. These are second, third line patients that our Kisqali combo patients, a lot of them, this is their third CDK4/6 regimen, right? So it's not clearly clear how much the CDK4/6 is contributing at that point. But it's all about DDI combinability. So we'll update. And that's so far we look pretty good. So just to follow up on the phase 2, Ribo or Kisqali combo update that's coming by the end of the first half, what should expectations be for that update relative to what others have shown, like Pfizer or Arvinas at San Antonio Breast? What should we expect from your update? Yeah. So what you want to see is reconfirmation with a much bigger, more robust data set that you can combine, that there's no when you look at that AE table, that it looks just like the Kisqali label, right? That you're not increasing neutropenia or you don't have any bradycardia, you don't have any QT prolongation. That's what you really want to see. Because ultimately, standard of care today is 24 months median PFS. For us to win in a first line trial, we got to get probably at least an extra six months to take it to 30+, right? And if someone's going to be taking this drug once a day orally for three years, you want it to be safe and well-tolerated, no question. So that's what you want to see first and foremost. And we'll show that. That should be very clear with the next update that we do because it'll be a big sample size. The efficacy, we'll show a swimmer plot. We'll show every single patient. And what you want to see is nice arrows of continued without radiographic progression, that those patients are doing well on the combo therapy. And it's going to take longer to see where you can start to show a Kaplan-Meier curve? It's going to take a while because you're not at the number of events yet because patients aren't progressing. Allen, you're also in the midst of planning a trial in breast cancer, an HR-positive breast cancer. What are kind of the main design elements that are still being worked out between you and maybe regulators? And when should we expect that trial to get underway? Just to clarify, you're talking about Alisertib, right? Yeah, for Alisertib. Yeah, yeah, sir. Yeah. Yeah. So we announced last year we had met with the FDA regarding the plan for Alisertib. We're looking to take the drug forward in ER-positive HER2-negative breast cancer. That's based on two prior data sets that were presented. One was a randomized study, paclitaxel plus Alisertib against paclitaxel alone that showed a PFS benefit. And then also a trial that was done called TBCRC 041 done by the TBCRC group. And in that one, it was Alisertib alone versus Alisertib plus endocrine therapy, which was fulvestrant, and again showing a good response rate in PFS. You know, as I mentioned, similarly in the small cell lung cancer, you know, we know that due to the drug's mechanism, any of the pathways that are involved in Aurora Kinase is where we should see the best activity. What we worked out with the FDA was, you know, the trial design, which we've, you know, already publicly announced, will be, alisertib in combination with, you know, a dealer's choice endocrine. So again, this will be kind of more in a, you know, third line, ER-positive, HER2-negative setting. So at that point, they have probably seen an AI. They may have seen a Fulvestrant. They may have seen, you know, a drug that's targeted for ESR1. So it's really a dealer's choice endocrine, whichever they look to, to, use with it. And again, similar to what I mentioned in small cell lung cancer, we're really going to be looking for the biomarkers we know are involved in Aurora Kinase A pathway to see if we see better activity with alisertib in those patients. You know, given that this is a novel biomarker strategy, I guess one thing we struggle with is how well do you have a sense of, you know, what the expectation is on standard of care in this type of in this population versus the general population, right? Yeah, we have a pretty good idea of that because we can obviously, you know, see that through other data that's been published. And, you know, thankfully with the drugs we're talking about, which is, you know, the AIs and, things like that, it's been very well published in terms of their biomarkers. So I think we've got a pretty good handle on what that should look like. I guess given that, you know, what, how would you define success? What is, you know, what's a good outcome here in this trial? So in the trial we're talking about, we'll be initiating in the second half of this year. So we'll get data on that next year. You know, and again, similar to what I mentioned in small cell, what we really want to see is to see, you know, a better ORR, a better PFS in these patients with the relevant biomarkers. Okay. We're running close on time, so I think we'll do kind of rapid fire. So if we can try to keep the answers brief, and then we'll just do kind of one each going forward. 5 minutes. 1 minute each. 5 breaths. So, Mark, we've been talking about the development in lung cancer, but also there's a whole nother side of 1535's development in GBM. Maybe just there, the opportunity and particularly what, you know, what does success look like as you get a little bit more mature data here? Yeah. Really big opportunity in GBM. More than half patients have an oncogenic EGFR mutation. No one succeeded there. They didn't have a compound that covered the relevant mutations, wasn't CNS penetrant, wasn't covalent, caused paradoxical activation. Our drug addresses all of those liabilities to prior attempts in GBM. And it is CNS penetrant, we know, based on seeing CNS mets in the lung study that shrink. So we had a phase one data set that we'll present at a medical meeting in the second quarter. We press released it last year. And we have this window of opportunity study that actually measures drug in the tumor of GBM patients who have a planned resection. So those data also be medical meeting second quarter. Should we see good drug levels, match that with the phase 1 data, the next step is, you know, a randomized study in first-line patients. Great. And then, Jack, really quickly, I just want to go back to the PRESERVE 2 study for a second. Can you just remind us what the final OS analysis in the study is powered to show? And then what are your expectations for OS and the placebo arm of the study? Yeah. So, it's 0.67 as a hazard ratio for the final readout. Just to put that in context, if you look at, again, the pembrolizumab study, they were for their ITT, they were at 0.89. For what they got approved on, which was just PDL1 positive, it was 0.73. So ours is 0.67 for the entire population. So that's why I say this will be the biggest improvement in triple-negative breast cancer seen to date. And, I'm sorry, the second question was. Yeah, just expectations for OS and the placebo. Yeah. And I thought the control arm is Gem Carbo. We think the best one is KEYNOTE-355. That had 14.7 months. So we think that's the most contemporaneous and accurate comparative force. Great. So, Filip, Monte Rosa, we've been talking about the GSPT1 program, but you also have declared a VAV1 degrader, which I think is a target people are not familiar with. It's definitely outside of the scope of breast and lung cancer. But you want to just talk about that target real quick and what, and why it makes sense and why it's an attractive opportunity? Well, one is actually super interesting. It's a well-validated target. It's a regulator of T-cell and B-cell receptor signaling. So obviously, a lot of opportunities in autoimmunity, but actually can be in oncology as well. It's a target which has been on the radar of the industry for quite some time, but it's a guanine exchange factor. It's been actually really hard to drug it. So, I mean, you can potentially drug it with the GAF inhibitors, but it also has a scaffolding function. So the GAF inhibitors might not actually fully address the meat, the meat which is actually there. So we believe that our degrader will actually fill that gap. So that's actually a program which is really going very quickly through the clinic. I mean, it's according to our guidance, we expect IND submission in this half of 2024. Great. While you guys at Olema excited by your new internally discovered KAT6 inhibitor. Yeah. So it wasn't entirely internally discovered because we started a collaboration with Aurigene out of India about two years ago. They had some chemical matter that we did a lot of lead optimization work on and just filed IND earlier this year. We're doing the IND-enabling studies right now and filing IND this year. It should be in the clinic, certainly by this time next year, I'd say. What's super interesting, obviously, the only program in the clinic on KAT6 is with Pfizer. They presented some early data at ASCO last June and then just updated at their oncology day last week. KAT6 is very clearly an active target in ER-positive breast cancer. It looks like also potentially in prostate. The mechanism is around chromatin unwinding to allow transcription. It looks like KAT6 is very specific to nuclear hormone receptor transcription, which goes to both ER and AR. Yeah, in second- and third-line patients, they showed a lot of activity. So they're still doing some dose ranging, getting some of the AE profile that they seem to have. But no question, it's an active target. It's like a ball in the glove for us because it goes and works in combination with an endocrine therapy. And it looks good. Okay. Alan, in turning to your other asset, the neratinib that is, you know, a commercial product generating sales, during the pandemic, obviously, a lot of physician visits and the marketing effort turned entirely virtual, at one point. And you had taken the opportunity to kind of, because there were some efficiencies there from a personnel perspective, to kind of bring down the size of the sales organization a bit. Now that things have switched back, is that organization still appropriately sized, or, you know, does that still need to be kind of adjusted, maybe back up a bit to properly resource the neratinib? Yeah. So, we previously had 70 sales reps. During the pandemic, we took that down to just a little under 40 because we weren't getting in to see the physicians as much. What's been interesting is that, you know, during the pandemic, we obviously took up this idea of virtual meetings and things like that. That is still in existence. I would say, you know, probably in a given month, 20% or 30% of our visits are still being done virtually. So it hasn't completely shifted back to 100% in person. The other aspect that we've seen is, and I don't know if this is something that's due to the pandemic, and the adoption of the technology there, or just something that's happening industry-wide, we've seen a lot more of an influence on nonpersonal promotion. On our recent earnings call, we mentioned that, you know, in the third quarter of last year, we started to see, you know, enrollments, which is new patients, dip significantly. We invested more in nonpersonal promotions. These are, you know, promotions where you're not involving a rep. We kind of shifted to that. And that actually has done a really nice job so far. And we mentioned this on our call. You know, we typically see a decline in new patients in Q4. We got a, you know, Cosela has a well-documented side effect, which is the first month they go on it, they can get a severe diarrhea. So we end up seeing patients in the fourth quarter who will delay taking it until, you know, the beginning of the year because they don't want to have the side effects during the holidays. We actually, for the first time in seven years of the launch of the drug, saw an increase in enrollments from Q3 to Q4. We believe it was due to the nonpersonal promotion. I think that personal aspect of an actual rep going in, we have seen in our experience it not be as important as some of the other aspects, like a virtual or, you know, nonpersonal promotion. Obviously, time will tell if that, that continues. Okay. Thanks. Unfortunately, that's all the time we have. So we're going to have to end the conversation there. But thank you for everyone on the panel for joining us, as well as in the audience or on the webcast. Thank you.